METHODOLOGICAL AND ETHICAL ISSUES IN THE STUDY OF MATERNAL SMOKING AND

ADVERSE PREGNANCY OUTCOMES

Matthew Roy Wong

A thesis submitted in conformity with the requirements for the degree of Master of Science

Graduate Department of Pharmaceutical Sciences University of Toronto

O Copyright by Matthew Roy Wong 2000

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METHODOLOGICAL, AND ETHICAL ISSUES LN

THE STUDY OF MATERNAL SMOKING AND

ADVERSE PREGNANCY OUTCOMES

Master of Science 2000

Matthew Roy Wong

Graduate Department of Pharmaceutical Sciences, University of Toronto

ABSTRACT:

In Canada an estimated 20 to 30 percent of women smoke during pregnancy. The study

of maternal smoking in adverse pregnancy outcornes presents complex methodological and

ethical issues, iiicluding potential reporting bias and maternal guilt.

Matemal reports of smoking before and afier an incident of fetal distress were compared.

Ethical issues surrounding matemal guilt and informed consent were articulated. The impact of

methodological and ethical issues was assessed in a feasibility study exarnining matemal

smoking as a risk factor in neonatal hypoxic-ischemic encephalopathy (HIE).

Among women who had events of fetal distress, a significant decrease in their report of

smoking occurred. Mothers who smoked during pregnancy with an adverse outcome may be at

risk for psychological damage fiom exposure to the research hypothesis. Methcdological and

ethical issues significantly affected the feasibility study, and preliminary data suggests a high

level of smoking may be occumng amongst mothers o f infants with HIE.

ACKNOWLEDGEMENTS

First and forernost, 1 wish to thank my supervisor Dr. Gideon Koren for his ongoing support and

direction for this work. He has taught me that research must be practical, and should be

conducted with an entrepreneurial spirit. 1 would especially like to express my appreciation for

the support of Dr. Andrew James who has been an integral part of my devetopment both

personally and professionaily. 1 am also particularly indebted to Drs. Shinya Ito, Reina

Bendayan, Ingeborg Radde and Christine Harrison for their guidance and instruction. 1 would

also like to thank, Dr. Max Perlman and Ms. Julia Klein at The Hospital for Sick Children for

their assistance and insights into this research. Finally, 1 am indebted to my farnily for their

invaluable encouragement, suggestions and providence.

iii

TABLE OF CONTENTS

1 INTRODUCTION 1.1 Matemal Smoking as a Risk Factor in Adverse Pregnancy Outcomes

1.1.1 The Problem of Bias in Matemal Self-Report of Smoking 1.1.2 Ethical Considerations in the Study of Maternal Smoking in Adverse

Pregnanc y Out comes 1.1.3 Maternal Smoking and Neonatal Hypoxic-Ischemic Encephalopathy

1.2 Purpose of Objectives of The Study 1.2.1 Reporting Bias 1 -2.2 Ethical Considerations 1.2.3 Maternal Smoking and Neonatal Hypoxic-Ischemic Encephalopathy

1.3 Research Hypothesis and Rationale for Hypotheses 1 -3.1 Reporting Bias 1.3.2 Ethical Considerations 1.3.3 Maternal Smoking and Neonatal Hypoxic-lschemic Encephalopathy

2 METHODS 2.1 Reporting Bias Methodology 2.2 Ethical Considerations Methodology 2.3 Maternal Smoking and Neonatal Hypoxic-Ischemic Encephalopathy

Methodology 2.3.1 Retrospective Studies 2.3.2 Prospective Studies

3 R E S a T S 3.1 Reporting Bias Results 3.2 Ethical Considerations Results

3.2.1 Ethical Concems 3.2.2 Outcome of REB/IRB Review 3 -2.3 Final Solution

3.3 -Matemal Smoking and Neonatal Hypoxic-Ischemic Encephalopathy Results 3.3.1 Retrospective Data 3.3.2 Prospective Data

3.3.2.1 Clinical Data and Hair Cotinine Analysis Results 3.3.2.2 Assessment of Feasibility

4 DISCUSSION 4.1 Reporting Bias 4.2 Ethical Considerations 4.3 Matemal Smoking and Neonatal Hypoxic-Ischemic Encephalopathy

4.3.1 Retrospective Data 4.3 -2 Prospective Data

4.4 Summary of Findings 4.5 Recommendations for Future Studies

Page 1 1 4 5

5 REFERENCES

6 APPENDICES

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

LIST OF TABLES Page

Causes of Fetal Asphyxia 8

Sarnat and Sarnat Staging of Hypoxic-Ischemic Encephalopatby (HIE)

Additional Information Provided by Mothers Reporting "Fetal Distress"

Materna1 Characteristics at Clinic 31

Follow-up Characteristics 32

Materna1 Self-Report of Smoking 34

Changes in Self-Report of Materna1 Smoking 35

Self-Reported Cigarette Consumption in Mothers of 43 Infants with HIE at the Hospital for Sick Children (1985-92) vs. All Live Births at the Ottawa Civic Hospital (1989-90)

Materna1 Characteristics of Infants with HIE Presenting 45 at the Hospital for Sick Children (Nov. 1998-July 1999)

Delivery Factors of Infants with HIE Presenting at the Hospital for Sick Children (Nov. 19984uly 1999)

Neonatal Characteristics of Infants witb HIE Presenting at the 48 Hospital for Sick Children (Nov. 1998- July 1999)

Smoking Status for Mothers of Infants with Neonatal HIE 50 Presenting at the Hospital for Sick Children (Nov. 1998JuIy 1999)

Maternal Characteristics Categorized by Smoking Status in Infants with Neonatal HIE Presenting at the Hospital for Sick Children (Nov. 1998-July 1999)

Delivery Factors of Infants with HIE Categorued by Maternal Smoking Status Presenting a t the Hospital for Sick Children (Nov. 1998-July 1999)

Neonatal Characteristics of Infants with HIE Presenting at the Hospital for Sick Children (Nov. 1998duly 1999) Categorized by Maternal Smoking

LIST OF APPENDICIES

Appendix 1 Maternal Smoking and Neonatal Hypoxic-Ischemic Encephalopathy (HIE)

Study: Clinical Data Collection Form

Appendix 2 Maternal Smoking and Neonatal Hypoxic-lschemic Encephalopathy (ME)

Study: Actual Hair Cotinine Values €rom Neonates with HIE (The Hospital

for Sick Children November 1998 - July 1999)

Appendix 3 Manuscript: "Proposed Non-Consensual Research to Avoid Potential

Iatrogenic Parental Guilt: An Example in Hypoxic-ischemic Encephalopathy

(HIE)" M Wong, BSc, C Hanison, PhD, A Moore, MD, G Koren, MD

Appendix 4 Manuscript: CLBias in Maternal Reports Of Smoking During Pregnancy

Associated With Fetal Distress" M Wong, BSc, G Koren, MD

Appendix5 Abstract from The Toronto Fetal Centre Newsletter Number 14/15:

"Proposed Non-Consensual Research to Avoid Potential Iatrogenic Parental

GuiIt: An Example in Hypoxic-ischemic Encephalopathy (HIE)"

Appendix 6 Abstract from Oral Presentation at the Canadian Bioethics Society meeting

October 1998 (Delta Chelsea Inn, Toronto, Ontario, Canada): "Proposed

Nonconsensual Research: An Example in Hypoiric-Ischemic

Encephalopathyn

1 INTRODUCTION

1.1 Maternal Smoking as a Risk Factor in Adverse Pregnancy Outcomes

Despite overwhelming evidence underlining the possible harms to the fetus, in Canada it

is estimated that approximately 20 to 30 percent of women continue to smoke during pregnancy

( B r e ~ a n , 1997). Increasing results indicate that smoking during pregnancy is associated with a

dose-dependent decrease in birth weight, an increased risk for spontaneous abortions, as well as

a higher likelihood of placental abruption and higher perinatal mortality rates (Brennan, 1997;

Cnattingius and Nordstrom, 1996; Koren, 1995). Maternal smoking has also been associated

with sudden infant death syndrome (SDS) (MacDoman MF et al., 1997; Golding, 1997; Oyen

et al., 1997).

Yet aithough these women continue to smoke during their pregnancies, the vast majority

of them experience a significant amount of guilt and self-blame because of their addiction and

largely express a desire to quit, but for a number of reasons feel incapable of doing so (Sherman,

Sanders and Tnnh, 1998; Cuskey and Wathey, 1982; Finnegan, 1980). In addition to the self-

imposed negative thoughts associated with this behaviour, society also contributes significantly

to this state of mind. Smoking is looked upon unfavorably by society and this serves to label and

stigmatize these women (Welte and Russell, 1993).

The societal exclusion and negative feelings caused by smoking during pregnancy can

lead to a significant problem in clinical research that relies on matemal report. Because of the

feelings of guilt and shame that some wornen rnay experience, they may not be tnithfbl when

answering questions relating to their smoking status, and may misrepresent the nurnber of

cigarettes which they smoke each day. With regards to smoking status, this may introduce a

severe bias in determining the proportion of women in a given cohort who smoked during

pregnancy. When asked, women who did in fact smoke during pregnancy may simply Say that

they did not. Further to this, if we assume that women who smoked during pregnancy correctly

2

identim that they did smoke, what if they misrepresent the amount that they smoked? If for

example they do not accurately report the number of cigarettes they smoked per day, if a dose-

response relationship exists, the effect rnay not be seen. Additionally, if such a bias existed in

previous research, those results rnay have in fact overstated the significance of what were

thought to be low levels of smoking but were in fact due to maternal underreporting.

Given that this bias rnay occur in mothers with uneventful pregnancy outcornes, how

much more powerful a sense of guilt and social disapproval might there be in light of an adverse

pregnancy outcome? And how much more an inclination to underreport behaviour which a

mother rnay attribute to causing her infant's condition? Fetal distress for example is a serious

perinatal condition associated with perinatal rnortaIity, and is well recognized by most women.

If a mother who srnoked during pregnancy were to have an infant who experienced fetal distress

during delivery, her report of smoking rnay potentially becorne highly unreliable.

In light of the fact that this source of bias rnay exist in maternal reports, we then turn to

the question of biological markers. Both neonatal meconium (a baby's first bowel movement)

(Ostrea, 1994) and neonatal hair (Eliopolous et al., 1994) have been identified as sensitive,

specific and non-invasive markers of fetal exposure to cigarette smoke. In addition to showing

positivity or negativity regarding smoking status, these rnarkers are also able to give ana

approximation of the extent to which smoking occurred. This being the case, biological markers

would most likely provide a more reliable indication of self-reported smoking status and some

estimate as to the quantity of smoking that took place.

Seeking to obtain a biological marker, we then tum to the question of obtaining this

sample. Would women be willing to consent to this research? In the context of an uneventful

pregnancy, some women might feel hesitant to consent. And again, what of the question about

seeking consent for this biological sample in the context of an adverse pregnancy outcome?

3

One such adverse pregnancy outcome exists in neonatal hypoxic-ischemic

encephalopathy (HIE). In this condition, a decrease in oxygen to the fetal brain during delivery

results in neurological sequelae, and in extreme cases c m potentially cause permanent brain

damage (Ekertet al., 1997; Thornberg et al., 1995; Sarnat and Sarnat, 1976). In addition to a

number o f other factors, because of the baseline decrease in oxygen supply to the fehis that

occurs during smoking (Schardein, 1993; Longo, 1977), there is concern that smoking could

potentially contribute to the etiology of neonatal HIE.

In light of this potentially devastating outcome, an important question presents itself

which can affect Our research methodology. First, if we were to examine the role of matemal

smoking during pregnancy in neonatal HIE and wished to use a biological marker, what impact

could simply posing the research question to the subject have? We have already stressed that an

underlying feeling of guilt and shame exists in a smoking mother. Hypothetically, what effect

would suggesting that her smoking was related to this outcome have? Although there is a

working hypothesis, nonetheless it is still unproven. The suggestion, however, that smoking

may have played some role in her baby's condition may cause considerable psychological

damage. In spite of this potential for h m , the importance of the research also needs to be

considered. If smoking was associated with the condition, it might be one of the few etiologic

factors that could be avoided in the development of neonatal HIE. Our ultimate ethical question

then becomes a question of whether it is possible to conduct this research without putting these

women at risk.

In summary, the study of matemal smoking as a risk factor in adverse pregnancy

outcomes presents two main problems. First, ethical issues that exist in these circumstances

need to be considered not only for their own sake (as this in of itself is a field of research) but

also in Iight of how these issues affect study methodology; narnely, in the case of neonatal HIE,

how methodology should be constructed in order to avoid potential psychologicai damage to the

4

research subject. Secondly, methodological issues need to be addressed regarding the validity of

rnaternal report in the context of an adverse pregnancy outcome and also regarding the feasibility

of investigating maternal smoking as a risk factor in a condition such as neonatal HIE. This

second question of feasibility is an important one in that the ethical issues may shape a

methodology such that it inay, although ethically sound, prove to be untenable for practical or

technical reasons.

These methodological and ethical issues in the study of matemal smoking and adverse

pregnancy outcomes are the focus of this thesis.

1 1 The Problem of Bias in Materna1 Self-Report of Smoking

Studies examining the potential adverse effects on the fetus of certain rnaternal

exposures, such as smoking during pregnancy, comrnonly rely on maternal self-reports. In the

event of a negative result, researchers will ofien cite undeneporting as a potential source of bias

(Jedrychowski et al., 1998). The problern of undeneporting of cigarette smoking during

pregnancy can have a profound effect on the results of such studies. n ie magnitude of this

problem can be appreciated when one compares matemal reports to a biological rnarker. Three

studies comparing biochemical markers of smoking, such as serum or urine cotinine levels, with

matemal report of smoking found that between 5 and 15 percent of wornen who identified

themselves as nonsmokers in fact had cotinine levels that were consistent with active smoking

(Klebanoff et al., 1998; Murray et al., 1993; Walsh et al., 1996). However, the use of biological

markers is not always feasible for a number of reasons including reluctance of patients to give

consent, which in of itself can introduce a severe bias, and particularly in the case of

retrospective studies where one has only a patient record to examine. Moreover, the existing

studies (Klebanoff et al., 1998; Murray et al., 1993; Walsh et al., 1996), while identiGing a

reporting bias of smoking dichotomously (i-e., yes or no smoking), were not designed to address

a bias in the amount of cigarettes reported.

5

At least two reasons for underreporting have been suggested. Firstly, because of the

diminishing social acceptance of smoking during pregnancy, expectant mothers rnay provide

false reports of their smoking which they believe will be more acceptable to the researcher and

to the public at large (Welte and Russell, 1993). Secondly, in the instance of an adverse event

during the pregnancy or delivery, it is possible that women may underreport a behaviour which

in their own minds rnay have been associated with these adverse events. This, however, has

never previously been demonstrated empirically.

1.12 Ethical Considerations in the Study of iMaternai Smoking in Adverse Pregnancy

Ou tcomes

The study of maternal behaviour and its effect upon fetal well-being is an extremely

complex task. Beyond the scientific or technical obstacles that rnay present themselves, there

are a multitude of psychosocial and ethical dimensions that rnay be difficult and, perhaps in

some cases, impossible to completely overcome.

In situations where a child was born with a condition resulting in permanent disability,

mothers often expenenced tremendous feelings of guilt even in situations where their behaviour

during pregnancy could not have had an impact upon the infant's outcome (Affleck et al., 1982).

Given that this occurs, it is Iikely that conducting research into a maternal behaviour such as

smoking during pregnancy in circumstances of an adverse pregnancy outcome rnay ampli@ any

underlying feelings of guilt that exist as the fact that there is a hypothesis put forward by the

researcher rnay point a finger of blarne towards the mother. This could potentially inflict serious

psychological damage upon the subject. The very act of obtaining an infonned consent could

initiate thoughts of self-blame that rnight not be warranted nor even be scientifically valid as at

that point in time it would be a reaction to an idea that was only a hypothesis and not a proven

fact.

