ASPECTS OF HUMAN TOCOLYSIS WITH ADRENERGIC AGENTS

Q.GLM. ESSED

Aan mijn ouders

Aan mijn opleiders

PROMOTORES

Prof. Dr. Τ.Κ.Ά.В. Eskes

Prof. Dr. Ch.B. Martin jr.

CO-REFERENT

Dr. H.W. Jongsma

copyrights to the author.

ASPECTS OF HUMAN TOCOLYSIS WITH ADRENERGIC AGENTS

With accent on the prevention of preterm labor

Proefschrift ter verkrijging van de graad van doctor m de geneeskunde aan de Katholieke Universiteit te Nijmegen, op gezag van de Rector Magnificus Prof dr Ρ G А В Wijdeveld, volgens besluit van het College van Decanen in het openbaar te verdedigen op vrijdag 20 februari 1981 des namiddags te 2 00 uur precies

door

GERARD GEORGE MARIA ESSED

geboren te Paramaribo

1981 Drukkerij en Uitgeverij Leiter-Nypels bv, Maastricht

VOOHWOORD

Het in dit proefschrift gepresenteerde onderzoek werd uitgevoerd in

de kliniek voor Obstetrie en Gynaecologie (Hoofden : Prof. Dr. J.L.

Mastboom en Prof. Dr. T.K.A.B. Eskes) van de Katholieke Universiteit

te Nijmegen.

Velen hebben een essentiële bijdrage geleverd aan het tot stand komen

van dit proefschrift.

Het wetenschappelijk klimaat waarbinnen dit onderzoek mogelijk was,

werd geschapen door de leiding van voornoemd instituut, die steeds

een verantwoord evenwicht tussen onderwijs, patiëntenzorg en onder­

zoek heeft nagestreefd.

In het bijzonder Drs. J.M.J. Dony zette zich destijds op niet te

evenaren wijze in voor het leggen van een solide klinische basis,

waardoor in een vroeg stadium van de opleiding tijd vrijgemaakt kon

worden voor wetenschappelijke oriëntatie.

Zr. C.E.M. Kroon-Leeflang had als hoofd van de verloskamers, tesamen

met haar excellent team, een belangrijk aandeel in de accurate

verzameling van klinische gegevens, waardoor het aantal "missing

values" tot een minimum beperkt bleef.

Op de kraamafdeling (Hoofd:Zr. м. Smits) zorgden Mej. H.M. Jansen op

de Haar, Mevr. M. Wibisonno-Lubeck en Mevr. Y. Beekman-Lotthrincx

voor een nauwkeurige registratie van patiënten die deel uitmaakten

van het onderzoeksprotocol.

De biochemische plasmabepalingen werden uitgevoerd in het labora­

torium van de afdeling Obstetrie en Gynaecologie van het St. Radboud

Ziekenhuis (Hoofd:Drs. P.C.W. Houx) waar de punctuele registratie der

gemeten waarden verzorgd werd door Dhr. K.T. Tjhwa en Mevr. J.C.M.

Geense-Appels.

In het computerlaboratorium van het Instituut voor Obstetrie en

Gynaecologie (Hoofd : Dr. H.W. Jongsma) werd het computerprogramna

ontworpen, waarmee de patiëntengegevens in frequentiehistograimen

konden worden beoordeeld en bewerkt, en een deel der statistische

toetsen kon worden uitgevoerd.

Ir. H.J.J. van Lier en Drs. Ph. van Eiteren (resp. stafmedewerker en

hoofd van de Mathematisch-Statistische Adviesafdeling van de Katho-

4

lieke Universiteit te Nijmegen) namen de moeilijke en tijdrovende

statistische bewerking voor hun rekening.

Veel medewerking werd ondervonden van de leden van het Productie-

bureau van de Rijksuniversiteit Limburg, de afdeling Medische Foto­

grafie van het Ziekenhuis St. Annadal en de Medische Bibliotheek van

de Rijksuniversiteit Limburg en het Ziekenhuis St. Annadal.

Drs. Hein Eersel, Mevr. Bny Renardus-Simons, Wilfred Lionarons,

Harold Braam en Drs. Max Essed sr. hadden een beslissende inbreng bij

de vertaling van de samenvatting in het Surinaams.

Zowel de voorbereidende als de definitieve tekstverwerking werd onder

moeilijke omstandigheden met grote accuratesse verzorgd door Wilma

Coenegrachts, hierin moreel en materieel gesteund door Gerda Haemers,

Anja Smeets, Anke Schmitt en Henk Jas.

Dit onderzoek was in deze vorm niet mogelijk geweest zonder de mede­

werking van alle collegae die destijds bereid waren de begeleiding

van patiënten met tocolytische therapie volgens het onderzoeksproto­

col uit te voeren ; de collegae Rinse de Boer, Henk Hoogland en Henk

de Koning Gans bleken telkenmale bereid een aantal klinische taken

van mij over te nemen, zodat dit onderzoek afgerond kon worden.

De continue dwingende belangstelling van Prof. Dr. Jelte de Haan

werkte (achteraf) zeer stimulerend.

Zonder dit bewust na te streven, werd periodiek de benodigde morele

steun aangedragen door Helen, Sacha, Camille en zelfs Marco-Miguel.

De grootste bijdrage aan het tot stand komen van deze studie werd

geleverd door Jane Crevels die vanaf de start van het onderzoek met

stimulerend enthousiasme en grootse inzet meewerkte aan het verkrij­

gen en bewerken der onderzoeksresultaten.

Ik ben U allen zeer erkentelijk.

Maastricht, november 1980,

Gerard Essed.

5

DEFINITIONS AND ABBREVIATIONS USED IN THIS THESIS

Amenorrhea : the time period after the first day of the

last normal menstrual period expressed in completed days

or completed weeks.

Gestational age : the duration of gestation as measured

from the first day of the last menstrual period expressed

in completed days or completed weeks.

Abortion : the expulsion or extraction of a fetus or em­

bryo before the 16th completed week of amenorrhea.

Immature delivery : delivery after 16 completed weeks and

before 28 completed weeks of amenorrhea.

Premature delivery : delivery after 28 completed and be­

fore 37 completed weeks of amenorrhea.

Term delivery : delivery after 37 completed weeks and be­

fore 42 completed weeks of amenorrhea.

Preterm : less than 37 completed weeks of amenorrhea.

Perinatal period : period between 28 completed weeks of

amenorrhea and the end of the seventh completed day after

delivery.

Hypoglycemia : plasma glucose levels lower than 1.65

mmol/1 (term infants) or lower than 1.1 mmol/1 (preterm

infants).

Gestational (pregnancy) diabetes : venous plasma glucose

levels exceeding, only during pregnancy, two or more

following concentrations after a 100 mg glucose load.

fasting top 2 hours

4.4 mmol/1 8.8 mmol/1 6.6 mmol/1

6

Hyperbilirubinemia

ceeding :

day of birth

day 2

day 3

day 4

day 5

day 6

day 7

plasma bilirubine concentration ex-

preterm infants

85 mcmol/l

135 mcmol/l

170 mcmol/l

185 mcmol/l

200 mcmol/l

225 mcmol/l

240 mcmol/l

term infants

85 mcmol/l

135 mcmol/l

185 mcmol/l

225 mcmol/l

255 mcmol/l

255 mcmol/l

255 mcmol/l

Criteria for IRDS (idiopathic respiratory distress syn­

drome:

- grunting

- increased respiratory rate and retraction of the supra­

sternal notch and intercostal spaces

- rising PCO- levels

- diffuse reticulogranular infiltrate throughout the lung

fields with an air-filled tracheobronchial tree

(air-bronchogram) on the chest roentgenogram.

t - d interval : time interval between the cessation of

treatment and delivery.

d - s interval : time interval between the delivery of the

infant and plasma sampling.

7

CONTENTS

GENERAL INTRODUCTION 13

Chapter 1.

PREMATURE LABOR 15

1.1. introduction 15

1.2. etiology 16

1.2.1. the conceptus 17

1.2.2. outside the conceptus 19

1.3. diagnosis 22

1.4. treatment 25

Chapter 2.

BETASYMPATHOMIMETIC AGENTS IN HUMAN OBSTETRICS 3 1

2 . 1 . introduction 31 2.2. his tory 31 2.3. clinical pharmacology 33

2.3.1. the effect of betamimetic stimulation 33

on the uterine muscle

2.3.2. pharmacokinetics 34

2.4. indications and contraindications 36

2.4.1. threatening premature labor 36

2.4.1.1. clinical trials 39

2.4.1.2. evaluation of success 44

2.4.2. possible usefulness of betamimetic

therapy in chronic placental

insufficiency 50

2.4.2.1. introduction 50

2.4.2.2. animal studies 50

2.4.2.3. studies in human subjects 52

2.4.2.4. discussion 54

2.4.3. fetal lung maturation after ß-mimetic

therapy 57

2.4.4. intrapartum tocolysis 59

2.4.4.1. fetal distress 60

9

2.4.4.2. other indications for intra­

partum tocolysis 65

2.4.5. contraindications 66

2.5. Side effects of betasympathomimetics in human

obstetrics 68

2.5.1. extrauterine effects 68

2.5.1.1. metabolic effects 68

2.5.1.2. cardiovascular effects 71

2.5.1.3. other extrauterine side

effects 74

2.5.2. transplacental transfer 76

2.5.3. effects on fetus and neonate 76

Chapter 3.

CLINICAL COMPARISON OF RITODRINE AND FENOTEROL IN

THEIR EFFICACY IN PREVENTING PRETERM DELIVERY 79

3 . 1 . i n t r o d u c t i o n 79 3 . 2 . m a t e r i a l s and methods 79

3 . 2 . 1 . p a t i e n t s 79

3.2.2. criteria for the diagnosis of threat­

ening early labor 80

3.2.3. treatment schedule 81

3.2.4. criteria for the judgement of success 82

3.2.5. procedure for the balancing of the two

groups of patients 84

3.2.6. statistical evaluation 97

3.3. results 99

3.3.1. efficacy of treatment 99

3.3.2. side effects 102

3.4. discussion 104

Chapter 4.

PLASMA GLUCOSE LEVELS IN THE NEONATE AFTER ANTENATAL

EXPOSURE TO BETAMIMETIC AGENTS 107

4 . 1 . i n t r o d u c t i o n 107 4 . 2 . m a t e r i a l s and methods 109

10

4 . 3 . r e s u l t s 4 . 4 . d i s c u s s i o n

112

122

5 . 2 .

5 . 3 .

5 . 4 .

Chapter 5.

INFLUENCE OF LONG-TERM ВЕТАМІІИЕТІС DRUG ADMINISTRATION

DURING PREGNANCY ON THE EARLY POSTPARTUM BLOOD LOSS

5 . 1 . i n t r o d u c t i o n

m a t e r i a l s and methods

r e s u l t s

discussion

5.4.1. comparability of subject groups

5.4.2. factors affecting blood loss at

delivery

5.4.3. effect of betamimetic treatment on

early postpartum blood loss

Chapter 6.

APPENDIX

SUMMARY

SJATU KONTENTI

SAMENVATTING

REFERENCES

CURRICULUM VITAE

127

127

127

131

139

139

140

140

145

147

150

153

156

175

11

General introduction

The specialty of obstetrics has traditionally been

preoccupied with the mechanics of human parturition. In

recent decades, however, this traditional approach has

been supplemented increasingly by the knowledge gained

from research into the physiology, biochemistry and endo­

crinology of reproduction in man and other species. As a

consequence of these developments, one can now glimpse

some of the secrets of human parturition. Although much

remains to be learned about the processes involved in the

maintenance and natural termination of pregnancy, means

are presently available to prolong or shorten the duration

of pregnancy, within limits, in many cases. In general it

has been much easier to terminate pregnancy than to pro­

long it ; however, even in this latter field some progress

has been made. In probably the majority of cases of

threatening preterm labor, prolongation of pregnancy can

be achieved by suppressing unwanted uterine contractions

pharmacologically, even though the cause of the contrac­

tions remains unknown. Mechanical measures (e.g., cervi­

cal cerclage) remain useful in a small minority of pa­

tients.

Today long-term relaxation of the uterus can be attained

effectively with uteroselective adrenergic drugs, and

these agents are increasingly used for indications other

than the prevention of preterm labor. Unfortunately,

however, this therapy is not without side effects on

mother and fetus in the dosage levels used in obstetric

practice.

In this thesis, some aspects of human tocolysis with

two different ß-2-sympathomimetic agents will be discuss­

ed.

13

Chapter 1

Premature labor

1.1. Introduction

Despite tremendous improvements in treatment by neo­

natal intensive care, premature birth is by far the most

important factor in the incidence of neonatal mortality

and morbidity and may thus be considered one of the

greatest problems of current obstetric and pediatric

practice.

If the premature infant survives the threats of the early

postnatal period, the possibility of long-term morbidity

such as psychomotor, intellectual and emotional deficits

may cause great concern to doctors and parents. There­

fore, the recent advances in neonatal medicine in no way

decrease the need for the obstetrician to prevent preterm

deliveries or, when these are not preventable, at least to

minimize the risk of developing respiratory distress or

other major complications after birth by appropriate man­

agement antenatally and during labor.

Prevention of premature delivery has become an even

greater challenge for the obstetrician now that in­

creasingly effective drugs are becoming available to post­

pone the moment of birth.

When referring to prematurity, not every obstetrician

or pediatrician is referring to the same group of chil­

dren. Because of problems associated with the frequent

uncertainty of the actual date of conception, the anam­

nestic duration of amenorrhea has often been considered to

be an inadequate measure of fetal maturity. In the past,

therefore, more attention has been given to the weight pa­

rameter (Cavanagh and Talisman, 1969). The following

definition was approved by the American College of Obste­

tricians and Gynecologists (1965) :

15

- Immature infant : the fetus weighs between 500 and 1000

grams

- Premature infant : the fetus weighs between 1000 and

2500 grams.

There are a great many disadvantages inherent in any arbi­

trarily defined weight standard, for birth weight is in­

fluenced by many factors other than gestational age, in­

cluding ethnic and nutritional factors, fetal disease and

perhaps socio-economic circumstances. Various other ob­

jective measurements, including biparietal diameter and

crown-rump length (ultrasound techniques), analysis of the

amniotic fluid and neurodevelopmental scoring of the new­

born, singly or in combination are used in many centres in

assessing the maturity either pre- or postnatally. Recent­

ly there has been a tendency towards using gestational

age, judged from the first day of the last menstrual pe­

riod, as the main criterion, in correlation with above

mentioned ultrasonic evaluation of fetal size and amniotic

fluid indices and regardless of birth weights. Premature

birth is thus defined as a delivery after 28 weeks (196th

day) of amenorrhea and before the end of the 38th week

(266th day) , or as a birth weight over 1000 grams and an

amenorrhea of less then 37 completed weeks (259 days)

(FIGO) (Kloosterman, 1977).

Although these definitions offer the possibility of

distinguishing clearly between prematurity and dysmaturity

at term, it must be stressed that the abandoning of the

pseudo-exact birth weight criterion places an extra

emphasis upon accurate recording and proper interpretation

of the menstrual history.

1.2. Etiology

Until a few decades ago prematurity was largely the

burden of the pediatrician. Obstetricians were unable to

16

play a significant role in prevention for they had very

few tools with which to handle the problem. Now that sev­

eral pharmacological and surgical possibilities are

available, it is essential to survey the possible causes

of prematurity, in order to anticipate these early deliv­

eries and thus to select appropriately the patients for

treatment.

A wide variety of diseases and circumstances have been

associated with an increased incidence of premature labor.

Many comprehensive studies have been carried out to deter­

mine the relative importance of various factors which

might contribute to the problem.

The etiologic and epidemiologic information may be clas­

sified for purposes of discussion into two major catego­

ries :

- factors relating to the conceptus (fetus, amniotic

fluid, fetal membranes and placenta) ; and

- factors outside of the conceptus (health, age and con­

stitution of the mother, uterine anomalies, socio-eco­

nomic factors, etc.).

In many instances factors in a category may be related to

factors in the other ; for example, the association be­

tween maternal vascular disease and placental pathology,

or between multiple pregnancy and pregnancy-induced hyper­

tension in the mother.

1.2.1. The conceptus

1.2.1.1. Multiple pregnancy

The duration of pregnancy is inversely proportional to

the number of fetuses in utero.

Overdistention of the uterus has long been considered to

be a major provocative element in shortening duration of

17

pregnancy. This assumption is supported by the fact that

in cases of multiple pregnancy with polyhydramnios, gesta­

tion is shorter than when the amount of amniotic fluid is

normal. (Van Bilderbeek, 1960).

1.2.1.2. Congenital abnormalities of the fetus

Several severe congenital malformations are associated

with a shortened duration of pregnancy (Specken, 1964).

The association may be partly secondary to the malforma­

tion itself and partly due to the possible accompanying

polyhydramnios, the severe degree of dysmaturity often

present or intrauterine death.

2 . 2 . 2 . 3 . The amount of amniotia fluid

An excessive amount of amniotic fluid is associated

with a shortened duration of gestation (van der Velden,

1957) . Overdistention of the uterus has already been

suggested as a possible trigger for premature labor.

1.2.1.4. Early rupture of the membranes

Rupture of the membranes may give such a strong stim­

ulus to the onset of labor that this procedure was one of

the first methods described to terminated pregnancy. Sev­

eral explanations for this phenomenon have been proposed,

including an unfavourable effect on the placental circula­

tion, mechanical stimulation of the lower uterine parts

and stimulation of prostaglandin synthesis.

1.2.1.5. The placenta

Bleeding from the placental site in case of placental

anomalies, premature separation or placenta praevia is

highly correlated with prematurity as is infarction of the

18

placenta.

In a group of pregnancies of at least 34 weeks dura­

tion, Kloosterman (1975) found a correlation between the

size of the placenta and the chance of prematurity. Among

the 17543 cases he reported upon the prematurity rate de­

creased with increasing placental weights.

In some species a change in placental steroid hormone

production precedes the onset of labor, but the evidence

for the existence of such a relationship in man is mixed.

Some observations suggest altered placental steroid hor­

mone production preceding the onset of labor (Turnbull et

al., 1974).

1.2.2. Outside the eonoeptus

1.2.2.1. Placental perfusion

Absolute and relative insufficiency of the maternal

vascular bed, as in the case of hypertensive disease,

leads to premature delivery, especially when there is

substantial placental infarction as well.

1.2.2.2. Cervieal insuffiaiency

Congenital or acquired incompetence of the internal os

of the uterine cervix, if untreated, results in the birth

of an immature fetus because of the inability of the cer­

vix to retain the enlarging conceptus in the uterus.

Prolapse of the conceptus usually occurs during the second

trimester before the fetus reaches the stage of extra­

uterine viability.

1.2.2.3. The uterus

Both congenital and acquired (fibromatosis) abnormal­

ities of the uterus may be etiologic elements in prema-

19

ture labor. Furthermore there might be an intrinsic

hypercontractility of the uterus in some women (see dis­

cussion of section 5.4.3).

1.2.2.4. Infectious diseases

Acute infectious diseases are often attended by an

increased contractility of the myometrium and may thus

initiate labor ; possibly as a result of enhanced

prostaglandin synthesis.

Acute and chronic infections of the urinary tract, with or

without symptomatology, are the most important causes in

this category from a quantitative point of view.

1.2.2.5. Endocrinologia diseases

Diabetes mellitus (even subclinical) and thyroid

disease bring about an increased risk of many of the

hazards of pregnancy including prematurity.

1.2.2.6. Other factors

Race, parity, maternal age, reproductive history,

emotional stress and psychogenic factors, dietary de­

ficiency, severe anemia, socio-economic circumstances, and

cigarette smoking are among the other factors assumed to

influence the incidence of prematurity.

Only a minority of these conditions or diseases of

fetus, mother or maternal genital tract have been so fre­

quently associated with the early onset of labor that they

can be regarded conclusively as causative factors, how­

ever; so in spite of the wide variety of factors possibly

related to the etiology of prematurity, in about half of

the cases of imminent premature birth, no apparent cause

can be found.

20

During recent years, research has produced several hy­

potheses regarding the initiation of human labor.

Csapo (1956) proposed a 'progesterone block' produced

by the placenta as a reason for relaxation of the uterus

during pregnancy and suggested progesterone withdrawal as

a major factor in the onset of labor (Csapo et al.r 1971,

1974). This hypothesis was supported by Turnbull and

associates (1974), who measured a significant fall in

progesterone and rise in oestradiol levels in human pe­

ripheral plasma during the 5 weeks preceding labor. A

number of other investigators have not, however, found any

changes in these hormones prior to labor.

Caldeyro-Barcia and Sereno (1961) believe that human

myometrium becomes progressively more sensitive to a rela­

tive constant level of circulating oxytocin during preg­

nancy, until a critical level is attained, producing la­

bor. Kumaresan and coworkers (1974), however, found

rising oxytocin levels in human plasma long before the on­

set of labor.

The fetus could exert an influence on the onset of la­

bor via its own oxytocin production (Chard et al., 1971)

or via increased adrenal corticosteroid production.

In sheep Cortisol has been shown to cause an increase in

estrogen production, decreased progesterone secretion, and

release of prostaglandins by the placenta (Liggins, 1975).

This mechanism has not been established as contributing to

the onset of labor in human pregnancy.

Based on studies by Klock and Jung (1973) , Csapo and

Csapo (1974) suggested that prostaglandins, synthetized in

response to progressive myometrial stretching, are the in­

trinsic uterine stimulants for the onset of labor. Other

reports give support to the hypothesis that local pros­

taglandin synthesis may be involved in the onset of labor

(Karim, 1968 ; Gustavii, 1977).

Brotanek and associates (1969) reported that in spon­

taneous labor, uterine (cervical) blood flow decreases for

21

about 30 seconds before the onset of contractions and sug­

gested that a decrease of uterine blood flow may have a

role in the initiation of labor. Flowmeter studies in

monkeys, however, have not demonstrated any pre-contrac­

tion drop in uterine artery blood flow (Martin, 1972) and

in fact an increase in myometrial blood flow during

contractions (Lees et al., 1971).

To date, no clear definition of the mechanism of the

initiation of labor in man has been established. Thus we

are presented with a variety of possible mechanisms, some

of which may function simultaneously in bringing about the

onset of parturition (Barden, 1974, 1977 ; Eskes, 1979).

1.3. Diagnosis

The diagnosis "imminent premature labor" is basically

the same as that of the onset of spontaneous labor at

term. In either case it is very difficult to make a posi­

tive diagnosis in an early stage of the process.

The onset of labor is to some extent an arbitrary point,

and only when the symptoms increase in the expected way,

can one say retrospectively that a woman has been in labor

for some time.

Unlike beginning labor at term, however, it is most impor­

tant to recognize premature labor early and clearly, for

the possibility of successfully postponing birth decreases

very rapidly as the process of parturition proceeds.

Several clinical criteria are employed in the diagnosis of

threatening premature labor :

1. recurrent, more or less painful, contractions of the

uterus, increasing in frequency and intensity ;

2. rupture of the membranes ;

3. "bloody show" ;

4. effaced or effacing cervix ; and

5. dilatation of the internal cervical os.

22

Utérine contractions (Braxton Hicks contractions) may

occur throughout the latter months of pregnancy, and need

not be associated with the onset of labor. The frequency

of these contractions is usually low, they are often hard­

ly recognized by the woman, and they do not produce

effacement and dilatation of a normal cervix. The fre­

quency of these contractions can easily be established by

external tocography.

Zahn (1978) presented data on contraction frequencies. He

observed an increase in the number of spontaneous contrac­

tions from 1/hr in the 25th week to 3/hr (primigrávida)

and to 3.5/hr (multigravida) at term (97th percentile)

with a remarkable incidence peak around the 32nd week.

There is a strong correlation with the onset of labor when

the contractions are "laborlike" : that is regular con­

tractions at intervals of less than 10 minutes, painful,

and leading to effacement and dilatation of the cervix.

Statistical analysis of 643 cases of threatened premature

labor of which 27 % (172) received intensive pharmacologic

treatment suggested that the frequency and regularity of

the contractions was of low prognostic value. Pain asso­

ciated with the contractions, however, seemed to be cor­

related better with a difficult-to-postpone labor

(Melchior and Bernard, 1974).

Rupture of the fetal membranes, whether spontaneous or

artificial, usually leads to the onset of labor after a

varying latent period. The diagnosis of ruptured mem­

branes is usually not difficult.

More difficulty may arise in differentiating between low

and high sites of membrane rupture, for the latter carries

a better prognosis with regard to successful lengthening

of the pregnancy than does the former. The exact mecha­

nisms by which rupture of the membranes stimulates the

onset of labor is not yet clear. A recent hypothesis,

which is supported by a number of laboratory observations,

is that mechanical disruption of the membranes and decidua

23

leads to increased prostaglandin synthesis (Gustavii,

1975) .

Mitchell and colleagues (1976) , found significantly

greater amounts of PgF and PgFM in amniotic fluid obtained

by amniotomy than in samples taken by amniocentesis.

Uterine haemorrhage due to placenta praevia, abruptio

placentae or placental anomalies can lead to labor,

possibly due to the accumulation of blood between the mem­

branes and the uterine wall resulting in irritation of the

myometrium, or to the release of prostaglandins from the

damaged decidua. Loss of mucus, often mixed with blood is

strong confirmative evidence of an effacing and dilatating

cervix and thus of the start of parturition.

Effacement and dilatation of the uterine cervix as a

result of regular uterine contractions are reliable indi­

cators of the presence of labor, especially if there are

other accompanying symptoms. According to Melchior and

Bernard (1974), dilatation has a higher prognostic value

than effacement. On the other hand a certain degree of

dilatation unrelated to the onset of labor is not uncommon

in the last trimester, especially in multiparae.

In the second trimester, however, any cervical dilatation

of the internal os is abnormal. In the absence of uterine

activity, the possibility of primary or acquired cervical

incompetence must be strongly considered.

Laboratory aids to the diagnosis of premature labor

are few and until now, not widely used.

Csapo and Herczeg (1977) advocate determination of the

peripheral plasma progesterone level. A low progesterone

value would favor the diagnosis of premature labor, where­

as a normal value would identify patients in whom the con­

tractions would subside spontaneously. In relatively few

hospitals, however, this determination can be made with

sufficient rapidity to be of value in management of pos­

sible preventive labor.

Measurement of rheobase values seems to be a promising

24

way to make the diagnosis in an early stage of premature

labor. (Schenk et al., 1975b ; Feichtinger and Frb'lich,

1979) . Rheobase values were found to be significantly

lower during labor or threatening preterm delivery, than

during pregnancy. Because of the large range of normal

values and the corresponding overlap of the normal and

pathologic groups, however, it is still difficult to

interpret rheobase values in an individual gravida.

