C O N T R A C E I O N

FE ILl R U TI IN NURSl W N. VI. Contracept e Effect eness of a Subde al Progesterone plant

S. Dfaz, O. Peralta, G. Juez, C. Herreros, M.E. Casado, A.M. Sal tlerra, P. Mira a a~ H.B. Cro t to

NSU ORIO P IFIC ION F ILIAR Centro National de la F ilia J.V. Lastarria 29 - Depto. I01

Santiago, I

ABST T

Six progesterone pellets implanted subdermally were tested as

contraceptive t d for lactating men. One pregnancy s diagnosed in 1614

w an- nths of observation, a failure rate which s s ilar that obse~ed

in a contemporary group of Copper T users. Nineteen pregnancies were

diagnosed in the 677 w an- nths obse ed in trea=ed iactati en. The

progesterone implants re effective en administered either at 30, 60 or 240

days after delivery. The duration of the effective llfe s 5 nths and

fertility s quickly restored after rds. There re no delete ous effects

u n maternal or i ant health or u n lactation and the rate of child gr th.

The main problem encountered s the occurrence of pellet expulsion at a

vari le rate ich ap ared related to the ma fact i procedure.

Submitted for publication Septe er 12, 1984 Accepted for publication Septe er 17, 1984

BER 1984 VOI.,. 30 NO. 4 311

C O N T R A C E P T I O N

INT DU ION

The inhibition of fertility associated with breastfeedl is highly

riable a ng individuals and tends to decrease as time elapses following

delivery. This fact dete ines the need for contraceptives that can be used

duri lactation thout interfering th milk production or child health (I,

2, 3)-

In previous p lications (4, 5) discussed the tential ad ntages

of using the natural hot ne, progesterone, as a contraceptive during

breastfeedl a the ellmlna results obtained with a s de al plant of

six o sterone pellets re re tied° is paper gives an updated account

of the contraceptive effect eness of ogesterone ministered by this means

and discusses the observed ad ntage8 of such a thod.

E D THODS

p~ation: Vol teers enrolled in the study re selected fr a healthy

postpartum en o met the Ii requlr ents: ages 18 to 35, parity 1

to 3, no a! e ancy and vaginal te delivery of a healthy infant with a

birth weight adequate to the gestatlonal age. They had to be regularly

c blti , free fr drug t ra and willing to rse their infants as long

as s s!ble.

Selectlon was done at the maternity rd ere instructions on the

tec ique of breastfeedl on de nd re gi n. ditional requirements at

the time of initiati treatment re no al postpart evolution, no al

physical e inatlon of ther and ild, h oglobin values higher than I0 g%

and a normal nutritional state. All cases re required to be in c sire

breastfeedl th an adeq te infant growth rate before admission.

Treatments: Progesterone was administered by subde al insertion of s

progesterone pellets. Contemporary control groups were fo ed by women

treated th an IUD or a placebo injection. The allocation to an injectable

met d or an IUD s at tlent olce.

- Progesterone pellets: Pellets were made by c esslng I00 of the

312 OC R 19 V O L 30 NO. 4

C O N T R A C E I O N

steroid into a cylinder of approxi rely 11.8 mm length by 3.2 mm diameter.

Three different batches (I, II and III)were manufact ed usl different

te niques. C pression s applied along the Longitudinal axis in batches II

and III and perpendicular to it in batch I. The progesterone used was

p dered in t es I and II and precompressed in batch III. Each subject

received 6 esterone llets that re inserted s de ally in the gluteal

region t ough a No. 9 gauge trocar under local anesthesia. Insertion of

pellets was done at day 30 or 60 after delivery. Pellets re petted to

ha an effecti life of 5 or 6 nths. cordingly, wo n o re treated

at day 60 were offered a second set of pellets at approximately day 240

post rtum provided they re still nursing their babies.

- Intrauterine device: The IUD used in this study s t Copper T 2 0 0

(supplied by the Asociaci6n Chilena de Protecci6n de la F illa). It s

inserted at d 30 or 60 postpartum to match the contemporary groups using

pr esterone llets.