6

The loss of a baby during childbirth is a devastating event associated with feelings of

extreme grief, disappointment, helplessness, and self-blame. Perhaps even more tragic and

ernotionally complex is an event during childbirth that may result in the chiId having a life-long

disability. One such outcorne can occur in babies who develop a perinatal condition known as

hypoxic-ischemic encephalopathy (HIE). Our group wished to investigate the hypothesis that

maternal smoking is a risk factor for HIE, using a combination of maternal obstetncal history

and biological waste products as markers of smoking. At the onset of developing Our

hypothesis, several ethical concems arose regarding Our study population. These included the

potential psychological harm to parents who might infer from the study that they were

responsibie for their child's condition, ambiguity regarding the moral status of biological waste

such as meconium (a baby's first bowel movement), and the apparently absolute requirements of

The Hospital for Sick Children's Research Ethics Committee to obtain informed consent.

Given the potentially fragile nature of the study population and the possibility of causing

psychological damage, the question of conducting non-invasive, observational, nonconsensual

research needed to be considered in order to protect the subject from the theoretical hami that

could be caused by being exposed to the research question.

1.1.3 Materna1 Smoking and Neonatal Hypoxic-Ischemic Encephalopathy

Neonatal Hypoxic-Ischemic Encephalopathy is a potentially devastating perinatal

complication affecting between 3 and 5 in every 1000 live births (Roberton, 1992). In this

condition, a decrease in the oxygen supply to the fetal brain occurs dunng the delivery process.

Although the pathogenesis of HIE is not h l ly understood, a number of causes related to either

decreased oxygenation of the maternal-fetal unit or restricted uteroplacental perfusion have been

identified (Perlman and Kirpalani, 1992), summarized in Table 1.

The severity of the hypoxic-ischemic insult to the central nervous system can ofien be

differentiated clinically, and infants are described as having mild, moderate, or severe HIE

7

(Stage 1, 2, and 3, respectively) according to clinical criteria (Sarnat and Sarnat, 1976) as

illustrated in Table 2. In the more severe forms, these infants may die or develop severe cerebral

palsy and/or cognitive deficits of varying degree (Cnattingius and Nordstrom, 1996; Ekert et al.,

1997; Thornberg et al., 1995).

Matemal smoking has been associated with a wide range of perinatal complications,

including increased rates of miscarriage, stillbirth, intrauterine growth restriction, prematurity,

and the Sudden Infant Death Syndrome (MacDorman et al., 1997; Golding, 1997; Oyen et al.,

1997). Tobacco smoke emits over one thousand different chemicals, some of which have been

shown to cause fetal toxicity. Dwing smoking, circulating levels of carbon monoxide (CO) may

cause as much as 20% of materna1 and fetal bemoglobin (Hb) to be converted into carboxy-Hb

which does not carry oxygen (Schardein, 1993). Because fetal Hb has a much higher affinity for

CO than adult Hb, carboxy-Hb levels tend to be higher, and are sustained for longer periods in

the fetus than in the mother (Longo, 1977). It is this binding to CO which results in decreased

oxygen carrying capacity in the blood for the mother and the fetus. In addition, CO also binds to

intracellular cytochrome enzymes, thus its effect on intracellular respiration is much greater than

those predicted by circulating CO levels (Longo, 1977).

Nicotine is a potent neurotoxin, shown in animal studies to affect the fetus morphologically and

developmentaHy (Schardein, 1993). As well, it acts as a vasoconstrictor, causing decreased

uteroplacental perfùsion (Schardein, 1993). In addition, inhibition of prostacydin activity has

been demonstrated in the umbilical cords of heavy smokers (Ahlsten et al., 1990). Prostacyclin-

dependent vasodilation is an important part of maintaining uteroplacental perfusion and, hence,

inhibition may cause reduced fetal blood supply. Gross anatomical differences in umbilical

cords between heavy smokers have also been observed. The presentation of an increased

number of blood vessels above the standard three in the umbilical cord has been documented in

heavy smokers (Gupta et al., 1993), which the authors believed to be consistent with chronic

8

hypoxia. It is also felt that with this abnorrnal profile, the vascular system may be less resilient

to compression or other insults during delivery.

Recently, it has also been shown that long term exposure to cigarette smoke has the

ability to cause an increase in the expression of CD18 integrin cell-surface molecules on

neutrophils, thereby facilitating their adhesion to other ce11 surfaces particularly during

extravasation (Ryder et al., 1998). Inhibition of CD18 adhesion molecules using monoclonal

antibodies has been shown to decrease ischemia-reperfusion injury in primates (Wim et al.,

1 998). Taken together, these observations suggest that exposure to cigarette smoke may cause

an upregulation of CD 18 molecu~es on neutrophils and may thereby potentiate hypoxic-ischemic

damage.

To date, despite great concerns regarding the adverse fetal effects of materna1 smoking,

no study has addressed the potential risks of tobacco smoke for causation of HIE. Because HIE

is characterized by fetal brain hypoxia, the current research sought to investigate feasibility of

conducting a study that addressed the hypothesis that materna1 smoking is a risk factor for HIE.

Maternal Hypoxemia

Respiratory failure (e.g. asthma)

Cardiac failure

Shock

Reduced oxygen-caiTying capacity of blood (carbon monoxide poisoning, rnethemoglobinemia, severe anemia)

Maternal Vascular Disease Causing Reduced Uterine Perfusion

Hypertensive vascular disease

Diabetes

Autoimmune diseases (e.g. systemic lupus erythematosus)

Pregnancy-induced hypertension @re-eclampsia and eclampsia)

Uterine Tetany

Placental Diseases and Disorders

"Placenta1 insufficiency" not associated with the above

Premature separation of the placenta: abruption, previa

Umbilical Cord Accidents

Prolapse

ff io ts

Compression (e.g. oligohydramnios, shoulder dystocia)

Fetal Causes

Reduced oxygen-canying capacity of blood (carbon monoxide poisoning, methemoglobinemia, severe anemia)

Fetal cardiac failure

Fetal Shock

Table 1 Causes of Fetal Asphyxia

Classification Cliaical Signs

Stage 1 (Mild) Hyperalertness

Hyperexcitabili ty

Stage 2 (Moderate) Lethargy

Hypotonia

Suppressed primitive reflexes

Stage 3 (Severe) Stupor

Flaccidity

Absent primitive reflexes

Table 2 Sarnat and Sarnat Staging of Hypoxic-lschemic Encephalopathy (HIE)

11

1.2 Purpose and Objectives of The Study

The purpose of this study was threefold. First, to determine if bias exists in the maternai

reporting of smoking in the context of an adverse pregnancy outcome, using fetal distress as an

example. Second, to explore the ethical issues that exist in circumstances of an adverse

pregnancy outcome which need to be considered and how these issues affect study methodology;

namely in the case of neonatal HIE, and how study methodology should be constmcted in order

to avoid potential psychological damage to the research subject. Third, to determine the

feasibility of investigating matemal smoking as a risk factor in the perinatal condition of HIE in

light of the ethical and methodological issues presented by the first and second purposes above.

To this end, the following three objectives were pursued.

1.2.1 Reporting Bias

The objective of this component of the present study was to investigate whether there is

bias in maternal reporting of the arnount of cigarette consumption when fetal distress is

diagnosed. Fetal distress is described as a cluster of clinical situations, including oxygen

deprivation (e.g. presence of meconium, low Apgar score), heart rate abnormality, or

biochemical disturbances (e-g. fetal acidemia) (Hill, 1979; Parer and Livingston, 1990; Mead,

1996). Fetal distress presented at birth often requires medical intervention and admission to a

neonatal intensive care unit; these infants may suffer long tenn sequelae (Gilstrap et al., 1989).

Although fetal distress is lacking an accurate clinical definition, most mothers are aware of its

significance and wiIl recall its occurrence. This research exarnined whether bias would occur in

matemal report of smoking if a woman had an event of fetal distress during delivery.

1.2.2 Ethical Considerations

The object of this component was to illustrate the ethical considerations involved in

determining a study methodology for the research of maternal smoking as a risk factor in

neonatal HIE. In particular, this component sought to investigate three areas. First, to describe

12

the nature of matemal guilt resulting from an adverse pregnancy outcorne surrounding the

question of a maternal behaviour such as smoking. Second, to delineate the requirements of

informed consent from an institutionaVregulatory perspective (venus a philosophical

perspective). Third, to determine the requirements for noninvasive, nonconsensual research in

light of the concems put forth in the previous two components. These areas were then to be

looked at in light of the Hospital for Sick Children's Research Ethics Cornmittee review decision

and incorporated with the cornmittee's requirements to form an ethically coherent study

rnethodology which took al1 ethical factors into account.

1.2.3 Materna1 Smoking and Neonatal Hypoxic-Ischemic Encephalopathy

The objectives of this part of the research were: One, to determine the ethical,

methodological, and practical feasibility of studying the incidence and degree of maternal

smoking during pregnancy as a risk factor for neonatal HIE at the Hospital for Sick Children.

Two, to validate the hypothesis for the study with retrospective and prospective data.

As there were a number of ethical concerns raised in the development of the research

protocol, the objective of this component was to evaluate the proposed methodology in the

process of obtaining consent from research subjects and to establish if the ethical guidelines

derived from the research outlined in Section 1.2.2 were feasible from an ethical perspective. In

essence, this component sought to address the question of whether the proposed solution by the

Hospital for Sick Children's ethics committee to the ethical problems was in fact entirely ethical,

and to make observations on any difficulties in the implementation of the solution.

Along with ethical feasibility, a critical appraisal of the methodological feasibility was

another objective. The methodology utilized in this feasibility study was to be scrutinized with

the idea of this methodology being used in the context of a larger definitive study of matemal

smoking and HIE.

13

An assessrnent of the practical feasibility of this research was also to be explored. This

was to include several elements including characterizing the study population with regard to

geographical concerns (for the purposes of matching in fiiture studies), logistical concems (how

to contact parents in order to obtain consent, etc.), and data collection concerns (quality of

information in charts, difficulty [not related to consent] in obtaining biological samples, etc.). In

addition, the rate of presentation (number of admissions in a given time) at the Hospital for Sick

Children's NICU for infants with HIE was to be assessed (to estimate how quickly data could be

collected from this institution) as well as the declination rate of subjects and establishing their

reasons for declining to participate.

Finally, the validity of our hypothesis was to be tested through an investigation of

existing data through retrospective analysis and prospective data collection. Retrospective data

at the Hospital for Sick Children NlCU between 1985 and 1992 were to be examined for

evidence of materna1 smoking, and to compare the prevalence or amount of smoking in mothers

of infants with HIE with a population-based historical control group. Prospective data were to

be collected from mother-infant pairs presenting at the Hospital for Sick Children's NICU with a

neonatal diagnosis of HIE in order to analyze both the prevalence and amount of cigarette

consumption during pregnancy through the use of a biological marker. These data were then to

be compared to population-based historical data for cornparison of the prevalence of smoking,

and the actual levels from infants of active smokers as indicated by the biological marker were to

be cornpared with historical data from infants who did not suffer from HIE.

14

1.3 Research Hypotheses and Rationale for Hypotheses

Although the hypotheses for scme of the cornponents of my research are dependent on

the results from previous components, the hypotheses below are stated independently for the

sake of clarity. Any assumptions are stated explicitly.

1.3.1 ReportingBias

The hypothesis was that women who smoke during pregnancy and have events of fetal

distress during delivery will decrease their report of smoking during pregnancy reported at the

time of follow-up when compared to their initial "reat time" report. That is, it was hypothesized

that the number of cigarettes consumed per day reported during pregnancy would decrease

postnatally due to the event of fetal distress.

It is well accepted that smoking during pregnancy puts the fetus at increased health risks.

Studies have clearly illustrated the nsk for decreased birthweight and an increased incidence of

perinatal mortality and deIivery complications, such as fetal distress (DiFranza and Lew, 1995;

Walsh, 1994). These nsks are oAen explained by health professionals to women who smoke

during their pregnancy, and these women are ofien cited as being aware of these risks pnor to

receiving counseling for smoking cessation (Haslam et al., 1997).

The rationale for the hypothesis is that, because of the additional social stigrna that rnay

be caused by admission of smoking during pregnancy in Iight of an adverse outcome potentially

due to smoking, a mother rnay actively decrease her report of smoking which she believes will

be more acceptable to the researcher and to the public at large (Welte and Russell, 1993).

1.3.2 Ethical Considerations

There were three hypotheses in this component of the research.

The first hypothesis was that women who have an adverse pregnancy outcome would

experience significant underlying feelings of guilt and would engage in self blame. The

rationale was based on two examples of anecdotal evidence. First, dunng pregnancy women

15

express great concems regarding their behaviour, particularly regarding exposures to cigarette

smoke. This is seen frequently in calls to the MotheRisk program at the Hospital for Sick

Children which answers questions regarding exposures during pregnancy and their effects on the

fetus. Second, in instances of an adverse pregnancy outcome requiring admission of the infant to

the Hospital for Sick Children's NICU, physicians often report that women ask numerous

questions regarding the potential causative role of their behaviour in the pregnancy outcome and

show a great degree of anxiety around this topic. Accordingly, it was hypothesized that this

group would be psychologically vulnerable and that, in investigating maternal smoking as a risk

factor for HIE, the posing of the research question might unjustifiably increase the feelings of

guitt and self-blame that preexisted and could result in psychological damage.

The second hypothesis was that, assuming the first hypothesis to be true, informed

consent might not be required in this unique research situation according to exceptions stated in

institutional regulations and requirements. The rationale being that since the research initially

proposed was non-invasive and to be completely anonymous, it could be hypothesized that

institutional guidelines would allow for a nonconsensual methodology to be adopted.

In light of the assumption in the first hypothesis that the potential existed for causing

considerable psychological damage to research subjects by highlighting the issue of smoking

during pregnancy, and assuming fiom Our second hypothesis that institutional policy would

allow exceptions for nonconsensual research, the ultimate hypothesis was that nonconsensual

research methods needed to be considered to avoid this serious potential harm.

1.3.3 Materna1 Smoking and Neooatal Hypoxic-lschemic Encephalopathy

The working hypothesis was that maternal smoking increases the risk for HIE by

decreasing fetal oxygenation. Both through diminishing oxygen transport by hemoglobin as well

as intracellular cytochrorne enzyme binding (Shardein, 1993; Longo, 1977), maternal smoking

increases the risk of decreasing fetal oxygenation, and therefore may increase the nsk for HIE.

16

This may be especially crucial if CO-factors such as placental abruption, insuficiency or previa

coexist. In addition, cigarette smoke may potentiate hypoxic-ischemic damage by increasing

neutrophil adhesion during ischemic-reperfusion injury (Ryder et al., 1998; W i n et al., 1998).

When this occurs in the brain, increased neutrophil adhesion in the cerebral vasculature creates

an excess of neutrophil aggregation in a damaged vesse1 which resû-icts normal blood flow

downstrearn. This deprives more distant tissues of oxygen and hence may exacerbate cerebral

injury.

A biological marker was to be used to identifL smokers and to quanti@ intrauterine

exposure to tobacco smoke.

Cotinine, the major metabolite of nicotine, has a longer elimination half life than nicotine

and is the most widely used rnarker of exposure to tobacco smoke (Koren, 1995). Matemal

serum concentrations of cotinine have been s h o w to reflect accurately the number of cigarettes

smoked by the mother, when the time of the last cigarette smoked is known. However, direct

measurement of fetal exposure to cotinine will allow a more accurate estimate of the intrauterine

burden of constituents of tobacco smoke (Eliopolous et ai., 1994). Umbilical cord levels of

cotinine rnay be spunously low if the mother has not smoked for 2-3 days before or during

delivery. On the other hand, cotinine is trapped in meconium (Ostrea et al., 1994) and hair

(El iopolous et al., 1 994) throughout the second half of pregnancy, and their measurement allows

long-term, cumulative estimates of fetal exposure.

Therefore, in addition to allowing us to determine positivity or negativity of smoking

status, measurement of cotinine allows for an estimation of the amount of cigarette smoking that

had occurred during the latter part of pregnancy. In this way, the prevalence and amount of

smoking can be compared to historical data.