Wolfs and van Leeuwen (1979) demonstrated with intra­

uterine electrodes and an intrauterine open tipped cathe­

ter that electrical activity of the myometrium preceding

the uterine contraction was observed in progressive labor

while electrical activity simultaneous with the uterine

contraction did not result in cervical dilatation. This

methodology using intrauterine electrodes is, however, not

clinically attractive in cases of early labor because of

the possibility of the induction of labor and/or intra­

uterine infection.

1.4. Treatment

It is of utmost importance in cases of imminent prema­

ture labor to try to determine the etiologic element and

if possible to treat the cause.

Although some progress has been made in recognition and

treatment of causative factors, in many cases the precipi­

tating factors remain unexplained or incurable. Even if

there is strong suspicion of a particular reason for the

premature labor and curative treatment is available, the

uterine activity as such must be arrested. Thus the

symptomatic approach, as well as prophylactic measures,

still form the basis of the efforts to avoid prematurity.

Several methods of treatment of premature labor have been

reported, with varying degrees of applicability.

25

1.4.1. Bed rest

Psychological and physical stress may provoke or in­

crease premature uterine contractions (Newton et al.,

1979). Thus, one of the oldest measures employed in

treatment has been absolute bed rest and, if necessary,

sedation. Bed rest still constitutes a major part of the

treatment in almost all cases.

1.4.2. Anes the tics

The general anesthetics fluothane and ether produce a

very strong relaxation of the uterine muscle ; but for ob­

vious reasons these agents are not useful for long-term

tocolysis (van Liere et al., 1964).

1.4.3. Ethanol

Since Fuchs (1965) reported on this subject, intrave­

nous ethyl alcohol has been used widely, mainly in the

U.S.A. The relaxing effect of alcohol upon uterine activ­

ity is presumably due to inhibition of oxytocin release

from the neurohypophysis, although an anti-prostaglandin

effect has also been proposed.

1.4.4. B-adrenergic drugs

Effective inhibition of uterine contractility can be

obtained by ^-sympathomimetic agonists (chapter 2). These

agents also produce cardiovascular and many other effects.

The pharmaceutical chemists have produced a series of

so-called ß-2-mimetic agents with greater affinity for the

ß-receptors in, for example, myometrium and bronchi and

lesser activity upon the heart and blood vessels. Even

with these agents, however, cardiovascular effects usually

constitute the dose-limiting factor.

26

1.4.5. Prostaglandin synthesis-inhibiting agents

There are reasons to believe that prostaglandins are

involved in the process of inititation of labor, at term

as well as prematurely. Several reports have been pub­

lished on the use of prostaglandin synthesis-inhibiting

agents (indomethacin, acetylsalicyl acid, naproxen) for

the treatment of premature labor (Zuckerman et al., 1974 ;

Wiqvist et al., 1975 ; Csapo et al., 1974a).

Besides the well-known possible side effects of indo­

methacin or aspirin upon the mother, these agents also

present some hazards to the fetus. In animal studies

indomethacin was found to reduce fetal renal function

(Friedman et al., 1976 ; Winther et al., 1977), and to

produce a dose dependent fetal neuronal necrosis in rats

(Altshuler et al., 1979). It has been shown by Sharpe et

al. (1975) that intrauterine closure of the ductus

arteriosus occurs in animal fetuses given indomethacin or

sodium salicylate shortly before term. Intrauterine

closure of the ductus arteriosus in association with

salicylate exposure during human pregnancy was first

reported by Arcilla et al. (1969), and there have been

several subsequent cases reported. Other case reports

about this presumed association were published by Csaba

and coauthors (1978) ; two deaths in 10 infants after

indomethacin therapy, and Levin et al. (1978) ; two

deaths, one each after salicylate and indomethacin

treatment. Persistent pulmonary hypertension,

abnormalities in blood clotting, and impairment of renal

function in the fetus after intrauterine exposure to

Naproxen was reported by Wilkinson and coworkers (1979) .

Manchester and associates (1976) documented a possible

association between maternal indomethacin therapy and

primary pulmonary hypertension of the newborn.

27

1.4.6. Diazoxide

Diazoxide, an antihypertensive agent, produces a re­

laxing effect upon the myometrium (Landesman et al.,

1969) . The attendant drop in blood pressure could, how­

ever, diminish maternal placental blood flow below the

level necessary to maintain optimal fetal oxygenation.

Diazoxide also affects carbohydrate tolerance adversely.

1.4.7. MgS04

Magnesium sulfate, widely used in clinical obstetrics

for the therapy of pre-eclampsia and eclampsia, has been

proved to have a relaxing effect on both striated and

smooth muscle including myometrium (Hutchinson et al.,

1964) .

The precise mechanism of magnesium sulfate action is not

yet clear. The most likely mechanism of action in uterine

relaxation is competition at the intracellular level of

Mg with the Ca necessary for muscular contraction.

There may also be an indirect influence on the contracting

uterus through the sedative effect upon the mother.

1.4.8. Calcium antagonists

The effect of the calcium antagonist nifedipine in the

excitation contraction coupling has been studied with

promising results (Ulmsten et al., 1980).

The tocolytic action is thought to come about via inhibi­

tion of influx into the cell of calcium necessary for con­

traction.

1.4.9. Progesterone

It was shown by Johnson and coworkers (1975) in a

double blind methodology, that after prophylactic adminis-

28

tration of 17-a-hydroxyprogesterone caproate to patients

with obstetric histories of preterm deliveries or small

for dates infants, the mean duration of pregnancy was sig­

nificantly greater (p < 0.025) than after placebo therapy.

However, once premature labor was started, progesterone

therapy was found to be ineffective in preventing delivery

(Fuchs and Stakemann, I960).

Efforts have been made to combine several forms of

therapy, not only in the form of additional symptomatic

treatment when a cause-directed approach is available, but

also combinations of agents with different presumed mecha­

nisms of action.

Thus, bed rest is an adjunct to pharmacologic treatment in

most cases. Trials of direct inhibition of myometrial ac­

tivity by betamimetics coupled with simultaneous suppres­

sion of oxytocin release with alcohol did not prove to of­

fer a great advantage over either treatment alone

(Bieniarz, 1971), although from a theoretical point of

view the combination of two drugs which have completely

different methods of action could be beneficial. In 1978

a double-blind, placebo controlled study was carried out

by Gamissans et al. (1978). Ritodrine and placebo were

compared to ritodrine and indomethacin. The latter treat­

ment regimen showed to be significantly better in pro­

longing pregnancy (p < 0.05).

Several substances have been tried in conjunction with

tocolytic treatment to minimize undesirable side effects.

Trials with 6-2-sympathomimetics simultaneous with

so-called cardioselective ß-adrenergic blocking agents, a

possibility suggested by Eskes and coworkers in 1965, have

in the past, been unsuccessful. Not only was the heart

frequency lowered to normal values, but the uterine con­

tractions returned in full strength (Esteban-Altirriba et

al., 1972 ; Müller-Tyl et al., 1974). Furthermore, as

ß-blockers cross the placenta, they might block the normal

29

fetal cardiovascular responses to hypoxia. Recently,

however, a smaller increase in maternal heart rate was

reported with the combined use of fenoterol and the

cardioselective З-1-Ыоскіпд agent metoprolol, compared

to fenoterol alone, with similar tocolytic results in both

groups (Trolp et al., 1980).

The Ca antagonist verapamilum has been used in addi­

tion to 8-mimetics in order to diminish the cardiovascular

side effects. The advantage of this substance is still

controversial from a clinical point of view (Hiltmann and

Weidinger, 1977 ; Richter and Hinselmann, 1979), although

from animal studies with relatively high doses (Flecken­

stein et al., 1978) and from in vitro organ cultures

(Hofmann et al., 1977) a cardioprotective effect was

suggested.

As has been stressed earlier, it is of the utmost im­

portance to start treatment of premature labor in an early

stage for the probability of successfully prolonging preg­

nancy decreases very rapidly as the process of parturition

proceeds.

Unfortunately, the tools for prompt and positive recog­

nition of true premature labor as opposed to "false" labor

are still lacking. The choice thus lies between overtreat-

ment, with many patients receiving unnecessary drug thera­

py, and undertreatment resulting in a definite incidence

of avoidable premature delivery.

When the treatment carries no serious side effects for

mother or fetus, this tendency to overtreatment is no

major problem from a medical or ethical point of view.

The inclusion of an unknown number of patients treated

unnecessarily does, however, complicate the evaluation of

the effectiveness of different treatment methods. And, as

already pointed out, side effects, sometimes serious, are

associated with essentially all treatment methods.

30

Chapter 2

Betasympathomimetic agents In human obstetrics

2.1. Introduction

This chapter presents a short review of present

knowledge about the use of 3-mimetic drugs in pregnant

women.

As the results of the investigations presented in chapters

3, 4 and 5 deal with the prevention of preterm delivery,

accent is placed upon long-term tocolysis.

Some of the major side effects of these agents upon mother

and fetus will also be discussed.

2.2. History

In 1927 Bourne and Burn reported inhibition of uterine

activity during labor by intravenous administration of

adrenaline.

Two years earlier Rucker (1925) had already published his

observation of transient relaxation of the uterus after

small injections of adrenaline.

Subsequent studies revealed a dose and species dependency

of the uterine response to adrenaline ; relaxation as well

as contraction of the uterine muscle could be achieved by

the same drug.

An explanation of this phenomenon was found after

Ahlquist's (1948) suggestion that sympathomimetic amines

could stimulate two distinct types of adrenotropic recep­

tors : α and β.

Stimulation of α-receptors in the myometrium was thought

to be responsible for contractions whereas relaxation of

the uterine muscle could be achieved by stimulation of

ß-receptors. With growing knowledge of the two types of

adrenoreceptors and their contradictory effects, efforts

31

were made to synthesize adrenaline-like compounds with a

more specific ß-mimetic action.

In I960, Lish and coworkers reported on the uterine in­

hibiting effect of such a drug (Isoxsuprine hydrochloride)

in vitro on uterine tissue from the human and the rabbit,

and in vivo on rabbits, cats and dogs. Among the first to

publish about human tocolysis with B-mimetic drugs were

Bishop and Woutersz (1961) ; Hendricks et al. (1961) ;

Stolte et al. (1965) and Eskes et al. (1965).

Another step towards clinical applicability of

ß-mimetic drugs was Lands' (1967) postulation of two types

of ß-receptors on the basis of their relative response to

adrenaline and noradrenaline :

3-1, predominantly in myocardium and fat cells, and

ß-2-receptors in uterus, bronchial muscle, liver and stri­

ated muscle cells. Subsequent studies have indicated that

there is no absolute organ separation of ß-1 and ß-2 re­

ceptors, although a particular organ might contain predom­

inantly B-l but also ß-2 receptors, or the reverse

(Carlson and Ablad, 1976) .

Ariens and Simonis (1976) have introduced a more phys­

iological separation of adrenoceptors into receptors for

the neurotransmitter noradrenaline and receptors for the

adrenal medullary hormone adrenaline. The neurotrans­

mitter receptors are classified as α-T and β-Τ according

to the response obtained with activation, and a parallel

division into α -Η and β-Η can be made for the adrenaline

receptors. In general, the difference in distribution of

β-Τ and β-Η receptors parallels the empirical occurrence

of ß-1 and ß-2 receptor sensitivity patterns. In this

paper the terms ß-2 receptor and ß-2-mimetic (agonist)

will be used, since these terms are still the ones most

frequently encountered in the literature.

32

2.3. Clinioal pharmacology

2.3.1. The effect of betamimetic stimulation on the uterine muscle

Like other smooth muscle, myometrium is characterized

by autogenous contractile activity. Changes in the state

and pattern of activity occur in physiological conditions

(menstrual cycle) as well as in response to pharmacologi­

cal substances.

Adrenotropic compounds are prominent among the pharmaco­

logic agents effecting the myometrium as noted previously

(section 2.2). Both a- and ß-adrenotropic receptors are

present in the myometrium, with α-receptor activation

leading to increased uterine contractility and ß-receptor

stimulation, to myometrial relaxation. Further, the uter­

ine β-adrenergic receptors fall into the β-2 category

according to Lands' (1967) classification.

The relaxing effect of β-sympathomimetics is consid­

ered to come about by stimulation of adenylcyclase in the

cell membrane.

Adenyl cyclase is believed to correspond functionally with

the ß-receptor (Robison et al., 1967). As a result of

this stimulation, ATP is converted intracellularily into

3-5-adenosinemonophosphate (cyclic AMP). An essential

mechanism of intracellular cAMP is its participation in

the absorption of intracellular calcium by the sarcoplas­

mic reticulum as well as mitochondria and microsomes, re­

sulting in a decrease in the ionized free intracellular

calcium level. This is an active process, the energy for

which is supplied by the decomposition of ATP. Ionized

calcium seems to be an essential element in the contrac­

tile properties of myofibrils (Schild, 1966 ; Rasmussen,

1970) . When an action potential occurs in the cell mem­

brane this ion mediates transmission of the activation

from the cell membrane to biochemical systems of contrac­

tile proteins (Czekanowski, 1977). Thus the effect of a

33

decrease of free calcium within the cell is an inhibition

of the uterine contractile activity.

Apart from interference with cellular contractile

activity through its effect on intracellular Ca , the

formation of cAMP is believed to cause initiation of

several other enzymatic processes in the cell in a manner

which is still not fully clear, leading to glycogenolysis,

lipolysis and, so far as the heart muscle is concerned,

inotrophy and chronotrophy. Thus, in addition to inhibi­

tion of uterine contractions, administration of ß-sympa-

thomimetics can produce hyperglycemia, increased free

fatty acid levels, and acceleration of the heart rate.

These several effects are summarized in table 2.1.

2.3.2. Pharmacokinetics

Pharmacokinetic profiles of 4 frequently used В-adren­

ergic agonists were collected from literature by Post

(1977).

Fenoterol : plasma levels of the sum of the active

agent and its metabolites were measured by Buchelt and

Romiger (1472). Because of the extensive conversion of

these agents to pharmacologically inactive products, the

data presented seem of little clinical interest.

Ritodrine : serum levels of ritodrine were determined

by radio-immunoassay, after oral and parenteral adminis­

tration. Intravenous infusion of 150 meg per minute for

one hour resulted in a peak serum level of about 41.0 +

1.9 ng/ml (mean + SEM) . After the end of the infusion a

distribution half life of 6-9 min was measured, followed

by a second phase with a half life of about 2 hours.

Finally a third phase with a half life of more than 15

hours could be calculated. Oral administration of 10 mg

gave a peak level of about 10 ng/ml in the 20- or 40- min

34

Table 2.1 EFFECTS OF ADRENERGIC RECEPTOR STIMULATION IN SOME ORGANS

ORGAN

Uterus

RECEPTOR TYPE EFFECTS

Blood vessels in uterus a

Heart

Coronary vessels

Bronchi

Pulmonary blood vessels

Liver

Pancreas

Wall of gut

Blood vessels in gut

Bi (62)

α

ß2 (Si)

62 (ßi)

α

ß2 (В,)

α

ßi

α

Kidney Bi (Вг)

Blood vessels in kidney о

Skeletal muscle ^2

Blood vessels in skeletal a

muscle 82 (Bi)

Fat tissue Bi (Вг)

Blood vessels in skin α

ß2

increase in contractility

decrease in contractility

vasoconstriction

vasodilatation

increase in heart rate

increase in contractility

vasoconstriction

vasodilatation

relaxation

vasoconstriction

vasodilatation

glycogenolysis, increase of plasma glucose

glycogenolysis, increase of plasma glucose

inhibition of insulin release

stimulation of glucagon release

stimulation of insulin release

relaxation

relaxation

vasoconstriction

vasodilatation

reni η release

vasoconstriction

tremor

glycogenolysis, increase of plasma lactate

vasoconstriction

vasodilatation

lipolysis, increase of plasma free

fatty acids

vasoconstriction

vasodilatation

35

sample.

Half lives of 1.3 hours and of 20 hours were discernible.

(Gandar et al., 1980) .

Salbutamol : Martin and coworkers (1976) presented

data qn plasma levels of salbutamol determined by a gas

chromatographic mass spectrometric technique after intra­

venous (one subject) and oral administration. After oral

administration of 4 mg, maximum peak plasma concentrations

of 6 - 9 ng/ml were attained in 1 to 3 hours.

The half life seemed to be about б hours.

Terbutaline : oral administration of 5 mg terbutaline

resulted in maximum serum levels of 6-7 ng/ml, attained

after 90 to 120 min (Leferink et al., 1977).

Comparison of ritodrine, salbutamol and terbutaline

with respect to the areas under their serum concentration

curves after parenteral and oral administration was done

by Post (1977) according to rough estimations of these

curves from data available from the literature. All doses

were converted to 1 mg/hour. With all three drugs the

biovailability after parenteral administration was marked­

ly greater than that after oral medication, indicating a

so called first-pass effect.

2.4. Indieations and contraindications

2.4.1. Threatening premature labor

The most frequent indication for the use of ß-mimetics

in obstetric practice is the treatment of threatening pre­

mature labor. This diagnosis is a clinical one, based

primarily on the presence of regular, frequent, more or

less painful uterine contractions. Other symptoms or

findings which may support the diagnosis of premature la­

bor include expulsion of the cervical mucus plug ("bloody

36

show"), progressive effacement and dilatation of the cer­

vix, and rupture of the fetal membranes. By the time

these findings are present, however, the premature labor

may be well established and the chance of successful

treatment, accordingly less.

At present, there are no laboratory tests which bear

directly on the diagnosis of threatening premature labor.

Determination of serum progesterone levels (Csapo and

Herczeg, 1977) and measurement of rheobase values (Schenk

et al., 1975b ; Feichtinger and Frölich, 1979) have been

suggested as useful indicators of an early stage of pre­

mature labor as opposed to a transient increase in uterine

activity which will subside spontaneously. However, clin­

ical experience with these measurements is still limited

and until now, there seems to be a large overlap between

results in normal patients and those with premature labor.

Increased uterine activity is sometimes a finding in

other pregnancy complications besides premature labor :

for example, with acute pyelonephritis or other acute

febrile complications, or with partial premature separa­

tion of the placenta. Accordingly, underlying factors

such as these should be looked for in each patient pre­

senting with pathologically increased uterine activity

prior to term and, when detected, treated appropriately.

The status of the fetus should also be investigated,

with regard both to nutrition (size appropriate for

gestational age) and oxygenation (CTG registrations). The

presence of fetal distress is a contraindication to

tocolytic therapy except as a temporary "resuscitative"

measure (see section 2.4.4.1.).

With regard to the period of amenorrhea within which

tocolytic therapy with B-mimetics may be indicated, most

authorities consider this to be the time from 16 to 34 or

36 weeks corrected menstrual age. Threatened pregnancy

termination earlier than 16 weeks is usually not treated

because of the high incidence of chromosomal and other

37

abnormalities found in these cases. Beyond 36 completed

weeks of gestation, prolongation of pregnancy would seem

to offer little benefit with regard to decreasing neonatal

morbidity and mortality. In some cases, it may become

apparent at an even earlier time that the fetus is better

off in the newborn nursery than in utero.

Particularly in pregnancies complicated by intrauterine

growth retardation or other conditions in which the risk

of fetal distress is increased, clinical and laboratory

information about the well-being and maturity of the fetus

must be taken into account in the decision as to whether

to initiate or continue tocolysis. A mature L/S ratio, if

this is known, is not per se a contraindication to toco­

lytic therapy since, as remarked by Puyenbroek and Stolte

(1975), "a neonate is more than a couple of lungs", and

pulmonary maturity does not assure maturity of other organ

systems.

The indications for inhibition of uterine activity

with ß-sympathomimetics are summarized in table 2.2.

Table 2.2

MAIN INDICATIONS FOR TOCOLYSIS WITH BETAMIMETICS IN HUMAN OBSTETRICS

1. Excessive uterine ac t i v i t y

2. Threatening preterm labor

3. Inh ib i t ion of uterine ac t i v i t y :

- during external version

- during internal version

- af ter intra-abdominal or uterine surgeiy

during pregnancy

4. Intrauterine "resuscitat ion" of the distressed fetus

38

2.4.1.1. Clinical trials of long-term toaolysis with betasympatho-

minetio agents

Several agents are known to decrease uterine activity

(section 1.4), however, most of them are not useful in

treatment of preterm labor because of side-effects which

make it impossible to administer them in adequate dosage

for sufficient periods of time.

Besides, even if it is possible to use a specific uterine

relaxant in an effective dose level for a sufficient

length of time, it may be difficult to prove the effec­

tiveness of such a drug for preventing early delivery ;

for in some women with threatening preterm labor, contrac­

tions disappear without any treatment at all.

Therefore, to assess the capacity of a specific tocolytic

drug to postpone the moment of birth, one has to compare

treated patients with a control group in a carefully

designed study with proper statistical analysis of the re­

sults. Data should be gathered prospectively and the

treatment and control groups must be comparable with re­

gard to relevant factors, either as a result of random­

ization of the subjects between the study groups or by

balancing of the groups. Double blind studies are unfor­

tunately not possible because of the clinical recognition

of the effective drug as a result of its side effects.

2.4.1.1.1. Adam (1966)

The first randomized placebo-controled study to inves­

tigate the suitability of a 3-mimetic agent for the pre­

vention of preterm labor was published by Adam (1966).

Isoxsuprine was given by intramuscular injection (40 -

80 mg per 24 hours) and orally to 26 patients, whereas 24

women were treated with a placebo preparation.

No beneficial effect of the isoxsuprine treatment re­

gime compared to the control patients could be demon­

strated in this trial.

39

2.4.1.1.2. Wesselius-de Casparis et al. (1971)

A multicenter placebo-controlled study was carried out

by Wesselius-de Casparis and associates (1971) in 63 pa­

tients. Ritodrine was given for 24 to 48 hours by infu­

sion at a rate of 200 meg per minute, followed by oral

therapy with 10 mg four times daily for 5 to 7 days. Rit­

odrine given according to this plan proved to be effective

in arresting premature labor (p = 0.02) and in lenghtening

the duration of gestation at delivery (p = 0.005) compared

to placebo-treated subjects.

However, in this trial patients in who symptoms of prema­

ture labor recurred after completion of the first course

of treatment were considered as a new case in the study.

Thus, the same woman could be counted several times and be

treated with more than one type of drug.

Moreover, the patients in this trial were given a variable

number of other drugs.

The results of the trial are therefore difficult to judge.

2.4.1.1.3. Ingemarsson (1976)

Terbutaline was compared to placebo by Ingemarsson

(1976) in 30 patients with intact fetal membranes. Only

women with imminent premature labor of unknown etiology

were included. Terbutaline was infused at an initial rate

of 10 meg per minute. The infusion rate was increased

every 10 minutes up to a maximum of 25 meg per minute or

until uterine contractions ceased.

After maintaining the minimal dose necessary to achieve

complete relaxation for one hour, the infusion rate was

decreased by 5 meg per minute every 30 minutes until the

lowest effective dosage was reached.

If uterine contractions had been absent for a period of 8

hours, intravenous therapy was followed by intramuscular

administration (250 meg four times daily for 3 days) .

40

Thereafter 5 mg of terbutaline was given orally three

times per day until the end of the thirty-sixth week.

Pregnancy was maintained to the thirty-seventh week in 80%

of the treated women whereas this was only seen in 20 % of

the control population (p < 0.01).

Side effects were more often seen in the terbutaline

group, but in no case did these lead to discontinuance of

therapy.

2.4.1.1.4. Csapo and Herczeg (1977)

Similar results were reported by Csapo and Herczeg

(1977) in their clinical trial in 36 patients with

threatening premature labor and distinct progesterone de­

ficiency.

Only patients with intact fetal membranes were included.

Isoxsuprine was given intravenously at an initial rate of

0.2 to 1.0 mg per minute for ten minutes as a loading

dose. For the next 25 hours the infusion rate was re­

duced to a maintenance level of 0.1 to 0.3 mg per minute.

Dose levels were adjusted individually to arrest progress

in premature labor without serious effects.

After the initial period of intravenous medication, oral

treatment was individually adjusted according to clinical

symptoms and side effects. The usual dose was 20 mg four

times daily.

Oral treatment was given for two to three weeks.

Labor was delayed by 46.3 + 6.6 days among treated

patients whereas in the placebo group pregnancy was pro­

longed by only 13.6 + 5.6 days (p < 0.001).

Similar differences were seen according to gestational age

at birth (p < 0.001) and fetal birth weights (p < 0.01).

As expected a greater number of side effects was reported

by the isoxsuprine-treated patients, but in no instance

was the discontinuation of treatment required.

41

2.4.1.1.6. Spellaay et al. (1979)

Ritodrine (14 patients) was compared to placebo (15

patients) by Spellacy and associates (1979) in a random­

ized methodology.

The drug was given intravenously for only 12 hours (maxi­

mum dose 350 mcg/min). During the next 24 hours the pa­

tients were given intramuscular therapy (5 - 10 mg every

3-8 hours, whether or not uterine contractions had been

suppressed, and thereafter oral therapy was substituted

(maximum 120 mg/day).

Within 24 hours of the beginning of (parenteral) medica­

tion 73 % of the placebo-treated and 43 % of the rit-

odrine-treated patients had delivered (p = NS).

With decreasing ritodrine serum levels (oral medication,

see section 2.3.2) the percentage of failures became sim­

ilar in the 2 groups : 73 % verus 71 % after 7 days.

Cardiovascular side effects were seen significantly more

frequently among the ritodrine-treated patients than among

the control subjects.

2.4.1.1.6. Christensen et al. (1980)

A placebo-controlled randomized trial to assess the

effect of ritodrine after premature rupture of the mem­

branes, was carried out by Christensen and coworkers

(1980).

The study included 30 patients between 28 and 36 weeks of

gestational age, pregnant with only one fetus, the cervix

dilated 4 cm or less, and without pyrexia or other signs

of uterine infection after premature rupture of the fetal

membranes.

Ritodrine was given by an initial infusion rate of 100 meg

per minute. In the presence of persisting uterine activ­

ity this dose was increased by 50 meg per minute every 10

minutes up to a maximum of 400 meg per minute.

42

After 6 hours the infusion rate was lowered to 100 meg per

minute and after 24 hours oral treatment (20 mg, 3 times

daily) was begun and continued until the end of the 35 th

week of gestation if no signs of infection appeared.

When uterine activity recurred during treatment a new se­

quence of infusions and oral medication was started.

The two groups were comparable with regard to the relevant

factors such as age, parity, duration of pregnancy etc.

Only with respect to the inhibition of labor during the

intravenous treatment period was a statistically

significant difference (p < 0.05) in favor of the rit-

odrine treated women found.

There were no differences between the 2 groups in the to­

tal duration of pregnancy nor in the clinical data of the

infants.