- Placebo: The placebo consisted of an injection of 3 of distilled

ter, offered as a test treatment to sustain lactation and therefore to

support the fertility inhibition associated with breastfeeding. Women

enrolled in this group re offered non-hormonal contraceptives at the 6th

postpartum month or earlier if suppl entary bottle fe~i s introduced.

The placebo was administered at day 30 postpartum. This group was

disconti ed en it bee ident that full rsl alone or rtial rsl

supple nted th rrler t ds ovlded poor protection (6).

Follow- : Follow-up s designed to dete ine the occurrence of egnancy,

breastfeeding perfo ante, i ant gr th, s~e effects a bleedl pattern.

Visits re scheduled at nt y intervals up to the sixth postpart month and

at two-month inte als =hereafter. At each visit, the mater I a infant

h i s t o r i e s r e r e c o r d e d a b o t h t h e r a i l d r e e x a n e d . B r e a s t f e e d i

perfo ante a i ant gr h re carefully I ted usl the Boston curve

f o r b o y s ( 7 ) a s =he r e f e r e n c e s t a n d a . S p e c i a l c a l e n d a r s r e d i s t r i b u t e d t o

r e c o r d a l l b l e e d i a s t t i y s a n d t h e e r o f b r e a s t f e e d i e p i s o d e s

p e r d a y .

P r e g n a n c i e s w e r e d i a g n o s e d b y c l i n i c a l e x a m i n a t i o n a n d u r i n a r y

ER 19 VOL. 30 NO. 4 313

C O N T R A C E I O N

unologleal tests for H . Pregnancy tests ;were performed when menses were

delayed for 20 days or mote, en enorrhelc w en reached the 6th stpart

month and before the insertion of a second set of progesterone pellets at day

240 after dellvery.

P r o g e s t e r o e ........ b l o o d ........... l e, v e l s : B l o o d s p l e s r e d r n a t 1 0 - o r ! 5 - d a y i n t e ~ a l s

fr a subsample of users of the 3 different batches of progesterone pellets

during the first segment of use and from control subjects. Progesterone

levels re dete~ined by R as iously described (8) usi the procedures

a reagents provided by the Programme for the Provision of Matched Assay

Reagents for the RIA of Hormones in Reproductive Physiology of the World

Health Organization.

Dat~a anal sls: The month of conception s est ated by adding 14 days to the

first day of the last bleeding run observed. It s confl ed or adjusted

when possible by reference to the esti ted gestational age of the neonate.

The Pearl Index was used to est te the o bility of pregnancy at various

inte Is during treat nt.

L_actatlon was classified up to the 6th month of age as full nursi or

exclusive breastfeedl if the breast s the only source of nutrients for the

:baby. After the 6th month, non-dalry food was prescribed routinely and

lactation s still classified as full nursing if the breast was the only

source of milk. The proportion of cases remaining in the full nursing

condition was used to assess the effect of treatment upon lactation.

Supplement was prescribed by the pediatrician when the rate of infant growth

indicated inadequate milk supply. In se ral cases, the supplement was self-

prescribed by the mother based upon her subjective evaluation of milk

production and child satisfaction.

The occurrence of severe interc!irrent disease, prolo ed or repeated

separation of mother and child, discontinuation of treatment or

los t-to-follo~up dete~ined cluslon of the case fr analysis o~ lactation

and infant gro h follo-w~,ng the la3t visit prior to the event.

~In order to assess the effect of treatment upon in~ant growth, the

rage absolute ight at each nth of llfe and the rage Ight increase

314 R 19 V 30 4

C O N T R A C E I O N

at monthly and daily intervals re calculated for each group. Only cases in

exclusive breastfeedl were included. Calculations re done up to the 8th

month of age.

The occurrence of uncomfortable or prolo ed bleedl was analyzed

through the proportion of n o experienced re than 6 days of bleeding

plus spottl per 30-day inte~al after trea ent.

Contingency table analysis and student's "t" test were used to assess

the statistical significance of differences in distribution and mean values,

respectively. 0nly p values <0.05 re considered significant.

~SULTS

The number of subjects enrolled in each treatment group is sh~n in

Table I. Ninety-two out of I12 women (82.1%) accepted the relnsertion of

progesterone pellets that was offered at day 240 ~stpartum.