Our specific hypotheses therefore were as follows. First, that in the retrospective study

an increase in either prevalence or amount o f cigarette smoking in active smokers as indicated by

17

materna1 report in the Hospital for Sick Children's patient charts for cases of infants with HIE

between 1985 and 1992 would be seen when compared to population-based historical data fiom

approximately the same time period. Second, that in a prospective study, infants with H E at the

Hospital for Sick Children would have a higher prevalence of smoking compared to the

population-based historical data of approxirnately the same time period, or that the actual

cotinine Ievels seen in active smokers would be higher than historical data fiom infants whose

mother smoked during pregnancy and who did not have HIE.

18

2 METHODS --

2.1 Reporting Bias Methodolow

The original data on smoking status were collected prospectively fiom pregnant patients

who were seen between 1988 and 1997 in clinic by a physician through The MotheRisk Program

(The Hospital For Sick Children, Toronto, Ontario, Canada) - a counseling service for women

with medicinal, chemical, illicit drug or other exposures in pregnancy. During the clinic visit,

maternal characteristics including age, gravidity, parity, and previous spontaneous or therapeutic

abortions were collected as were details of any underlying medical condition and previous

pregnancy outcornes. Detailed reports of the patient's exposures during the pregnancy were

made ascertaining the time of exposure, dose and frequency of use, where applicable. These

included the exposures that the patient had corne to ch i c for specifically, as well as other

exposures including cigarettes, alcohol and illicit drugs.

Afier collection of al1 data, the concept of a baseline nsk that exists in every pregnancy

for a woman to have a child with a major birth defect even in the absence of any teratogenic

exposure was explained to the patients. Patients were then informed of the potential risk to the

fetus (if any) of such fetal exposures by way of critical evaluation of the current medical

literature. Documentation of the counseling along with the specific literature references is then

forwarded to the physician caring for the woman and also to the patient directly if requested.

As a part of this research program, patients seen in clinic are followed up with a

telephone interview one to two years after their clinic visit to confirm exposure details and to

inquire about pregnancy outcome.

For the present study, patients were selected based on three cnteria: 1) Live birth with

completion of the follow-up interview, 2) documented delivery details, and 3) documented

details of maternal smoking bebaviour in both clinic and follow-up files. Exclusion was based

on documentation in the tiles of intentional decrease or cessation of smoking, or where details of

19

smoking were not complete for either clinic or follow-up information (e.g. 16 cigarettes per day

at c h i c vs. response of only 4'yes" at follow-up). During follow-up interviews, patients were

asked if there was an event of "Fetal Distress" during delivery and the interviewer then gave

examples summarized in Table 1. The mother's response to this question was documented and

any narrative coxnments made by the mother about the delivery were detailed. Patients were

categorized into one of two groups based on their report of "Fetal Distress" or "Uneventful

delivery".

These two groups were then compared with regards to materna1 characteristics at clinic,

number and nature of exposures (teratogenic, unknown, nonteratogenic), use of alcohol or illicit

drugs, presence of matemal illness, and incidents of fetal distress in a previous delivery.

Neonatal characteristics at follow-up including gestational age, birthweight and presence of

major malformations as well as the time between clinic visit and follow-up were also compared.

Cornparisons between the two groups were done using the Student's t-test, Mann-Whitney Rank

Sum Test or Chi-square, as appropriate.

The primary endpoint of interest was the difference in the reported daily number of

cigarettes in the first trimester between the first interview ("real time") and the second (post

partum) interview. The raw number of cigarettes smoked per day as reported at clinic, at follow-

up and the difference between the two values (follow-up value minus clinic value) were

compared between women reporting "Fetal Distress" venus "Uneventful Delivery" using the

Mann-Whitney Rank Sum Test. The numerical difference in number of cigarettes per day

reported in the second compared to the first interview was then categonzed as having increased

(positive value), remained the same (zero value), or decreased (negative value) and these were

then compared using Chi-squared.

20

2.2 Etbical Considerations Methodology

In order to determine the ethical factors involved in developing a methodology for the

"Matemal Smoking and Neonatal HIE" study, a literature review was conducted exarnining the

areas of materna1 guilt surrounding an adverse pregnancy outcome, informed consent, and the

specific requirements for conducting ethically acceptable nonconsensual research.

A MEDLINE search was conducted to locate articles relating to matemal guilt resulting

fiom an adverse pregnancy outcome using the keywords and textwords "guilt, pregnancy,

outcome, infant, newborn, mother/psychology, emotions, attitude". Relevant articles were then

selected and sumrnarized.

For the components of infonned consent and requirements for nonconsensual research,

the American Department of Health and Human Services Code of Federal Regulations for

conducting Human Research (DHHS, 1983), and the Medical Research Council of Canada's

Guidelines on Research Involving Human Subjects (MRC, 1987) were used to identiQ relevant

ethical considerations surrounding informed consent and allowable exceptions to this doctrine in

the context of nonconsensual research. Although there was a considerable body of literature on

the theoretical rationale for the doctrine of informed consent, these documents represented the

most recent statements publicly available at that time and were considered to be authoritative as

they were federat guidelines.

These elements were then articulated in a chronological account of the application to the

Hospi ta1 for Sick Children's Research Ethics Commi ttee (alternatively known as a Research

Ethics Board (REB) or Institutional Review Board (IRB)) for the "Materna1 Smoking and

Neonatal H I E study in the following order:

1) Ethical Concerns

2) Outcome of REB/IRB Review

2 1

3) Final Solution

The ethical concerns resulting fiom the literature review were stated first as a surnmary of the

ethical arguments put forth to the Research Ethics Cornmittee. Second, the outcorne of the

cornmittee's review was detailed as the committee's reaction to the proposai highlights

alternative perspectives on the ethical situation at hand. This is of course largely important as

the committee's response gives suggestions to the researcher as to how the methods should be

changed. Lastly, the final solution to the ethical problem in light of the committee's response

was documented as this illustrated the methodological changes that were made as a result, and

also presented the reaction of the investigators to the cornmittee's initial response.

22

2.3 Maternal Smoking and Neonatal Hypoxic-Ischemic Encephalopathy Methodology

2.3.1 Maternal Smoking and Neonatal Hypoxic-Ischemic Encephaiopathy:

Retrospective Studies

Retrospective analysis of HIE cases was done by reviewing the original data which

supplied information for The Hospital for Sick Children's NlCU computerized database on

outcornes of infants presenting with neonatal HIE (maintained by Dr. Max Perlman). This

database consists of al1 cases of infants with HIE seen at The Hospital for Sick Children NICU

between 1985 and 1992, including details of clinical care and conesponding outcorne. As

information on matemal exposure to cigarette snioke during pregnancy was not included in the

computerized database, the original data collection forms were retrieved and analyzed.

Al1 information relating to materna1 exposure to cigarette srnoke during pregnancy was

documented exactly as it appeared in the original records with regards to positivity (where "yes"

or "no" was indicated) and the number of cigarettes smoked per day where available. The data

were tabulated and categorized where possible in order to be compared with population based

historical matemal smoking data from the Ottawa Civic Hospital during the years 1989 and 1990

(Perkins, Belcher and Livesey, 1997), in order to infer differences in either prevalence or amount

of smoking among pregnant mothers. These particular historical data were used for three

reasons. First, the data was based on a population sample of al1 pregnant women who were seen

at the Ottawa Civic Hospital between July 1989 and May 1990. Second, the geographical area

from which the sample originated was in close proximity to the Hospital for Sick Children and in

fact these two service areas see some degree of overlap for cases of neonatal HIE. Third, this

data was collected in the middle of the time period in which the data in the Hospital for Sick

Children's NICU database was collected. This is particularly important as smoking prevalence

amongst pregnant women has been s h o w to change over time (Britton, 1998; Stewart et al.,

1995).

23

The Chi-square test was then used to test for a significant difference in the proportion of

smokers in each group, and to test for a significant difference in the distribution of the amount of

smoking in each group.

2.3.2 Maternai Smoking and Neonatal Hypoxic-Ischemic Encephalopathy:

Prospective Studies

The study group consisted of al1 term (237 weeks gestational age) infants with a

diagnosis of HIE who presented to the Hospital for Sick Children's Neonatal Intensive Care Unit

over a 9-month period between November 1998 and July 1999. Inclusion was based on a

diagnosis of HIE as determined by the guidelines set forth by the American College of

Obstetricians and Gynecologists (Poland and Freeman, 1992). In order for this diagnosis to be

made, one or more of the following must be present:

1) 5-minute Apgar score 13, metabolic acidosis (serum bicarbonate 4 2 mrnoVL in the

first hour of Iife), or delayed onset of spontaneous respirations beyond 5 minutes.

2) Mechanical ventilation at birth.

3) Evidence of encephaIopathy including clinical seizures, altered state of

consciousness, atypical neuroimaging, or electroencepalographic findings.

4) Evidence of multisystem involvement (i.e., encephalopathy and at least one other

organ system, including abnormal renal function (urine output c l ml/kg/hour for 2 24

hours after birth and a rising serum creatinine after birth), electrocardiographic

evidence of myocardial ischemia, hypotension, coagulopathy (clinical bleeding with

abnormal results of clotting studies consistent with disseminated intravascular

coagulation or hepatic coagulopathy), bone marrow depression (platelet count

400,000 per cu.mm), elevated liver transaminase leveis (AST >200 IU, ALT HO0

IV , pulmonary hypertension (a PO, difference >20 torr between pre- and postductal

24

sites, or evidence of right-to-left shunting through the ductus arteriosis or foramen

ovale on echocardiography).

Exclusion of infants fiom the study was based on the presence of either of the following

criteria:

1) A diagnosis of HIE due to an insult that occurred prior to the delivery

process (e-g., intracranial hemorrhage)

2) A gestational age (37 weeks

The severity of HIE was established by the cnteria described by Sarnat and Sarnat

(Sarnat and Sarnat, 1976) in Table 2.

Afier obtaining consent from the subjects, a one-page data sheet (see Appendix 1) was

completed where a chart analysis was done to collect the relevant obstetrical details fiom patient

records. In addition, a limited number of questions were asked to ascertain parental

socioeconomic status and to clarify any data that were missing or unclear in the charts.

Socioeconomic status was determined using the Hollingshead Four Factor Index of Social Status

(Hollingshead, 1975). Materna1 and paternal characteristics including education and

employment, and factors affecting matemal health, reproductive history, previous pregnancy

outcornes, delivery factors, abnormalities of the placenta or umbilical cord, and neonatal heaIth

were documented. An identification number was assigned for each data form in order to link

clinical data with laboratory results.

A sample of hair was taken fiom the neonate using scissors and methods described by

EIiopolous (Eliopolous et al., 1994), and a meconium sample was obtained using the methods of

Ostrea (Ostrea et al., 1994). According to these established methods, hair samples were stored at

room temperature until the time of analysis in individual envelopes with an identification

number corresponding to that of the data fom. As only one meconium sample was available, it

25

was stored at -70°C and was not analyzed. Ailet the linking of the clinical data to the biological

sample, al1 identiSing personal information for each subject was removed

Cotinine concentrations in neonatal hair were measured by radioimmunoassay (RIA)

(EliopoIous et al., 1994). Hair samples were first washed with a miId detergent, rinsed with

distilled water, and dried in a warm (37°C) oven ovemight. The following day, each neonatal

hair sarnple was cut into small segments and thoroughly mixed in order to determine the average

content of cotinine in the hair sample. Two to five milligrams of each hair sample were weighed

on an analytical balance (Mettler AE 100) and placed in a glass container with 1 rnL of 0.6 N

sodium hydroxide in order to digest the hair samples. The glass vials were sealed with parafilm

to prevent evaporation of the solutions. The samples were agitated overnight at 50°C to allow

for digestion. The following day, the samples were neutralized with 50 to 70 pL of concentrated

hydrochloric acid, and 100 pL aliquots of the neutral solutions were used to measure cotinine

concentrations by M A as originally described by Langone (Langone et al., 1973). The results

were expressed in nanogram of cotinine per milligram of neonatal hair.

The RIA materials required for determination of cotinine were purchased from the

Department of Biochemistry, Brandeis University, Massachusetts. The procedures used in this

study involved adding fixed amounts of tritiated cotinine to each sample, followed by incubation

for one hour at 37°C with the respective rabbit antiserum. A sufficient amount of antibody was

used in these assays to bind 40% to 95% of the total radioactive ligand. After allowing the

reaction to reach equihbrium, a goat anti-rabbit gamma globulin was added to each sample to

separate the antibody-bound cotinine from the free analyte. After overnight storage at 4"C, the

antibody-bound fiactions were precipitated from solution by centrifugation at 1000 x g for 45

minutes. The temperature of the centrifuge (Beckman TJ-6) was also set at 4°C.

26

The amount of radioactivity in the precipitate was expressed as the average counts per

minute (CPM) with a counting time of two minutes per sample using a Beckman LS 5000 CE

scintillation counter.

The concentration of cotinine in each sample was determined by cornparison to a

standard curve. The standard curve was prepared at the same time and in the same manner as the

samples in order to account for day-to-day variability and decay of the isotope. Standards were

prepared by diluting stock of 500 pL of cotinine in isogel TRIS HCl (trimethamine

hydrochloride) buffer. Cotinine standards of 0.25, 0.5, 1, 2, 5, 10, and 25 ng/mL were used for

quantification. The total binding of antibody by radiolabeled antigen was represented by a zero

standard which did not contain any quantity of unlabeled cotinine. In addition, an antibody

blank which did not contain the unlabeled antigen or the rabbit antiserum was used to determine

nonspecific binding (i-e. possible binding of the radiolabeled antigen to test tube contents and

components other than the antibody). The counts per minute value of the antibody blank was

then subtracted fiom al1 values obtained for standards and samples to correct for nonspecific

binding.

To produce the standard curve, the log standard concentration of cotinine was plotted on

the abscissa against the respective logit per cent radioactivity on the ordinate. This type of plot

gives a straight line rather than a curve simpliQing calculation. The line of best fit was

determined by least square regression analysis using the Stat View SE+ graphicsM statistics

software (Abacus Concepts, Inc., 1988) on an Apple Macintosh cornputer. The unknown

concentrations of analyte in the samples were extrapolated from the regression equation.

Al1 standards and samples were run in duplicate and positive and negative controls were

run with each batch of samples assayed.

27

When 2 mg of hair was used, the lowest sensitivity of the assay was 0.1 ng cotinine per

mg hair. In this assay, 3-hydroxycotinine, a metabolite of cotinine, exhibited less than 10%

cross-reactivity.

Recovery of analytes was established by adding known amounts of cotinine to a negative

hair sample afier it had been digested in solution. An aliquot of the same hair sample had been

tested prior to spiking and confirmed to be negative for cotinine. AIiquots (100 uL) of the

spiked solution were analyzed and the recovery of each analyte was calculated. A recovery

value of 92% for cotinine had been calculated in six previous experiments (Eliopolous et al.,

1994).

For the purposes of this study, a neonatal hair cotinine value 5 2.6 ng cotinine per mg of

hair was defined as indicating that the mother was a nonsmoker or a passive smoker as jn

previous work by Elipolous and her colleagues illustrated that amongst nonsmokers and passive

smokers the range of neonatal cotinine was between 0.04 ng cotininelmg hair (the limit of

detection) and 2.54 ng cotinine/mg hair (Eliopolous et al., 1996). Accordingly, any value greater

than 2.6 ng cotinine/mg hair was defined as being positive for active smoking.

After this determination of smoking status, the clinicai characteristics were summarized

both collectively disregarding smoking status and comparatively by categorizing smokers and

nonsmokers into two groups. Where appropriate, student's t-test and Fischer's exact test were

used to test for statistically significant differences between these groups.

The resulting data were then compared with population-based historical data collected in

the Ottawa-Carleton region during 1992 (Stewart et al., 1995) using the Fischer's exact test to

determine if a significant difference existed in the HIE infants with respect to the proportion of

mothers smoking during pregnancy. As with the retrospective studies, these historical data were

chosen due to their being based on a population sarnple, originating from a similar geographical

28

area and being sarnpled at a tirne as close as possible to the time when the prospective data were

being collected.