From these trials several conclusions can be drawn :

1. When given by the intravenous route in high dosage

levels and for a sufficient period of time, some

3-mimetic agents are capable of prolonging pregnancy

despite threatening premature labor.

2. Better results are achieved when dosage levels and

treatment periods are adjusted according to the pa­

tient's needs, than with fixed treatment schemes.

3. Oral therapy, in the doses employed, is not effective

before the uterine contractions have been completely

suppressed and remain absent on a low parenteral con­

centration of the agents used in the mentioned trials.

4. In 20 to 30 % of the patients, no further progress of

the supposed labor was seen following bed rest alone.

43

2.4.1.2. Evaluation of success in treatment of threatening premature

labor

In order to e s t i m a t e the potency of i n h i b i t o r s of

u t e r i n e a c t i v i t y with r e s p e c t t o t h e i r long term u t e r i n e

r e l a x a t i o n c a p a c i t y , and for the e v a l u a t i o n of success of

d i f f e r e n t methods of management, s e v e r a l parameters a re

e s s e n t i a l :

- the o b s t e t r i c s i t u a t i o n a t the s t a r t of t r e a tmen t ;

- the number of days gained as a r e s u l t of t r e a tmen t ;

- the amenorrhea reached a t d e l i v e r y ; and

- the c o n d i t i o n of the i n f an t a t b i r t h and dur ing the

e a r l y newborn p e r i o d .

2.4.1.2.1. Tooolytic index (premature labor score)

In an a t t empt to a s s e s s the o b s t e t r i c s i t u a t i o n a t the

onse t of t r e a t m e n t , Baumgarten and Grüber (1974) developed

a t o c o l y t i c index ( t a b l e 2 . 3 ) .

Table 2.3 TOCOLYTIC INDEX (BAUHGARTEN and GRÜBER, 1974)

1 2 3 4

Contractions i rregular regular

Rupt. membranes - high - low

Bleeding spotting bleeding

Di latat ion 1 cm 2 cm 3 cm ΐ 4 cm

This s c o r e , in which u t e r i n e c o n t r a c t i o n s , v a g i n a l b l e e d ­

ing, c e r v i c a l d i l a t a t i o n and the s t a t u s of membranes a r e

taken i n t o a c c o u n t , was based on the fol lowing c o n d i t i o n s :

44

- calculation must be done easily and securely ;

- it must use only factors that can be recognized objec­

tively ;

- it must be reproducible by different examiners within

the same period of time ; and

- it must be easily remembered, for use at any time neces­

sary.

To meet these requirements, Baumgarten and Grüber were

obliged to exclude some undoubted important parameters.

The degree of effacement and the consistency of the

cervix are not included directly.

These cervical parameters, however, are closely correlated

with the degree of dilatation and are thus involved in an

indirect way. Moreover, Melchior and Bernard (1974) found

cervical dilatation to correlate much more strongly to la­

bor than did effacement of the cervix uteri.

The relative size of the uterine content was not taken

into account in assessing the premature labor score,

although the findings 'fundus large for dates' (twins,

polyhydramnios) and 'fundus small for dates' (placental

insufficiency, chromosomal disorders) are known to corre­

late with the outcome of pregnancy in terms of gestational

age at birth and condition of the neonate.

An important shortcoming of the tocolytic index is

that not every element of the index is of equal prognostic

significance, nor will each element change in the same way

during successful treatment. The symptoms of uterine con­

traction and bleeding may decrease or even disappear

completely, while ruptured fetal membranes and dilatation

of the cervix uteri usually will not. For example con­

sider 2 patients, each with a tocolytic index of 4. In

one patient, however, the points have been awarded for

regular uterine contractions and vaginal bleeding, whereas

the other patient received her score on the basis of high

rupture of the fetal membranes and 2 cm cervical dilata-

45

relative gain

%100 Ho о о

90 -

80 -

60 -I

50 -о о

40 -

30 -

20 -

10 - 0

о

О •

оо о оо о

оооооо о

о о о о оо

0000 о О о

о О о

о о

оо оо

О 8°

о 000

о оо

о о

оо о

о 00 о о о о 8°

о о

8 о оо

R = - 0.60 (Pearson)

1 2 3 4 5 6 7 8 9 10 tocolytic index

Figure 2.1

Scatterdiagvam of the aorvelation between tooolytio index and relative

gain in the patients included in the aliniaal trial described in

chapter 3.

The relative gain is defined in section 2.4.1.2.2.

Each circle represents one subject.

(¡represents > 9 subjects.

46

tion. After 1 week of treatment the index in the first

patient could have reverted to 0, whereas in the second

example, the index will remain 4. Thus the latter situ­

ation presents a considerably more serious threat to the

outcome of pregnancy than the former, especially at low

gestational age, but the initial tocolytic indices were

equal.

Another important shortcoming of the index is the fact

that the week of amenorrhea is not included ; for con­

tractions occuring at 30 as opposed to 34 weeks of amenor­

rhea may make only a slight difference in the outcome of

pregnancy, but rupture of the membranes in the 30th week

is a much more severe threat than the same event at 34

weeks of pregnancy.

Even so, we found the tocolytic index to be a suitable

parameter in the clinical judgement of the prognosis of

treatment (fig. 2.1).

2.4.1.2.2. Judgement of success

Considering threatening premature delivery as reason

for tocolysis, the most rational success-criterion would

be the amenorrhea at delivery, for prematurity is defined

by the duration of amenorrhea. Thus successful tocolysis

should result in a mature (̂. 38 weeks = 266 days (former

WHO definition) or >, 37 weeks = 259 days (FIGO)), live

born neonate. However, to look at gestational age as the

only criterion would be inadequate as may be illustrated

by the following considerations :

- an individual fetus may be mature even before the 37th

week of pregnancy ;

- in some cases of placental dysfunction the condition of

the neonate and the prognosis for healthy development is

favoured by premature delivery instead of artificial

prolongation of pregnancy to term. In such cases post­

ponement of labor from early to late premature may be a

47

better result than exceeding the 37th or 38th week.

Also when membranes are ruptured after 34-35 weeks of

amenorrhea during or before tocolysis, accepting or even

inducing labor could be the better alternative, espe­

cially if the L/S ratio in the amniotic fluid indicates

lung maturity, because of the possibility of ascending

intrauterine infection ;

- treatment resulting in a term delivery may be considered

a greater success (at least, less easily achieved) when

the threat of labor occurs in an early stage of preg­

nancy compared to a later phase.

These objections can be partly met if success is

measured by judging the condition of the neonate only.

Several parameters such as Apgar scores, umbilical cord

blood analysis, incidence of hyperbilirubinemia, hypogly­

cemia and abnormal neurologic scores can be used in this

respect. Morbidity of neonates, however, will be strongly

influenced by factors unrelated to maturity as such ; for

example, placental dysfunction and complications during

labor.

Success could be related to the number of days preg­

nancy is prolonged after administration of a tocolytic

agent. However, it is clear that the earlier in pregnancy

tocolysis is started, the more days can be gained. There­

fore it could be more appropriate in this respect to ex­

press the number of days that pregnancy was prolonged as a

percentage of the number of days that could be gained till

the 40th week.

As tocolysis is seldom continued after the 37th complete

week of amenorrhea, it would be even better to express the

number of days that pregnancy was prolonged as a percent­

age of the number of days that was aimed at, i.e., the

days remaining until the beginning of the 38th week.

Another important element is the time in pregnancy at

which labor first threatens to occur, for the length of

time between the moment the premature threat becomes mani-

48

fest and the expected date of delivery is inversely cor re­lated with the chance of delivering a healthy mature in ­fant . So when evaluating the success of a therapeutic regime i t is e s sen t i a l to take the amenorrhea on admission into ac­count e i ther when assessing the obs te t r i c s i tua t ion at the s t a r t of treatment or when measuring the r e su l t s of t r e a t ­ment at del ivery .

In an attempt to meet th i s requirement Richter (1977) introduced a so called prolongation index which is calcu­lated by taking 100 times the value of the time interval between the onset of the ß-mimetic treatment and del ivery, divided by the ges ta t ional age on admission (f ig. 2 .2) .

Estimation of the effect of longterm betamimetic drugs by means

of the prolongation index (Richter, 1977)

Formula :

At PI = . 100

to

t = gestational age at onset of uterine relaxant treatment

At = lag time between onset of treatment and delivery

Figure 2.2

In a series of 135 patients with signs of threatening pre­

mature labor ?nd intact fetal membranes on admission,

treated with various drugs, he could find good correla­

tions between the prolongation index and the clinical

signs as well as the neonatal outcome.

In a series of 372 consecutive patients treated for

threatening early labor, including patients with ruptured

fetal membranes, Eskes and Essed (1979) also found the

prolongation index to correlate well with the tocolytic

index of Baumgarten.

49

2.4.2. Possible usefulness of betamimetic therapy in chronic

placental insufficiency

2.4.2.1. Introduction

The syndrome of placental insufficiency is a very

complex oner for this organ is responsible for a great

variety of functions. These functions of the placenta can

be grouped under the general headings : maternal - fetal

exchange and pregnancy maintenance. That functional

performance in these 2 categories does not always follow a

parallel course is easily seen from 2 examples : progres­

sive fetal growth retardation and eventual fetal demise

before labor ; and premature labor with expulsion of a

normally-grown, well oxygenated but unripe infant.

Maternal placental blood flow is a factor of paramount

importance with regard to placental exchange.

The relationship between placental blood flow and preg­

nancy maintenance is less well documented, although a

relationship has been suggested (Brotanek et al.,

1969a,b).

It seems useful, therefore, to examine the possible ef­

fects of ß-mimetic agents on blood flow in the pregnant

uterus.

2.4.2.2. Animal studies

Since to date there are no reliable and reproducible

techniques of measuring uteroplacental flow in women,

knowledge about effects of ß-mimetics upon hemodynamics in

the placenta must be gathered from observation and experi­

ments in animal models.

In the absence of uterine contractions. Cosmi and

Condorelli (1972) observed in a chronic sheep preparation

with electromagnetic flow probes, a significant increase

in uterine blood flow with no significant changes in

50

maternal arterial and uterine pressures when a small dose

of orciprenaline (0.24 mcg/kg/min) was given. High doses

(20 mcg/kg/min), on the other hand, produced pronounced

maternal and fetal tachycardia, a decrease in blood

pressure and uterine artery blood flow, and fetal

acidosis, indicating that the effect of β-mimetics on

placental flow might be dose-dependent.

It was suggested by Brennan and coworkers (1977) and

Ehrenkranz et al. (1976, 1977a,b) that there may be only

an initial depression of uterine blood flow, abating with

time during continued drug infusion, or that the effects

of the various ß-mimetics might not be similar. In chron­

ic sheep experiments, Brennan et al. (1977) and Ehrenkranz

et al. (1976, 1977 a,b) found an initial small decrease of

uterine blood flow following salbutamol (0.5 mcg/kg/min)

and a much larger decrease with ritodrine (8 mcg/kg/min),

but no initial change during fenoterol (0,1 mcg/kg/min)

all three administered intravenously.

After 60 - 120 minutes, uterine blood flow, which was

continuously monitored with an electromagnetic flow trans­

ducer applied to the main uterine artery, began to in­

crease and rose above control levels in the sheep given

salbutamol and fenoterol. In the sheep which received

ritodrine, also, uterine blood flow increased after the

second hour of infusion. But in this case, the uterine

blood flow returned only to the preinfusion level, and

this was reached only during the 6th hour of infusion.

Brennan could also demonstrate an increased resistance in

the uterine vessels during ritodrine infusion and de­

creased uterine vascular resistance with salbutamol and

fenoterol.

51

2.4.2.3. Studies in human subjects

2.4.2.2.1. Aoute experiments

Brettes and associates (1976) published a double blind

cross-over study on 29 patients in the third trimester of

pregnancy. With a low dose of ritodrine (PreparR) given

by the intravenous route, no statistically significant

effect could be demonstrated on the blood flow measured

with a thermister probe inserted into the anterior lip of

the cervix in women with normal pregnancies. In the group

of pregnancies complicated by intrauterine growth retarda­

tion or hypertension, however, they observed an increased

cervical blood flow.

It must be stressed however, that a thermister probe in­

serted into the cervix at best measures local flow and

this may not reflect total uterine blood flow or placental

perfusion.

The uteroplacental blood flow was measured by Luotola

and associates (1977) in 26 pregnant women between 36 - 43

weeks of gestation without complication of pregnancy be­

fore and after administration of isoxsuprine intravenously

(5 mg i.v. bolus injection or 16 mg i.v. during 30 min­

utes) . Measurements were made by an intravenous 133

Xe-method and no significant short-term effects of isox­

suprine upon myometrial or placental flow were found.

Rondinelli and Vangelista (1975) reported on 38 high

risk pregnant women in the third trimester in whom they

compared the rate of appearance and intensity of counts

from 1.5 mCi 113m In, injected intravenously, in the area

over the placenta under basal conditions and during the

administration of orciprenaline (10 mcg/min). They found

a statistically significant increase in radioactivity over

the placental site during orciprenaline infusion in the

dose mentioned. An even more marked increase was observed

in the 5 patients with severe preeclampsia.

52

Supportive evidence for all of the experiments mentioned

above was given by Suonio et al. (1978). Using a radio­

nuclide accumulation method with doses of 0.08 and 0.2 mCi

of 113m In, he measured no statistically significant dif­

ferences in placental perfusion (p > 0.2) before and one

hour after an intramuscular dose of 10 mg of ritodrine

hydrochloride in 11 healthy gravidas between 31 and 41

weeks of amenorrhea, whereas 10 pregnant women with

preeclamptic hypertension and 11 with essential hyper­

tension, showed significant increases (p < 0.05 and

ρ < 0.01 resp.) in placental blood flow.

Lippert and coworkers (1976) investigated the actions

of fenoterol (partusisten1*) upon placental and myometrial

blood flow in 11 patients with various pregnancy compli­

cations during the first stage of labor. the observations

were made by continuous recording of isotope activity over

placenta and placenta-free myometrium after injecting 0.5

mCi of 113m Indium intravenously. The results reported

show that in the human gravida, fenoterol (60 meg i.v.

during 5 to 12 minutes) induced an increase in placental

and myometrial blood pool which was not entirely due to

cessation of uterine contractions. They suggested that

the enlarged placental blood pool represented an augmen­

tation of the volume of blood in the intervillous space,

probably due to a dilatation of the spiral arteries.

However, enlargement of the intervillous space blood pool

does not prove that turn-over (flow through) is increased,

for the same phenomenon can occur as a result of an in­

creased venous resistance to drainage of blood from the

intervillous space. Furthermore, the possibility must be

considered that only resting myometrial tension is de­

creased by ß-mimetics, leading to an increase in intervil­

lous space volume with no change in inflow rates or

pressures.

Another possibility is that the increased blood volume

accumulates not in the intervillous space, but in the

53

large veins in the endometrium and myometrium underlying

the placenta.

2.4.2.3.2. Chronic experiment

Janisch and coworkers (1974) studied the influence of

ritodrine and fenoterol intravenously administered in

patients with EPH gestosis and an insufficient placental

blood supply, as assessed by the Y -emissions following

113m Indium or 99m Tc. The 44 patients were divided into

three groups of 12, 14 and 18 women, who received ritodri­

ne, fenoterol and "conventional" treatment, respectively.

After a treatment period of 14 days, a highly significant

improvement of uteroplacental blood flow was measured in

the patients treated with 50 mg ritodrine (p < 0.001) or

0.08 mg fenoterol (p < 0.001) slowly intravenously twice a

day, whereas the "conventionally" treated patients showed

a trend toward improvement but no significant difference

from the initial values.

2.4.2.4. Disaussion

The good results in patients with EPH gestosis (Ja­

nisch et al., 1974) and the tendency to a better result in

"pathological" pregnancies (intrauterine growth retarda­

tion, hypertension) reported by Brettes et al. (1976) and

Suonio et al. (1978), combined with the absence of

significant changes in normal gravidas, give support to

the hypothesis that besides an indirect influence on

placental blood flow via an increased cardiac output,

^-sympathomimetics might have a direct effect on the uter­

oplacental arteries by way of spasmolytic action on the

smooth muscle of the arteriolar wall. The enhanced effect

might reflect a state of increased vasoconstrictor tone,

independent of myometrial activity, in these conditions.

If g-mimetics indeed cause vasodilatation in the

54

uteroplacental vascular bed, the site of this action is

probably proximal to the spiral arteries, in the radial

and arcuate arteries and perhaps even in the main uterine

arteries. Brosens (1964), Ramsey et al. (1976), and

others have demonstrated that smooth muscle disappears

from the walls of the spiral arteries during pregnancy in

man and some other primates, probably as a result of inva­

sion by trophoblast cells.

Thus, it seems unlikely that these vessels are capable of

vasomotor activity. Furthermore, the spiral arteries are

quite widely dilated over most of their length and for

this reason also are unlikely to be the site of the con­

trolling resistance in the uteroplacental vascular bed.

This concept is supported by the observation of Moll et

al. (1978) that pressures within the spiral arteries are

only slightly greater than the pressure within the

intervillous space. The physiological advantage of a

shift in the site of the controlling resistance to more

proximal, larger vessels during pregnancy has been sug­

gested by Anderson and associates (1977) . According to

their hypothesis, a greater degree of vascular smooth

muscle concentration would be necessary in larger than in

smaller vessels, to produce the same degree of increase in

vascular resistance. This would have the effect of

"protecting" the fetus from large changes in placental

blood flow as a consequence of relatively minor stresses.

Another important concept with regard to the possible

site(s) of action of ß-mimetics on the uterine circulation

is that of differing reactivity between the utero-placen-

tal arteries (those arteries supplying the maternal ex­

change area(s) of the placenta) and the myo-endometrial

vascular beds. Greiss and coworkers (1976) have demon­

strated that as pregnancy progresses in sheep, the capac­

ity for autoregulation of flow in response to changes in

perfusion pressure disappears from the uteroplacental

(cotyledonary) arteries, but remains present in the myo-

55

endometrial vessels. Rosenfeld et al. (1976a) and Ander­

son and coworkers (1977) have shown that the degree of

vasoconstriction induced by adrenaline and noradrenaline,

respectively, in myoendometrial vessels of the pregnant

ewe is much greater than that produced in the cotyledonary

arteries. It would appear that the reactivity of the

uteroplacental vessels is markedly blunted during preg­

nancy, whereas the myoendometrial vessels retain their

normal capacity for dilatation and constriction. This

suggests that a dilator effect of g-adrenergic agents

would be more likely, and of stronger degree, in the

non-placental than in the placental portions of the uter­

ine vascular bed during late pregnancy. Caution is there­

fore necessary in interpreting either direct measurements

of total uterine blood flow (e.g. Brennan et al., 1977 ;

Ehrenkrantz et al., 1976, 1977a,b) or indirect indices of

blood flow over the placental site (and overlying myo­

metrium) (Brettes et al., 1976 ; Lippert et al., 1976 ;

Janisch et al., 1974 ; Suonio et al., 1978) as represent­

ing an increase in maternal flow in the exchange portion

of the placenta.

An increase in maternal placental blood flow in re­

sponse to ß-mimetics or other agents remains a real possi­

bility, however. A decrease in the frequency and inten­

sity of uterus contractions would increase average blood

flow in proportion to the degree in which contractions

were initially present. That some reserve capacity for

vasodilatation remains in the uteroplacental vascular bed

is demonstrated by the observation that estrogens produce

an increase in cotyledonary blood flow in sheep (Rosenfeld

et al., 1976b), although the per cent increase in cotyle­

don flow was far less than that observed in myometrium and

endometrium.

Still another possible mechanism for increased placen­

tal flow is suggested by the observation that in the rhe­

sus monkey, not all placental lobules are perfused at all

56

times even in the absence of uterine contractions (Martin

et al., 1964 ; Ramsey et al., 1979). In these radioangio-

graphic studies, some spiral arteries (and the placental

lobules they supplied) were found to be inconsistently

visualized in successive radioangiograms made during uter­

ine relaxation, suggesting the presence of intermittent

vasoconstrictor activity, probably proximal to the spiral

artery itself (Martin et al., 1964). Recent observations

with real-time echography have suggested that a similar

phenomenon occurs in human pregnancy (Hoogland, 1980).

A vasodilator effect of β-mimetic agents could conceivably

overcome temporary vasoconstriction in portions of the

uteroplacental vascular bed, resulting in greater total

placental perfusion.

It is, of course, self evident that, in pathologic

pregnancies, a vasodilator effect of any agent on the

uteroplacental vascular bed is meaningful only to the

extent that any reduction in maternal placental blood flow

present is the result of spasms of the more proximal

uteroplacental vessels and not the consequence of anatomic

lesions of the spiral arteries.

Circulation in the portions of the intervillous space

downstream from markedly stenotic or occluded spiral ar­

teries will not be improved by vasodilator therapy,

because of the compartimentalization of the intervillous

space (Wallenburg, 1971 ; Brame et al., 1969).

2.4.3. Fetal lung maturation after ЪеЬатітеіъс therapy

The leading element in reducing the chances for

healthy neonatal life, or even survival, of prematurely

born infants is functional immaturity of the lungs.

A number of drugs including heroin (Glass et al.,

1971) and thyroxine (Redding et al., 1972), are believed

to have some influence on the incidence of RDS in the

neonate.

57

Evidence for the role of corticosteroids in the stimula­

tion of fetal lung maturation has been given by several

authors (Liggens and Howie, 1972 ; Caspi et al., 1976).

In a retrospective analysis. Boog and associates

(1975) reported a tendency toward a lower incidence of

RDS among premature infants whose mothers had been treated

with ritodrine as compared with a control group of

untreated subjects.

From a similarly designed analysis Bergman and Hedner

(1978) reported a significantly lower proportion of RDS

among infants from mothers treated with terbutaline com­

pared to control babies (p < 0.05).

Gamissans et al. (1975) studied the effect of rit­

odrine on the L/S ratio in a prospective, placebo-con­

trolled trial. After 1 week of treatment (10 mg orally

every б hours), they could only report upon a trend toward

an improvement of L/S ratio's compared with the untreated

patients (p < 0.08).

Recently, the effect of ritodrine (10 mg 4 times per

day orally), upon amniotic fluid palmitic acid levels was

investigated by Cabero and coworkers (1979) in a prospec­

tive, randomized, placebo-controlled methodology, in­

cluding 20 normal pregnant women. Treatment was started

in the 33th week of amenorrhea and lasted for 10 days. A

significant increase in amniotic fluid palmitic acid

levels was seen in the treated women (p < 0.001), whereas

no such increase occurred in the control subjects. Also a

significant difference was found between the two groups of

patients in palmitic acid levels after treatment

(p < 0.05).

The mechanism of action is not clear. Hypotheses in­

clude an increase of endogenous corticosteroid secretion

resulting from stimulation of the maternal or fetal pitui­

tary to release ACTH, direct stimulation of adrenal ster­

oidogenesis, and stimulation of surfactant synthesis as a

result of an increase in fetal pulmonary blood flow.

58

2.4.4. Intrapartum tooolysis with ß-sympathomimetios

With i n c r e a s i n g c l i n i c a l expe r i ence with ß -mimetic agen t s in o b s t e t r i c s , t he se drugs have been used more f r e q u e n t l y for i n d i c a t i o n s o ther than the suppress ion of e a r l y l a b o r . Important examples of t h i s inc lude t h e i r p o s s i b l e b e n e f i c i a l e f f e c t upon p l a c e n t a l blood flow, or when a r ap id but s h o r t l a s t i n g r e l a x a t i o n of the u t e r u s i s d e s i r e d dur ing l a b o r . Severa l i n d i c a t i o n s for i n t r apa r tum t o c o l y s i s have been sugges t ed . These a re summarized in Table 2.4

Table 2.4 INDICATIONS FOR INTRAPARTUM TOCOLYSIS WITH BETAMIMETICS

I . Intrapartum fetal distress

- umbilical cord complications

- excessive uterine activity

- placental insufficiency

I I . Impending rupture of the uterus

I I I . External or internal version

IV. Before cesarean section to avoid further engagement of a breech

V. Manual removal of the placenta complicated by a contraction ring

VI. Manual reposition of an inversion of the uterus

V I I . "Uterine dystocia"

Relaxa t ion of the u t e r u s may be a l i f e saving tempor iz ing method u n t i l caesa rean s e c t i o n can be performed in case of an impending r u p t u r e of the u t e r u s .

When a f e t o - p e l v i c d i s p r o p o r t i o n i s diagnosed in a breech p r e s e n t a t i o n with a high degree of c e r v i c a l d i l a ­t a t i o n , t o c o l y s i s may be he lp fu l whi le awai t ing the abdom­ina l d e l i v e r y .

Most impor tant from a q u a n t i t a t i v e p o i n t of view,

59

however, is the administration of 3-mimetics in case of

intrapartum fetal distress.

2.4.4.1. Treatment of fetal distress with Q-mimetic agents

Uterine contractions at any time may reduce or even

totally arrest blood flow in the pregnant uterus and in­

tervillous space of the placenta by compression of the

intramyometrial blood vessels (Borell et al., 1964), and

thus can be an asphyxiai stress for the fetus.

Because of the recovery time between contractions these

periodic decreases in uterine blood flow do not neces­

sarily lead to severe fetal hypoxia and acidosis.

In cases of abnormally intense uterine motility, however,

the fetomaternal exchange can be diminished to such an

extent that as a consequence fetal PO- and pH will de­

crease progressively. Even normal uterine activity during

labor may affect the fetus in the same way when materno-

fetal exchange is hampered, for reasons such as umbilical

cord complications or placental insufficiency.

Considering these facts, it seems rational to try to im­

prove deteriorating fetal condition in these circumstances

by diminishing uterine activity (de Haan et al., 1971).

The first reports of treatment of intrapartum fetal

distress with ß-mimetics came from South America when

Caldeyro-Barcia and associates (1969) described 2 cases of

fetal distress with normal uterine contractions ; after

tocolysis (orciprenalin intravenously), late decelerations

disappeared and the pH of the fetal scalp capillary blood

rose to normal values, and from Spain (Gamissans et al.,

1971) .

Schmidt and Hirdes (1974) reported of 60 caesarean

sections for fetal or mixed fetal-maternal indication.

Half of the patients were alternatively treated prior to

the operation with fenoterol (0.08 - 0.1 mg i.V.). A

significant difference was found between the treated and

60

untreated patients in the pH of umbilical venous blood,

the fenoterol group being less acidotic (7.29 + 0.08 vs.

7.22 + 0.08 ; ρ < 0.01) .

With a considerably lower dose of the same agent,

K'unzel and Reinecke (1973) found a significant rise in

fetal POj during normal labor but no alteration in pH of

mother or fetus.