The plasma progesterone levels achieved ~th the 3 different batches

of pellets are show~n in Figure i. They reached their ~xlmum within ten days

of insertion and declined gradually thereafter remaining elevated at least for

5 months in comparison to the control group. Levels obtained with the 3

batches were of slmilar magnitude.

The local tolerance to progesterone pellets was poor. Expulsion

occurred in 2.4% of subjects from batch I, in 31.7% of subjects from batch II

and in 9.9% of subjects from batch Ill. ~e t e elapsed between insertion

and expulsion varied from several days to five months.

Table II shows the occurrence of pregnancy in women treated with

progesterone pellets according to the breastfeeding status and the time of

treatment. This table includes only the first 5 months after each

progesterone plant insertion. For this reason, the 8th postpartum month is

not included. No pregnancies re obse~.,ed in the first 5 nths of urea ent

in full nursing women when treatment was given at day 30, 60 or 240

postpartum. Only one pregnancy s diagnosed in rtlally nursl w~en and

it occurred in the 4th month after insertion. The overall incidence of

pregnancy was I in 1614 months. This figure is c table to the fertility

inhibition obtained w~th the Copper T in the s postpart intervals. Both

treatment groups showed a significantly lower incidence of pregnancy as

O-CToBER 1 9 8 4 VOL. 3 0 NO. 4 3 1 5

C O N T R A C E I O N

I

Distribution of Subjects Accordl to Trea nt

and Day of inistration

Initiation of Trea ent No. of S Jeers Postpart D

Progesterone Pellets

D 30 : Batch !

Day 60: Earth II

Batch III

Day 240: tch Ill

84

41

152

92

Copper T

30

D 60

125

121

Placebo

D 30 130

316 R 19 VOL. 30 NO. 4

C O N T R A C E I O N

ng/ml

6 o

m

a

~Im

a

O

Q Batch I

Batch II

0 Batch Ill

4 . on, o

, , , * ÷ ¢, • o * •

......... -~-- ~ °~'T =--~ .... :-i .............. ~. .............................. , ...... , ............................... . ........ = i .... ~ .... -, ..... - ..... , ....... ........ l ............. ...................... --= . ....... -, ..... . ..... .............

0 30 60 90 120 150

T R E A T M E N T DAYS

Fig. i" Plasma progesterone levels (X + S.E.) in lactati w en treated

th progesterone pellets from Batch I ([~), Batch II (~) and

Batch III (o) and in control cases (e).

B E R 1 9 V O L 3 0 N O . 4 3 1 7

C O N T R A C E ION

BLE II

Contraceptive Effectiveness of Progesterone Pellets versus Copper T and

Placebo cording to the Breastfe i Status and the Obsereatlon Period

Treatment Breastfeeding No. Pregnancies / No. man-months Status Ohse~,,a tlon Period*

( Po 8 t pa r t Hon th s )

2 - 68 3 - 7h 9 13c TOT

Progesterone Pellets

clus e 0/339 0/594 0/144 Supple nted 0/17 I1199 0/205 Wean 0 / 1 0 0/37 0/69

1 0 / 3 6 6 1 / 8 3 0 0, /418 ~/16!4

Copper T clusive 1/471 0/420 1/252 Supple nted 0/43 0/164 0/268 Weaned - 0/'39 0/72

1 1 / 5 1 4 0 / 6 2 3 1 / 5 9 2 2/1,729

Placebo a Exclus e 91502 - 1/49

Sup pleme n ted 4 / 49 - 5/77 Wean - - -

l i3/551 - 6/126 t9/677

* 13, the first five nths postpartum ~IIo ng insertion were considered el e this is the eat ated effective llfe of progesterone plants (See Tab le II I).

a Treatment Inltlat at day 30 ~stpart .

b Trea ent initiated at day 60 postpart . c Trea nt initiated at day 240 post rt in progesterone pellets gr p

and at day 30 or 60 in the oEher o groups. d S e men used s £clde8 ~fter the sixthpostpart n~h.

3 1 8 BER 19 VOL. 30 NO. 4

N T R A C E ION

compared to the place gr p in i 19 pregnancies ~ere diagnosed in the

6 7 7 a nthe o b s e ed in c par le st rtum inte is.