The actual cotinine levels in the hair of infants whose mothers were identified as active

smokers were then compared with previous data (Eliopolous et al., 1996) for infants who did not

suffer fiom HIE. As these previous data were not population-based, no statistical tests were

performed.

Feasibility was also assessed in several ways.

First, the ethical feasibility of this study was characterized by documenting ethical issues

that arose during the course of conducting the research in light of the guidelines set forth by the

Hospital for Sick Children's Research Ethics Cornmittee and by reevaluating the stance of the

ethics cornmittee in light of these ethical issues which presented themselves.

Second, methodological feasibility was assessed through documenting any dificulties

that arose through the use of the proposed methods and cntically appraising the methodology

and comrnenting on its suitability in light of these difficulties.

Lastly, the practical feasibility of examining the role of materna1 smoking as a risk factor

for neonatal HIE was explored through documenting and highlighting problerns that arose in

terms of geographical concems, logistical concerns such as contacting parents for consent, and

data collection concerns such as the collection of chart information and the problems in

obtaining biological samples. The rate of presentation was also detennined based on averaging

the number of cases which arriveci at the Hospital for Sick Children's NICU between November

1998 and July 1999.

29

3 RESULTS

3.1 Reporting Bias Results

In total, 132 cases were collected which met the inclusion criteria. However, in 7 cases the

patients had expressly mentioned that they had quit, and in 2 cases had mentioned that they had

been successful in decreasing their smoking. In 2 cases the data were not sufficiently quantified

to be analyzed and in one case the patient told the interviewer that she had "memory problerns".

Afier these exclusions, there were 120 eligible cases. Of these 120 women, 95 reported an

uneventful delivery and 25 reported an event which foltowed the definition of "Fetal Distress".

These women provided details of the events in narratives which are summarized in Table 3.

Materna1 charactenstics at clinic between women who had an uneventful delivery and those

who had "Fetal Distress" were not significantly different (Table 4). There were no significant

differences in matemal age, gravidity, parity, spontaneous or therapeutic abortions. The number

of exposures to agents with teratogenic or nonteratogenic effects did not differ. Use of illicit

dmgs or aicohoi during pregnancy also did not differ between the two groups. The two groups

did not significantly differ with regards to the proportion of women who had a chronic illness in

general or a psychiatrie illness in particular. Finally, there were no significant differences in the

number of women who had an event of "FetaI Distress" during a previous pregnancy.

Other than the selection critena of "Fetal Distress", pregnancy outcome characteristics at

follow-up also did not differ significantly between the two groups as shown in Table 5. There

was no difference between the two groups in the number of infants bom with major

malformations, nor were there any differences in gestational age at birth or birth weight. in

addition, there was no significant difference in the number of months that had elapsed between

clinic visit and follow-up among the two groups.

Comment No. of Occurrencesa

Emergency Caesarian Section Performed

Baby's Heart Rate Was Low 5

Cord Around Neck 4

Baby's Heart Rate Elevated 3

Induced Labor 3

Baby Admitted to NICU 2

No Additional Commentsm 2

Decreased Oxygen to Fetus 1

Presence of Meconium 1

Baby Aspirated Meconium 1

"Baby Was Blue" 1

Baby Received Oxygen 1

*-2 women did not elaborate on the circumstances of Fetal Distress a-Not mutually exclusive

Table 3 Additional Information Provided by Mothers Reporting "Fetal Distress"

Uneventful Delivery

n=95

Materna1 Age' 29.1 k4.9

Gravidityb 2 [l-71

TA^ O [O-21

No. Exposures for C h i c b 1 [l-71

( No. Exposures Teratogenicb 1 O [O-11

I No. Exposures Unknownb

No. Exposures Nonteratogenicb

1 Use of Illicit Drugs b

Use of Alcohol 37 (38.9%)

1 Maternal Illness 1 72 (75m8%) Psychiatric Illness 27 (28.4%)

1

I Prev. "Fetal Distress" l O (0%) - - --

a - Values expressed as mean + S.D. b - Values expressed as median with range I - Student's t-test 2 - Mann-Whitney Rank Sum Test 3 - Chi-squared

Table 4 Materna1 Characteristics at C h i c Visit

l Major Malformations

( Gestational Age ( ~ k ) ~ 1 40 [35-421 1 40 [3442] 1 0.502

P value Uneventful Delivery ' b6Fetal Distress" n=9S

Time to Follow-up OS)^ 1 16[7-35-51 1 20[236.5] 1 0.3 l2

n=ZS

Birth Weight (g)'

a - Values expressed as mean I S.D. b - Values expressed as median with range 1 - Student's t-test 2 - Mann-Whitney Rank Sum Test 3 - Chi-squared

Table 5 FoUow-up C haracteristics

327 1k546 3250k565 0.86'

33

Details of materna1 self-report of smoking are shown in Table 6. There was no

significant difference between the two groups in the number of cigarettes smoked per day dunng

pregnancy as reported at c h i c . There was also no significant difference @=0.32) in the

proportion of mothers who at follow-up declared themselves to be non-srnokers (decreased to

zero cigarettes). There was, however, a statistically significant difference between the two

groups in the change in reporting of cigarette consumption during pregnancy in c h i c versus at

follow-up afler pregnancy. That is, mothers who experienced Fetal Distress in their babies

reported significantly !ess smoking during pregnancy at follow-up than during their initial c h i c

visit. This difference was categonzed and compared as shown in Table 7. The two groups were

significantly different in terms of the change in the report of number of cigarettes per day at

follow-up with respect to whether it had increased, remained unchanged or decreased. These

resuits indicate that mothers who had events of fetal distress during delivery were significantly

more likely to decrease their subsequent report of smoking during pregnancy cornpared to

mothers who had uneventhl deliveries, who did not change their reports.

Uneventful Delivery n=93

No. Cig/d reported at Follow-up'

No. Cig/d reported at Clinic'

Difference in No. Cig/d reported at Follow-up vs. Clinics

10 [O-401

Values expressed as median with range Mann-Whitney Rank Sum Test

Tab Materna1 Self-Report of Smoking

Change in No. Cig/d Reported at Follow-up vs. Clinic

Uneven tful Delivery n=95

Increased

Table 7 Changes in Self-Report of Materna1 Smoking

"Fetal Distress" n=25

Same

Decreased

P value

24 (25.3%)

34 (35.8%)

37 (38.9%)

5 (20%)

3 (12%)

17 (68%)

0.02'

3.2 Ethical Consideratioos Results

3.2.1 Ethical Concerns

At the onset of developing the hypothesis, several ethical concems arose regarding the

study population. These included the potential psychological harm to parents who might infer

from the study that they were responsible for their child's condition, ambiguity regarding the

moral status of biological waste such as meconiurn, and the apparently absolute requirements of

the Research Ethics Board / Institutional Review Board (REBARB) of the Hospital for Sick

ChiIdren to obtain infonned consent.

Whereas previously it was believed that women who smoked during pregnancy were less

aware than nonsmokers of the specific risks to the fetus (Butters and Howie, 19901, from the

results of several studies it now appears that women who smoke during pregnancy are becoming

increasingly aware of at least some of the risks that this behaviour poses to the fetus (Buist and

Yu, 1987; Haslarn, Draper and Goyder, 1997; Lelong et al., 1995). In one prenatal survey study

(Buist and Yu, 1987), it was demonstrated that both smoking and non-smoking expectant

mothers during pregnancy are generally aware of the known potential risk of low birth weight as

a result of smoking during pregnancy. Additionally, in this particular study, the investigators

used open-ended questionnaires which allowed women to suggest any risks that they thought

might exist while smoking during pregnancy. Amongst their responses, although more senous

possible outcomes such as increased mortality were suggested, very few women in fact felt that

these were a possibility. Therefore, we assumed that women who smoke during pregnancy may

not envision a potential nsk for a condition such as HIE which if moderate or severe may result

in a number of severe adverse outcomes including cerebral palsy, cognitive deficits or death

(Shaywitz and Fletcher, 1993).

37

In a study examining maternai reaction to the birth of an infant who suffered fiom a long-

term disability (of genetic or perinatal cause), three types o f causal attributions have been

documented (not mutually exclusive)(Affleck et al., 1982):

The behaviour of others (e-g. obstetrician - 22%)

Materna1 behaviour (self-blame) - 26%

No behavioral causes (e.g. chance, Act of God, "fate") - 57%

Although the final category does not directly attribute the outcome to a particular person,

the author states that it may lead to self-blarne as some mothers developed the idea that

somehow they "deserved it". This category is also believed to be associated with depression and

low self-esteem both of which have been linked with smoking populations (Fidler et al., 1992;

Fergusson et al., 1996; Hurst et al., 1997). In cases where a child is born with a long-tenn

disability, mothers will undoubtedly look for some reason for this outcome; even in cases where

there was an obvious genetic cause for the outcome, mothers still felt some degree of

responsibility and had begun to examine their own behaviour in order to look for some cause.

In light of this potentially vulnerable study group, we felt that seeking consent would

represent a risk for psychological harm as exposure to the hypothesis itself might provide a

mechanism for developing self-blame. Sirnply stating that there was a possibility of a mother

being responsible for this outcome might convert ail of the smokers to the seif-blame category.

In addition, any underlying anxiety of the non-smoking mothers might be exacerbated by

thoughts of exposure to second hand smoke, which has also been shown to have an effect on the

fetus (Koren, 1996). One may argue that since our hypothesis is pure speculation, that it has no

potential for h m ; however, just the fact that the research is being undertaken may suggest to

the mother the likely validity of the hypothesis.

Given the importance of this project and the nature of the study population, we began to

consider carrying out this research without consent. As we sought to obtain a biological marker

38

of maternal smoking, we felt that using the discarded waste meconiurn (a baby's first bowel

movement) would be appropriate as it is non-invasive, can be collected unobtrusively, and is an

excellent indicator of maternal smoking status (Ostrea et al., 1994). We could then link this

information with relevant obstetrical information from a baby's chart. AAer linking, al1

identifiing characteristics would be removed maintaining anonymity for both the babies and

their parents.

As stated by the American Department of Health and Human Services (DHHS)

conditions under which research can be conducted without consent must conforrn to the

following guidelines (DHHS, 1983):

1) Procedure(s) involve minimal risk

2) No violation of nghtslwelfare of subject

3) Could not be carried out otherwise

4) When appropriate, subjects be informed after participating

(Section 46.1

As our proposed research involved no risk to the subject, condition 1

16d)

. was met. The

interpretation of the criteria set out under conditions 2 and 3, however, was not as clear. Under

condition 2, Our research could be interpreted as a violation of the subject's right to privacy. As

we would be examining the baby's waste, it could be regarded in a similar light to police

searches through garbage being considered an illegal invasion of privacy as the baby's waste

would provide insight into the prenatal activities of the baby's mother. However, the study of

biological waste products, in the past, has been seen as not requiring consent (Medical Research

Council of Canada, 1987). We would also be examining the baby's and the mother's medical

information, both from the baby's chart. Historically, conducting retrospective "chart studies"

without consent had been common practice, although this practice has been looked upon less

favorably in recent years (Emson, 1994). Although there was room for debate, we felt that as we

39

had proposed to eliminate any identiQing characteristics, thereby retaining anonymity, that

violation of privacy would be minimal and hence this would sat ise condition 2. We viewed

Condition 3 as being satisfied in that we felt that we would not be able to carry out the research

obtaining consent as it could put some mothers at risk for psychological harrn. Again, with

regards to Condition 4 we would seek to avoid causing harm to the subjects, and hence we would

likely not be informing subjects aAer participating.

Upon reviewing the cnteria set out in the DHHS, we felt that we had fulfilled al1 of the 3

essential criteria required for permission to conduct nonconsensuaI research. We subsequently

made our request to Our REBARB in the Spring of 1998 to do our research without consent,

presenting the above arguments. Because we felt that seeking consent would represent an

unjustifiable nsk to the subject, we considered a nonconsensual methodology to be the most

ethically reasonable.

3.2.2 Outcome of REB/IRB Revîew

Our request to conduct this research without consent was subsequently denied and

several suggestions were made by the REBIIRB:

First, we were required to inform parents and obtain consent for this study. At the time

of our submission, the Medical Research Council of Canada (MRC) was in the process of

releasing its "Tri-Council Policy Statement on Code of Ethical Conduct for Research Involving

Humans". In Article 1.1 the Code States that al1 research must be consensual and that subjects

must be given the opportunity to make an informed choice in accordance with the principle of

autonomy (MRC, 1998). In light of the Code, The R E B W felt that it was of utmost

importance to obtain consent in showing respect for persons. As well, in the interests of

planning fhture pregnancies the REB/IRB felt that parents should be informed of the

hypothetical link between smoking and HIE.

40

Second, we were required to present to the parents a list of potential causes of HIE and

to include smoking in that list, thereby diMusing the unconfirmed association with smoking.

Hence, the posing of the study question was to be such that it appeared that we were in fact in

search of new risk factors, or clarification of the roles of known nsk factors. The REB/IRB felt

that because our study would at best be only able to show an association between materna1

smoking and HIE that this listing of potential risk factors would be suitable. This is to Say that

our study would not be able to show that matemal smoking was a cause of HIE, but rather that it

is one of several factors which together or in combination with other unknown reasons could

potentially cause HIE. Hence, this study would not in fact be able to show that a mother had a

causative role in this outcorne.

Finally, it wos also requested that counseling be available to any mothers who were

experiencing any fonns of self-blarne and that the results of this study be provided to families

with personalized comments where appropriate. At this point, the REB/IRB assigned a member

to Our case in order to handle any further issues which did not require a full cornmittee review.

3.2.3 Final Solution

In accordance with the decision of the REB/IRB, we complied with their requests. As

hlly infonned consent would be sought, we expressed Our desire to obtain more biological

samples and to obtain detailed obstetrical information which would enhance the quality of the

study and make Our results more valid. The REB/IRB approved our request at which point we

proceeded to compose a parent information and consent form requesting permission to obtain

these samples and information. The consent form included smoking as a risk factor in a large

list of possible risk factors. This first version of Our information form was then approved by Our

REBARB.

Afier REB/IRB approval, we then proceeded to inform staff rnembers in the Neonatal

Intensive Care Unit (MCU) as to the particulars of our study. Several staff members, however,

4 1

had concems regarding the information form. They cited that physicians do everything in their

power to try and reassure parents of these babies with HIE that there is no evidence that they

were in no way at fault, and they felt that such an information form was contrary to this notion,

The physicians felt that al1 references to smoking should be removed fkom the fonn and that the

information should be presented in a more general fashion in order to convey the idea that we

were searching for new risk factors with no suggestion that we had a working hypothesis and

that this was in fact more of a "fishing expedition" than anything else. Accordingly, a second

finalized version which did not have smoking Iisted as a risk factor, but included a reference to

decreased oxygen as a risk, was submitted to the assigned member of the REBnRB and was

approved.

42

3.3 Materaal Smoking and Neooatal Hypoxîc-Ischemic Encephalopathy Results

3.3.1 Retrospective Data

A total of 300 infants with HIE presented to the Hospital for Sick Children's NICU

between 1985 and 1992. Hence during this time period, the rate of presentation of infants with

HIE to this institution was approximately 3 per month. For the purposes of the aforementioned

outcome study reported by Ekert et al. (Ekert et al. 1997), 133 infants were excluded as their HIE

was considered to be mild or where there was evidence of head trauma or a gross physical insult

unrelated to asphyxia. Hence, a total of 167 cases were reviewed and were utikw! for the

current research.

Of the 167 cases, 7 1 had documentation of smoking status. Among these 7 1 cases, 13

(18%) mothers reported smoking during pregnancy. In the research reported by Perkins et al., in

a population sample of al1 pregnant women who delivered their babies at the Ottawa Civic

Hospital between the months of July 1989 and May 1990, 734 (23%) out of 3220 identified

themselves as active smokers (Perkins et al., 1997). After comparing these proportions with the

Chi-squared test using Yates correction, it was found that the proportions of smokers in each

group were not significantly different w . 4 5 ) .