Another approach to influence the fetal oxygenation

and fetal acid-base status in normal labor was made by

Humphrey and coworkers (1975). They studied 35 women in

the second stage of labor, specifically excluding patients

with clinical signs of fetal distress. In a double blind

controlled study, women were given either a placebo, 1.5

mcg/kg/min ritodrine i.V., or 3.0 mcg/kg/min ritodrine

i .v.

A progressive fall in pH, PO, and oxygen saturation was

seen in the fetal scalp blood of the control group whereas

in the ritodrine groups these changes were abolished or

even reversed.

In general, the improvements were more pronounced in the

group of patients treated with the larger dose.

Kastendieck and associates (1974) found in 14 patients

with established fetal acidosis in the second stage of

labor not only a significant rise of pH and base excess

following a 50 meg bolus of fenoterol i.v. followed by an

infusion of 2.5 meg/min for 15 minutes, but also a corre­

lation between the severity of the acidosis and the rise

of pH and base excess.

Gamissans et al. (1971, 1972) demonstrated a signifi­

cant improvement of fetal acidosis of hypoxic origin after

intravenous administration of a contraction inhibiting

dose of ritodrine to women at the end of the first or dur­

ing the second stage of labor. Another report came from

Lipshitz (1977), who treated six patients with severe

fetal distress intrapartum with a 10 meg intravenous bolus

of hexoprenaline (IpradolR) as a temporizing measure

61

before instrumental delivery. In all cases, a rapid

improvement of the fetal heart rate and a rise in the

fetal pH was observed, reflecting an improvement in the

fetal condition probably due to the reversal of the

aggravating factors which had caused the fetal distress.

The first trials of intrapartum treatment of fetal

distress with ß-mimetic agents were carried out with con­

tinuous infusion of the drug. Recently, there has been a

tendency to the "one shot" therapy, for a bolus injection

seems to be a convenient and rapid method of stopping

(excessive) uterine activity for a limited period of time.

In our department we have modified the bolus treatment by

injecting the ß-mimetic agent slowly over a period of

several minutes.

In our experience such an approach causes prompt cessation

of uterine activity with less maternal cardiovascular side

effects than a rapid bolus injection of the same total

dose.

Whether intrapartum administration of ß-mimetics in

cases of fetal distress may be considered as curative

treatment depends largely upon the nature of the etiolog­

ical factor. Several of the causal factors are revers­

ible. Excessive uterine contractility can be reduced by

position change of the mother (Caldeyro-Barcia et al.,

1960), or intravenous administration of tocolytic agents,

continuously if necessary. Although in many instances

umbilical cord compression can be effectively relieved by

changes in maternal position, the recovery time for the

fetus may be shortened by simultaneous complete relaxation

of the uterus. The same strategy may be applied in the

correction of fetal hypoxemia due to aortocaval compres­

sion. A true knot in the cord, partial abruption of the

placenta or severe placental insufficiency as a cause of

fetal jeopardy, however, will certainly limit the effect

of uterine inhibiting agents in increasing fetal PO and

pH. In such cases, the use of these drugs should be re-

62

garded as a temporizing measure only and should not lead

to postponement of delivery.

Whatever the reasons for fetal asphyxia, and whether

the etiologic factors are reversible or not, the rate of

progression of the fetal hypoxia is enhanced by uterine

contractions. Therefore, rapid deterioration of the fetus

can be avoided or at least minimized by prompt, complete

relaxation of the myometrium.

2.4.4.1.1. Meahanisms of action of ß-mimetic agenta in the treatment

of fetal distress

1. Because of the reduction of the blood flow in the uter­

us and intervillous space during contraction of the

myometrium (Borell et al., 1964), relaxation of this

muscle must be considered a major contributing factor

in the process of intrauterine fetal recovery after

tocolytic treatment. This applies even more when

excessive uterine motility is present.

2. The possible influence on uterine and placental blood

flow has been discussed earlier (2.4.2).

3. β -mimetic stimulation results in an increased glyco-

genolysis in liver and skeletal muscle and, as a conse­

quence, a raised plasma glucose level both in mother

and fetus (Unbehaun et al., 1974). This increase in

blood glucose level could be beneficial to the fetus in

distress, as long as the fetus maintains a certain

degree of oxygenation. In more severe fetal hypoxia,

however, this carbohydrate load can have a deleterious

effect on fetal brain structures probably as a result

of the markedly greater extent to which lactic acid

accumulates in brain tissue in a hyperglycemic state

(Myers, 1977). Fetal hyperglycemia may also acceler­

ate the rate of fall in pH during fetal hypoxia by

providing more substrate for anaerobic metabolism to

lactic acid (Shelley et al., 1975).

63

Even when there is no fetal hypoxia present, adminis­

tration of ß-mimetics can produce a mild degree of mater­

nal and fetal metabolic acidosis. Because of the lack of

glucose-6-phosphatase in muscle cells, glycogenolysis in

muscle leads to production of lactic acid, much of which

diffuses into the blood stream from which it is largely

removed by the liver and (in the presence of adequate Oj)

reconverted to glycogen or glucose.

The net effect is an increase in the maternal plasma level

of lactic acid. This results in a slight metabolic acido­

sis which, because of the placental transfer of lactate,

(Weidinger and Mohr, 1973) also affects the fetus. More­

over, the lipolytic action of these agents will also con­

tribute to a fall in maternal pH and base excess. In the

absence of hypoxemia, however, such a "passive" mild

metabolic acidosis appears to be innocuous for the fetus.

2.4.4.1.2. Administration of the drug

To achieve prompt suppression of unwanted uterine

activity for a limited period of time, the ß-mimetic agent

can be given either intravenously or in aerosol form.

The effect of an intravenous bolus injection of the drug

is more rapid than that of an equivalent dose administered

as a timed infusion. Equivalent bolus doses are 25-50 meg

of fenoterol, 3-6 mg of ritodrine and 100-200 meg of sal-

butamol (Lipshitz et al., 1976).

Because of compression of pelvic vessels in the supine

position, bolus injections are preferably administered

with the patient in the lateral position.

A precautionary intravenous infusion, and, recording of

heart rate and blood pressure are recommended and an an­

tagonist should be available.

The cardiovascular effects of the ß-mimetics may be

neutralized by the intravenous administration of proprano­

lol, which antagonizes more selectively the cardiovascular

64

effects. Oxytocics antagonize only the tocolytic action

of ß-mimetics.

2.4.4.2. Other indications for intrapartum tooolysis

Zandvoort (1975) described successful regulation of

hyperactivity, hypertonus and dysregulation of uterine

contractility in the first stage of labor by infusion of

fenoterol (0.5 meg per minute).

Hyperactive labor with excessive amplitude and fre­

quency, hypertonic labor with excessive basal tone, as

well as incoordinate labor with an irregular sequence of

multishaped contractions, were reported to be effectively

regularized by administration of ß-mimetics in a double

blind, placebo-controlled study (Hüter, 1977).

Saling and Müller-Holve (1977) reported upon 57

pregnant women near term in whom 67 attempts at external

version of a fetus from breech to vertex presentation were

made. The procedure was carried out after complete re­

laxation of the uterine muscle by intravenous injection of

fenoterol. In 34 of these patients, the duration of

pregnancy exceeded 37 weeks, a time beyond which external

version is frequently unsuccessful. In 25 of these 34

patients with uterine relaxation, however, version was

successful.

In only one case was the attempted version followed by

severe fetal acidosis.

In the immediate postpartum period ß-sympathomimetics

can be employed if contracture of the lower uterine seg­

ment complicates manual removal of the placenta, or in

cases of acute puerperal inversion of the uterus (Thiery

et al., 1978).

65

2.4.5. Contraindications

Contraindications for the inhibi t ion of uter ine con­t rac t ions with ß-mimetics are summarized in table 2 .5 .

In hyperthyroid pa t i en t s , administration of ß-adren-ergic drugs can be dangerous because of the already exis t ing greater sympathetic ac t iv i ty in these persons.

Combination with other drugs such as antihypertensive agents or some general anaesthet ics (e .g. fluothane) can lead to pronounced hypotension and cardiac arrhythmias or asys to le . Monoamine oxidase i nh ib i to r s , used in the treatment of some psychiat r ic d isorders , can modify the metabolism of ß-agonis ts . Several authors have warned against the combined use of ß-adrenergic drugs to inh ib i t

Table 2.5 RELATIVE CONTRAINDICATIONS FOR THE USE OF BETAMIMETICS

Thyrotoxicosis

Heart disease

Diabetes mell i tus

Dystrophia myotonia

Feochromocytoma

Infections - fever

Coagulation disorders

Shock

Some other drugs

Preeclampsia *

Fetal growth retardation *

Fetal distress (chronic use)

Severe fetal malformations

Abruptio placentae

Ruptured membranes with demonstrated or probable fetal lung

maturity

Severe blood loss from the placental site

According to some authors, these oonditions car. sometimes

also constitute indications for betammetic therapy.

66

labor and corticosteroids to stimulate fetal lung maturi­

ty. Several cases of maternal death have been attributed

to this combination, death occurring by pulmonary edema

and heart failure (section 2.5.1.2).

Infections with high fever increase the endogenous

levels of catecholamines. Antibiotic treatment is more

appropriate than ß-adrenergic drugs. Nevertheless, in

urinary tract infections with slight temperature eleva­

tions and uterine contractions, the temporary

administration of ^-adrenergic drugs can be helpful.

Premature rupture of the membranes forms a separate

entity because of the risk of intrauterine infection,

which increases with time after membrane rupture. If the

fetus has no chance of survival outside of the uterus

because of the degree of immaturity, inhibition of labor

seems indicated.

Dystrophia myotonia (syndrome of Curschmann Steinert)

is considered a contraindication to the use of ¡3-mimetic

drugs because of aggravation of the symptoms of myotonia.

In cases of severe preeclampsia the maternal and/or

fetal condition can deteriorate rapidly. Termination

rather than prolongation of pregnancy is often the better

choice.

In diabetes mellitus careful control of blood glucose

levels is needed during ß-mimetic therapy.

Heart disease and especially disturbances of intra­

cardiac conductance form a relative contraindication.

Electrocardiograms taken before and during treatment are a

wise precaution.

Vaginal bleeding from placenta praevia accompanied by

uterine contractions is not necessarily a contraindication

to tocolysis unless blood loss is excessive. In cases of

placental abruption ß-adrenergic drugs might only be

indicated when placental reserve guarantees continuing

fetal well-being. The relationship between uterine activ­

ity and the maternal coagulation defect is not clear.

67

Some believe that a hypertonic and hypercontractile uterus

forces intrauterine material into the maternal circula­

tion. Others believe that the hypertonus prevents entry

of thromboplastic material into the maternal circulation

(Eskes, 1966). This question is presently unresolved.

Fetal growth retardation, if secondary to a deficient

uteroplacental circulation, can signify an increased risk

of intrauterine death, and hence might be regarded as a

contraindication to β-adrenergic treatment. It might be

unwise to interfere with the endogenous trigger for labor

and delivery since this may be a protective mechanism for

the fetus. On the other hand some authorities advocate

the use of ß-adrenergics because of their possible bene­

ficial effect on placental perfusion.

Fetal distress can be regarded as a relative contra­

indication to the chronic use of ß-mimetics because as

soon as the diagnosis is established by CTG and blood-gas

analysis, pregnancy or labor should usually be terminated

promptly. An exception is the rapid temporary inhibition

of uterine activity during labor by an intravenous bolus

injection as described above, while preparations for

operative delivery are being carried out.

2.5. Side effects of betasympathonrimetios in human obstetrics

Я.5.1. Extrauterine effects

2.5.1.1. tfeLabolio effects

β-sympathomimetic drugs exert an influence on carbohy­

drate metabolism by stimulation of adenylcyclase in liver,

muscle and probably pancreas cells.

ß-adrenergic stimulation in liver cells causes an ele­

vation of the serum glucose level as a result of at least

three mechanisms (Weidinger and Wiest, 1973).

68

1. activation of Phosphorylase, which leads to conversion

of glycogen to glucose ;

2. inactivation of glycogen production from glucose ; and

3. stimulation of gluconeogenesis.

In muscle cells, glucose-6-phosphatase is lacking.

Thus, glycogenolysis in striated muscle cells will lead to

production of lactic acid. After diffusion into the

bloodstream, the lactate is largely removed by the liver

and reconverted to glucose.

In the pancreatic beta cells, there also seems to be a

direct influence via β-adrenergic receptors, leading to

increased blood insulin levels (Taylor et al., 1976).

There may also be an increased insulin resistance secon­

dary to g-mimetic induced lipolytic activity (Weidinger

and Mohr, 1973).

Although the exact mechanism of action is not clear, the

measured net effect of these actions is a transient

elevation in blood glucose concentration in spite of

increased insulin secretion.

When treatment with g-mimetic drugs is continued, a

new equilibrium within the normal range may be established

(Unbehaun et al., 1975).

These observations, and the fact that with respect to

the tocolytic and cardiovascular effects no or incomplete

adaptation is seen during long-term treatment have led to

several speculations including the proposal that there

might be a separate intracellular receptor system for the

metabolic effects.

Another explanation could be compensation of the dia­

betogenic effects of β-mimetics by a correspondingly

higher level of insulin production, either after indirect

or direct stimulation of the β-cells of the pancreas

(Weidinger and Mohr, 1973).

Adjustment of carbohydrate metabolism as judged from

normal blood levels of glucose and free fatty acids is no

69

proof of an unaffected carbohydrate metabolism. There­

fore, glucose tolerance during long-term treatment with

ß-mimetics has been studied by several investigators.

Blouin and colleagues (1976) studied the effect of

ritodrine (10 mg orally, 4 times per day) from the 25th

week of pregnancy until delivery on the carbohydrate

tolerance of eight pregnant women and their newborn

infants. They observed no diabetogenic influence on the

50 gram oral glucose tolerance test or the 24 hour glucose

profile on the 7th day of treatment, nor after 10 weeks of

oral ritodrine therapy, as compared with matched control

women.

These observations are in agreement with the results of

Unbehaun et al. (1974), who found a compensation and nor­

malisation of the changes in carbohydrate metabolism

within 72 hours after the start of treatment.

Lang and associates (1977) studied the glucose toler­

ance at the end of a 48 hour infusion of 1 meg fenoterol

per minute in 6 women during the last trimester of

pregnancy. Comparison of the assimilation constant (Kg)

of the intravenous glucose tolerance test (i.v. GTT) prior

to and during fenoterol infusion in the same patients

demonstrated a slight deterioration in the Kg. A definite

elevation of glucose levels during fenoterol administra­

tion above control levels, particularly under fasting

conditions, was also observed.

When basal glucose values were taken into account, how­

ever, no difference was found between glucose tolerance

before and during fenoterol administration. The insulin

profiles during the two glucose tolerance tests were not

found to be different.

Because of their effects on carbohydrate metabolism,

ß-mimetics are contraindicated in patients with unstable

diabetes mellitus. As to patients in whom no carbohydrate

intolerance has been detected, frequent assessment of

glucose homeostasis is advisable.

70

Serum potassium levels can decrease during ß-adrener-

gic treatment because of a shift of potassium from the

extra- to the intra-cellular compartment. In addition to

the extracellular to intracellular shift of potassium

during the first days of ritodrine therapy, Hondros and

Schaller (1980) also demonstrated an increased urinary

excretion of potassium.

These observations could not be confirmed by Grospietsch

and coworkers (1980) in their trial with fenoterol

(2 mcg/min intravenously) and verapamil (75 mcg/min intra­

venously) . Indeed, within two hours a marked decrease in

the serum potassium concentrations was measured, followed

by a slow increase to preinfusion levels within 24 hours

of the start of therapy ; the urinary potassium excretion

per hour (as well as the excretion of sodium), however,

decreased and did not reach preinfusion levels within the

first 48 hours following the start of treatment.

Furthermore, ß-mimetic agents stimulate a specific

lipase leading to lipolysis, with a rise in free fatty

acids and free glycerol (Lang et al., 1977).

This, and the previously mentioned rise in lactic acid

levels following glycogenolysis in muscle, may lead to a

transient metabolic acidosis.

2.5.1.2. Caraiovasoular effects

Betamimetics have a positive inotropic and chronotrop­

ic effect on the maternal heart, resulting in an increase

in maternal heart rate.

Stimulation of the ß-adrenergic receptors in blood

vessels relaxes vascular smooth muscle, producing a de­

crease in peripheral vascular resistance and a varying

degree of hypotension with increased pulse pressure.

Within the therapeutic range of S-2-selective

ß-mimetics used for long-term tocolysis, the net effect of

these actions is usually a moderate increase in cardiac

71

output (Bienarz et al., 1974). The increased cardiac

output with concomitant peripheral vasodilatation could

increase placental perfusion, if the uteroplacental cir­

culation participates in the vasodilatation (section

2.4.2). In the treatment of threatening preterm labor,

however, these cardiovascular effects are unwanted ; for

especially the resulting maternal tachycardia considerably

limits the dosage level of 3-mimetics which can be used in

tocolysis.

In order to study the possibility of myocardial damage

during long-term tocolysis, Wellstein and associates

(1977) and Meinen and coworkers (1978) , analysed the heart

muscle-specific isoenzyme creatine kinase MB 3 times week­

ly in 50 and 100 women respectively, who were treated with

fenoterol and verapamil (maximum dose 4 meg and 40 meg per

minute, respectively, intravenously in both studies). In

none of their patients could a significant rise in enzyme

levels in serum be shown.

Similar results were reported by Steyer and associates

(1979) , in 128 women receiving long-term tocolysis with

fenoterol, most of them treated orally (30 - 60 mg daily),

and by Gerris and colleagues (1980) in 33 gravidas,

undergoing chronic tocolysis with ritodrine, both studies

without administration of verapamil.

However, in the rat (Rona et al., 1959) and in

cultured human fetal myocardial cells (Hofmann et al.,

1977), morphologic lesions interpreted as myocardial

necrosis have been reported in connection with the use of

ß-mimetic agents.

Jung et al. (1978) studied the maternal and fetal

electrocardiographic alterations in 18 healthy women in

labor, during and after infusion of fenoterol. During

treatment an early ST rise and an increase in the Τ wave

were observed in the maternal ECG. Similar alterations,

however, occur during sympathetic stimulation from

physical stress or emotional excitement as signs of

72

sympathetically altered de- and repolarization of the

myocardium. Thus, the authors concluded that these

alterations in maternal ECG were merely functional and not

a sign of damage to the heart.

On the other hand, there is a growing number of anec­

dotal reports of maternal morbidity and mortality in

relation to the combined administration of g-adrenergic

drugs and corticosteroids (Bender et al., 1977 ; Elliott

et al., 1978 ; Jonatha et al., 1978 ; Stubblefield, 1978;

Babenerd and Flehr, 1979 ; Wolff et al., 1979 ; Tinga and

Aarnoudse, 1979 and Rogge et al., 1979), and in relation

to a preexisting cardiomyopathy (Eskes et al., 1980),

leading to severe maternal pulmonary edema within 72 hours

after the start of therapy.

Special attention was placed on the role of ergomet-

rine in this situation by Davies and Robertson (1980) , for

especially after delivery when there is a physiological

autotransfusion due to uterine contraction, the vaso­

constrictor effect of ergometrine could cause a sudden

increase in the tonus of both the resistance and capaci­

tance vessels, resulting in a simultaneous overload of

both the left ventricle and pulmonary circulation.

As a result of these cardiovascular effects, ß-mimet-

ics are contraindicated in patients with heart disease.

Also, combination with corticosteroids in order to in­

crease fetal pulmonary maturity can be dangerous. As for

healthy women, non-invasive examination of the heart is

recommended to assess the influence of these drugs on

cardiac function, the more so because of the initial

decrease in potassium levels (section 2.5.1.1). Special

attention should be given also to the fluid balance to

avoid volume overload (section 2.5.1.3) and ergot alkal­

oids should be avoided when there is a short interval

between the end of treatment and delivery.

73

2.5.1.3. Other extrauterine side effects

Various subjective side effects are related to β-mi­

metic drugs, especially when these are given in tocolytic

dosage levels. The most frequent complaints are palpi­

tations, anxiety, tremor, slight headache, constipation,

nausea, vomiting and sweating.

Besides the well known influence of 8-mimetics upon

uterine, pulmonary and cardiovascular smooth muscle, these

agents also affect other smooth muscle (urinary tract,

digestive tract) and striated muscle.

Horowitz and Creasy (1978) reported 2 cases of aller­

gic dermatitis following the administration of isoxsup-

rine.

Jutting and coworkers (1973) studied the total estro­

gen excretion in ß-mimetic-treated women.

A significantly lower estrogen excretion compared to

control patients was found when fenoterol was given intra­

venously. This could, however, be the result of an anti­

diuretic effect of ß-adrenergic agents as postulated by

Beri et al. (1974), Schrier et al. (1972) and Kords et al.

(1978a).

Schrier's (1972) investigations in the dog, suggested that

the antidiuretic effect of ß-mimetic agents is not the

result of an alteration of the water permeability of the

renal tubular epithelium, but rather that the primary

mechanism involves the integrity of the hypothalamus-neu-

rohypophysical system and the release of ADH.

Although the antidiuretic effect of ß-mimetic stimulation

is a transient one according to Grospietsch et al. (1980),

it may be harmful in cases of EPH gestosis or renal

insufficiency and may lead in combination with an excess

of fluid intake and/or corticoid treatment to hypervolemia

and maternal pulmonary edema (section 2.5.1.2).

As a result of the water retention within 48 hours

after the onset of treatment, an increase in weight and a

74

decrease of hemoglobin concentration, hematocrit, and

serum albumin concentration may also be observed

(Grospietsch et al., 1980).

In contrast to the findings of Kords and associates

(1978a) with fenoterol, Bibby and colleagues (1978)

demonstrated a fall in peripheral plasma concentrations of

progesterone and estradiol-17- β when salbutamol was given

intravenously.

These values returned to pretreatment levels after discon­

tinuation of therapy.

No change was seen in plasma human placental lactogen

concentrations during treatment, which suggests, according

to the authors, that the fall in steroid hormone levels is

not likely the result of altered uterine or placental

blood flow.

During a 24 hour fenoterol infusion in nine gravidas,

Kords et al. (1978b) observed a transient fall in plasma

aldosterone concentration corresponding to the fall in

plasma potassium concentration, in spite of an elevation

in plasma renin level.

The influence of fenoterol upon the platelet aggrega­

tion and the number of platelets in peripheral blood was

investigated by Ardelt (1978) . As a result of ß-mimetic

stimulation platelet aggregation was found to decrease and

a dose-dependent transient reduction in the number of

platelets was reported.

However, these observations could not be confirmed by

Schander et al. (1978), whereas Briel et al. (1978) re­

ported a transient decrease in platelet aggregation after

intravenous administration of fenoterol but no effect upon

the peripheral platelet count. As a result of these

observations of possible alteration in platelet number and

function, plus the relaxing effect of 3-mimetics upon the

myometrium, the fear of increased blood loss postpartum

after prolonged treatment with β-adrenergic drugs or after

intrapartum tocolysis may be justified. However, our own

75

investigation demonstrated no increase in post partum

blood loss after long-term B-mimetic treatment (chapter

5).

Fenoterol treatment was found to have a significant

influence upon the oxygen dissociation curve of pregnant

women with gestational ages between 30 and 35 weeks (Meier

et al. 1978). Compared to untreated and acetylsalicylic

acid-treated patients, the actual as well as the standard­

ized partial pressure of oxygen at which hemoglobin was

50% saturated (Pen) was found to be 1.5 mm Hg higher in

women with long-term fenoterol treatment.

2.5.2. Transplacental transfer

Wiest et al. (1977) using radioisotopically labelled

fenoterol in 31 cases of legal abortion, proved that

partusisten crosses the human placental barrier in early

pregnancy.

Transplacental transfer of ritodrine was demonstrated

by Gandar and coauthors (1980), who measured serum levels

of ritodrine in venous cord blood of neonates born from

mothers after intravenous infusion of ritodrine at various

dosage levels.

However, monoamine oxidase as well as catechol-O-methyl

transferase have been identified in placental tissues

(Thompson and Tickner, 1949 ; Morgan et al., 1972), so

inactivation and protection may be possible to some

extent.

2.5.Ó. Effects en fetus and neonate

The fact that so many different organs including the

central nervous system are involved in the actions of

ß-mimetic agonists, plus the ability of these agents to

cross the placenta, make these drugs potentially dangerous

to the unborn child.

76

Thus, assessment of the effects on the developing fetal

organism is essential to judge the appropriateness of

these drugs for use in human obstetrics.

Furthermore, the potential effects to be investigated

include not only short-term actions during the fetal or

immediate neonatal periods, but also possible long-term

effects on later physical health and mental development.

Direct or indirect influence of β-mimetic treatment on the

fetus is, however, very difficult to measure in man.

Since transplacental transfer has been proven for some

drugs in this category (section 2.5.2) and is likely for

all of them, efforts have been made to measure the influ­

ence upon fetal heart rate and fetal electrocardiogram

(Stander et al., 1964 ; Junge et al., 1978). Studies of

the magnitude of acceleration of fetal heart rates have

not been in agreement. Several authors have reported no

or only a slight increase in human fetal heart rate even

during maternal treatment with high doses of ß-mimetics

(Landesman et al., 1971 ; Bieniarz et al., 1972), whereas

others have noted significant fetal tachycardias (Stander

et al., 1964). No satisfactory explanation has thus far

been offered for this phenomenon, but it may well be due

to a "first pass" effect of the placenta and/or fetal

liver, and possibly also a diminished vasodilator-hypo-

tensive response of the fetal systemic circulation.

Freysz and colleagues (1977) performed a long-term

evaluation of infants who were exposed to ritodrine while

in utero.

Forty-two neonates with intra-uterine exposure of 2 to 93

days duration (maternal daily dose 60-80 mg) were matched

with 42 control neonates.

No statistically significant differences were found in

psychomotor development (Denver Developmental test),

clinical examination, electrocardiograms, and other

investigated parameters between the two groups of infants.

A negative influence on the body weight gain until the

77

fifth day of life was reported by Stormi and colleagues

(1977) in the newborn who was exposed to ritodrine while

in utero, compared to control neonates.

Hofmann et al (1977) reported myocardial necrosis

following fenoterol exposure in an in vitro study of

myocardial strips from fetal hearts from legal abortions

treated in organ cultures. The combination of fenoterol

with verapamil resulted, according to the investigators,

in much less injury of the myoplasma.

Neither Spelger and associates (1980) nor Plieth and

colleagues (1980) were able to demonstrate pathological

cardiac findings (CK-MB, electrocardiograms and echocar­

diograms) in newborns following tocolysis with fenoterol

or isoxsuprine and verapamil, which were related to the

preceding medication.