Table III shows the overall contraceptlve effectiveness of six

progesterone pellets for different treatment le ths, regardless of the

ti of insertion. Treatment was hlghly effective during the first five

months of use. The effectiveness decreased en t obse tlon s extended

to nth8 6 and 7 ere 3 and 6 pregnancle8 w~re dla~nosed i~ 239 and 72

W n-months of expos e , respect ely.

The cumulates distribution of n co ~ng to their breastfeedi

status at the 6th postpart nth is sho in Table IV. Treatment groups

~nltlated a~ day 30 or 60 st rt h breastfeedi evolutions s ilar to

thelr coat orary ntrol gr ps. Both serie~ initiated at day 60 showed a

higher proportion of su 1 eared cases ~t e 6th n c pared to the

series started at day 30.

The gr th of elusively breastfed ~nf~ts s s ilar In treated and

control groups en analyzed through the averase absolute body Ight at each

nth of age and the aver e mont y a daily Ight inc ass. Table V s

the average ight crease of 8 ely breastfed i ants ~ fr birth to the

6th month of age. Values fo~ all groups were within the normal range

according t o the standard used f comparlson.

No m~Jor side effects re detected. The bleedlnH pattern sh ed

disruption during the first month of use of pellets comparable to =hat

obse~ed after ~nsertlon a Copper T. ble VI sho the proportion of full

nursing ~ w e erienced 6 or re d s of b edln~ p s spotting per 30-

day inte al. cessna bleedi s infrequent in all gr ps after the first

n of treat nt. tar the insertion of the secon~ set of implants at day

240 postpartum, the proportion of women who reported more than 6 days of

bleedln E per interval ranged fr 6Z (third nth of treatment) to 16Z (flfth

month). In t sa ~rlod, the oportlon of Cop r T use o experienced

re than 6 d s of bleeding ran d fr 21~ to 31%.

DIS SSION

The results of this st y s w that the cont~ ous mln~stration of

progesterone by ans of an ~mplant i ibits fertility in lactatlng women and

BER 1984 VOL. 30 NO. 4 .t19

C O N T R A C E I O N

TA E III

Duration of t h e Contracept e Effectiveness of S!x Progesterone Pellets

Months of Pregnancies/ Pearl Treatment Wo nths Index

1 t o 5 ! / 1 6 1 4 0 . 7 4

6 3 / 2 3 9 1 5 . 1

7 6 / 7 2 I 0 0 . 0

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TABLE IV

C ulatlve Distribution of en Accordlr~ to their

Breastfeedi~ Condition at the 6th Postpartum Month

A NT Insertion

(Postpartum day)

Excluslve U s e of Supplementa~ Feedi Breastfeeding dical ternal

Prescriptlon Decislon z Z z

Progesterone

Pellets 30 73 68 21 11

60* 127 53 39 7

Cop~r T 30 106 60 29 11

60 105 50 36 14

Placebo 30 105 71 26 3

N ffi N er of cases observed at day 180.

* ~ses treated w~th pellets from Batch II ~re excluded because of the

bias introduced by the high nu er of expulsions.

OC BER 19 VOL. 30 NO. 4 321

C O N T R A C E P T I O N

TABLE V

erage Weight Increase of Exclus~.,ely Breastfed Infants

from Birth to the 6th Month of Age

Initiation of Treatment N ~~ght Increase (g) (Post rt Days) X + S.D.

Progesterone Pellets

Day 30

Day 60

46 4515 + 621

60 4730 + 670

Copper T

Day 30

Day 60

64 4801 + 817

49 4798 + 546

Placebo

Day 30 68 4663 + 529

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BLE Vl

Percentage of Full Nursi Women who Experienced More than 6 Days

of Bleedlng or Spotti per 30-Day Inte~al

te al (Postpart Progesterone Pellets Copper T Placebo

days ) 30* 60* 30* 60* 30*

31 - 60 46 - 52 - 22

61 - 90 12 18 10 30 4

9 1 - 120 8 5 14 16 5

121 - 150 6 5 12 15 8

151 - 180 9 4 17 15 7

* Postpart day of insertion.