Of the 13 mothers who reported smoking in the HIE group, their reported quantity of

smoking ranged fiom 2 cigarettes per day up to 60 cigarettes per day. The distribution of this

data is s h o w along with the distribution found at the Ottawa Civic Hospital in Table 8. Chi-

square testing showed a statistically significant difference @<0.001) in the distribution of

smoking suggesting that in this limited sample, mothers of infants with HIE smoked

significantly more cigarettes per day compared to the population of pregnant mothers seen at the

Ottawa Civic Hospital.

Self-Reported

Cigarettes/Day

Ottawa Civic Hospital

1989-90

(n=734)

Hospital for Sick Children

HIE Cases 1985-92

(n=13)

a-C hi-square test

Table 8 Self-Reported Cigarette Consumption in Mothers of Infants with HIE at the

Hospital for Sick Children (1985-92) vs. All Live Births at the Ottawa Civic

Hospital (1989-90)

3.3.2 Prospective Data

3.3.2.1 Clinical Data and Hair Cotinine Analysis Results

A total of 12 term infants presented to the Hospital for Sick Children NICU with a

diagnosis of hypoxic-ischemic encephalopathy (HIE) between November 1998 and July 1999.

In total the parents of 11 cases agreed to participate and were enrolled in the study. The parents

of one infant refused to participate in the study specifically indicating that they were doing so

under legal counsel as a Lawsuit against the delivering obstetrician was being pursued.

A summary of the matemal characteristics for the 11 infants is s h o w in Table 9.

Matemal age ranged fiorn 22 to 43 years of age, with an average of age of 33. The Hollingshead

Scores for the parents of these infants were consistent with a low to mid-level socioeconomic

status (Socioeconornic status of IV or V). For 5 of the 1 1 mothers, this was their first pregnancy.

Of the remaining 6 mothers, two had at least one child, and the remaining 4 mothers had

between I and 3 spontaneous abortions in previous pregnancies. Arnongst these 1 1 mothers, 5

had ongoing medical concems during their pregnancy and 1 had a pregnancy induced medical

condition. Of these 6 cases, 4 were identified as potential causes of fetal asphyxia as per Table

1, namely, two cases of diabetes, one case of asthrna, and one case of pregnancy induced

hypertension. One woman also experienced polyhydramnios during her pregnancy.

No. of Occurrenccs @=il)

Maternal Age (yrs.)

Gravidity

Parity

Spontaneous Abortion

None

One

Three

Maternal Health Problem

Essential Diabetes

Asthma

Infertility Requinng Treatment

Hepatitis B Carrier

Abnormal Prenatal Conditions

Pregnancy-Induced Hypertension

Pol y hydramnios

a-mean value + standard deviation

b-rnedian value with range in brackets

Table 9 Materna1 Characteristics of Infants with HIE Preseoting at the Hospital for

Sick Children (Nov. 1998-July 1999)

46

Deliveiy factors for the case infants are displayed in Table 10. In 5 cases, delivery was

induced and in 6 cases assistance during delivery was required (forceps or vacuum). In 3 cases

emergency caesarian section was required due to abnormalities of fetal heart beats, and 1 case

presented as a breech birth. One case of placenta previa, one case of an umbilical ho t , 3 cases

of nuchal cord (cord wrapped around the baby's neck) and one case of cord prolapse were seen

and are identified as risks for asphyxia as per Table 1. In a11 but one case there was evidence of

fetal cardiac abnormalities during delivery. Of the 11 infants, 8 had meconium staining during

delivery and in 4 cases there was evidence of meconium aspiration.

Characteristics of the 1 1 neonates are shown in Table 1 1. These infants had an average

gestational age of approximately 39 weeks, with 4 cases greater than 40 weeks gestation. The

infants had an average birthweight of approximately 3.4 kg and there were 6 females, and 5

males. Apgar scores for these infants were low with a 1 minute average score of 1.5, and 5

minute average score of 5 . The severity of HIE in these infants was primarily moderate as one,

eight and two infants had Stage 1,2 and 3 HIE, respectively.

No. of Occurrences (n=ll)

Precipitous Delivery

Forceps Used

Rotation

Extraction

Vacuum Used

Emergency Caesarian Section

Breech Birth

Placental Factors

Previa

Cord Factors

Urnbilical Cord Knot

Nuchal Cord

Proiapsed Cord

Fetal Cardiovascular Factors

Bradycardia

Decelerations

Loss of Variability

Meconium Aspiration

Meconium Staining

Table 10 Delivery Factors of Infants with HIE Presenting nt the Hospital for Sick

Children (Nov. 1998-July 1999)

No. of Occurrences @=il)

Gestational Age (wk)

No. Postmature (>40 wk)

Gender

Male

Female

Birthweight (g)

Apgar Scores

1 Minute

5 Minute

HIE Severity

Stage 1

Stage 2

Stage 3

a-mean value + standard deviation

b-median value with range in brackets

Table 11 Neonatal Characteristics of Infants with HIE Presenting at the Hospital for

Sick Children (Nov, 1998-July 1999)

49

The results of neonatal hair cotinine analysis are summarized in Table 12 (actual cotinine

values for each case are available in Appendix 2). Eight of the 11 mothers were categorized as

nonsmokers based on their infants hair cotinine value ( a . 6 ng/mg hair), and 3 mothers were

categorized as active smokers based on their infants hair cotinine value (>2.6 ng/mg hair) as per

previous findings (Eliopolous et al., 1996).

Based on the results in Table 12, infants were then categorized by matemal smoking and

compared by category.

Materna1 characteristics of smokers and nonsmokers are shown in Table 13. There were

no statistically significant differences between the two groups including differences in matemal

age, gravidity or parity. Amongst al1 active smokers, this was the first pregnancy, and none of

these women had any underlying health problems (one woman had pregnancy-induced

hypertension).

Delivery factors of smokers and nonsmokers are summarized in Table 14. There were no

statisticaily significant differences between the two groups. Although not statistically

significant, it is noteworthy that a higher proportion of infants in the materna1 smoking group

required assistance in delivery, showed signs of fetal heart monitoring abnormalities and had

incidents of meconiurn aspiration than the infants of nonsmokers.

Number of Cases

Table 12 Smoking Status for Mothers of Infants with Neonatal HIE Presenting at the

Hospital for Sick Children (Nov. 1998-July 1999)

-

Range (ng cotinine/

mg neonatal hair)

Nonsmoker / Passive Smoker

Active Smoker

8 (73%)

3 (27%)

0.05-0.98

15.05-45.5

1 Maternal Age (yrs.)

Parity

1 Spontaneous Abortion

1 Three

Maternal Health Problem

Essential Diabetes

1 Infertility Requiring Treatment

1 Pregnancy Induced Hypertension

1 Hepatitis B Carrier

Abnormal Prenatal Conditions

a-mean value f; standard deviation b-median value with range in brackets

Non-Smoker/ f assive Smoker

(n=8)

Table 13 Materna1 Characteristics Categorized by Smoking Status in Infants with

Neonatal HIE Presenting at the Hospital for Sick Children (Nov. 1998-July

1999)

Active Smoker (n=3)

O [O-21 0 [O-O]

Non-Smokerl Passive Smoker

(n=8)

Forceps ~ s e d I

1 , Precipitous Delivery

Rotation I O (0%)

4 (50%)

Extraction I 2 (25%)

Vacuum Used O (0%)

Emergency Caesarian Section

Placental Factors I

2 (25%)

Breech Birth

Previa I 1 (12.5%)

1 (12.5%)

Cord Factors

--

Nuchal Cord I 1 (12.5%)

Umbilicai Cord h o t

Prolapsed Cord 1 (12.5%)

1 (12.5%)

Fetal Cardiovascular Factors I Bradycardia

LOSS of Variability ( 3 (37.5%)

5 (62.5%)

Decelerations 3 (37.5%)

-

' Active Smoker I (n=3)

Meconium Aspiration

Meconium Staining -- - - - - - -- - - -

Table 14 Delivery Factors of Infants with HIE Categorized by Materna1 Smoking

Status Presenting at the Hospital for Sick Childrea (Nov. 1998-July 1999)

2 (25%)

6 (75%)

53

Neonatal characteristics categorized by matemal smoking are shown in Table 15. There

were no statistically significant differences between the groups. The birthweight for infants in

the group of active srnokers was lower and almost reached statistical significance (p=0.07).

Although not statistically significant, a difference was seen in the two groups in the proportion

of infants who were born afier 40 weeks gestation as there were 4 cases (50%) in the nonsrnoker

group and none in the smoking group. Further to this, although amongst nonsmokers there was

some degree of difference in the severity of HIE, al1 infants of rnothers who smoked were of the

moderatdy severe category of HLE (Stage 2).

In this cohort, 3 of 11 (27%) mothers smoked, assumedly, throughout their pregnancy.

This proportion was found not to be statisticaIIy significant @=0.73) compared to the

population-based data fiom the Ottawa-Carleton region in 1992 where the investigators found

that amongst 7940 women, 1485 (18.7%) continued to smoke throughout pregnancy (Stewart et

al., 1995)

Amongst active smokers, cotinine values ranged fiom approximately 15 up to 45 ng/mg

hair. Based on the data reported by Eliopolous and her colleagues, this would be consistent with

a minimum leveI of 40 cigarettes or approximately 2 packs per day (Eliopolous et al., 1996). In

the previous data neonatal hair fiom 36 active smokers was measured and cotinine values above

19 ng/mg hair were not seen and hence estirnates of the nurnber of cigarette per day consumption

of the two remaining mothers could not be calculated.

Non-Smokerl Passive Smoker

(n=8)

1 Female 1 5 (62.5%) 1 1 (33.3%)

Active Smoker (II=~)

Gestational Age (wk)

No. Postmature

Gender

1 Birthweight (g) 1 3514k376" 1 30325249'

39.5k2.3"

4 (50%)

1 Stage 1 ( 1 (12.5%) I o (0%)

38.7k2.3"

O (0%)

Apgar Scores

1 Minute

5 Minute

a-mean value I standard deviation b-median value with range in brackets c-data unavailable

1.5 [l-61b

5 [l-71

I

Stage 2

Stage 3

Table 15 Neonatal Characteristics of Infants with HIE Presenting at the Hospital for

Sick Children (Nov. 1998-July 1999) Categorized by Materna1 Smoking

C -

C -

5 (62.5%)

2 (25%)

3 (100%)

O (0%)

3.3.2.2 Assessrnent of Feasibility

Ethical Feasibility

During the course of this research several ethical issues were brought to light by the

researcher and the staff of the Hospital for Sick Children's NICU. First, as docurnented in

Section 3.2.3 several staff physicians expressed concem about the idea of smoking as a potential

risk entering into the minds of the mothers of infants with HIE. There was ongoing concern

dunng the course of the research as to how this topic would be addressed if the researcher was

asked by parents about the exact nature of the research and what the working hypothesis was.

Second, as the nursing staff was closely involved in contacting parents and reminding them of

the study during the tirne when parents were reading over the consent form (which usually took

place over one to hvo days), there was concem on behalf of the nursing staff about the exact

scientific nature of the study. Third, there was ongoing concem on behalf of the researcher

about the possibility of parents persisting in questioning the nature of the research and the exact

rationaIe behind it.

Taken together, the above ethical concems posed serious concerns as to the requirements

of the ethics cornmittee as the research environment seerned to leave parents open to the

potential psychological harms illustrated in Section 3.2.1 as there was an ongoing possibility of

being exposed to the research hypothesis.

Met hodological Feasibility

The methods utilized in the research examining materna1 smoking as a risk factor for

neonatal HIE worked efficiently when elements of practical feasibility were not a concem (i.e.,

excellent methods can oniy work well when one can successfûlly contact subjects and obtain

consent). The only limitation noted was that neonata1 meconium proved difficult if not

impossible to obtain. in many instances as seen in Section 3.3.2.1, meconium was passed in

utero and hence was not obtainable. In addition, due to the severity of the asphyxia1 insult, many

56

infants had multiple organ damage which ofien resulted in the inability to pass their first bowel

movement for several days. Neonatal hair by contrat was easy to obtain and no parents

objected to the taking of the sample. As well, discarded neonatal hair was occasionally available

if an infant required a medical intervention requiring shaving of the head.

Practical Feasibility

Several practical concerns arose during the course of the research.

Geographical issues could pose a theoretical problem in that because the Hospital for

Sick Children admits infants boni throughout central and northern Ontario. Hence, if

geographically matched controls were needed, it could potentially be very difficult to obtain

them.

Logistical concerns also emerged as contacting parents proved to be difficult for at least

two reasons. First, as mothers had ofien undergone caesarian section they Frequently remained

at the refemng hospitai during recovery for a number of days while the infant was attended to at

the Hospital for Sick Children. Second, parents frequently did not have any fixed pattern of

visiting hours at the hospital and their location was otten unknown which rendered contacting

them in order to obtain consent dificult.

Data collection concems aside from the methodological concems sunounding meconium

did not occur. Patient charts were adequate for obtaining the necessary clinical information, and

determining socioeconomic status through parental report was not difficult.

A total of 12 term infants with HIE presented to the Hospital for Sick Children over the

course of 9 months between November 1998 and July 1999. This presentation rate of less than 2

per month could prove to be a serious impediment for future studies. Staff physicians felt that

this rate was considerably less than in previous years and may have been due to ongoing

cutbacks resulting in limited bed space.

5 7

4 DISCUSSION

4.1 Reporting Bias

The problem of underreporting in epidemiological research poses a threat to the validity

of a study. Our results suggest that in studies of adverse outcomes during pregnancy, mothers

tend to underreport their smoking which they may feel had in some way contributed to the event.

Because the two groups were similar in many matemal charactenstics and outcome

measures, it is highly probable that it is the adverse pregnancy outcome that led to the reporting

bias. Moreover, women who had uneventfui pregnancy outcome did not change their reported

number of cigarettes (median change=O), indicating that because of the chronic and stable nature

of smoking, there is no problem of recall per se (Feldman et al., 1989).

The major limitation in a i s study was sample size. Because of the limited sarnpfe size,

the statistical power to show a tme difference between groups was low. Gravidity and parity for

example were higher in the group of women who had uneventhl deliveries but were not

statistically different fiom the cases of women who had events of fetal distress. It is possible

that women who had uneventhl pregnancies had previous pregnancies in which they smoked

and had no adverse outcomes that they may have become more socially confident in their ability

to admit to their smoking behaviour during pregnancy. Use of alcohol is another factor that did

not reach statistical significance. Its reported value was in fact higher in women who had events

of fetal distress. If in fact there was a link between alcohol use and fetal distress, this also would

not be seen because of limited sample size.

It is noteworthy that the event of fetal distress may in fact have caused women to have a

better recall of their smoking during pregnancy. In a study looking at bottled water consumption

during pregnancy and pregnancy outcome, it was concluded that women who had spontaneous

abortions in fact had a significantly better recall of their water intake when compared to women

5 8

with normal outcomes (Neutra e t al., 1992). Hence, it is not an issue of recall per se, but rather

of recall bias.

The results of our study reinforce the need to obtain biological markers of exposures

during pregnancy as we have demonstrated that in instances of adverse outcomes, materna1 self-

report may be unreliable. However, while biological markers such as blood, urine or hair

cotinine can help distinguish smoken from nonsmokers, they may not be adequate for the

detection of changes in pregnancy consumption, as nicotine undergoes pharmacokinetic changes

during pregnancy (Seaton and Vessell, 1993). These changes can result in altered nicotine

clearance making dose estimates by extrapolation unreliable.