The direct and/or indirect effects of S-mimetics on

fetal and neonatal carbohydrate metabolism are discussed

in chapter 4, together with a description of our own

findings.

78

Chapter 3

Clinical comparison of ritodrine and fenoterol in their efficacy in preventing preterm delivery

3.1. Introduction

The use of ß-mimetic drugs for the treatment of

threatening premature labor has proved to be valid not

only for the inhibition of uterine activity, but also for

the delay of the onset of labor (Wesselius-de Casparis et

al., 1971 ; Ingemarsson, 1976 ; Csapo and Herczeg, 1977 ;

Christensen et al., 1980).

Two ß-mimetic drugs were tested for their capacity to

lengthen the duration of pregnancy after symptoms of

threatening immature or premature labor had occurred. The

two drugs were also compared to some side effects.

3.2. Materials and methods

3.2.1. Patients

The original population for this investigation con­

sisted of 319 consecutive patients with threatening prema­

ture labor, for which treatment was started between Janu­

ary, 1974 and January, 1977.

Further selection criteria applied for inclusion in

the study were, that the patient had received either rit­

odrine only or fenoterol only as tocolytic agent (28 pa­

tients received both drugs), absence of premature placen­

tal separation (3 ; 3)*, singleton or twin pregnancy (1 ;

1 triplets)* and that the last menstrual period preceding

the pregnancy was normal in character and that its dates

between brackets the number of patients (ritodrine ; fenoterol)

removed for this reason

79

were known with assurance (23 ; 32)*. Application of

these criteria resulted in the removal of 91 patients,

leaving 228 study subjects. Subsequently during data

analysis, 34 further patients were removed from the final

comparison groups to achieve acceptably equivalent distri­

butions of background variables between the respective

subgroups (section 3.2.5).

The final number of subjects analysed in the compari­

son of the two tocolytic agents was 194 (ritodrine, 94 ;

fenoterol, 100) .

3.2.2. Criteria for the diagnosis of threatening early labor

Threatening early labor was diagnosed clinically by

judging uterine contractions recorded externally

(corometrics fetal monitor 101 Β), the status of the fetal

membranes, the condition of the cervix, and the amount and

character of vaginal bleeding or discharge (if present).

Uterine contractions (¡j. one per ten minutes) were

obligatory to establish the diagnosis of threatening early

labor.

In about half of the patients, there were also other symp­

toms to support the diagnosis. Forty-nine patients (rit­

odrine = 23 ; fenoterol = 26) had no other symptoms than

regular uterine contractions (>, 12 per hour) when therapy

was begun.

In 48 patients (ritodrine = 23 ; fenoterol = 25) the only

symptoms were irregular uterine contractions (6 - 11 per

hour) without other symptoms.

Because of the painfulness of their contractions these

patients were considered to be at high risk for an early

delivery and therefore treatment was started.

Inherent in this policy (and, as noted earlier in

section 1.3 and 1.4, in almost every clinical trial of

tocolytic drugs) is the possibility that a number of our

subjects were treated unnecessarily.

80

3.2.3. Treatment schedule

Ritodrine and fenoterol were given by intravenous

pump-infusion and/or orally.

In general treatment was started intravenously. When u-

terine contractions were absent for 24-48 hours, the infu­

sion-rate was decreased, and at levels of 100 meg ritodri­

ne per minute or 0.1 meg fenoterol per minute without de­

tectable uterine activity, oral medication was installed.

In a number of women these dose-levels could not be

reached and intravenous medication was continued.

Several times treatment was started orally and in

these cases intravenous medication was only given when

oral treatment failed.

Mean and standard deviation, median and range of the

maximum dosage levels during the intravenous treatment

period of both drugs are given in Table 3.1.

Table 3.1

MEANS AND STANDARD DEVIATIONS, MEDIANS AND RANGES OF THE MAXIMAL DOSE

LEVELS (ug/min) DURING INTRAVENOUS INFUSION OF RITODRINE AND FENOTEROL

Ritodrine

Mean + S.D. median range

311 + 168 300 67 - 732

Fenoterol

Mean + S.D. median range

4.6 + 2.3 4.0 1.3 - 9.3

During the oral treatment period highest doses were 12

tablets of ritodrine 10 mg (120 mg) or fenoterol 5 mg

(60 mg) per 24 hours.

When the condition of the fetus, assessed by the en-

Si

largement of the uterus, the urinary excretion of estriol

and cardiotocograms, remained stable and the fetal mem­

branes were intact, treatment was continued until the end

of the 37th week of amenorrhea and/or the finding of a

lecithin / sphingomyelin ratio exceeding 2.0 (according to

Gluck), or until uterine contractions had been suppressed

and remained absent during tapering-off of the β-mimetic.

Mean, median and range of the duration of treatment were

28, 15, 1 - 125 days and 32, 23, 1 - 120 days for the

ritodrine and fenoterol treated patients respectively.

Verapamil (IsoptinR) was not given to prevent circulatory

side-effects.

3.2.4. Criteria for the judgement of success

The difficulties that may arise in comparising the

efficacy of tocolytic agents are discussed in chapter 2

(section 2.4.1.2.2).

Because of the subdivision that has been made accord­

ing to the duration of amenorrhea at the start of treat­

ment (section 3.2.5) it seemed justified to use the

condition of the neonate as a measure of success. So all

neonates were scored according to an arbitrarily defined

Table 3.2 NEONATAL SCORE USED AS A MEASURE OF SUCCESS

Value :

0 : healthy mature neonate

1 : healthy neonate born before the completed 37th week of

amenorrhea

2 : neonate with hyperbilirubinemia

neonate with hypoglycemia

4 : neonate with respiratory distress syndrome

10 : perinatal death

82

Table 3.3 NEONATAL SUCCESS SCORES OF TWIN PREGNANCIES

RITODRim

Equal suaaese

patient nr. 6

49

151

209

250

Greater success

inferni 1

patient nr. 148

278

Greater success

infant 2

patient nr. 194

281

Score

infant 1

1

1

0

1

7

3

3

10

10

Score

infant 2

1

1

0

1

7

7

7

5

1

FENOTEROL.

patient nr,

patient nr.

patient nr,

. 52

57

58

253

, 18

84

.177

279

Score

infant 1

0

10

0

1

0

0

3

10

Score

infant 2

0

10

0

1

2

2

1

1

score in which the variables gestational age, hyperbiliru­

binemia, hypoglycemia, respiratory distress syndrome and

perinatal death were weighted (Table 3.2).

In case of a twin pregnancy, the parameters of the

first infant were used for comparison. This was thought

to be justified because in most cases a good correlation

between the condition of the two infants was found (Table

3.3) .

Besides in the condition of the neonate, results were

also expressed in the number of days gained from the first

day of treatment till the day of delivery, the gain of

days in relation to the lengthening of pregnancy that was

aimed at (37th completed week) and the prolongation index

(Richter, 1977, section 2.4.1.2.2, figure 2.2).

83

Several other variables e.g. gestational age at deliv­

ery, birth weight, Apgar score and pH of the umbilical

artery blood were compared for the two treatment groups.

3.2.5. Procedure for the balancing of the two groups of patients

In studies comparing two groups of patients, it is

usually required that these groups differ only in the fea­

ture or features being investigated. Other differences,

however small, may sometimes make it impossible to draw

valid conclusions.

This risk may be dealt with by comparing the two

groups using a prospective randomized, allocated and/or

double-blind methodology. To reduce the chance of unbal­

anced groups, however, the number of patients has to be

large and it may be difficult to get these large numbers

in clinical research.

When patients are not treated in a prospectively

randomized way, it is often possible to analyse the data

by methods which will assure retrospectively that the

study subpopulations are truly comparable :

- to select from the total population those patients which

make up balanced patient groups ; or

- to include in the data analysis a comparison of the dif­

ferent groups with respect to all of the recognized fac­

tors or variables which might bias the outcome of the

study.

Selection of patients for the comparison groups can be

performed according to several methods.

Requirements for a good procedure are :

-the method must lead to a previously defined balance in

the two groups ;

-patients with the same features must have the same chance

of being selected for the definite group ; and

-not too many patients should be removed.

Θ4

3.2.5.1. Possible measures of balance

Absolute measure

There are η patients (n, for the first group, n^ for

the second, ni

+ n2

= n)

a n^

m discrete variables with k.

numbers of features (i = 1, 2, ,m) .

For each patient it is recorded which feature of each of

the variables is present. The numbers of patients having

the same feature in each group are called a,· and a..

m

Σ ι=1

ki> (i = If 2, , j, j =

The absolute measure of balance Τ is defined as

J Τ = Σ

i=l 'li - a 2i

If there are equal numbers of patients with all features

in both groups, then Τ equals 0 (complete balance) . With

a complete nonbalance Τ = η χ m.

Relative measure

Instead of wanting a specific feature to appear with

absolutely equal frequency in both groups, one could also

desire that the feature occurs in both groups with the

same relative frequency.

The relative measure of balance R is defined as :

J Σ i=l

_li

11

a2i

If there are relatively equal numbers of all features in

both groups, then R equals 0 (complete balance). By a

complete nonbalance R equals 2 χ m.

85

χ2 - measure

For each variable, a 2 χ к. contingency table can be

made with a classification according to group and feature.

The X value can be calculated to test the independence of

both classifications (in case of a 2 χ 2 contingency table

a correction for continuity is incorporated) .

Ρ is calculated for X2 with k· - 1 degrees of freedom. Ρ

is maximally 1.0 (complete balance) and minimally 0.0

(complete nonbalance). Since the χ2-test is used here as

an approximation, the usual conditions for its application

are not taken into account. Ρ is used only as a measure

of balance.

Elimination of patients

For each woman in the two groups n, and n- the values

of Τ and R could be calculated with this patients removed

from the population. The patient with the lowest value of

Τ or R can be removed.

This procedure could be repeated until most P's are

greater than a predetermined value.

3.2.5.2. The elimination of patients in the present investigation

As the results of tocolytic treatment might depend up­

on the duration of amenorrhea at the time of administra­

tion, the patients were divided into 4 subgroups (Am

groups) according to the gestational age at the start of

treatment (Table 3.4).

In every Am group the ritodrine and fenoterol treated

patients were balanced for the variables : uterine con­

tractions (UC), vaginal bleeding (BD), status of the fetal

membranes (RM), dilatation of the uterine cervix (DI), the

fundus being (̂. 2 weeks) large for dates (FL) and infarcts

of the placenta (IP) (Table 3.5), following the above de-

86

scribed methodology (section 3.2.5.1).

The ρ value for each of these variables which was aimed at

was ρ > 0.40.

Table 3.4

SUBDIVISION OF THE TREATMENT GROUPS INTO 4 SUBGROUPS ACCORDING TO

THE DURATION OF AMENORRHEA AT THE START OF TREATMENT

Amenorrhea at the start of

treatment

< 28 weeks

28 - 31 weeks

32 - 33 weeks

Ϊ, 34 weeks

Am group

Am group

Am group

Am group

1

2

3

4

3.2.5.2.1. Balancing of patients of Am group I

The exclusion of 12 patients led to an increase in the

probability level ρ of 4 of the 6 variables from minimally

0.35 to minimally 0.63. The ρ values of the variables :

dilatation (DI) and uterine contractions (UC) of 0.25

both, were somewhat dissatisfactory, however, for a

further increase removal of a considerable number of pa­

tients would be necessary.

The difference in the mean tocolytic index (Baumgarten and

Gruber, 1974, section 2.4.1.2.1, table 2.3) for both

treated groups fell from 0.59 to 0.33 (Table 3.6).

3.2.5.2.2. Balancing of patients of Am group II

The basic material of this Am-group was poorly bal-

87

Table 3.5 VARIABLES FOR WHICH THE AH GROUPS WERE BALANCED

VARIABLE CODE FEATUftE

Uterine contractions UC 0 : none

1 : i r regular

2 : regular

Bloody discharge BD 0 : absent

1 : present

Rupture of membranes RM 0 : no

1 : high

2 : low

Di latat ion DI 0 : 0 cm

1 : 1 cm

2 : 2 cm

3 : 3 cm

4 : 4 cm or greater

Fundus large for dates,

e.g. polyhydramnios, mul­

tiple pregnancy, large

fetus

FL 0 : no

1 : yes

Infarcts of placenta IP 0 : no

1 : yes

88

Table 3.6 AM GROUP I (balanced)

ritodrine : η = 26

fenotevol : π = 27

mean tooclytio index - 2.77

mean tocolytic index =2.44

Variable * Number

0 1 2

(Ρ before balancing)

UC

BD

ritodrine

fenoterol

ritodrine

2

0

20

15

14

6

9

13 0.25

0.94 fenoterol 22

(0.23)

(0.39)

RM ri todrine 26

fenoterol 27 1.00 (0.35)

DI ri todrine 16 3

fenoterol 21 0.25 (0.13)

FL ritodrine 15 11

fenoterol 16 11 1.00 (0.78)

IP гг Ьоаггпе

fenoterol

24

25 1.00 (1.00)

for explanation see table 3.5

Distribution of features among the patients in Am group I after being

balanced, with corresponding probability levels.

Between brackets probability values before balancing (xz-test)

89

Table 3.7 AM GROUP II (balanced)

ritodrine : η = 29

fenoterol : η = 26

mean tocolytic index = 2.45

mean tocolytic index = 2.27

Variable Number

0 1

(P before balancing)

UC vitodrine

fenoterol

9

10

19

15 0.84 (0.68)

BD ritodrine 27

fenoterol 22 4 0.57 (0.54)

RM ritodrine 29

fenoterol 26 1.00 (0.08)

DI ritodrine 19 7 0

fenoterol 18 б 2 0.29 (0.29)

FL ritodrine 23 6

fenoterol 16 10 0.25 (0.22)

IP ritodrine 27 2

fenoterol 24 2 1.00 (1.00)

for explanation see table 3.5

Distribution of features among the patients in Am group II after being

balanced, with corresponding probability levels.

Between brackets probability values before balancing (x2-test)

90

Table 3.8 AM GROUP I I I (balanced)

ritodrine : η = 18

fenoterol : η = 27

mean tocolytic index = 3.06

mean tocolytic index = 3.11

Variable Number

0 1 2 3 4

Ρ (Ρ before balancing)

UC ritodrine 0 7 11

fenoterol 4 8 15 0.22 ( 0 . 1 1 )

BD ritodrine 17 1

fenoterol 22 5 0.42 (0.09)

ritodrine RM

14 1

fenoterol 20 0.81 ( 0 . 6 7 )

ritodrine DI

14

fenoterol 21 0.99 (0.42)

ritodrine FL

14

fenoterol 22 1.00 (1.00)

ritodrine IP

15

fenoterol 21 0.94 (0.63)

for explanation see table 3.5

Distribution of features among the patients in Am group III after being

balanced, with corresponding probability levels.

Between brackets probability values before balancing (x2-test)

91

Table 3.9 AM GROUP IV (balanced)

ritodrine : η = 21

fenotevol : η = 20

mean tocolytic index = 2.86

mean tocolytic index - 2.50

Variable Number

0 1 2

(P before balancing)

UC ritodrine

fenoterol

12

11 1.00 (1.00)

ritodrine BD

18

fenoterol 15 5 0.64 (0.54)

RM

DI

ritodrine

fenoterol

ritodrine

fenoterol

20

20

13

14

1

0

4

4

2

0

2

1

0

1

1.00

0.50

(0.40)

(0.39)

FL ritodrine 17 4

fenoterol 17 3 1.00 (1.00)

ritodrine 20 1 IP

fenoterol 20 1.00 (1.00)

for explanation see table 3.5

Distribution of features among the patients in Am group IV after being

balanced, with corresponding probability levels.

Between brackets probability values before balancing (x2-test)

92

anced for the variable : ruptured fetal membranes (RM).

After excluding 10 patients among whom all patients with

high and low ruptured fetal membranes, probability levels

ρ were still < 0.40 for the variables DI and FL, being

0.29 and 0.25 respectively. This was accepted for only

after removal of another 7 patients all probability levels

ρ would exceed 0.42. The difference in the mean tocolytic

index decreased from 0.34 to 0.16 (Table 3.7).

3.2.5.2.3. Balancing of patients of Am group III

Probability values ρ of 0.11 and 0.09 were measured

for UC and BD in the basic material.

Removal of 9 patients led to satisfactory ρ levels except

for UC (0.22). The difference in the mean tocolytic index

fell from 0.15 to 0.05 (Table 3.8).

3.2.5.2.4. Balancing of patients of Am group IV

With the elimination of 2 patients balance of all

variables was reached, ρ values exceeding 0.50.

The difference of the mean tocolytic index decreased from

0.40 to 0.26 (Table 3.9).

3.2.5.3. Comparison of the two treatment groups with respect to other

factors which might influence the outcome of the experiment

The two treatment groups were compared with respect to

several variables which might bias the results of the

trial. The incidence of the fundus being {>, 2 weeks)

small for dates was judged and proved to be balanced for

the two populations ; ρ values for the separate Am groups

and the whole population being al more than 0.50. A dif­

ference was seen in the route of administration for the

two groups (Table 3.10).

A frequency histogram of the maternal ages of the patients

93

Table 3.10 ROUTE OF ADMINISTRATION OF RITODRINE AND FiNOTEROL

AM GROUP I

% rit. % fen.

I.V. 31 30

Oral 19 26

I.V. and oral 50 44

Ρ " 0.84

AM GROUP II

% rit. % fen.

28 23

24 46

48 31

0.21

AM GROUP III

% rit. X fen.

44 26

23 48

33 26

0.20

AM GROUP IV

% rit. % fen.

42 25

29 45

29 30

0.42

ALL PATIENTS

% rit. % fen.

35 26

24 41

41 33

0.03

" chi square test

is given in figure 3.1.

The reproductive history revealed a trend towards a

greater number of previous abortions and live born term

neonates among fenoterol treated women (table 3.11).

Maternal age (years)

12-1

10 20 30 40 SO 10 20 30 40 50

Median 27 Mean 27 SO 4 Mm-ma« 19-39

Figure 3.1

Median 28 Mean 2Θ SD 4 Mm -max 20 - 43

p - 0 11 (Iwo-lailed)

94

Table 3.11 REPRODUCTIVE HISTORY OF WOMEN IN THE TWO GROUPS

Number : 0

1

2

3

4

5

Ρ "

PARITY

pit.

50

33

9

2

0

0

94

0.

" хг - test

"" In this of amene

"""in this of amene

fen.

43

32

15

7

0

3

100

11

table premature irrhea.

ABORTION

rit. fen.

74 62

11 23

4 10

2 4

3 1

94 100

0.05

delivery is

IMMATURE STILLBIRTHS

pit. fen.

88 94

6 6

94 100

0.91

defined as del'

table term delivery is defined as delivery irrhea.

IMMATURE ALIVE

Ht. fen.

87 91

6 6

1 2

0 1

94 100

0.74

i very after

after 38 о

PREMATURE** STILLBIRTHS

rit. fen.

92 96

2 2

0 2

94 100

0.39

28 completed weeks

ompleted weeks and

PREMATURE ALIVE

vit. fen.

77 77

15 16

2 5

0 2

94 100

0.37

χ* TERMXxx

STILLBIRTHS

rit. fen.

91 100

2 0

1 0

94 100

0.20

TERM"»"« ALIVE

rit. fen.

77 67

16 30

1 0

0 2

0 1

94 100

0.07

and before 38 completed weeks

before 42 completed weeks

Table 3.12

FACTORS TO INFLUENCE THE DURATIi

Twi ns

Polyhydramnios

Congenital malformation

of uterus

Fibroids in uterus

Scar in uterus

Diabetes mellitus

Prediabetes

E.P.H. gestosis

Placenta circumvallata

Placenta praevia

Low-lying placenta

Marginal sinus rupture

Total of mentioned abnorma­

lities of placenta

Vaginal bloodloss during

pregnancy

- first half of pregnancy

- second half of pregnancy

Diastolic bloodpressure

> 90 turn Hg

- before pregnancy

- developed during

pregnancy

Smoking

- mild (1 -10 sig/24 hrs)

- severe (> 10 sig/24 hrs)

ON OF PREGNANCY

Ritodrine

η

9

5

7

3

3

0

12

5

4

0

4

2

10

18

5

3

22

22

9

IN THE

Fenoterol

η

8

8

8

3

4

3

24

6

7

1

4

4

16

9

10

4

12

17

9

TWO GROUPS OF

x2

0.02

0.21

-

-

-

1.23

3.34

-

0.27

-

-

0.11

1.49

3.36

0.94

-

3.61

-

~

PATIENTS

Ρ

0.89

0.65

-

-

-

0.27

0.07

-

0.61

-

-

0.74

0.48

0.07

0.34

-

0.06

-

~

96

Several factors which might influence the duration of

pregnancy are filed up for the two groups in table 3.12.

Fig. 3.2 gives the comparison of the tocolytic index ac­

cording to Baumgarten and Grüber (1974) for the ritodrine

and fenoterol treated patients.

Tocolytic index Ritodrine Fenolerol

Median 2 Median 2 Μ | - · Ί " 2 7 M e a n 2 6

S D 1 6 S D 1 6

Mm max 1 7 Mm m a x ι β

y _ - HOBS ρ 0 4 4 (Iwo tailed)

Figure 3.2

3.2.6. Statistical evaluation

Balancing for some background variables was done in

advance for the distinct Am groups as described in section

3.2.5. When several features of a variable were involved,

comparability of the treatment groups was assessed with

the χ2 - test in contingency tables with correction of

continuity.

With the other variables, comparability of the two groups,

and differences in efficacy and side effects were tested

with the so called distribution free (non-parametric) Mann

and Whitney U-test.

When Am groups were tested separately as well, a combined

97

g Table 3.13

MEANS + SD OF NEONATAL SUCCESS SCORE, PROLONGATION INDEX, DAYS GAINED AND RELATIVE GAIN FOR THE TWO GROUPS OF PATIENTS

NEONATAL χ SUCCESS SCORE Ρ

PROLONGATION κ INDEX Ρ

DAYS GAINED χ Ρ

RELATIVE GAIN к Ρ

ritodrine AM GROUP I

fenotevol

4.12

3.51 0.59

38 + 31

43 + 28 0.40

62 + 47

72 + 42 0.42

61 % + 41

74 % + 39 0.14

AM GROUP II rttodrine

fenotevol

1.52

2.15 0.58

21 + 12

22 + 9 0.99

46 + 24

48 + 18 0.89

79 t + 34

87 % + 23 0.60

ritodvine AM GROUP III

fenotevol

2.22

1.93 0.53

9 + 7

10 + 7 0.87

22 + 16

24 + 17 0.86

63 % + 39

66 % + 37 0.88

vitodrine AM GROUP IV

fenotevol

1.33

0.75 0.10

6 + 6 < 0.05

9 + 5

16 + 14

23 + 11 < 0.05

76 % + 28

95 % + 16 < 0.01

vi todrine ALL PATIENTS

fenotevol 0.48 0.12

71 % + 36 0.13 < 0.03

79 % + 33

- Mann and Whitney U test (2-tailed) for the distinct Am-groups

- combined Mann and Whitney U test for the total population

Mann and Whitney ü two sample t e s t was employed for the whole populat ion. Results are presented in frequency h i s tograms and as medians + s tandard d e v i a t i o n s and ranges.

3. 3. Results

3.3.1. Efficacy of treatment

Perinatal outcome as measured by the neonatal success

score described in section 3.2.4 was not significantly

different for the patients in Am groups I, II and III or

the total population. Only with respect to Am group IV

{>, 34 weeks), a trend was seen toward better results among the fenoterol treated patients (p = 0.10) (table 3.13).

Differences were more evident for the other

success-variables. Although results seemed on the average

better in the fenoterol groups, statistical significance

was only evident in Am group IV.

When the results of the 4 AID groups were combined, there

was a significant difference in only one parameter : the

fenoterol-treated women exhibited a greater relative gain

after the start of treatment (p < 0.03 ; table 3.13).

The birth weights of the children born to mothers

treated with ritodrine did not differ significantly from

those treated with fenoterol (p = 0.12 ; fig. 3.3), nor

was a statistically significant difference seen in the

percentiles of birth weights (Kloosterman, 1977) of both

groups (p = 0.38).

Means, medians and standard deviations of the placen­

tal weights were 433, 435 and 131 grams and 449, 450 and

129 grams respectively (p = 0.47) when twin pregnancies

were excluded. The mean duration of amenorrhea at

delivery was 251 + 30 days for the women treated with

ritodrine and 254 + 28 days for those treated with fenote­

rol (fig.3.4).

99

Birth weights (grams) (twins excl.) Ritodrme Fenolerol

1 2 -

e-

4 1

•J iJ \JÊ 0 1000 2000

Median

Mean

S D Mm max

> 2 5 0 0

2000 2499

< 2 0 0 0

Hi jure 3

2740

2613

831 250 4000

56%

20°o 2 4 %

3

J |

d • 3000

I L 4000 5000

12

В

4

0

• 1 . и шШ

Ι ι 0 1000 20«

Median

Mean

S D

Mm max

> 2 5 0 0

2000 2499

< 2 0 0 0

3000

2760

81β

390 4150

6 5 %

IS-o

2 0 %

As far as the pH of the umbilical artery blood (p = 0.99 ;

fig. 3.5) and 5 minutes Apgar scores (p = 0.76) were con­

cerned, no statistically significant differences were

found.

Other relevant factors regarding the fetal outcome in

the two treatment groups are listed in table 3.14.

Amenorrhea at delivery (days) Rilodrme Fenolerol

100 ISO 200 250 300 350 100 150 200 250 300 350

Median 255

Mean 251

S O 30

Mm max 137 293

Median 261

Mean 254

S D 2β

Mm max 150 290

U 4 4 1 8 5 ρ 0 4 7 [Iwo lailed)

Figure 3.4

100

pH umbilical artery blood

10 T

5

β.70 6.90 7.10 7.30 7.50

Median 7 24

Mean 7 23

S D 0 08

Mm -max 6 87-7 36

A 6.70 6.90 7.10 7.30 7.50

Median 7 24

Mean 7 23

S D 0 09

Mm -max 7 00-7 42

U 2611 ρ 0 99 (two tailed)

Figure 3. S

In the group of patients treated with ritodrine there were

three intrauterine deaths and 7 neonatal deaths.

Among the fenoterol treatment women one stillbirth and 8

neonatal deaths occurred.

The details of the cases of perinatal (between 28 weeks

amenorrhea and the end of the 7th day after delivery)

Table 3.14 FETAL OUTCOME

Stillbirth

Neonatal death

Hyperbilirubinemia

Hypoglycemia

(diabetes mellitus and

pregnancy diabetes ex­

cluded)

Congenital malformation

IRDS

IN THE TWO

ritodrine

3

7

25

4

1

6

GROUPS OF PATIENTS

fenoterol

1

8

26

9

3

6

Ρ

0.57

-

-

0.16

0.66

-

101

Table 3.15 DETAILS OF THE PERINATAL DEATHS

Patient nr.