BER 19 VOL. 30 NO. 4 323

C O N T R A C E I O N

t h a t i t c a n b e u s e d f o r c o n t r a c e p t i p u r p o s e s , e p r e g n a n c y r a t e o b s e r v e d

during the period of elevated plasma levels of the steroid is highly

satisfactory and thin the ran of a Copper T IUD. The high incidence of

pregnancies observed in the placebo group all s the conc slon that the 1

fertility of the treated groups was not determined exclusively by

breastfeedi .

The duration of elevated plasma progesterone levels and of an

acceptable contraceptive efficacy s limited to 5 nths. After this period,

fertility was quickly restored as can be inferred from the number of

preg ncles observed at the 6th and 7th nth after insertion, is led us to

offer a second set of Implants after the haustlon of the first rese olr to

wo n o re still iactati at t t tl . 1 incidence of egnancies

observed in the second segment is reassuring of the contraceptive

effectl ness of progesterone plants during lactation and shows that its

efficacy applies also to io -te lactation.

e use of progesterone ind ed no ad rse side effects on lactation

as judged by the ortion of cases in clus e breastfeedlng a the gr th

rate of exclusively breastfed infants up to the 6th postpartum month.

Treatment with progesterone pellets or a Copper T resulted in a higher

proportion of subjects who experienced more than 6 days of bleeding as

c pared to t treat n. eft less, this s a transient obl ,

limited to the postlnsertlon period and did not represent a reason for

discontinuation or a health risk for the s jeers, deleter s effects

upon Inf t health re detected.

The percentage of women who were willing to use a second set of

progesterone plants indicates that this is a Ii accepted alternatl .

The main problem encountered during this experience was the high

incidence of expulsion of the progesterone pellets Ich appears to be

partially related to the manufacturing technique. The results reported

justify n efforts to d el an o d st r the long-term delivery

of ogestero .

3 OC R 19 V O L 30 NO. 4

C O N T R A C E I O N

A EDGE NTS

The authors are grateful to the authorities of the Hospital Paula

Jaraquemada and the Central Health Area of Santiago for the facilities

provided for this study, to the Instituto Bioqufmlco Beta for the provision of

progesterone pellets, to the 0 Progra for the Provision of tched Assay

Reagents for the RIA of Hormones in Reproductive Physiology, and to the

International Develo nt Research Centre of Canada and to the International

Committee for Contraception Research of The Population Council for their

support.

FE NCES

I e

0

O

I

O

O

0

0

Van Ginneken, J.K. The chance of conception during lactation. J Biosoc

Sci, Supp 4-41-54 (1977).

Lau ran, V.H. Contraceptive choices for lactating women" suggestions for

postpartum family planning. Stud Faro Plann 12:156-163 (1981).

McCann, M.F., Liskin, L.S., Piotrow, P.T., Rinehart, W. and Fox, G. La

lactancia materna, la fecundidad y la planlfleaci6n familiar.

Population Reports J 24, October 1982.

Croxatto, H.B. , D~az, S. , Peralta, O. , Juez, G. , Casado, M.E.,

Salvatlerra, A.M. and Dur~n E. Fertility regulation in nursing women.

II. Comparative perfo nee of progesterone implants versus placebo and

Copper T. J Obstet G ecol 144:201-208 (1982).

Croxatto, H.B., D~az, S .... , Peralta, O., Suez, G., Herreros, C., Casado,

M.E., Salvatlerra, A.M. and randa P. Subdermal progesterone implants

for fertility regulation in rsi women. Presented at the International

rkshop on Long-Actlng Contraceptive Delivery Syst s. P FR~ May 1983.

D~az , S. , Peralta, O., Juez, G., Salvatierra, A.M., Casado, M.E.,

Dur~n, E. and Croxatto, H.B. Fertility regulation in nursing women. I.

e probability of conception in full nursing ~omen living in an urban

setti . J Biosoc Scl 14 -329-341 (1982).

Nelson, W.E., Editor. Textbook of Pediatrics, 8 ed. W.B. Saunders Co.,

Philadelphia P.A., 1964. p. 42.

Croxatto, H.B., DKaz, S., Peralta, O., Sal tlerra, A.M. and Brandeis,

A. Plas progesterone levels folio ng s de a! plantation of proges-

terone pellets in lactating women, ta Endocrinol I00"630-633 (1982).

OCTOBER 1984 VOL. 3 0 NO. 4 3 2 5