59

4.2 Et hical Considerations

In this unique ethical situation, there is perhaps no one answer that would satisQ al1

individuals involved. Clinical and research ethics is the process of striking a balance between

what provides appropriate protection to human subjects and what best fiirthers medical research

and patients' wellbeing. While seeking to obtain consent shows respect for the study participant

and a desire to enter into a "contract" of mutual exploration we also realize that in some

situations, as proposed by our REB/TRB, that partial disclosure, or deception, is permissible if it

is "not Iikely to be harmfbl in and of itself and that sufficient information will be disclosed to

give subjects a fair opportunity to decide whether they want to participate in the research."

(Levine, 1988)

In this situation, however, tbere are two consciences at risk. First, there is the individual

who is involved in obtaining the consent. This penon is asked to approach a potential subject

knowing that he/she is required to interact with these particularly vulnerable subjects attempting

to obtain their consent and inform them and at the same time insulate them fiom knowledge

which could potentially be harmfùl. In this context, it can be interpreted as the obtaining of an

invalid consent as we are not in fact disclosing our true purpose. These conflicting obligations

may cause moral distress in the person seeking the consent, confemng a sense of dishonesty and

deceit. Secondly, there is the subject of the research. It is generally held that within the

allowance of incomplete disclosure, "investigators should always give truthfûl answers to

questions" (Levine, 1988). This being the case, there is still a possibility within this framework

that parents could be "exposed" to our potentially damaging hypothesis by virtue of the fact that

if they demand to know exactly what we are looking for then we are obliged to be tmthfùl in our

response.

The notion of protecting the subjects fiom potential psychological h m in this instance

hinges upon the hope that subjects are in fact ignorant of or uninterested in the fact that we are

60

indeed only investigating one hypottiesis. Hence, although the final solution of the R E B m

combined with the suggestions of the NICU staff seems to be the most reasonable, it still leaves

individuals at risk for psychological h m . In this situation, it is diffiçult to see how the goal of

protecting hurnan subjects would best be achieved.

This portion of the research highlights the way in which ethical considerations shape

study methodology at the onset of the research initially during the proposa1 stage, in the

secondary phase of the response to the concerns of the research ethics comrnittee and through to

the point of the final phase at the point of initiating the research.

4.3 Materna1 Smoking and Neonatal Hypoxic-Ischemic EncephaIopathy

4.3.1 Retrospective Data

The retrospective data in this research suggest that women who had infants with HIE

smoked significantly more cigarettes per day when compared to a population based historical

control within the sarne time period. This suggests that a dose-response relationship may be

occumng such that high levels of maternal smoking are associated with an increased risk for

infants developing neonatal HIE dunng delivery. This strengthens the overall hypothesis

governing the present research. The overall difference in prevalence of smoking between the

hvo groups, however, was not statistically significant. If in fact this is sbown to be true in a

larger sample size, it suggests that maternai smoking in general may not be a risk for neonatal

HIE, but that a certain threshold exists in dosage after which point there is an increased risk for

this condition.

This component of the research had three main limitations. First, the small sample size

of infants with known materna1 smoking status provided low statistical power and hence if a true

difference existed between groups, this could not have been seen. Second, out of 167 cases, only

71 (43%) had documentation of smoking status. As smoking was not considered in the

retrospective study conducted by Ekert and his colleagues on infant outcome (Ekert et al., 1997),

the availability of data on smoking was sporadic. Because of this fact, it is impossible to know if

the data used for the retrospective study of maternal smoking as a risk factor for HIE are tmly

representative of that infant population. If for example the question was not asked because

parents seemed particularly distraught, and the reason for this psychological state was partially

due to guilt because of smoking during pregnancy, this would introduce a severe bias in the

results. Third, as this research relied on maternal report and did not utilize a biological marker,

it is subject to al1 of the shortcomings illustrated by the current research into reporting bias due

to an adverse pregnancy outcome. Although the results suggest that a higher amount of smoking

62

was occwring, it is possible that an even higher amount was actually taking place and this fact

would be lost due to underreporting.

During the time when the retrospective data were originally collected, there was a higher

rate of infants presenting to the Hospital for Sick Children's NICU than there is currently

(approximately 3 per month between 1985 and 1992 versus less than 2 per month in 1998/99).

At this time, the hospital saw a wider range of HIE cases than is seen currently. For example,

during those years it was quite cornmon for an infant with Stage 1 or mild HIE to be referred to

the Hospital for Sick Children. In recent years, mild cases of HIE are rarely adrnitted as these

infants can often be cared for adequately at the refen-ing hospital. The effect of this selective

presentation of more severe cases of HIE to the hospital in recent years is that cases with more

severe etiologies will arrive at the hospital. Accordingly, cases where there is an obvious,

physically traumatic cause of HIE make up the majority of cases seen in the Hospital for Sick

Children's NICU. As a result, the more subtle cases where there is no obvious cause are lost to

the Hospital for Sick Children as they remain at the referring hospital. This makes previous data

that much more robust, but has senous implications for the qualityhreadth of data that can be

collected fkom the Hospital for Sick Children's NICU.

4.3.2 Prospective Data

The results of this prospective component of the research further support the

retrospective data and serve to reinforce the working hypothesis. Through the prospective

research, it was determined that three women were active smokers dunng their pregnancy.

Arnongst these women, cotinine values ranged from approximately 15 up to 45 ng/mg hair.

Based on the data reported by Eliopolous and her colleagues, this would be consistent with a

minimum level of 40 cigarettes or approximately 2 packs per day (Eliopolous et al., 1996). In

fact, these three cases represent a level of smoking that was only seen in the top 1% of the data

based on the Ottawa Civic Hospital population (Perkins et al., 1997). This high level supports

63

the hypothesis that a nsk for developing neonatal HIE is associated with an elevated level of

maternal smoking.

The clinical findings in this prospective research also veri@ the likelihood of a high level

of smoking. The birthweight of the three infants bom to women who smoked actively dunng

pregnancy was lower than that of infants bom to nonsmokers and almost reached statistical

significance (p=0.07), although there was no difference in gestational age. This finding of

decreased birthweight has been s h o w in numerous stcdies to be associated with maternal

smoking (MacDorrnan et al., 1997; Golding, 1997; Oyen et al., 1997; Koren, 1995).

The prospective component of the research did show a significant difference in

proportion of smokers amongst mothers of infants with HIE when compared to historical data

from the Ottawa-Carleton region (Stewart et al., 1995). This result was not surprising given the

sample size; however, this finding brings to light an interesting finding in the study. During the

study period, a total of 12 eligible infants with HIE were seen at the Hospital for Sick Children.

Eleven of these cases were enrolled into the study; however, there was one refusa1 on the

grounds that they had been instructed by their lawyer not to participate. If in fact the parents in

this case refùsed participation because the mother had actively smoked during her pregnancy,

which could potentially weaken a legal case alleging negligence on behalf of the attending

obstetrician, this would be a source of a powerful bias. During the course of the study, the

parents of two infants who had enrolled in the study had asked the researcher confidentially

about what was required for an investigation of obstetrician cornpetence for the purposes of a

potential lawsuit. Given that this occurs, there is a concem that this potential knowledge of

smoking behaviour through a methodology that is not completely anonymous may be a serious

disincentive for parents to participate in future studies.

The results of the prospective research also suggest some interesting roles for maternal

smoking in the etiology of HIE. In the cornparison of delivery factors between nonsmokers and

64

smokers, it was noted, that although not significantly different, a higher proportion of women,

who actively smoked during pregnancy, required assistance during delivery and showed more

abnormalities of fetal heart monitoring. If there was an underlying problem of decreased

oxygenation of the feus at the start of the delivery due to smoking, then this could in

combination with other factors which although may restrict oxygen supply or blood flow but are

normally not suffrcient to cause a severe degree of hypoxia, could potentially result in fetal heart

rate abnormalities due to hypoxia (Perlman and Kirpalani, 1992; Hill, 1979). These events

usually prompt the obstetrician to move for a prompt extraction of the fetus which necessitates

the use of assistance such as forceps and vacuum. In two of three cases of active smokers, these

events unfolded, albeit without the knowledge of the potential role of smoking in the etiology of'

HIE. If this supposition about smoking is true, this may establish smoking as a risk factor in that

it potentiates the risk of other events which normally would prove innocuous.

However, the role of smoking may be more serious than this. In one case of neonatal

HIE in this cohort, there were no obvious risk factors identified. This young woman had no

underlying health problems, and no history of reproductive problems. By definition, the infant

was a tenn infant and was normal in every regard other than the diagnosis of HIE. However, this

particular infant showed al1 of the documented signs of fetal heart rate abnormalities consistent

with fetal hypoxia. In addition, this infant gave the highest level of hair cotinine at

approximately 45 ng/mg hair. If we were to assume a linear relationship in the arnount of

smoking and the amount present in neonatal hair, it is possible that this woman was smoking 4

packs of cigarettes per day, or was in an environment which together with her own smoking

resulted in that level of exposure. In this particular case, it is possible that there was an as yet

undocumented risk factor at work in the etiology of HIE. It is of greater concern that because of

this level of smoking, the oxygen supply was so greatly reduced to the fetus that it was not able

to endure the process of an otherwise normal delivery.

65

The main limitation to this component of the research, as with other components, was

sample size. Possibly due to this small sample, no difference in smoking prevalence was seen.

In addition, it was not possible to effectively compare clinical factors between smokers and

nonsmokers because of the limited numbers.

One of the strengths of this research is that a bioIogica1 marker was used to determine

smoking status and an estimation of the actual level of smoking that occurred. This method

allowed the research to minimize the problems inherent in relying on maternal report of smoking

which was demonstrated in the current research, and is a potential limitation in the retrospective

study of maternal smoking as a nsk for neonatal HIE.

In addition to seeking to strengthen the working hypothesis of the research, this purpose

of this study was to determine the feasibility of doing research into the role of matemal smoking

in neonatal HIE at the Hospital for Sick Children. While conducting the research, several

concems arose considering the ethical feasibility of investigating this problem using the

proposed rnethods. The primary concem is the problem of potential psychological damage due

to a vulnerable subject being exposed to the research hypothesis. This is a novel concept in

bioethics as the need to seek an informed consent has become paramount and there has been no

prior consideration in the literature as to the risks of seeking consent in such a context as this

one.

Two problems remain regarding the ethical feasibility of this study. First, there is an

ongoing concem that due to either persistent questioning on behalf of parents, or lack of

discretion on behalf of staff or the individual obtaining consent, or for other reasons, that there is

still a potentiaI for vulnerable subjects to be exposed to the research hypothesis and therefore the

possibility of psychological damage still exists. As was illustrated in Section 4.2, this is an

exceedingly dificuit situation as it has become imperative to obtain an infonned consent (MRC,

1998). As a non-invasive, anonymous nonconsensual methodology was not considered to be

66

ethically acceptable, in subsequent designs it may be necessary to h e the research question as

a more generalized research problem which does not make the "background" hypothesis of

smoking as a risk factor known to anyone other than the pnmary investigîtor and others

performing data analysis. In this way, not even the individual obtaining consent would be aware

as to what the tnie objective was and hence the potential for psychological damage could

theoretically be reduced to a minimum. Yet by the same token, this practice is inherently

dishonest and poses a serious problem in that the "background" hypothesis is of great

importance to explore and drives the need to conduct the study. The second problem that

became evident is the question of the ethical status of the investigator or the individual obtaining

consent if they know the hypothesis. If ethics seeks to provide a solution where no one comrnits

a wrongfùl act, then it will likely be impossible to attain this goal given the current methodology

and circumstance. This affects feasibility in that if there is to be another person obtaining

consent, for example an investigator at a different site in a multicentre study, then if this person

is to be made aware of the "background" hypothesis they must be willing to engage in the same

deceptive behaviow as the primary investigator. It is quite possible that other persons, and their

institutions, will not be willing to do this.

The methodology utifized in this research proved to be efficient. Data collection using

the developed fonn (Appendix 1) was straightforward and required a minimum arnount of time

to complete once consent was obtained. A physician who was fmiliar with a particular case

could likely complete the clinical details in 5 minutes. Determination of socioeconomic status

was easily done with the Hollingshead index (Hollingshead, 1975). Using this index, marital

status, and the highest levels of education and employment are al1 that need be obtained from

each parent. As mentioned in Section 3.3.2.1, meconium was difficult to obtain for a number of

reasons. In planning future studies, due to the diffculties noted and also the problems in storing

and shipping the matenal it should not be included as a biological sample, but rather neonatal

67

hair should exclusively be used. Ln addition to being a sensitive and specific biological marker,

neonatal hair is conveniently obtained, easily stored in an envelope at room temperature and is

easily shipped.

The practical issues of geographic distribution, logistics, and presentation rate have

important implications for future research. In a subsequent study design, the methodology

shouId seek to address the issue of matching index cases with geographically similar controls.

This present research at first sought to enroll infants fiom the Hospital for Sick Children's NICU

as controls which would address this problem. This, however, proved to be difiicult as the

majority of infants without HIE were premature andor often had severe congenital defects

which would have made approaching parents for consent extraordinarily difficult. In light of

this, future studies will need to address this concem. Logistical problems arose due to

difficulties in contacting parents. This could be addressed by a different methodology that

utilized hospitals where the NICU is located on site with the rnatemity ward. In this way,

parents would be physically accessible to researchers much more easily. Finally, there is a large

concem regarding presentation rate. Between November 1998 and July 1999, a total of 12

eligible infants with HIE were seen at the Hospital for Sick Children. This resulted in a rate of

presentation of less than 2 per month, which was lower than what would have been predicted by

previous data. In order for further studies to be conducted expediently, other centres will need to

be included in order to collect data at an appropriate speed.

68

4.4 Surnmary of Findings

This research addresses the larger question of how to conduct research examining the

role of materna1 smoking in adverse pregnancy outcornes, both fiom a methodological and

ethical standpoint.

The results from the first part of this research highlight the fact that maternal report of

smoking dwing pregnancy may be unreliable, particularly in the context of an adverse

pregnancy outcome. It was demonstrated that in situations of fetal distress during detivery,

mothers may reduce their report of smoking that occuned during pregnancy. This bias can

severely affect the results of a study seeking to delineate the role of matemal smoking in this

outcome. Our study has hvo major advantages over previous attempts to characterize this

reporting bias: This was a prospectiveiy collected cohort, and at the time of the initial interview,

women were very open about their smoking habits as they were eager to receive accurate

estimates of their risk. Secondly, we could assess not just smoking status, but also changes in

the number of reported cigarettes.

From these results, it was inferred that maternal report will not be adequate to address the

study question. This prompted a consideration of the use of a biological marker such as cotinine

trapped in neonatal meconium. The question then becarne that of how to obtain this marker,

which led to the questions of informed consent, institutional policy, and the prospect of doing

noninvasive, nonconsensual research. This was proposed in order to avoid psychological h a m

to the research subject that could result from the indirect accusation that her behaviour played a

role in the adverse outcome of her infant.

In the process of submitting the proposa1 for this research to the Hospital for Sick

Children's research ethics cornmittee, it was required that a partially informed consent be

obtained and that the study proceed seeking to obtain neonatal meconium and neonatal hair.

From the course of arguments put forth to support Our initial hypothesis and in light of the ethics

69

comrnittee's decision, it was demonstrated that indeed there were indeed possible risks to the

subject in the form of induced maternal guilt by the nature of the research hypothesis. It was

also illustrated that this potential risk exists in the study methodology proposed by the ethics

cornmittee.

The pilot research into the role of maternal smoking and neonatal HIE provided data,

both retrospectively and prospectively, that support Our hypothesis that maternal smoking may

confer an increased risk for the development of neonatal HIE during delivery. Although having

several limitations, the retrospective data suggest that a significantly higher amount of smoking

had occurred amongst mothers of infants with HIE compared to a general population of women

who had also smoked during pregnancy. Prospectively, there was also an initial signal that this

supposition may indeed be true as evidenced by very high levels of neonatal hair cotinine

amongst mothers who smoked and had infants with HIE.

In addition, this pilot research also highlighted several issues of feasibility in the research

on materna1 smoking and neonatal HIE.