3

63

74

154

194

216

243

Death within

stillbirth

24 hrs

48 hrs

24 hrs

24 hrs

24 hrs

intrapartum

24 hrs

Amenorrhea

34 wks 2 days

28 wks 5 days

28 wks 2 days

32 wks 4 days

29 wks 2 days

29 wks 2 days

28 wks 3 days

37 wks 3 days

Treatment

ritodrine

ritodrine

ritodrine

fenoterol

ritodrine

ritodrine

fenoterol

fenoterol

placental insufficiency

asphyxia RDS

breech - extraction hemorrhagia cerebri RDS

asphyxia RDS

f i r s t chi ld of twin hemorrhagia cerebri asphyxia RDS

second chi ld of twin hemorrhagia cerebri asphyxia RDS

intrauterine asphyxia

severe congenital malformations

deaths are given in table 3 .15 .

3.3.2. Side effects

Prior to the s t a r t of treatment, maternal heart rates were s imilar for both groups of women, ( f i g . 3 . 6 ) .

During t r e a t m e n t , r i t o d r i n e as w e l l as f e n o t e r o l caused an increase of the maternal heart frequency ; the f i r s t drug, however, showed a more pronounced e f f e c t (p < 0 . 0 2 ) . The means, medians and standard dev ia t ions of the maximal maternal heart frequenc ies , measured af ter the second day of treatment when adaptation to the medication had taken p l a c e , are given in a frequency histogram in f i g . 3 . 7 .

102

Initial maternal heart frequency (b.p.m.) Ritodnne Fenolerol

7 0 90 110 130 70 90 110 130

Medtan BO

Mean Θ2

S D 7

Mm -max 6 5 - 1 0 0

Median 80

Mean 82

S D 7

Mm -max 64 -105

U = 2416 5 ρ - 0 79 (two-tailetl)

Figure 3.6

The mean increase in maternal heart rate was 48 %

(mean + SD) for the ritodrine treated women and 41%

when fenoterol was given (p < 0.02).

Maternal heart frequency during treatment (b.p.m.)

30-1

80 100 120 140 160 180

Median 120

Mean 120

S D 11

M m - m a x 9 2 - 1 6 0

Θ0 100 120 140 160 180

Median 118

Mean 115

S D 12

Mm -max 85 -140

U = 2700 5 p < 0 02 {two tailed)

Figure 3. 7

3.4. Discussion

3.4.1. Comparability of study groups

Balancing of the separate Am groups for the 6 charac­

teristics given in table 3.5 (section 3.2.5.2) led to good

comparability of the two treatment groups in all param­

eters (table 3.16) .

Table 3.16 PROBABILITY LEVELS*BEFORE AND AFTER BALANCING OF THE AH GROUPS

AM GROUP I AM GROUP II AM GROUP III AM GROUP IV ALL PATIENTS

UB В UB В UB В UB В UB* В*

0.23

0.39

0.35

0.13

0.78

1.00

0.25

0.94

1.00

0.25

1.00

1.00

0.68

0.54

0.08

0.29

0.22

1.00

0.84

0.57

1.00

0.29

0.25

1.00

0.11

0 09

0.67

0.42

1.00

0.63

0.22

0 42

0.81

0.99

1.00

0.94

1.00

0.54

0.40

0.39

1.00

1.00

1.00

0.64

1.00

0.50

1.00

1.00

0.98

0.27

0.22

0.12

0.34

0.55

0.81

0.Э2

0.88

0.49

0.83

0.91

= χ2 measure

κ UB = probability levels before balancing

В - probabil ity levels after balancing

Other characteristics which might influence the dura­

tion of pregnancy, including the tocolytic index which, in

previous investigations (Baumgarten and Grüber, 1974 ;

Richter, 1977 ; Eskes and Essed, 1979) was found to be a

suitable test of threatening premature labor, were reason­

ably similar between the two study populations. The route

104

of administration, however, was found to be different for

the two groups, for which finding no clear explanation was

visible.

Reproductive history revealed a greater number of both

previous first trimester abortions and liveborn term neo­

nates among fenoterol-treated patients.

The incidence of spontaneous preterm labor was related to

previous abortions and previous preterm deliveries in a

retrospective study of 8404 consecutive patients by Keirse

and colleagues (1978).

The incidence of preterm labor in subsequent pregnancies

was not found to be increased if reproductive history

included only first trimester abortions. Patients with

previous mid-trimester abortions and third trimester

preterm labor were at significantly higher risk for sub­

sequent preterm delivery than the remainder of the popula­

tion.

3.4.2. Effioacy of therapy

Richter and Hinselmann (1979) reported a lower success

rate with ritodrine alone (n = 35) (p < 0.05) than with

ritodrine plus verapamil or with fenoterol with or without

verapamil. The patients in their investigation treated

with ritodrine alone, however, possessed more pronounced

features of impending premature labor, as evident in a

difference in tocolytic index (p < 0.05), than the pa­

tients in the other 3 groups.

The present study revealed a trend towards differences

with respect to the efficacy of treatment for the total

populations, but not for all of the separate Am groups.

This suggests that differences between these two drugs are

subtle, and that large numbers of patients will be needed

to demonstrate conclusively any difference in efficacy.

105

3.4.3. Side effects

Because of the difficulties encountered in studying

subjective side effects, an objective cardiovascular side

effect was measured in this study, specifically, the

change in maternal heart rate. Although blood pressure

might also be considered such an objective parameter, the

difficulties in accurate indirect measurement of blood

pressure (van Dongen, 1979) , and the marked effect of

position on blood pressure mitigated against inclusion of

this measurement in the analysis.

The differences in degree of acceleration of the

maternal heart rate observed between the two treatment

groups are in agreement with those reported in the liter­

ature (Hüter et al., 1972 ; Richter and Hinseimann, 1979).

Of the 28 patients who developed tachycardia and/or

palpitations requiring a change of tocolytic agent, 19

initially received ritodrine ; 9 subjects could not toler­

ate fenoterol in the dosage required to obtain tocolysis

and did better with ritodrine.

So there seem to be individual differences in acceptabil­

ity for these two drugs.

106

Chapter 4

Plasma glucose levels in the neonate after antenatal exposure to betamimetic agents

4.1. Introduction

Betasympathomimetic drugs exert an influence on

carbohydrate metabolism by stimulation of adenylcyclase in

liver, muscle and probably pancreas cells (section

2.5.1.1.).

In liver cells β-adrenergic stimulation causes an

elevation of the serum glucose level as a result of at

least three mechanisms (Weidinger and Wiest, 1973) .

-Activation of Phosphorylase, which leads to conversion

of glycogen to glucose ;

-Inactivation of glycogen production from glucose ; and

-Stimulation of gluconeogenesis.

In muscle cells glucose-6-phosphatase is lacking.

Thus, glycogenolysis in striated muscle cells will lead to

production of lactic acid. After diffusion into the

bloodstream, the lactate is largely removed by the liver

and reconverted to glucose.

In the pancreatic β-cells, there also seems to be a

direct influence via ß-adrenergic receptors, leading to

increased insulin blood levels (Taylor et al., 1976).

The net effect of these actions will be a transient ele­

vation in blood glucose concentration even in spite of an

increased insulin secretion.

The maternal carbohydrate intolerance which is induced

by these drugs and the fact that ß-mimetics do cross the

placental barrier (Weidinger et al., 1975) give support to

the suggestion that long-term B-mimetic medication, as

used in the suppression of premature labor, could result

in fetal hyperinsulinism.

For the same reason, the assumption has been made that

107

fetal macrosomia might result from the diabetogenic effect

of these drugs. Indeed, Sivasamboo (1972) reported a

higher birth weight of children born from mothers treated

with ritodrine, compared to a control group. However,

these observations could not be confirmed by Seidl and

colleagues (1972) and Brettes and associates (1976).

Blouin and colleagues (1976) studied the effect of

ritodrine (10 mg orally, 4 times per day) from the 25th

week of pregnancy on the carbohydrate tolerance of eight

pregnant women and their newborn infants. They observed

no diabetogenic influence on the 50 gram oral glucose

tolerance test or the 24 hours glucose profile on the 7th

day of treatment and neither after 10 weeks of oral

ritodrine therapy.

These observations are in agreement with the results of

Unbehaun and coworkers (1975), who found a compensation

and normalisation of the changes in carbohydrate metabo­

lism within 72 hours after the start of treatment.

As to the carbohydrate metabolism of the neonates,

Blouin et al. (1976) could not demonstrate a significant

difference between the glucose and insulin values for

ritodrine-treated and control patients, in a study group

of 8 patients and 6 controls. Samples were taken from the

umbilical vein and by a heel prick 2 hours after delivery

and before the first feeding.

Epstein and co-workers (1979) studied umbilical cord blood

insulin levels and neonatal blood glucose values at 30, 60

and 90 minutes after birth in 12 infants whose mothers had

received ß-mimetic therapy (fenoterol and terbutaline).

In 5 of the 6 cases where the interval from termination of

ß-mimetic therapy to delivery was 2 days or less, the in­

fants exhibited sustained hypoglycemia. This was not

observed in any case where the interval exceeded 2 days.

The mean cord blood insulin levels in the 6 infants with a

short termination-delivery time was 50 % greater than in

the larger interval group.

108

Umbilical cord glucose levels were not significantly dif­

ferent. No comparison was made with untreated neonates.

In retrospect, Brazy and Pupkin (1979) found a signif­

icantly higher incidence of hypoglycemia in premature

neonates (gestational ages at birth 26 - 35 weeks) whose

mothers were treated with isoxsuprine within 48 hours of

delivery (n = 43) in comparison with a reference popula­

tion of 107 untreated infants.

As diabetogenic influences upon the fetus, as far as

the risk of hypoglycemia is concerned, have more pro­

nounced effects on the newborn in the first extra uterine

hour than at birth, the present investigation was under­

taken to assess the possible influence of prenatal expo­

sure to ß-adrenergics upon the neonatal glucose levels in

the first 30 minutes after delivery.

4.2. Materials and methods

From January 1976 until January 1979, plasma glucose

levels were measured in the first 30 minutes of extra­

uterine life in neonates from mothers treated with β-mi­

metic drugs (fenoterol and/or ritodrine) for the preven­

tion of premature birth.

In general, these tocolytic agents were administered

intravenously for at least 2 days at the minimum dose

necessary to stop labor successfully (dose i.v. 67 - 700

mcg/min ritodrine, 1.0 - 9.3 mcg/min fenoterol).

The dosage was then decreased ; and if uterine contrac­

tions did not return, oral treatment with 5 mg fenoterol

or 10 mg ritodrine 6 to 12 times daily, was substituted.

With several patients, however, it was possible to avoid

parenteral medication and to start with oral ß-mimetic

therapy.

In general, medication was continued until the end of the

37th week of gestation.

Treatment was started prior to the 28th week of ges-

109

ta t ion in 27 p a t i e n t s . Gestational age at the s t a r t of

treatment was 28 weeks or more in 114 p a t i e n t s (range :

17-36 weeks) . Intravenous therapy alone was used in 61

p a t i e n t s , oral therapy only in 35 p a t i e n t s and 45 p a t i e n t s

were t reated both intravenously and o r a l l y .

Ritodrine was given to 83 p a t i e n t s ; and fenoterol , to

43 p a t i e n t s . Fifteen women were t reated with both β-ago­

n i s t s . The duration of medication is given in table 4 . 1 .

Table 4.1 DURATION OF MEDICATION IN THE TREATED PATIENTS

< 24 hrs 8 patients 6 %

24 - 48 hrs 4 patients 3 %

2 - 7 days 23 patients 16 %

·}! days 106 patients 75 1

The interva l s between the end of treatment and delivery

(t - d interval) are presented in table 4.2.

Table 4.2

TIME INTERVAL BETWEEN THE END OF TREATMENT AND DELIVERY (T - D INTERVAL)

t - d interval number of patients %

< 24 hrs 45 32 %

24 - 48 hrs 18 13 %

48 - 72 hrs 3 2 %

>, 3 days 75 53 1

110

For every patient in the treatment group who gave

birth in 1976 and 1977, the next subsequent patient who

delivered with the same duration of amenorrhea (+ 4 days)

was taken as a control. Mean +_ SD and range of gestation­

al age at delivery were 257 + 19 days (203-294) for the

treated neonates and 259 + 15 days (206 - 290) for the

control infants. Only patients who delivered vaginally

were included in the study. There were 12 twin pregnan­

cies (Θ %) in the treatment group, whereas the control

patients included 7 sets of twins (6 % ) .

In these cases, only the first infant was included in the

study. Children of patients with diabetes mellitus,

gestational diabetes, severe dysmaturity (below 2.3th per­

centile of birth weight for gestational age) and congeni­

tal malformations were not included or removed afterwards,

because of the influence that these factors may have upon

the serum glucose level. For the same reason neonates

with pH values of the umbilical artery blood under 7.10

and neonates whose body temperature, measured exactly at

30 minutes after delivery, had dropped below 35.0 degrees

Celsius, were excluded.

Mean + SD of the pH of the umbilical artery blood were

7.26 + 0.07 for the treated neonates and 7.25 + 0.07 for

the control infants (p = 0.29).

Body temperatures 30 minutes after birth, were 35.7 +

0.4 (35.2 - 36.6) and 35.9 + 0.5 (35.0 - 36.8) respective­

ly.

After exclusion of patients according to the mentioned

criteria, 141 treated patients and 110 control babies were

left for comparison. The blood samples were taken at var­

ious times (one sample per patient) in the first 30 min­

utes after delivery and before the first feeding, by means

of a heel stick (table 4.3).

Plasma true glucose concentration were determined en-

zymatically (glucose-oxidase method) within 10 minutes of

sampling in a BeekmanR glucose analyser.

111

Table 4.3 TIME INTERVAL BETWEEN DELIVERY AND PLASMA GLUCOSE SAMPLE

(D - S INTERVAL) IN 141 TREATED NEONATES AND 110 UNTREATED INFANTS

d - s interval

0 - 5 min

6 - 1 0 min

11 - 15 min

16 - 20 min

21 - 25 min

26 - 30 min

number of treated

neonates

29

31

28

32

12

9

141

21

22

19

23

9

6

100

%

%

t

% 0/

г

%

number of

neonates

27

18

30

19

8

8

ПО

untre;

25 %

16 t

27 %

17 %

8 %

7 t

100 %

The d i f f e r e n c e s in the s e v e r a l p a r a m e t e r s were t e s t e d

by means of the Mann-Whitney U - t e s t (Wilcoxon) ( t w o - t a i l ­

ed) and by means of the Kruskal-Wal l i s one-way a n a l y s i s of

v a r i a n c e by r a n k s . R e s u l t s a r e expressed in means + s t a n ­

dard d e v i a t i o n s .

4.3 . Results

After exclusion of twin pregnancies, the birth weights

of the treated and control babies were similar : mean + SD

and range being 2728 + 614 grams (1300 - 4220) and 2837 +

696 grams (1386 - 4450), respectively.

To analyse the influence of the time interval between

delivery and sampling, comparison was made of glucose

concentrations measured 1-10, 11-20 and 21-30 minutes

after delivery. This was done separately for the control

patients and for the treatment group (Table 4.4).

112

Table 4.4 MEAN + SD OF PLASMA GLUCOSE LEVELS OF UNTREATED AND TREATED NEONATES

ACCORDING TO DIFFERENT DELIVERY - SAMPLING (D - S) INTERVALS

plasma

glucose (A)

d - s interval mmol/l

plasma

glucose (B)

mmol/l

1 - 10 min

11 - 20 min

21 - 30 min

3.1 + 0.7

3.1 + 1.0

2.8 + 0.4

ρ x = 0.59

23

19

7

3.5 + 0.8

3.4 + 0.9

3.3 + 0.9

ρ * = 0.72

22

30

9

d -

1

11

21

s interval

- 10 min

- 20 min

- 30 min

plasma

glucose (С)

mmol/l

2.5 + 0.5

2.9 + 0.9

2.4 + 0.5

„ * _ η IO

η

34

28

9

plasma

glucose (D)

mmol/l

3.1 + 0.7

3.2 + 0.7

3.5 + 1.2

η

26

32

12

plasma

glucose (E)

mmol/l

2.6 + 0.5

2.7 + 0.8

2.2 + 0.4

η

24

19

7

= 0.61 = 0.15

A = untreated neonates gestational age < 37 wks

В = untreated neonates gestational age 5. 37 wks

С = treated neonates < 37 wks

D = treated neonates > 37 wks

E = treated neonates gestational age < 37 wks

treatment - delivery interval < 48 hrs

Kruskal-Wallis

113

No s igni f icant differences were found in glucose values of

the control neonates with respect to the delivery - sample

(d - s) i n t e r v a l . This was true for both premature (< 37

weeks gestat ion) infants and the term neonates.

Nor did the t reated pat ients differ in t h i s regard, a l ­

though prematurely born neonates in the treatment group

had s l i g h t l y lower plasma glucose concentrations when

sampled 21-30 minutes after b i r t h (2.4 + 0.5 mmol/1) than

when the d - s interval was 1 - 1 0 minutes (2.5 + 0.5

mmol/1), especial ly when the time interval between the

cessation of treatment and delivery had been less than 48

hours ; however, these differences were not s t a t i s t i c a l l y

s igni f icant according to Kruskal-Wallis.

No re la t ionship was found between the duration of the

second stage and the blood glucose levels of the treated

neonates (p > 0.10 ; Table 4 .5) .

Table 4.5 MEAN + SD OF PLASMA GLUCOSE LEVELS OF TREATED NEONATES WITH

DIFFERENT DURATION OF THE SECOND STAGE OF LABOR

Durat ion 2nd 1 - 1 0 1 1 - 2 0 21 - 30 31 - 60 stage minutes minutes minutes minutes

Plasma glucose 2 . 9 + 0 . 7 2 . 8 + 0 . 8 3 . 0 + 0 . 7 3 . 2 + 0 . 9 l e v e l s (mmol/1) η = 48 η = 45 η = 24 η = 21

Ρ = NS (Kruskal - W a l l i s )

There was a s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e

between the plasma glucose values of premature and term

infants in the control group (p < 0.05 ; Table 4 .6) .

114

Plasma glucose concentrations (MMOL/L) treated (π -141) untrealedfn 110)

О 2.0 4.0 6.0 Θ.Ο

median 2 θ Mean 2 9 SD 0Θ Min -Max 1 6 - 6 5

Ρ < 0 001 (two-tailed)

0 2 0 4.0 6.0 8 0

Median 31

Mean 3 3 SD OB Mm -Max 1 6-5 6

Figure 4.1

This difference was more pronounced (p < 0.0001) when

treatment was given, probably as a result of the fact that

far more premature (70 %) than term neonates (19 %) were

born with a t - d interval of less than 48 hours.

The plasma glucose levels of the treated and control

neonates are presented in figure 4.1 and table 4.6.

Table 4.6 MEAN + SD OF PLASMA GLUCOSE LEVELS (MMOL/L) OF TREATED AND

CONTROL NEONATES

treated patients

control patients

MEASURED WITHIN

all patients

2.9 + 0.8

Ρ

3

ι = 141

< 0.001

.3 + 0.8

η = 110

30 MINUTES AFTER

patients <

I 2.7 + 0.7

r

Ρ

3

= 71

< 0.001

1 + 0.8

η = 49

37

- Ρ

— η

DELIVERY

wks

< 0

* η

0001 -

пч

patients > 37 wks

| 3.2 + 0.8

Ρ

3

τ = 70

= 0.14

4 + 0.9

η = 61

115

Significantly lower plasma glucose concentrations were

measured in babies from treated mothers than were found in

the control group : 2.9 + 0.8 versus 3.3 + 0.8 mmol/1

(p < 0.001). After subdivision, these differences were

evident in prematurely born infants (2.7 + 0.7 versus

3.1 + 0.8 mmol/1 ; ρ < 0.001), whereas the glucose values

of the treated infants born after the 37th week of amenor­

rhea did not differ significantly from control neonates of

the same gestational age. As mentioned above, it must be

stressed that the mothers of 70 % of the prematurely born

infants were still being treated 48 hours before delivery,

in comparison to only 19 % when delivery occured after the

completed 37th week of gestation.

To assess the influence of the route of administration

of the β-mimetic agent, plasma glucose levels were com­

pared for the neonates whose mothers were treated intra­

venously and orally (Table 4.7).

Table 4.7 MEAN + SD OF PLASMA GLUCOSE LEVELS FOR DIFFERENT ROUTES OF ADMINISTRATION

A = TREATED INTRAVENOUSLY

В = TREATED ORALLY

A В

intravenous treatment η oral treatment η ρ

All patients 2.7+0.7 61 3.1+0.8 35 < 0.03

t - d interval < 48 hrs 2.5 + 0.5 39 2.9 + 0.5 8 0.05

Lower plasma glucose levels were found in the intravenous­

ly treated patients in comparison to the group that re­

ceived tablets (p < 0.03). This difference may be influ­

enced by the fact that a larger proportion of the i.v.

group was treated until within 48 hours before delivery,

116

for the time interval between termination of treatment and

delivery was < 48 hours in 39 of 61 intravenously t reated

p a t i e n t s (64 %) and in 8 of 35 (23 %) women who got only

oral medication.

When the analysis was r e s t r i c t e d to neonates with t - d

in terva l s less than 48 hours, the difference was numeri­

cal ly the same (p = 0.05).

In t h i s invest igat ion, no corre la t ion was found be­

tween the number of days treatment was given and the p l a s ­

ma glucose levels after delivery (Table 4 .8) .

Table 4 . 8 MEAN + SD OF PLASMA GLUCOSE LEVELS (MMOL/L) OF NEONATES FROM WOMEN

STILL TREATED WITHIN 48 HOURS BEFORE DELIVERY WITH DIFFERENT TREATMENT PERIODS

treatment < 2 days 2.7 + 0.5 (n = 12)

ρ = 0.53

treatment » 3 days 2.6 + 0.7 (n = 51)

A strong influence could, however, be measured accord­

ing to the number of days treatment had been stopped be­

fore a premature baby was born. Neonates born before the

37th week of gestation had lower plasma glucose levels

when treatment was continued to within 72 hours of deliv­

ery (2.6 +0.6 mmol/1) than with an interval of 3 or more

days (3.0 + 0.8 mmol/1) (p < 0.05 ; table 4.9).

In the comparison of premature infants of the treated

patients subdivided in different treatment-delivery inter­

vals and untreated women, a statistically significant dif­

ference was found according to Kruskal-Wallis (p = 0.003).

Tested with the two-tailed Mann Whitney U test plasma glu­

cose levels of treated infants were significantly lower

when the t - d interval was 0 or 1 day (p < 0.001 for

117

Table 4.9 MEAN + SD OF PLASMA GLUCOSE LEVELS (MMOL/L) OF PREMATURE

NEONATES IN RELATION TO THE TIME INTERVAL BETWEEN THE END OF

TREATMENT AND DELIVERY (T - D INTERVAL)

t - d interval < 72 hrs 2.6 +0.6 η = 52

ρ < 0.05

t - d interval >, 3 days 3.0 + 0.8 η = 19

both) , compared to untreated chi ldren, whereas plasma

glucose levels of t reated neonates with t - d interva l s of

3 or more days did not differ s igni f icant ly from control

neonates (Table 4.10).

Table 4.10 MEANS + SD OF PLASMA GLUCOSE CONCENTRATIONS (MMOL/L) OF TREATED

PREMATURE NEONATES WITH DIFFERENT TIME INTERVALS BETWEEN TERMINATION OF

TREATMENT AND DELIVERY (T - D INTERVAL) AND UNTREATED PREMATURE NEONATES

treated

t - d interval of prematurely born treated neonates

< 24 hrs 2.6 + 0.7 (38)

24 - 48 hrs 2.4 + 0.3 (12)

3 - 7 days 2.9 + 0.7 ( 8)

» 7 days 2.9 + 0.9 (13) p

untveated

ρ = 0.003 (Kruskal-Wallis)

3.1+0.8 (49)

Mann Whitney U test (two tailed)

0.001 0.001

118

Comparison between patients according to the tocolytic

agent used revealed no differences in age, gestational age

at the start of treatment, the time interval between the

cessation of drug administration and delivery, gestational

age at delivery, birth weights, duration of second stage,

the time interval between delivery and blood sample, the

pH values of the umbilical artery blood and the neonatal

body temperature measured at 30 minutes after delivery

(Table 4.11) . Intravenous treatment was given in 85 % of

the ritodrine- and 70 % of the fenoterol-treated patients.

The tocolytic indices (Baumgarten and Gr'uber, 1974), were

somewhat higher in the fenoterol treated patients :

3.1 + 1.6 versus 2.6 + 1.3 (p = 0.10).

Among the patients treated with ritodrine, there were 11

twin pregnancies and none in the fenoterol group.

During the intravenous treatment period, the means + SD of

the maximum dose used were 254 + 21 mcg/min when ritodrine

was used and 3.1 + 0.5 mcg/min for fenoterol (range 67 -

700 mcg/min and 1.0 - 9.3 mcg/min).

A significant difference was found between the plasma

glucose concentrations of neonates exposed to ritodrine

and fenoterol, with the fenoterol group having the lower

plasma glucose values in the first 30 minutes after deliv­

ery (p < 0.05).

When analysis was restricted to the preterm neonates, a

trend towards lower plasma glucose values of fenoterol-

treated babies compared to ritodrine-treated infants was

seen when treatment was still given 48 hours or less

before delivery (p = 0.09).

Also, term neonates had lower plasma glucose levels when

exposed in utero to fenoterol than to ritodrine

(p < 0.02). After exclusion of twin pregnancies, this

difference was even more pronounced (p < 0.01). When

patients with t - d intervals of more than 2 days were

compared, plasma glucose concentrations of the fenoterol

group were still lower than those after exposure to rit­

odrine (p = 0.05 ; Table 4.12).

119

Table 4.11

Age

Gestational age start of treatment

t-d interval

< 48 hours

Gestational age at delivery

< 37 weeks

:> 37 weeks

Birth weights twins excl.

Duration of second stage

1 - 10 min

11 - 20 min

21 - 30 min

> 30 min

D-S interval

1 - 10 min

11 - 20 min

21 - 30 min

PH umb. art. blood

Body temperature 30 min p.p.