Regarding methodology and study design, frorn a purely technical perspective it was

suggested that a study collecting clinical data and neonatal hair samples would be relatively easy

and effective. Appropriate controls would need to be obtained and issues of contacting parents

quickly to consent needs to be addressed, perhaps in centres where the NICU and maternity

wards are located close to each other. When the presentation rate at the Hospital for Sick

Children is considered, it would be imperative for this study to adopt a multicentre design to

collect data at an appropriate speed.

When we examine the ethical considerations involved in this potential multicentre design

however, two issues come to bear. First, although there currently exists a form of insulative

deception in the obtaining of a partially informed consent in the study, this still leaves a

possibility of subjects learning of the Eue hypothesis and hence the potential for psychological

70

damage remains. Second, the requirement of the site investigator to be involved in some degree

of deception may dissuade potential site investigators, or their institutions fiom collaborating in

this study. Because of these concerns, the presentation of the study may have to be done in such

a way as to keep site investigators uninformed so as to avoid any accidental leaks of the

hypothesis that could potentially cause damage. It may in fact be necessary to address the study

as a "fishing expedition" as the ethics cornmittee had suggested.

From these results, it has been demonstrated that there are numerous methodological and

ethical issues in the study of maternal smoking and adverse pregnancy outcomes. This research

shows not only that these aspects are substantial, but that they interact in the research process.

Methodology has an impact on ethics in that methods may potentially be subject to ethical

scmtiny. This issue is well known to researchers, yet in this unique context the method of

obtaining an informed consent itself poses an ethical concern not from the principle of

autonomy, but rather fiom that of "doing no ham". This results in the formation of ethical

judgments regarding the methodology, and hence the methodology is shaped by the ethics in

order to meets its demands. In the study of maternal smoking and adverse pregnancy outcomes,

this delicate interplay between methodology and ethics is of great importance.

7 1

4.5 Recommendations for Future Studies

Areas of need for hture investigation are extensions of the related areas of study

presented in this thesis.

Further studies in the area of underreporting should be undertaken in order to determine

if there is some predictive value that can be elucidated. If one cari determine a consistent pattern

of underreporting or detenninants leading to underreporting, this would be important

information in an attempt to improve the understanding of the matemal fetal toxicology of

tobacco smoke or other addictive substances.

Bioethics is a rapidly expanding field, yet the topic of adverse pregnancy outcomes and

the surrounding ethical questions of investigating matemal behaviour as a risk factor in these

outcomes has been poorly studied. Future research into the specific topic of materna1 guilt

resolution in light of scientific evidence and hypotheses should be explored. Knowledge on the

nature of how mothers weigh scientific evidence or hypotheses in their development of self-

blame would allow better formulation of methods and consent forms that would be sensitive to

these issues. Although perhaps dificult to realize, criticisms of the institutional policies used in

determining ethical solutions should be undertaken. In Canada, the Medical Research Council

now requires informed consent as a blanket policy (MRC, 1998). Perhaps this policy should be

reviewed in order to allow exceptions that represent minor infkingements such as those

exceptions delineated in the United States (Levine, 1988).

It has been suggested that a multicentre study will be necessary in order to more clearly

establish the role of materna1 smoking in neonatal HIE. This is clearly a future research

direction as a larger sample size is most certainly required.

If matemal smoking proves to be associated with HIE, a full scale study will need to be

designed based on these results to adâress the following questions:

1) Dose-response characteristics: How much fetal exposure is associated with how

much risk? Also, is there a correlation between materna1 smoking and the clinical

severity of the encephalopathy?

2) Confounders: Large sample sizes will be needed to control for potential confounders.

3) The relative validity of different biological markers (e.g. where hair and meconium

are readily obtainable).

HIE is a devastating pennatal complication, ofien leading to serious lifelong morbidity. If an

association exists between HIE and smoking, this may be one of very few etiologies of HIE

which can be prevented.

Finally, studies examining the interplay between methodology and ethics should be

undertaken. If it is possible to delineate underlying principles that existed in the modification of

proposed methodologies because of ethical considerations, perhaps it would be possible to

incorporate those principles into the methodology earlier, such that it might enable the

production of more ethically sound protocols. It is hoped that this research would serve not only

to expedite the study development and review process, but also to raise the awareness of

researchers to the ethical requirements involved in research design.

73

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6 APPENDICES

Appendix 1

HIE STUDY fORY MatemaUPaternal Characteristics and SES MATERNAL AG€ G e - SA - TA - GESTATIONAL AGE wks MARITAL STATUS- MOTHER'S: EDUCATION

OCCUPATION FATHER'S: EDUCATION

OCCUPATION COMMENTSIOTHER Matemal Disease ANXIETY P HYPOTENSION O PIH O ESS HTN P GESTDIABETES P An/ DECREASE O AFV INCREASE O SEV M D TRIM APH P THYROXINE TREAT O COMMENTSfOTHER Maternal CV Factors HY POXlA P CARDIACCOND O PULMONARYCOND O COMMENTSIOTHER Reproductive History INFERTlLlTY RX O PREV STILLBIRTHS Q NEONATAL DEATHS O COMMENTSIOTHER Previous Neonatal Mortality SEIZURES O INTRACRANIAL HEMORRHAGE P FRACTURED SKULL O HIE O SlBLlNG HEALTH PROBLEMS O COMMENTSIOTHER Maternal Infections RUBELLA O CMV 0 HERPES O GBS O COMMENTSIOTHER Delivery Factors HOME BIRTH O ABN UTERINECONT O PROM Q C-SECTION P HEADTRAUMA Q PRECP. DELIV Q UTERlNERUPTURE O VACUUM O If yes, RURAL? P If yes, CAST SB O BREECH O BLOOD LOSS Ci

FORCEPS (Rotation) O FORCEPS (Extraction) O IUGR SYM Q IUGR ASYM P SGA O CEPHALOHEMATOMA P COMMENTSIOTHER Placental Factors ANTPLACENTA P PL PRNlA O ABRUPTION O PLANOMALY Q COMMENTS/OTHER Cord Factors UMBlLlCAL KNOT P PROLAPSED CORD O NUCHAL CORD O

If yes, SGA Q CORD HEMATOMA O COMMENTS/OTHER Neonatal Characteristics s u - BIRTH WEIGHT g / kg / lb APGARs 1 min 5 min CO TWlN SIB P MECASP P MEC STAlN O PPHN O COMMENTS/OTHER Fetal CV Factors FETAL BRADY O DECELS O LOSS OF VARlABlLlTY O COMMENTSIOTHER Neonatal Infections NEC O PNEUMONIA O MENlNGlTlS O COMMENTSIOTHER SequenceIAdditional Comment8

Actual Hair Cotinine Values from Neonates with HIE (The Hospital for Sick Children November 1998 - July 1999)

Sample Cotinine (nglmg hair)

Appendix 3

Proposed Non-Consensual Research to Avoid Potential Iatrogenic Parental Guilt: An Example in Hypoxic-ischemic Encephalopathy (HIE)

Matthew Wong, BSc, Christine Hamson, PhD, Aideen Moore, MD, Gideon Koren, MD

The Division of Clinical Pharmacology/Toxicology (MW,GK), The Department of Bioethics (CH), The Division of Neonatology (AM) and The MotheRisk Program (GK), The Hospital for Sick Children, Toronto. The Faculty of Pharmacy (MW,GK), The Department of Pharrnacology (GK), The Faculty of Medicine (AM,GK), The Institute of Medical Science (CH,GK), The University of Toronto Joint Centre for Bioethics (CH), The Department of Pediatrics (CH,AM,GK), and the CIBC Wood Gundy Children's Miracle Foundation Chair in Child Health Research (GK), University of Toronto.

Dr. Aideen Moore was the Chair of the Hospital for Sick Children's Research Ethics Cornmittee during the time of subrnitting the proposa1 described in the text.

Supported in part by the Medical Research Council of Canada, and the Seed Grant Program, The Hospital for Sick Children.

Address for Correspondence:

Gideon Koren, MD, ABMT, FRCPC The Division of Clinical Pharmacology and Toxicology The Hospital for Sick Children 555 University Ave. Toronto, ON M5G 1 X8 Canada Tek (416) 813-578 1 Fax: (416) 8 13-7562

Abstract

The loss of a baby during childbirth is a devastating event associated with

feelings of extreme grief, disappointment, helplessness, and seIf-blame. Perhaps even

more tragic and emotionally complex is an event during childbirth that may result in the

child having a life-long disability. One such outcome occurs in babies who develop a

perinatal condition known as hypoxic-ischemic encephalopathy or HIE. In HIE, the

oxygen supply to the fetus is decreased during delivery resulting in temporary or

permanent brain damage. Although many obstetrical risk factors have been identified, a

Iarge number of cases present no obvious cause. Our research is to investigate the

hypothesis that maternal smoking is a risk factor for HIE.

In light of this psychologically vulnerable study group, we sought to do an

anonymous study using discarded meconiurn (a baby's first bowel movernent) as an

indicator of maternal smoking status. As smoking has not been established in this role,

we felt that it would be unethical to suggest to a mother of a baby with this serious

condition that she might be in some way responsible for this tragedy. However, given

the importance of this project, we consequently requested that our REBARB allow us to

cany out this research without consent as it would be anonymous and completely non-

invasive. Our request was subsequently denied and we were required to inform parents

of the study. This article documents the ethical framework which prompted our request,

an account of the REBARB response, and the final solution to this dilemma.

Background

The loss of a baby dun ng childbirth is a devastating event associated with

feelings of extreme grief, disappointment, helplessness, and self-blarne. Perhaps even

more tragic and emotionally complex is an event during childbirth that may result in the

child having a life-long disability. One such outcome can occur in babies who develop a

pennatal condition known as Hypoxic-Ischemic Encephalopathy (HIE). In this

condition, the oxygen supply to the fetus is decreased during delivery potentially

resulting in significant brain damage. The etiology of this condition is not fully

understood, and although many obstetncal risk factors have been identified, a Iarge

proportion of these cases present no obvious cause (1). Because of the potential for a

baseline decrease in oxygenation and vascular changes that can occur during smoking

(2,3), Our group wished to investigate the hypothesis that materna1 smoking is a risk

factor for HIE, using a combination of matemal obstetncal history and biological

markers of smoking.

Ethical Concerns

At the onset of developing our hypothesis, several ethical concerns arose

regarding our study population. These included the potential psychological harm to

parents who might infer from the study that they were responsible for their child's

condition, ambiguity regarding the moral status of biological waste such as meconium,

and the apparently absolute requirements of Our Research Ethics Board / institutional

Review Board (REBARB) to obtain informed consent.

Whereas previously it was believed that women who smoked during pregnancy

were less aware than nonsmokers of the specific risks to the fetus (4), from the results of

several studies it now appears that women who smoke during pregnancy are becoming

increasingly aware of at least some of the risks that this behaviow poses to the fetus (5-

7). In one prenatal s w e y study (9, it was demcjnstrated that both smoking and non-

smoking expectant mothers during pregnancy are generally aware of the known potential

risk of low birth weight as a result of smoking during pregnancy. Additionally, in this

particular study, the investigators used open-ended questionnaires which allowed women

to suggest any risks that they thought rnight exist while smoking during pregnancy.

Amongst their responses, although more serious possible outcomes such as increased

mortality were suggested, very few women in fact felt that tbese were a possibility.

Therefore, we assumed that women who smoke dunng pregnancy may not envision a

potential risk for a condition such as HIE which if moderate or severe may result in a

number of severe adverse outcomes including cerebral palsy, cognitive deficits or death

In a study examining materna1 reaction to the birth of an infant who suffered fiom

a long- tenn disabiiity (of genetic or perinatal cause), three types of causal attributions

have been documented (not mutually exclusive)(9):

The behaviour of others (e.g. obstetrician - 22%) Matemal behaviour (self-blarne) - 26% No behavioral causes (e.g. chance, Act of God, "fate") - 57%

AIthough the final category does not directly attribute the outcorne to a particular person,

the author states that it may lead to self-blame as some mothers developed the idea that

somehow they "deserved it". This category is also believed to be associated with

depression and low self-esteem both of which have been associated with smoking

populations (10-12). In cases where a child is boni with a long-tenn disability, mothers

will undoubtedly look for some reason for tbis outcome; even in cases where there was

an obvious genetic cause for the outcome, mothers still felt some degree of responsibility

and had begun to examine their own behaviour in order to look for some cause.

In light of this potentially vulnerable study group, we felt that seeking consent

would represent a nsk for psychological h m as exposure to the hypothesis itself rnight

provide a mechanism for developing self-blame. Simply stating that there was a

possibility of a mother being responsible for this outcorne might convert al1 of the

smokers to the self-blame category. In addition, any underlying anxiety of the non-

smoking mothers might be exacerbated by thoiights of exposure to second hand smoke,

which has also been shown to have an effect on the fetus (13). One may argue that since

Our hypothesis is purely speculation that it has no potential for h m , however just the

fact that the research is being undertaken may suggest to the mother the likely validity of

the hypothesis.

Given the importance of this project and the nature of the study population, we

began to consider carrying out this research without consent. As we sought to obtain a

biological marker of materna1 smoking, we felt that using the discarded waste meconium

(a baby's first bowel movement) would be appropriate as it is non-invasive, can be

coIlected unobtrusively, and is an excellent indicator of matemal smoking status (14).

We could then link this information with relevant obstetrical information from a baby's

chart. After linking, al1 identiQing characteristics would be removed maintaining

anonyrnity for both the babies and their parents.

As stated in the American Department of Health and Human Services (DHHS),

conditions under which research can be conducted without consent must conform to the

following guidelines (1 5):

1) Procedure(s) involve minimal risk 2) No violation of rightdwelfare of subject 3) Could not be carried out otherwise 4) When appropriate, subjects be informed afier participating

DHHS, Section 46.1 16d

As our proposed research involved no risk to the subject, condition I was met. The

interpretation of the criteria set out under conditions 2 and 3 however was not as clear.

Under condition 2, our research could be interpreted as a violation of the subject's right

to privacy. As we would be examining the baby's waste, it could be regarded in a similar

light to police searches through garbage being considered an illegal invasion of privacy

as the baby's waste would provide insight into the prenatal activities of the baby's

mother. However, the study of biological waste products, in the past, has been seen as

not requiring consent (16). We would also be examining the baby's and the mother's

medical information, both fiom the baby's chart. Historically, conducting retrospective

"chart studies" without consent had been common practice, although this practice has

been looked upon less favorably in recent years (17). Although there was room for

debate, we felt that as we had proposed to eliminate any identifying characteristics

thereby retaining anonymity, that violation of privacy would be minimal and hence this

would satisfi condition 2. We viewed Condition 3 as being satisfied in that we felt that

we wouId not be able to carry out the research obtaining consent as it could put some

mothers at risk for psychological harm. Again, with regards tu Condition 4 we would

seek to avoid causing h m to the subjects, and hence we would likely not be informing

subjects after participating.

Upon reviewing the criteria set out in the DHHS, we felt that we had fùlfilled al1

of the 3 essential critena required for permission to conduct nonconsensual research. We

subsequently made our request to our REB/IRB in the Spring of 1998 to do Our research

without consent, presenting the above arguments. Because we felt that seeking consent

would represent an unjustifiable risk to the subject, we considered a nonconsensual

methodology to be the most ethically reasonable.

Outcome of REBflRB Review

Our request to conduct this research without consent was subsequently denied and

several suggestions were made by the R E B W :

First, we were required to inform parents and obtain consent for this study. At the

time of our submission, the Medical Research Council of Canada (MRC) was in the

process of releasing its "Tri-Council Policy Statement on Code of Ethical Conduct for

Research Involving Humans". In Article 1.1 the Code states that al1 research rnust be

consensual and that subjects rnust be given the opportunity to make an informed choice

in accordance with the principle of autonomy (18). In Iight of the Code, The REB/IRB

felt that it was of utrnost importance to obtain consent in showing respect for persons. As

weI1, in the interests of planning future pregnancies the REBARB felt that parents should

be informed of the hypothetical link between smoking and HIE.