Toc. index

Ritodrine (n

MEAN + SD

27 + 4 years

216 + 28 days

11 + 18 days

46 %

257 + 19 days

56 %

44 %

2700 + 614 gr

19 + 14 minutes

39 %

30 %

13 %

18 %

13 + 7 minutes

44 %

42 %

14 %

7.25 + 0.08

35.7 + 0.4

2.6 + 1.3

- 82)

RANGE

18-37

125-256

0-91

203-294

1650-4220

3-80

1-30

1-6

Fenoterol (n

MEAN + SD

27 + 5 years

219 + 26 days

15 + 26 days

48 %

258 + 19 days

43 %

57 %

2672 + 658

19 + 16 minutes

34 %

32 %

20 %

14 %

14 + 8 minutes

34 %

46 %

20 %

7.27 + 0.07

35.8 + 0.4

3.1 + 1.6

= 4¿)

RANGE

18-42

140-258

0-116

210-290

1300-4030

3-90

2-29

1-7

Ρ

0.83

0.66

0.85

0.56

0.89

0.76

0.51

0.16

NS

0.10

120

*.

Table 4.12

MEAN + SD OF PLASMA GLUCOSE LEVELS (MMOL/L), DETERMINED 1 - 30 MINUTES AFTER

DELIVERY, OF NEONATES EXPOSED EITHER TO RITODRINE OR FENOTEROL

Ritodrine

3.0 + 0.8

2.8 + 0.8

3.4 + 0.8

2.7 + 0.7

3.3 + 0.9

N

83

46

37

38

45

Fenoterol

2.7 + 0.7

2.4 + 0.6

2.9 + 0.7

2.5 + 0.6

2.9 + 0.7

N

43

18

25

21

22

Ρ

< 0.05

0.13

< 0.02

0.25

0.05

All patients

Gestational age < 37 wks

Gestational age > 37 wks

t - d interval < 48 hrs

t - d interval 5. 48 hrs _

Gestational age < 37 wks

t - d interval < 48 hrs 2.7 + 0.7 32 2.4 + 0.6 14 0.09

Gestational age £ 37 wks t - d interval > 48 hrs 3.5 + 0.9 31 2.9 + 0.8 18 < 0.03

121

4.4. Discussion

Several clinical conditions are known to affect the

blood glucose level of the neonate.

The mode of delivery exerts a strong influence upon

the glucose concentration in venous cord blood at delivery

and in capillary blood of the neonate during the first

hours of life (Cornblath et al., 1961). For this reason,

patients who delivered by a caesarean section were not

included in this study.

In their study of the effect of several factors (such

as pretreatment of the mother, mode of delivery and

exposure to labor) on the course of the blood glucose

concentration during the first hours of life and on the

ability of the normal infant to regulate his level of

glucose, Cornblath and associates (1961) also showed that

the maternal blood glucose level had a significant in­

fluence upon the glucose concentration of fetal venous

cord blood, but not on the glucose levels of the newborn

in the first hour after delivery. Although umbilical cord

glucose concentrations were 49.4 % higher in infants from

vaginally delivered mothers who received glucose prior to

delivery than when no intravenous fluids or only saline

solution had been given (127 mg/100 ml versus 85 mg/lOO

ml respectively), the capillary blood glucose levels 30

minutes after delivery were strikingly similar in the two

groups (54 + 8.4 mg/100 mg and 55 + 5.8 mg/100 ml).

Also for this reason, in the current study comparisons

were made between the plasma glucose levels during the

first half hour of extrauterine life.

Gestational age proved to be a relevant factor in re­

gard to neonatal blood glucose levels (Table 4.6), so

separate comparisons were made for preterm and term

infants.

As pointed out previously, the control patients were

carefully matched with the treated ones for gestational

122

age at delivery.

The duration of the second stage of labor was inves­

tigated and did not turn out to be an important element in

respect to the plasma glucose levels of the neonates in

the present trial (table 4.5).

The similarity in birth weights of the exposed and

control neonates was in disagreement with the higher birth

weights of children born from treated mothers reported by

Sivasamboo (1972).

Although Unbehaun and co-workers (1975) concluded that

a balancing out of the initial β-stimulated metabolic

changes occurs in the maternal metabolism, the hypoglyce­

mic response of the fetal organism after delivery was not

diminished when tocolytic treatment had been given for a

longer period of time (table 4.8).

In disagreement with Blouin and associates (1976),

strong evidence was found in this study for a fall in

neonatal plasma glucose levels soon after birth as a

result of antenatal exposure to a ß-mimetic agent.

A highly significant difference was measured between

the plasma glucose concentrations of infants whose mothers

were treated within 48 hours before delivery and control

neonates of the same gestational ages. This difference

was not seen when treatment had been stopped for three

days or more before delivery.

Moreover, when the treated infants were compared according

to whether the treatment - delivery interval was 2 days or

less, or 3 days or more, infants with shorter intervals

between exposure and delivery were found to have lower

plasma glucose concentrations than those with the larger

t - d intervals. These findings are in line with the

greater incidence of hypoglycemia reported by Brazy and

Pupkin (1979) and Epstein and associates (1979) in

neonates from patients who received ß-mimetic substances

shortly before delivery. So adequate time to recover from

exposure to the ß-adrenergic influence seems to be of

123

importance in the infant's ability to maintain a certain

blood glucose level directly after birth.

There was no significant correlation between the

delivery-measurement interval and the plasma glucose

concentration which was found in either the control or

treated patients on the whole. When analysis was re­

stricted to preterm infants who were still exposed to

3-mimetics 48 hours before delivery, however, a downward

trend in the mean plasma glucose levels was seen within

the first 30 minutes of life. This could be the result of

a synergism between two hypoglycemic threats :

prematurity, and recent exposure to a ß-mimetic agent.

With relation to the metabolic alterations in the

fetal organism after ß-mimetic treatment of the mother,

there are principally two levels to consider :

A. Indirect, via ß-mimetic drug influence upon the mater­

nal organism

The drug-induced increase in maternal glucose concen­

trations may alter the maternal-fetal transfer of carbo­

hydrate, fat metabolites and minerals during and after the

establishment of a new maternal metabolic homeostasis.

Because of the prompt transport across the placenta, this

may lead to an elevation in fetal blood glucose concentra­

tion. It has been shown that repeated or continuous fetal

hyperglycemia can trigger the fetal pancreatic ß-cell to

increase its secretion of insulin.

Alteration of the uteroplacental circulation as a re­

sult of the changed maternal cardiac output and also pos­

sible direct effects of the ß-mimetic agent upon the

uteroplacental vascular bed may influence the amount of

substrate available to the fetal carbohydrate metabolism.

These alterations which can effect either an increase or

decrease in the uteroplacental blood flow, have been shown

to be drug, dose and duration dependent in animals

124

(Brennan et al., 1977).

В. Direct ß-stimulated responses of the fetus itself

Recent evidence indicates that increased fetal blood

glucose levels after B-mimetic treatment of the mother

could partially be attributed to ß-stimulated effects

within the fetal organism. In a chronic sheep prepara­

tion, Ehrenkranz and associates (1976) found a significant

rise in fetal blood glucose concentration after infusion

of ritodrine directly into the fetus, without changes in

the maternal blood glucose level.

In human pregnancy, Esteban-Altirriba and colleagues

(1974) noted an elevation in fetal blood glucose concen­

tration, independent of maternal blood glucose changes and

thus probably as a direct effect of ritodrine on the

fetus, after simultaneously infusing ritodrine and practo-

lol. The resulting hyperglycemia could stimulate insulin

secretion by the fetal pancreas.

As mentioned before, there also seems to be a direct in­

fluence on the pancreatic ß-adrenergic receptors, leading

to increased insulin secretion (Taylor et al., 1976).

Indeed, Epstein and coworkers (1979) measured increased

insulin levels in umbilical cord serum when fenoterol or

terbutaline had been administered shortly (< 48 hours)

before delivery.

The potential mechanisms predisposing to a neonatal fall

in glucose concentration after direct ß-mimetic influence

upon the fetal organism are twofold ; for not only may

this lead to an elevation in fetal blood insulin concen­

tration at delivery secondary to the elevated glucose

level or via a possible direct effect on the fetal pan­

creas, but also ß-mimetic stimulation could lead to de­

pletion of fetal glycogen stores as a result of ß-stim­

ulated glycogenolysis in the fetal liver.

125

An unexpected difference was found between the neo­

natal plasma glucose levels with respect to the specific

drug that was used. Children exposed in utero to fenote-

rol had lower plasma glucose levels than those whose

mothers were treated with ritodrine. These differences

were found whether or not twin pregnancies had been ex­

cluded and also after subdivision according to gestational

age and t - d interval.

Even more suprising was the finding of the same difference

in plasma glucose levels in full term infants with t - d

intervals of more than 2 days. Among ritodrine treated

patients, differences in neonatal plasma glucose levels

were found to disappear with increasing t - d intervals

whereas among infants whose mothers received fenoterol,

this "recovery" was not observed.

No bias factor could be found in the patient populations

to account for these differences (Table 4.11), thus the

possibility of qualitative as well as quantitative differ­

ences in the effects of these two agents on carbohydrate

metabolism must be considered. A comparison of these two

drugs in their capacity to lengthen the duration of

pregnancy after symptoms of imminent preterm delivery, and

cardiovascular side effects has previously been published

(Essed et al., 1978) .

Certainly this subject deserves further investigation.

One additional point of clinical relevance is evident

from the data relating neonatal glucose values to the in­

terval between delivery and sampling. That is, that in the

premature infants recently exposed to ß-mimetics a hypo­

glycemic tendency may already be established within 30

minutes after birth.

Therefore, monitoring of glucose values should be started

very early in these infants in order to recognize and

correct promptly neonatal hypoglycemia. Furthermore, when

fenoterol has been employed, the early hypoglycemic effect

may persist even when the interval from last dose to de­

livery has been several days.

126

Chapter 5

Influence of long-term betamimetic drug administration during pregnancy on the early post partum blood loss

5.1. Introduction

Among the factors responsible for post partum hemor­

rhage one has to consider the incomplete contraction and

retraction of the myometrium. Beta-adrenergic drugs are

known to inhibit uterine contractions. Therefore the in­

fluence of these drugs on post partum blood loss was

studied.

If there is any influence of ß-mimetic drugs on the

blood loss after delivery, this could be expected mainly

in those patients who were treated until the day of deliv­

ery. The current study was therefore confined to patients

delivered before the 38th week of amenorrhea, for only

among prematurely delivering mothers were a substantial

proportion of the patients still being treated until

within 24 hours of delivery.

5.2. Materials and methods

Blood loss was measured during the 45 minutes after

delivery of the fetus in all patients treated with ß-mi­

metic drugs for the prevention of premature birth who

delivered vaginally from January, 1975 until January,

1979, with amenorrheas at delivery between 29 and 38 weeks

(n = 129). Beginning immediately after clamping and

division of the umbilical cord, fluid blood and clots were

collected in a basin placed beneath the patient's hips.

The volume of this blood loss was measured directly. The

amount of blood absorbed by sponges and drapes was obtain­

ed by weighing.

For comparison with the treated patients the amount of

127

blood loss post partum was measured in the same way in all

other (not treated) patients who delivered vaginally after

an amenorrhea between 29 and 38 weeks (n = 176) , from

January 1975 until January 1977.

Patients with polyhydramnios, myomas of the uterus, pa­

thology of the placenta, manual removal of the placenta,

forceps- or vacuum-assisted delivery, laceration of cervix

or vagina, third-degree perineal laceration or multiple

pregnancy were not included in the study, because of the

influence that these factors may have upon the blood loss

post partum.

The treated patients had received fenoterol and/or

ritodrine. In general, these tocolytic agents were admin­

istered intravenously for at least 2 days at the minimum

dosage necessary to stop labor. The mean of the maximum

i.v. dosages were 300 + 199 mcg/min, range : 67 - 800

mcg/min for ritodrine, and 4.3 + 2.4 mcg/min, range : 1.0

-8.0 mcg/min for fenoterol.

The dosage was then decreased ; and if uterine contrac­

tions did not return, oral treatment with 5 mg fenoterol

or 10 mg ritodrine, 6 to 12 times daily, was substituted.

With several patients, however, treatment was started

orally. In general, medication was continued until the

end of the 37th week of gestation. Intravenous therapy

only was used in 56 patients, oral therapy only in 23

patients, and 50 patients were treated both intravenously

and orally.

Ritodrine was given to 61 patients ; and fenoterol, to 58

patients. Ten women were treated with both β-agonists.

The duration of medication was less than 7 days in 35

patients (27 % ) . Ninety-four patients were treated for

one week or more. The intervals between the end of treat­

ment and delivery (t-d interval) are presented in table

5.1.

Management of the third stage of labor was similar in

all deliveries and did not change during the 4 year study

128

Table 5.1 TIME INTERVAL BETWEEN THE END OF

TREATMENT AND DELIVERY (T - D INTERVAL)

< 24 hrs 64 patients (50 %)

24 - 48 hrs 19 patients (14 %)

Ì. 48 hrs 46 patients (36 %)

period : after watchful waiting until the placenta had

separated, which was indicated by the umbilical cord pro­

truding farther out of the vagina, and ascertaining that

the uterus was contracted, the patient was asked to bear

down, while at the same time the muscles of the abdominal

wall were supported manually without touching the fundus

(Baer method). During this manoeuvre, the umbilical cord

was kept slightly taut. After removal of the placenta,

the uterus was watched constantly for at least 45 minutes

during which time repair of the episiotomy, if performed,

was carried out. if at any time excessive or brisk

bleeding was observed, uterine contractility was assessed

and the cervical, vaginal and perineal regions were

promptly inspected to identify the source of the bleeding.

Five units of oxytocin was injected intramuscularly after

the delivery of the infant in 31 % of the treated and also

in 31 % of the control patients.

Fundal pressure to hasten delivery at the end of the

second stage was applied in 20 % of the treated patients

and in 23 % of the controls.

A mediolateral episiotomy mainly to protect the head

of the premature infant was performed in 57 % of the β-mi­

metic treated patients and in 51 % of the control women.

The mean duration of the second stage of labor was

similar for both groups of patients : 17 + 14 min when

treated with a 6-agonist and 19 + 13 min for the control

patients (P = 0.40).

129

In 15 % of the treated patients, labor was induced by

intravenous administration of oxytocin, mostly following

spontaneous rupture of the membranes without effective

contractions. For the controls, this percentage was 28 %.

Birth weights were similar in both groups : 2453 + 577

grams versus 2462 + 676 grams, for treated and control

infants respectively (P = 0.52), altnough a difference was

found in the placental weights ; mean + SD of the placen­

tal weights in the group of treated women were 438 + 122

grams, compared to 394 + 118 grams among the untreated

patients (p < 0.002). All placentas were prepared in the

same way before weighing : membranes and umbilical cord

were removed and a period of at least 10 minutes was

allowed for drainage of liquid blood from the intervillous

space and major fetal vessels.

The gestational ages of the groups were not the same,

the ß-mimetic treated patients being more premature : 247

+ 14 days versus 251 + 14 days in the control group

(P < 0.001).

Table 5.2 COMPARISON OF PARITY IN THE TREATED AND

UNTREATED PATIENTS *

(previous pan

0

1

2

3 and more

ty)

treated

58 (45 %)

43 (33 %)

15 (12 %)

13 (10 %)

untrem ed

101 (57 %)

48 (23 %)

21 (12 %)

6(3·.)

129 176

* ρ < 0.05 Mann-Whitney U-test

130

The distribution of parities is given in table 5.2.

Parities were higher among the treated patients

(P < 0.05).

The significance of differences in the several parame­

ters was tested by means of the Mann Whitney U-test (two

tailed) and the Kruskal-Wallis one-way analysis of

variance by ranks.

Results are expressed as means + standard deviations.

5.3. Results

In the control group, post partum blood loss was found

to be significantly affected by the presence of an episio-

tomy, and by placental weight. In the treated patients,

also, blood loss was increased with episiotomy ; however,

the relationship with placental weight was less profound.

Comparison between ß-mimetic treated and non-treated sub­

jects demonstrated no increase in postpartum blood loss

after 0-mimetic treatment. In some categories, blood loss

was significantly less in the treated than in the un­

treated patients.

In the control group the average post partum blood

loss was found to be about 100 ml higher for patients with

an episiotomy than for those without (mean + SD : 417 +

342 ml, η = 89, versus 308 + 315 ml, η = 87 ; ρ < 0.002).

The difference in placental weights between patients with

an episiotomy and patients without was not significant

Op = 0.82), but a tendency was found towards higher birth

weights in the patients with episiotomy (2585 + 552 grams

versus 2336 + 766 grams ; ρ = 0.07).

When comparison was restricted to patients with babies

weighing over 2500 grams at birth, the mean increase of

blood loss after episiotomy was 117 ml.

Among the treated patients, the amount of post partum

blood loss in the women who had an episiotomy was in aver­

age about 125 ml greater than when no episiotomy was

131

performed. No differences between the placental weights

of these two subgroups were found (p • 0.94), but here the

birth weights of the infants born from mothers who had an

episiotomy were lower than birth weights of infants of

mothers who had no episiotomy (2348 + 603 grams versus

2594 + 511 grams ; ρ < 0.01). In the case of treated

mothers whose infants had birth weights over 2500 grams,

the extra blood loss after an episiotomy was 199 ml (438 +

293 ml as compared to 239 + 179 ml ; ρ < 0.002).

Table 5.3 MEAN + SD OF THE AMOUNT OF EARLY POST PARTUM BLOOD LOSS OF UNTREATED AND

TREATED PATIENTS IN RELATION TO THE DURATION OF THE SECOND STAGE OF LABOR

Not treated

Duration of second stage 1 - 10 mm 11 - 20 mm 21 - 60 min

al l patients

% episiotomy

without episiotomy

placental weight

350 - 600 gr

322 + 298 ml (61) 380 + 354 ml (57) 398 + 349 ml (56)

33 % 54 % 64 %

335 + 289 ml (26) 420 + 507 ml (16) 311 + 198 ml (15)

I Ρ = 0.67 — I I Ρ = NS Ρ = 0.92

Treated

Duration of second stage 1 - 10 m m 11 - 20 mm 21 - 60 mm

al l patients

% episiotomy

without episiotomy

placental weight

350 - 600 gr

271 + 233 ml (50) 348 + 257 ml (44) 364 + 298 ml (34)

46 % 6 8 % 59 %

179 + 108 ml (18) 248 + 164 ml (11) 253 + 203 ml (11)

I Ρ = NS 1 I Ρ = NS 1 I Ρ = NS 1

Table 5.3 gives the means and S.D. of the post partum

blood loss of treated and untreated women in relation to

the duration of the second stage of labor with considera-

132

Table 5.4 MEAN + SD OF THE AMOUNT OF EARLY POST PARTUM BLOOD LOSS OF UNTREATED

AND TREATED PATIENTS ACCORDING TO THE WEIGHT OF THE PLACENTA

Not treated

All patients

Birth weights 2500 - 3500 gr

Placental weight

^ 400 gr

282 + 271 ml (105)

264 + 216 ml ( 34)

Without episiotomy 247 + 318 ml ( 56)

Gestational age :

Placental weight

> 400 gr

483 + 379 ml (71)

497 + 382 ml (52)

419 + 282 ml (31)

< 0.0001

< 0.002

< 0.0005

36 - 37 weeks 303 + 210 ml ( 62) 456 + 362 ml (50) < 0.05

Treated

All patients

Birth weights 2500 - 3500 gr

Placental weight

< 400 gr

254 + 191 ml (SO)"

345 + 265 ml (12)

Without episiotomy 219 + 184 ml (23)

Gestational age : - 37 weeks 276 + 244 ml (18)

Placental weight Ρ

> 400 gr

363 + 290 ml (76) < 0.05

338 + 272 ml (42) 0.82

255 + 177 ml (31) 0.22

357 + 295 ml (39) 0.32

3 missing values

tion of placental weights and episiotomy. Among the

untreated patients, the duration of the second stage was

found to be of little influence upon the blood loss after

delivery. In the treated group the differences in post

partum blood loss between shorter and longer durations of

the second stage of labor seemed to be more pronounced,

but these data were biased by a higher episiotomy rate in

the patients who had longer expulsion times.

Moreover, treated patients with episiotomy who delivered

133

after a second stage of more than 15 minutes were found to

have higher birth weights and placental weights.

When the comparison was standardized according to placen­

tal weights, no significant difference in the amount of

post partum blood loss with respect to the duration of the

second stage of labor was found.

A highly significant difference in the amount of blood

loss after delivery was found according to the weight of

the placenta in the untreated patients. With the smaller

placentas (•£ 400 grams) a significantly lower blood loss

was measured than when the placental weight was over 400

grams (p < 0.0001). These differences were also found

after standardizing for birth weight, gestational age and

episiotomy. Among treated patients, a dissimilarity in

the amount of post partum blood loss was only evident for

the entire group of patients, and this difference disap­

peared after standardizing for birth weights, episiotomy,

or gestational age (table 5.4).

Fundal pressure was not found to increase the quantity

of post partum blood loss to a significant degree either

among treated patients or in the control group.

Nor was the intramuscular injection of 5 units of

oxytocin after the delivery of the child of significant

influence upon the total blood loss.

Table 5.5 and 5.6. summarize the data with respect to

the effect of birth weight and gestational age on the

amount of blood loss after delivery ; when the patients

were grouped according to equivalent placental weights, no

significant differences in early post partum blood loss

were seen among either the treated or non-treated women.

When treated patients (as a whole) were compared to

non-treated patients, the mean amount of blood loss after

delivery seemed quite similar in the treated and control

groups : 321 + 261 ml (n = 129) versus 363 + 333 ml

(n = 176) (p = 0.37 ; table 5.7). However, when the pa­

tients were compared after subdivision according to pla-

134

Table 5.5 MEAN + SD OF THE AMOUNT OF EARLY POST PARTUM BLOOD LOSS ACCORDING

TO THE BIRTH WEIGHTS

Not treated

All patients

Patients with placental weights 350 - 600 gr

Patients without episiotomy

Treated

All patients

Patients with placental weights 350 - 600 gr

Patients without episiotomy

Birth weights

4 2500 gr

306 + 296 ml (84)

376 + 367 ml (38)

274 + 335 ml (46)

Birth weights

ΐ 2500 gr

311 + 264 ml (72)

335 + 301 ml (47)

260 + 205 ml (26)

Birth weights

> 2500 gr

415 + 356 ml (92)

428 + 377 ml (74)

346 + 290 ml (41)

Birth weights

> 2500 gr

332 + 258 ml (57)

307 + 250 ml (43)

239 + 179 ml (29)

Ρ

< 0.03

0.74

0.11

Ρ

0.45

0.91

0.90

cental weight, duration of the second stage of labor, or

presence of episiotomy, differences were found between the

treated and non-treated women : patients with placental

weights of over 400 gr (p < 0.05) as well as patients with

a short duration (1 - 10 min) of the second stage of labor

(p = 0.09), and women without episiotomy had lower blood

loss after delivery when they were treated with ß-mimetic

drugs during pregnancy compared to those who were not

treated (table 5.7).

A tendency to an increase in post partum blood loss

was seen in patients who were treated until within 24

hours before delivery in comparison to the women in whom

treatment had been stopped for several days (p = 0.10),

and, moreover, when these subgroups were compared sépa­

las

Table 5.6 EFFECTS OF GESTATIONAL AGE UPON THE EARLY POST PARTUM BLOOD LOSS

.Vot treated

All patients

Patients with placental wei 350 - 600 gr

Treated

All patients

Patients with placental wei 350 - 600 gr

ghts

ghts

Amenorrhea

23 - 36 weeks

350 + 390 ml (64)

475 + 473 ml (34)

Amenorrhea

29 - 36 weeks

313 + 247 ml (71)

329 + 270 ml (46)

Amenorrhea

36 - 37 weeks

371 + 296 ml (112)

382 + 318 ml ( 78)

Amenorrhea

36 - 37 weeks

330 + 278 ml (58)

314 + 287 ml (44)

Ρ

0.07

0.70

Ρ

0.91

0.47

Presented are the mean values and standard deviations.

rately with the control patients, only the patients in

whom treatment had been terminated more than 24 hours

before delivery were found to have significantly lower

post partum blood loss than the untreated women (p < 0.01;

table 5.7).

The duration of treatment was not found to effect the

amount of blood loss after delivery.

No difference in post partum blood loss was found with

respect to the specific drug which was used (table 5.8).

The ritodrine-treated patients and the fenoterol-treated

women were comparable according to the relevant factors

including incidence of episiotomy, placental weight and

duration of pregnancy. However, a significant difference

was found with relation to the duration of the second

stage of labor, with the ritodrine-treated women having a

136

Table 5.7

MEAN + SD OF THE EARLY POST PARTUM BLOOD LOSS OF UNTREATED AND TREATED PATIENTS

Untreated Treated

I. All patients 363 + 333 ml (176) 321 + 261 ml (129) 0.37

II. According to placental weight *x

ΐ 400 gr 282 + 271 ml (105) 254 + 191 ml

> 400 gr 483 + 379 ml ( 71) 363 + 290 ml

III. According to episiotomy *

with episiotomy 470 + 394 ml ( 55) 404 + 323 ml

without episiotomy 352 + 343 ml ( 57) 218 + 155 ml

IV. According to duration of second stage

1 - 10 min 363 + 324 ml ( 37)

11- 20 min 438 + 453 ml ( 30)

21- 60 min 434 + 358 ml ( 44)

V. According to treatment-delivery interval

< 24 hours 410 + 372 ml (112) 366 + 297 ml

Ï. 24 hours 410 + 372 ml (112) 281 + 253 ml

255 + 239 ml

334 + 256 ml

408 + 332 ml

( 35)

( 29)

( 25)

0.09

0.54

0.72

50) 0.72

76) < 0.05

50) 0.37

40) < 0.05

43) 0.69

47) < 0.01

to unbias the comparison from the larger placental weights in the treated patients,

comparisons under III, IV and V are restricted to patients with placental weights

350 - 600 gr

3 missing values among the treated patients

137

Table 5.8 MEAN + SD OF THE AMOUNT OF EARLY POST PARTUM BLOOD LOSS OF PATIENTS

EITHER TREATED WITH RITODRINE OR FENOTEROL

Ritodrine (n) Fenoterol (η) Ρ

All patients 324 + 294 ml (61) 295 + 212 ml (58) 0.83

Without episiotomy 250 + 199 ml (27) 236 + 165 ml (25) 0.92

With episiotomy 382 + 344 ml (34) 340 + 235 ml (33) 0.88

Placenta « 400 gr 254 + 188 ml (25) 258 + 205 ml (23) 0.91

Placenta > 400 gr 385 + 349 ml (34) 319 + 216 ml (35) 0.94

Duration second stage

« 15 min 299 + 280 ml (41) 267 + 185 ml (32) 0.91

Duration second stage

> 15 min 389 + 325 ml (19) 329 + 241 ml (26) 0.76

t-d interval < 24 hrs 352 + 310 ml (37) 296 + 169 ml (24) 0.94

t-d interval > 24 hrs 280 + 269 ml (24) 294 + 241 ml (34) 0.61

greater proportion of short expulsion phases than the

fenoterol patients (Table 5.9).

Table 5.9 COMPARISON OF DELIVERY PARAMETERS

AND FENOTEROL TREATED PATIENTS

Amenorrhea at delivery

Parity

Birth weight

Placental weight

% episiotomy

Duration second stage

* mean + SD **

Ritodrine (n -

246 + 14 days *

0.5 **

2358 + 497 g *

427 + 116 g *

56 %

10.3 min *м

median

BETWEEN RITODRINE-

61) Fenoterol (n -

248 + 14 days

0.8

2516 + 650 g

443 + 135 g

57 %

15.0 min

S8) Ρ

0.31

0.17

0.25

0.52

< 0.05

138

5.4. Discussion

δ. 4.1. Comparability of subject groups

As stated in the materials and methods section, the

3-mimetic-treated patients in this investigation were

collected over a 4-year period, whereas untreated subjects

from only the first 2 years of this 4-year period were

included in the control group. Comparison of patient

groups collected over non-identical time periods was felt

to be justifiable in this study for several reasons.

First, these time limits resulted in treatment and control

groups of approximately equivalent size for statistical

comparison, while permitting exactly the same selection /

exclusion criteria to be applied for both the treated sub­

jects and the potentially much more numerous control pa­

tients. In both cases, all patients delivered during the

stated periods and meeting the stated criteria with regard

to duration of pregnancy, singleton fetus, and route of

delivery were included in the study. Second, there were

no differences in age, parity, pregnancy duration at de­

livery, placental weight or average blood loss between the

treated patients in the 3rd and 4th project years and

those in the first 2 years of the study, suggesting that

there was no significant change in patient population in

the second half of the study period. Finally, there were

no changes during the entire 4 year period in the manage­

ment of the third stage of labor, in the indications for

operative delivery or episiotomy, or in the indications or

techniques for stimulation of labor in this clinic. Thus,

there is no reason to suspect that the dissimilar intake

periods for treated and control patients introduced any

bias into the results of the study, and simultaneously

there are positive reasons to assert that patients and

policies were similar during the first and second halves

of the project period.

139

5.4.2. Factors affecting blood loss at delivery

In the control group, blood loss at delivery was

increased as the placental weight and, presumably, also

the size of the placental site increased. This finding

was not unexpected, although the relationship between size

of the placental site and the amount of early post partum

blood loss has not been stressed in the literature. In

most textbooks, the tendency towards increased blood loss

with fetal macrosomia or multiple gestation has been

ascribed chiefly to impaired contraction and retraction of

the previously overdistended uterus - as stated by Davis

and Russell (1966), the amount of blood loss is "directly

proportional to the size of the intrauterine mass". The

finding in this study of increased blood loss with in­

creased placental size in prematurely ending singleton

pregnancies suggests that the larger size of the placental

site may also play a role in increasing the post partum

blood loss with very large babies, multiple pregnancies,

or indeed other conditions where the area of the placental

site is increased.

Also as expected, early post partum blood loss was

increased in patients who had an episiotomy.

Duration of the second stage of labor up to one hour

did not consistently affect total blood loss. Perhaps an

effect of uterine fatigue in promoting hypocontractile

uterine bleeding might have become apparent had patients

with prolonged second stage durations been included j

however, prolongation of the second stage beyond 1 hour

was considered an indication for operative delivery (for­

ceps, vacuum extraction). These patients therefore fell

under the exclusion criteria for the present study.

5.4.3. Effect of ß-mimetic treatment on early post partum blood loss

Because of the demonstrated effects of placental size

140

and episiotomy on early post partum blood loss in the

control group, these factors were taken into account in

comparing blood loss between treated and untreated pa­

tients. When treated and untreated patients were grouped

according to similar placental weights and episiotomy

status, there was clearly no increased blood loss in the

treated patients. In some categories, moreover, blood

loss was less in the β -mimetic treated than in the un­

treated controls. This was the case when the placenta was

relatively large (> 400 grams), for patients with com­

parable placental weights who had no episiotomy, and a

tendency towards such a difference was found when the 2nd

stage of labor was short (10 minutes or less). Further,

the difference in blood loss between patients with large

(> 400 grams) or smaller placentas seemed less in the

treated than in the control group, and was not significant

for treated patients without episiotomy. These obser­

vations indicate that control of placental site bleeding

was not only unimpaired by chronic 3-mimetic treatment,

but may have been even more efficient than usual in this

group.

There are several possible explanations for these

findings of no increase, or even a decrease, in early post

partum bleeding after chronic 3-mimetic treatment. It

should be noted first that decreased blood loss, in the

cases where it was observed, reflected decreased bleeding

from the placental site, for extra blood loss contributed

by episiotomy was similar in treated and in untreated

patients. Since the major mechanism for control of pla­

cental site bleeding is contraction and retraction of the

myometrium, the findings with regard to placental site

bleeding of the ß-mimetic treated patients must be related

to uterine contractility. One clear index that effective

uterine contractility had been restored in the treated

patients was that in 85 %, parturition began spontaneously

and all patients had spontaneous deliveries. Thus the

141

tocolytic activity of the ß-mimetic drug had, in every

case, either disappeared as a result of cessation of

therapy and subsequent inactivation of the drug, or had

been overwhelmed by whatever contraction-stimulating

factors were responsible for the premature labor (when

effective contractions occurred despite continuing treat­

ment) .

The observation that, in some comparison categories,

treated patients lost less blood at delivery than the

untreated patients, together with the fact that these

patients had been treated on the indication of clinically

increased uterine activity, suggests that there may have

been a quantitative difference in uterine contractility

between the treated and untreated patients. Both groups

delivered prematurely, but the amenorrhea at delivery was

significantly shorter in the treated than untreated pa­

tients. To that must be added the fact that treatment was

begun an average of 35 days before delivery. Thus, clini­

cally significant increased uterine activity had appeared

earlier in pregnancy in the group of treated patients than

in the control group.

The decrease in blood loss was statistically signifi­

cant only in those patients where the t - d interval ex­

ceeded 24 hours. In these patients, presumably, the myo­

metrium had regained its full contractile potential. With

a shorter t - d interval, the difference in the average

blood loss between the treated and control patients was

not significant. It is possible that this finding may

reflect some small degree of persisting tocolytic effect

of the ß-mimetics when the t - d interval was relatively

short ; however, as stated above, the effect was insuf­

ficient to interfere with delivery or hemostasis at the

placental site.

These findings do not negate the fear of increased

post partum blood loss after intrapartum application of

ß-mimetics in term deliveries, for not only is there no

142

selection towards higher contractility characteristics of

the myometrium in those cases, but also some degree of

persisting tocolytic effect could interfere with hemo-

stasis at the placental site. Thus it seems reasonable to

employ oxytocics (not ermetrine ; section 2.5.1.2) during

the third stage of labor as a prophylactic measure when

ß-mimetics (with half-lives similar to fenoterol and rit-

odrine) have been given during labor.

143

Table 6.1

SUMMARY OF OBSTETRICAL STATISTICS FROM THE DEPARTMENT IN WHICH THIS RESEARCH WAS

CARRIED OUT, FOR THE YEARS 1974 THROUGH 1978

partus ì 16 weeks

children £ 16 weeks

immature partus

%

premature partus

%

partus ^ 28 weeks

children 5. 28 weeks

% perinatal mortality ^ 28 weeks

% fetal death

% neonatal death

% CS.

% forceps or vacuum

1974

1634

1657

25

0.5

114

7.0

1609

1628

2.2

1.4

0.8

6.4

11.5

1975

1649

1672

11

0.7

109

6.6

1638

1660

1.1

0.6

0.5

7.4

14.3

1976

1736

1766

13

0.7

162

9.3

1723

1753

2.1

1.2

0.9

7.4

13.7

1977

1827

1872

21

1.2

157

8.6

1806

1849

1.8

1.1

0.7

8.5

15.5

1978

1919

1953

28

1.6

148

7.7

1891

1922

1.4

0.5

0.9

10.9

11.7

Chapter 6

Appendix

This study describes the influence of ß-mimetic drugs

used for the inhibition of uterine contractions and the

lengthening of pregnancy. Furthermore two ß-mimetic

agents (ritodrine and fenoterol) were compared in their

effects and side-effects.

Perinatal mortality and morbidity data of the immature

and premature infants mentioned in this study must be ap­

preciated in the context of the total perinatal services

given in the years 1974 - 1978 (Table 6.1).

The policy of the department concerning preterm labor in

the years studied can be described as follows : when labor

had to be accepted fetal monitoring was instituted using

scalp-electrodes and also microblood investigations when

indicated. Fetal scalp blood pH was not permitted to de­

crease below 7.10 before caesarean section, forceps

delivery or vacuumextraction was performed. Episiotomies

were preferable in vaginal deliveries, especially in nul-

liparous women with a longer duration of the second stage.

In case of a breech presentation, caesarean section was

favoured in the stage of early prematurity (28 - 34

weeks) .

When premature rupture of the fetal membranes was

diagnosed, labor was induced in case of suspected intra­

uterine contamination or infection, as soon as L/S deter­

mination suggested fetal lung maturity, and, when no

reliable sample of amniotic fluid could be obtained, after

34 weeks of amenorrhea if the estimated fetal weight

exceeded 2000 grams.

Neonatal intensive care could be given immediately

after birth, when necessary, by neonatologists who were

available around the clock and were usually alerted before

the delivery.

145

During pregnancy, labor or post partum the mother was

evaluated for contributing factors for premature delivery;

i.e., infections, metabolic disturbances, congenital uter­

ine anomalies, etc. Because these features were not

studied prospectively and therefore were incomplete they

were not included in detail in this chapter. It must be

said, however, that apart from the self-evident causes as

mentioned above and twins, these maternal investigations

are disappointing, leaving too many "unknowns". This

stresses the need for further investigations on the initi­

ation of labor (Eskes, 1979).

146

SUMMARY

Chapter 1

This chapter deals with the obstetrical involvement in

by far the most important factor in the incidence of

neonatal mortality : premature birth. Some aspects of the

etiology, diagnosis, and prevention of preterm labor are

reviewed from the literature and some theories about the

initiation of labor are summarized.

Chapter 2

This chapter presents a review of present knowledge

about the applications of β-adrenergic agents in human

obstetrics.

Clinical pharmacological aspects, indications for use

and contraindications as well as some major side effects

are discussed.

A section of this chapter deals with some methods for

the evaluation of success of different treatment regimens

for the prevention of preterm labor.

Also the possible usefulness of ß-mimetic therapy in

chronic placental insufficiency, the probable beneficial

effect upon fetal lung maturation, and the intrapartum use

of these drugs are discussed.

Chapter 3

Chapter 3 presents the results of a clinical compar­

ison of ritodrine and fenoterol in their ability to

lengthen the duration of pregnancy after the occurrence of

threatening preterm labor.

The patient groups were subdivided according to gesta­

tional age at the start of treatment and balanced accord­

ing to a procedure described in section 3.2.5.

147

Only subtle differences in the efficacy of therapy

were found between the two drugs. In general the increase

in maternal heartrate was more pronounced in the ritodri-

ne-treated patients.

However, there seemed to be individual differences in

acceptability of these drugs.

Chapter 4

The effect of long-term intrauterine exposure to

ß-sympathomimetic tocolytic therapy (fenoterol or ritodri-

ne) on plasma glucose concentrations in the first 30

minutes after delivery was examined in 251 infants.

Significantly lower plasma glucose concentrations were

measured in the first 30 minutes of neonatal life in

children born from mothers who were treated with ß-mimet-

ics until within 48 hours before delivery, compared with

babies from untreated mothers.

These effects were more pronounced in premature in­

fants.

The total period of time treatment has been given was

not found to be of much influence.

Infants whose mothers were treated with fenoterol had

lower plasma glucose values in the first 30 minutes after

delivery than those infants who were exposed to ritodrine.

A recommendation is made to start monitoring blood

glucose concentrations of the neonates immediately after

delivery when ß-mimetic tocolytic treatment has been given

to the mother, and especially if delivery occurs within 48

hours after the termination of therapy.

Chapter S

During a 4 year period, early post partum blood loss

was measured for all patients who had been treated with

ß-mimetics for the prevention of preterm labor.

148

For comparison, post partum blood loss was measured in

the same way in all other (not treated) patients who

delivered with the same gestational ages during the first

two years of the investigation.

Only vaginal deliveries were included and some pa­

tient-categories were excluded from both groups.

Placental weight and episiotomy status were found to

affect the amount of early post partum blood loss at a

statistically significant level.

The blood loss after delivery was not found to be

increased by long-term ß-mimetic treatment, even when this

treatment ended less than 24 hours before delivery.

Moreover, when the treatment - delivery interval exceeded

24 hours, the average amount of blood lost by treated

patients was less than that of the untreated patients in

some comparison categories. A possible explanation for

these findings is discussed.

No differences in the amount of blood loss was found

according to the specific drug that had been used.

Appendix

The appendix presents some information about the inci­

dence and management of preterm deliveries in the depart­

ment in which the study was done.

149

SJATU KONTENTI

Kapitel 1

A kapitel disi e taki fu a obstetrisi sey fu a moro

principali orsaki fu dede ini a fosi wiki baka na gebortu:

data na te na gebortu kon turnsi fruku.

A e tjari kon na fesi, san buku skrifi fu na etiologi, fu

a fasi fa a diagnosu musu roeki nanga fa wi kan tapu na

fruku meki, so srefi leki sonwan teori fu fa a gebortu fu

na pikin e bigin.

Kapitel 2

Na ini a kapitel disi wi e luku na bradi san wi sabi

nojaso fu oten bere-uma musu kisi ß-adrenergica.

Baka makandra den klinis-pharmakologisi sey, den indikasi,

den kontra-indikasi, nanga den sey-efekti e kon na fesi.

Moro farà prakseri e kenki na tapu sonwan fu den

wrokofasi, fu tjari den resultati kon na doro fu den

difrenti fasi fu tapu fruku meki.

Fu kaba, wi sa taki, fa den β-mimetica kan kobroiki na

te a placenta no man fu du a wroko so bun moro, fa na fasi

e seti fu meki na logo-logo fu berepkin kon lepi, en a

fasi fa den dresi disi musu kobroiki na den juru fu a

gebortu fu a pikin.

Kapitel 3

A kapitel disi e presenter! den resultati fu wan marki

makandra fu atoso-ondrosuku, fu kan sabi, fa ritodrine

nanga fenoterol kan meki a marna hori bere moro langa, te

na ten kisi, efu te fruku meki e sori en srefi.

Den pasjenti di kobroiki ritodrine noso fenoterol wi prati

na ini fo grupu na a bigin fu na kisi dresi, en wi poti

den na ini balans nanga makandra na a maniri fa paragraf

150

3.2.5. sor i.

Den tu dresi no e sori bigi difrenti na ini a hori-bere-

moro-langa-wroko.

A ati fu a mama ben e naki moro esi nanga ritodrine. Toku

a sori, leki ibri wan suma e piki en eygi fasi na tapu den

dresi disi.

Kapitel 4

Wan ondrosuku ben meki ondro 251 pikin fu luku san e pasa

nanga a konsentreri fu glucose na ini na brudu-plasma te a

pikin ben ondrofeni langa ten na ini na muru a wroko fu

den dresi san e wroko wan ß-adrenerge tocolytisi fasi.

A ondrosuku disi ben meki ondro den pikin na ini na ten fu

wan afu juru baka di den ben gebore.

Efu wi poti den pikin disi na wan sey, nanga wan grupu

pikin fu marna di no ben kisi den dresi dati na tra sey,

dan den pikin fu na fosi grupu, sobun fu den mama di ben

kisi g-mimetica te na 48 juru befosi den meki a pikin, ben

sori wan krin-krin moro lagi warde glucose na ini den

brudu, na fosi afu juru baka di den gebore, leki a kriboi

grupu, di den mama no ben kisi dresi.

A piki disi ben de fu si moro krin, na fruku-meki pikin.

A glucose konsentreri fu na plasma fu den pikin na ini na

fosi afu juru baka di den gebore, ben de moro lagi, efu

den mama ben kisi fenoterol prefu ritodrine. Fu gi wan

bun rai : bigin wantron-wantron baka di a pikin gebore fu

marki omeni glucose de na ini na brudu, efu na marna ben

kisi ß-mimetica, funamku efu a meki na pikin befosi 48

juru pasa, baka di a tapu nanga a dresi.

Kapitel S

Fo jari langa, na ala den urna di ben kisi ß-mimetica, fu

hori bere, a brudu san lasi na baka di na pikin gebore,

ben marki.

151

Den urna disi ben poti na sey wan grupu urna, di no ben kisi

na dresi en di ben hor i bere net so langa leki na fosi

grupu.

Tu jari langa den urna disi, di no ben gebroiki ß-mimetica

dresi, ben ondrosuku.

Soso den, di текi den pikin sondro fu den bere ben musu fu

koti opo, ben teki prati na ini a ondrosuku disi.

Ά brudu san lasi, ben marki na srefi fasi na ala den marna.

A hebi fu na placenta, nanga te wan episiotomi ben de

fanowdu, den tu sani disi ben gi wan tru-tru kenki na ini

brudu san lasi, wantron na baka di na pikin gebore.

Awinsi den urna ben kisi na dresi langa ten di den ben bori

bere, toku den no ben lasi moro furu brudu, awinsi na ten

no ben kisi 24 juru srefi di na dresi tapu, befosi na

pikin gebore.

Efu na dresi ben tapu moro langa leki 24 juru befosi na

pikin ben gebore, sonwan fu den urna di ben kisi na dresi,

no ben lasi so meni brudu srefi leki den urna di no ben

kisi na dresi.

A disertasi srefi e ferteri moro krin, fa dat du kon.

Awinsi sortu wan fu den dresi ben kobroiki, den urna no ben

sori difrinti na ini brudu san ben lasi.

Bakapisi

A bakapisi e gi den reglement! fu na atoso, pe na

ondrosuku ben meki.

152

SAMENVATTING

Hoofdstuk 1

Dit hoofdstuk behandelt de obstetrische aspecten van

de belangrijkste oorzaak van neonatale mortaliteit : de

premature geboorte. Etiologische aspecten, diagnose­

stelling en preventie van de vroeggeboorte, alsmede enige

theorieën omtrent het begin van de baring worden belicht

vanuit de literatuur.

Hoofdstuk 2

In dit hoofdstuk wordt een overzicht gegeven van de

huidige inzichten in de toepassing van ß-adrenergica in de

humane verloskunde. Klinisch-pharmacologische aspecten,

indicaties, contraindicaties en bijwerkingen worden

achtereenvolgens besproken.

Verder wordt aandacht besteed aan enkele methoden ter eva­

luatie van het resultaat der verschillende wijzen van be­

handeling ter voorkoming van vroeggeboorte.

Tot slot volgt een beschouwing over de toepasbaarheid van

^-mimetica bij chronische "placentaire insufficiëntie", de

invloed op de foetale longrijping en het gebruik van deze

medicamenten tijdens de baring.

Hoofdstuk 3

Hierin worden de resultaten van een vergelijkend kli­

nisch onderzoek naar de zwangerschapsverlengende werking

van ritodrine en fenoterol bij een dreigende vroeggeboorte

gepresenteerd. De met ritodrine en fenoterol behandelde

patiënten werden naar amenorrhoeduur bij de aanvang van de

behandeling in 4 klassen onderverdeeld en met elkaar in

evenwicht gebracht volgens een in paragraaf 3.2.5. be­

schreven procedure. De zwangerschapsverlengende werking

153

toonde slechts geringe verschillen voor beide middelen.

De gemiddelde toename in hartfreguentie was groter bij de

met ritodrine behandelde patiënten. Er lijken echter

individuele verschillen in tolerantie voor deze geneesmid­

delen te bestaan.

Hoofdstuk 4

De gevolgen van langdurige intrauteriene blootstelling

aan ß-adrenerge tocolytische medicatie op de plasma

glucose concentratie gedurende de eerste 30 minuten na de

geboorte werden bestudeerd bij 251 kinderen.

Vergeleken met kinderen van niet behandelde moeders, wer­

den in de eerst 30 minuten post partum, significant lage­

re glucose spiegels gemeten in het plasma van neonaten

wier moeders tot 48 uur voor de bevalling behandeld werden

met ß-mimetica.

Dit effect was het duidelijkst waarneembaar bij prematuur

geboren kinderen.

Kinderen waarvan de moeders met fenoterol behandeld wer­

den, hadden in de eerste 30 minuten post partum gemiddeld

een lagere plasma glucose concentratie dan zij bij wie

ritodrine was toegediend.

Aanbevolen wordt onmiddellijk na de geboorte de plasma

glucose spiegel van de neonaat te bepalen, wanneer de

moeder behandeld werd met β-mimetica, zeker indien de be­

valling plaatsvindt binnen 48 uur na het staken van de

therapie.

Hoofdstuk 5

Gedurende een onderzoeksperiode van 4 jaar werd het

direct na de bevalling optredend bloedverlies bepaald bij

alle patiënten die ter preventie van een vroeggeboorte met

ß-mimetica werden behandeld. Een controle groep werd

gevormd uit alle andere (niet behandelde) patiënten die

154

bij dezelfde amenorrhoeduur bevielen in de 2 eerste jaren

van het onderzoek en waarbij het bloedverlies post partum

op dezelfde wijze gemeten werd.

Alleen patiënten die vaginaal bevielen, werden onderzocht

en in beide groepen werden diverse categorieën patiënten

uitgesloten van het onderzoek. Het placentagewicht en een

episiotomie bleken een significante invloed op het bloed­

verlies direct na de bevalling te hebben.

Het bloedverlies bleek niet verhoogd te zijn na langdurige

behandeling met S-mimetica tijdens de graviditeit, zelfs

niet wanneer deze minder dan 24 uur ante partum nog

plaatsvond.

Indien de behandeling meer dan 24 uur voor de bevalling

gestaakt werd, was in enkele subgroepen het bloedverlies

na de bevalling bij de behandelde vrouwen gemiddeld zelfs

geringer dan bij de onbehandelde patiënten. Een mogelijke

verklaring hiervoor wordt besproken.

Met betrekking tot het middel waarmee werd geremd, werden

er bij de behandelde patiënten geen verschillen in bloed­

verlies gevonden.

Appendix

De appendix bevat enige informatie over de incidentie

van, en het beleid bij, de voortijdige bevalling in het

instituut waar het onderzoek werd verricht.

155

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174

CURRICULUM VITAE

De auteur van dit proefschrift werd geboren te Paramaribo

op 2-12-1945.

Het diploma H.B.S.-B werd behaald aan het Sint Canisius

College te Nijmegen, waarna hij aan de Katholieke Univer­

siteit te Nijmegen geneeskunde studeerde.

Het artsexamen werd met goed gevolg afgelegd in januari

1974.

Aansluitend was hij 6 maanden als arts-assistent werkzaam

in de Kliniek voor Obstetrie en Gynaecologie van het Aca­

demisch Ziekenhuis te Paramaribo (toenmalig hoofd : Prof.

Dr. R. Ali; huidig hoofd: Prof. Dr. R.W. Jessurun).

De opleiding tot vrouwenarts genoot hij in de Universi­

teitskliniek voor Obstetrie en Gynaecologie (Hoofden Prof.

Dr. J.L. Mastboom en Prof. Dr. Т.К.A.B. Eskes) van het St.

Radboud Ziekenhuis te Nijmegen (1974 - 1978} en in de

B-Opleidingskliniek voor Obstetrie en Gynaecologie (Oplei­

der : Dr. J.H.A. de Leeuw) van het St. Laurentius Zieken­

huis te Roermond (1978 - 1979).

Sedert medio 1979 is hij als gynaecoloog verbonden aan de

Rijksuniversiteit Limburg en het Ziekenhuis St. Annadal te

Maastricht.

175

Stellingen behorend bij het proefschrift: "Aspects of human tocolysis with adrenergic agents"

G. G. M. ESSED, 20 februari 1981

I

Bij pasgeborenen die intra-uterien aan ß-adrenergica zijn bloot­gesteld, dient binnen 30 minuten post partum de glucose concen­tratie in het plasma gecontroleerd te worden.

Dit proefschrift.

II

Zwangerschapsverlenging uitgedrukt als percentage van de na­gestreefde therapieduur is een betere maat voor de potentie van een tocolyticum dan de zwangerschapsverlenging op zich.

Ill

Bij een aanzienlijk deel van de vrouwen die wegens een dreigende vroeggeboorte met bedrust en tocolytica worden behandeld, is bedrust alléén als therapie voldoende.

IV

Gezien de invloed van ß-adrenergica op de bloedstolling dient bij langdurig intraveneus gebruik, thrombose profylaxe te worden toe­gepast.

Göser, R. et al. (1980)

Arch. Gynecol. 230, 89.

V De ligging van Puddicombe vormt een waardevolle bijdrage aan de preventie van een occipito-posteriore achterhoofdsligging in de uitdrijvingsperiode.

Puddicombe, J. F. 11955) J. int. coll. surg. 23, 73. VI

Fluor genitalis is een juistere benaming voor het symptoom dat thans nog te vaak met fluor vaginalis wordt aangeduid.

VII

Het gebruik van jodiumtinctuur in de nabijheid van elektrische ap­paratuur is niet zonder risico.

Vili

Het risico ten aanzien van het herhaald optreden van een vroegge-boorte bij een partus praematurus in de voorgeschiedenis kan ver­kleind worden door specialistische prenatale zorg.

Smits F. (1981) Academisch Proefschrift, Nijmegen.

IX

De trage verandering van de attitude ten aanzien van het roken, van sociale activiteit tot asociaal gedrag, is voor menig roker nau­welijks bij te houden.

X

Het effect van door rokers geproduceerde luchtvervuiling op niet-rokers dient in wetenschappelijk onderzoek naar de gevolgen van tabaksgebruik betrokken te worden.

White, J. R. en Froeb, H. F. (1980) N. Eng. J. Med. 302, 720.

XI

Echoscopisch onderzoek draagt bij tot de betrouwbaarheid van een LU .CD. als contraceptivum.

Schmidt, E. H. et al. (1979) Geburtsh. u. Frauenheilk., 39, 138.

XII

Staande blijven op het hellend vlak dat ontstaat wanneer de demo­cratische principes in een land wegvallen, vereist een hoge graad van acrobatisch vermogen.

XIII

De nauwelijks ontwikkelde afscheidingsgedachte in Limburg ge­tuigt van een hoge mate van zelfbeheersing in deze provincie.