Second, we were required to present to the parents a list of potential causes of

HIE and to include smoking in that list, thereby diffising the yet unconfinned

association with smoking. Hence, the posing of the study question was to be such that it

appeared that we were in fact in search of new risk factors, or clarification of the roles of

h o w n nsk factors. The REB/IRB felt that because our study would at best be only able

to show an association between materna1 smoking and HIE that this listing of potential

risk factors would be suitable. This is to Say that Our study would not be able to show

that matemal smoking was a cause of HIE, but rather that it is one of several factors

which together or in combination with other unknown reasons could potentially cause

HIE. Hence, this study would not in fact be able to show that a mother had a causative

role in this outcorne.

Finally, it was also requested that counseling be available to any mothers who

were experiencing any forms of self-blame and that the results of this study be provided

to families with personalized comrnents where appropriate.

At this point, the REB/IRB assigned a member to our case in order to handle any

fiirther issues which did not require a full cornmittee review.

Final Solution

In accordance with the decision of the REBARB, we complied with their requests.

As fully informed consent would be sought, we expressed Our desire to obtain more

biological samples and to obtain detailed obstetricai information which would enhance

the quality of the study and make our results more valid. The REB/IRB approved Our

request at which point we proceeded to compuse a parent information and consent form

requesting permission to obtain these samples and information. The consent form

included smoking as a risk factor in a large list of possible risk factors. This first version

of our information f o m was then approved by our REBflRB.

After REB/IRB approval, we then proceeded to inform staff members in the

Neonatal Intensive Care Unit (NICU) as to the particulars of Our study. Several staff

members however had concerns regarding the information fonn. They cited that

physicians do everything in their power to try and reassure parents of these babies with

HIE that there is no evidence that they were in no way at fault, and they felt that such an

information form was contrary to this notion. The physicians felt that al1 references to

smoking should be rernoved fiom the form and that the information should be presented

in a more general fashion in order to convey the idea that we were searching for new risk

factors with no suggestion that we had a working hypothesis and that this was in fact

more of a "fishing expedition" than anything else. Accordingly, a second finalized

version which did not have smoking listed as a risk factor, but included a reference to

decreased oxygen as a risk, was submitted to the assigned member of the REB/IRB and

was approved.

Discussion

In this unique ethical situation, there is perhaps no one answer that would satisQ

ail individuals involved. Clinical and research ethics is the process of stnking a balance

between what provides appropriate protection to human subjects and what best furthers

medical research. While seeking to obtain consent shows respect for the study

participant and a desire to enter into a "contract" of mutual exploration we also realize

that in some situations, as proposed by Our REBARB, that partial disclosure, or

deception, is permissible if it is "not likely to be harmful in and of itself and that

sufficient information will be disclosed to give subjects a fair opportunity to decide

whether they want to participate in the research." (19)

In this situation however, there are two consciences at risk. First, there is the

individual who is involved in obtaining the consent. This person is asked to approach a

potential subject knowing that he/she is required to interact with these particularly

vulnerable subjects attempting to obbin their consent and inform them and at the same

tirne insulate them from knowiedge which could potentially be harrnful. In this context,

it can be interpreted as the obtaining of an invalid consent as we are not in fact disclosing

Our tnie purpose. These conflicting obligations may cause moral distress in the person

seeking the consent, confemng a sense of dishonesty and deceit. Secondly, there is the

subject of the researcb. It is generally held that within the allowance of incomplete

disclosure, "investigators should always give tnithful answers to questions" (19). This

being the case, there is still a possibility within this fiamework that parents could be

"exposed" to our potentially damaging hypothesis by virtue of the fact that if they

demand to know exactly what we are looking for then we are obliged to be tmthfûl in Our

response.

The notion of protecting the subjects from potential psychological harm in this

instance hinges upon the hope that subjects are in fact ignorant of or uninterested in the

fact that we are indeed only investigating one hypothesis. Hence, although the final

solution of the REB/IRB combined with the suggestions of the NICU staff seems to be

the most reasonable, it still leaves individuals at risk for psychologicaI ham. In this

situation, it is diffkult to see how the protection of human subjects, would best be served.

References

Hill A, Volpe JJ. Perinatal asphyxia: clinical aspects. Clinics in Perinatology. l6(2):435-57, 1989. Cnattingius S, Nordstrôm M-L. Materna1 smoking and feto-infant mortality: Biological pathways and public health significance. Acta Paediatrica 8S(lS): 1400-2, 1996 Dec. Gupta 1, Hillier VF. Edwards JM. Multiple vascular profiles in the umbilical cord; an indication of materna1 smoking habits and intrautenne distress. Placenta. 14(1): 1 17-23, 1993 Jan-Feb. Butters L, Howie CA. Awareness arnong pregnant women of the effect on the fetus of commonly used drugs. Midwifery. 6(3): 146-54, 1990. Buist A, Yu D. Smoking and pregnancy: awareness, attitudes and habit changes. Fiealth Bu1 letin. 45(4): 1 79-84, 1987. Haslam C, Draper ES, Goyder E. The pregnant smoker: a preliminary investigation of the social and psychological influences. Journal of Public Health Medicine. I9(2): 1 87-92, 1997. Lelong N, et al. Attitudes and behavior of pregnant women and health professionals towards alcohol and tobacco consurnption. Patient Education & Counseling. 25(1):39-49, 1995. Shaywitz BA, Fletcher JM. Neurological, cognitive, and behavioral sequelae of hypoxic-ischemic encephalopathy. Seminars in Perinatology. 17(5)357-66, 1993. Affïeck G, Allen D, McGrade BJ, McQueeney M. Matemal causal attributions at hospital discharge of high-risk infants. Amencan Journal of Mental Deficiency. 86(6):575-80, 1982. Fidler W, Michel1 L, Raab G, Charlton A. Smoking: a special need? British Journal of Addiction. 87(11): 1583-9 1, 1992. Fergusson DM, Lynskey MT, Horwood LJ. Comorbidity between depressive disorders and nicotine dependence in a cohort of 16-year-olds. Archives of General Psychiatry. 53(11): 1043-7, 1996. Hurst DF, Boswell DL, Boogaard SE, Watson MW. The relationship of self- esteem to the health-related behaviors of the patients of a primary care clinic. Archives of Family Medicine. 6( 1):67-70, 1997. Koren G. The fetus as a passive smoker. Canadian Family Physician. 42: 1301- 3, 1996. Ostrea EM Jr, et al. Meconium analysis to assess fetal exposure to nicotine by active and passive matemal smoking. Journal of Pediatrics. l24(3):47 1-6, 1994. Department of Health and Human Services. Title 45 Code of Federal Regdations 46. Mach 8, 1983. Medical Research Council of Canada: Guidelines on research involving human subjects. MRC, Ottawa, 1987. Emson HE. Minimal breaches of confidentiality in health care research: a Canadian perspective. Journal of Medical Ethics. 20(3): 165-8, 1994.

18. Medical Research Council of Canada (MRC). Tri-Council Policy Statement Document: Code of Ethical Conduct for Research Involving Humans. Ottawa, 1998.

19. Levine, W. Ethics and Regulation of Clinical Research. Yale University Press, New Haven, 1988.

Appendix 4

Title:

Bias in Maternal Reports Of Smoking During Pregnancy Associated With Fetal Distress

Running Title:

Bias in Maternal Reports of Smoking

Matthew Wong, BSc, Gideon Koren, MD

The Faculty of Pharmacy, University of Toronto (MW,GK) and The Division of Clinical Phannacology/Toxicology, The Hospital for Sick Children, Toronto (MW,GK), The MotheRisk Program and The Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, Toronto, The Departments of Pediatrics, Pharmacology, and Medicine, University of Toronto and the CIBC Wood Gundy Children's Miracle Foundation Chair in Child Health Research, University of Toronto (GK).

Supported in part by the Medical Research Council of Canada, and the Seed Grant Program, The Hospital for Sick Children.

Address for Correspondence and Reprints:

Gideon Koren, MD, FACMT, FRCPC The Division of Clinical Pharrnacology and Toxicology The Hospital for Sick Children 555 University Ave. Toronto, ON M5G 1x8 Canada Tel: (416)813-5781 Fax: (4 16) 8 13-7562

Abstract

BACKGROUND: Studies examining the adverse effects of smoking during pregnancy

comrnonly use matemal reports. We hypothesized that if an adverse event occured during

pregnancy, women rnay underreport smoking. This study looked for bias in matemal report of

smoking if fetal distress occurs.

METHODS: Data was collected prospectively fkom patients attending The MotheRisk Program

who smoked during pregnancy. Categorized by delivery outcome, matemal and neonatal

charactenstics, and the raw number of cigarettes smoked per day during pregnancy reported at

cIinic, at follow-up, and the difference between the two values were compared.

RESULTS: 95 wornen had uneventfiil deliveries and 25 had fetd distress. Women who

reported fetal distress decreased their report of smoking after delivery compared to their original

report during pregnancy, whereas wornen with an uneventhl labour did not @=0.04).

CONCLUSIONS: Our results suggest that if an adverse pregnancy outcome occurs, mothers

rnay tend to underreport their cigarette consumption.

Keywords: Bias (Epidemiology). Fetal distress. Pregnancy. Pregnancy outcome. Prospective

studies. Smoking.

Introduction

Studies exarnining the potential adverse effects on the fetus of certain maternal exposures

such as smoking during pregnancy cornmonly rely on matemal self-reports. In the event of a

negative result, researchers will often cite underreporting as a potential source of bias.(l) The

problem of underreporting of cigarette smoking during pregnancy c m have a profound effect on

the results of such studies. The magnitude of this problem c m be appreciated when one

compares maternal reports to a biological marker. Three studies comparing biochernical markers

of smoking, such as s e m or wine cotinine levels, with maternal report of smoking found that

between 5 and 15 percent of women who identified themselves as nonsrnokers in fact had

cotinine levels that were consistent with active smoking.(2-4) However, biological markers are

not always feasible for a number of reasons including reluctance of patients to give consent,

which in of itself can introduce a severe bias, and particularly in the case of retrospective studies

where one has only a patient record to examine. Moreover, the existing studies (24) , while

identifying a reporting bias of smoking dichotomously (i.e. yes or no smoking), were not

designed to address a bias in the amount of cigarettes reported.

At least two reasons for underreporting have been suggested. Firstly, because of the

dirninishing social acceptance of smoking during pregnancy, expectant mothers may provide

false reports of their smoking which they believe will be more acceptable to the researcher and

to the public at large.(5) Secondly, in the instance of an adverse event during the pregnancy or

delivery, it is possible that women may underreport a behaviour which in their own minds may

have been associated with these adverse events. This however has never previously been

demonstrated empirically.

It is well accepted that smoking during pregnancy puts the fetus at increased health risks.

Studies have clearly illustrated the risk for decreased birthweight and an increased incidence of

perinatal rnortality and delivery complications.(6,7) These risks are often explained to %orner?

who smoke during their pregnancy by health prokssionals, and these women are often cited as

being aware of these risks pnor to receiving counseling for smoking cessation.(g)

The objective of the present study was to investigate whether there is bias in maternal

reporting of the amount of cigarette consumption if fetal distress is diagnosed. Fetal distress is

described as a cluster of clinical situations, including oxygen deprivation (e-g. presence of

meconium, low Apgar score), heart rate abnorrnality or biochemical disturbances (e.g. fetal

acidemia).(9-11) Fetal distress presented at birth, often requires medical interventions,

admission to a neonatal intensive care unit and these infants may suffer long term sequelae.(l2)

Although fetal distress is lacking an accurate clinical definition, most mothers are aware of it and

report it.

Methods

The original data on smoking status were collected prospectively fkom pregnant patients

who were seen between 1988 and 1997 in clinic by a physician through The MotheRisk Program

(The Hospital For Sick Children, Toronto, Ontario, Canada) - a counseling service for women

with medicinal, chemical, illicit h g or other exposures in pregnancy. Dunng the clinic visit,

maternal characteristics including age, gravidity, parity, and previous spontaneous or therapeutic

abortions were collected as were details of any underlying medical condition and previous

pregnancy outcornes. Detailed reports of the patient's exposures during the pregnancy were

made ascertaining the time of exposure, dose and frequency of use, where applicable. These

included the exposures that the patient had corne to clinic for specifically, as well as other

exposwes including cigarettes, alcohol and illicit dmgs.

After collection of al1 data, patients were explained the concept of a baseline risk that

exists in every pregnancy for a woman to have a child with a major birth defect even in the

absence of any teratogenic exposure. Patients were then infomed of the potential risk (if any) of

their exposures to the fetus by way of critical evaluation of the current medical literature.

Documentation of the counseling along with the specific literature references is then forwarded

to the physician caring for the woman and also to the patient directly if requested.

As a part of our research program, patients seen in c h i c are followed up with a

telephone interview one to two years afier their clinic visit to confirm exposure details and to

inquire about pregnancy outcorne.

For the present study, patients were selected based on three criteria: 1) Live birth with

completion of the follow-up interview, 2) docurnented delivery details, and 3) documented

details of materna1 smoking behaviour in both c h i c and follow-up files. Exclusion was based

on documentation in the files of intentional decrease or cessation of smoking, or where details of

smoking were not complete for either clinic or follow-up information (e.g. 16 cigarettes per day

at c h i c vs. response of only "yes" at follow-up). During follow-up interviews, patients were

asked if there was an event of "Fetal Distress" during delivery and the interviewer then gave

examples surnrnarized in Table 1. The mother's response to this question was docurnented and

any narrative comrnents made by the mother about the delivery were detailed. Patients were

categorized into one of two groups based on their report of "Fetal Distress" or "Uneventful

de 1 ivery".

These two groups were then compared with regards to materna1 characteristics at chic ,

number and nature of exposures (teratogenic, unknown, nonteratogenic), use of alcohol or illicit

dmgs, presence of matemal illness, and incidents of fetal distress in a previous delivery.

Neonatal charactenstics at follow-up including gestational age, birthweight and presence of

major malformations as well as the time between clinic visit and follow-up were also compared.

Cornparisons between the two groups were done using the Student's t-test, Mann-Whitney Rank

Sum Test or Chi-square as appropriate.

The primary endpoint of interest was the difference in the reported daily number of

cigarettes in the first trimester between the first interview ("real time") versus the second (post

partum) interview. The raw number of cigarettes smoked per day as reported at clinic, at follow-

up and the difference between the two values (follow-up value minus clinic value) were

compared between women reporting "Fetal Distress" versus "Uneventfiil Delivery" using the

Mann-Whitney Rank Sum Test. The numerical difference in number of cigarettes per day

reported in the second versus the first interviews was then categorized as having increased

(positive value), rernained the same (zero value), or decreased (negative value) and these were

then compared using Chi-squared.

Results

In total, 132 cases were collected which met the inclusion criteria. However, in 7 cases

the patients had expressly mentioned that they had quit, and in 2 cases had mentioned that they

had been successfiil in decreasing their smoking. In 2 cases the data were not sufficiently

quantified to be analyzed and in one case the patient told the interviewer that she had "memory

problems". Afier these exclusions, there were 120 eligible cases. Of these 120 women, 95

reported an uneventhl delivery and 25 reported an event which followed the definition of "Fetal

Distress". These women provided details of the events in narratives which are summarized in

Table 1.

Matemal charactenstics at c h i c between women who had an uneventfùl delivery and

those who had "FetaI Distress" were not significantly different (Table 2). There were no

significant differences in matemal age, gravidity, parity, spontaneous or therapeutic abortions.

The number of exposures to agents with teratogenic or nonteratogenic effects did not differ. Use

of illicit drugs or alcohol during pregnancy also did not differ between the two groups. The two

groups did not significantly differ with regards to the proportion of women who had a chronic

ilIness in general or a psychiatric illness in particular. Finally, there were no significant

differences in the nurnber of women who had an event of "Fetal Distress" during a previous

pregnancy.

Other than the selection criteria of "Fetal Distress", pregnancy outcome characteristics at

follow-up also did not differ significantly between the two groups as shown in Table 3. There

was no difference between the two groups in the number of infants bom with major

malformations, nor were there any differences in gestational age at birth, or birth weight. In

addition, there was no significant difference in the number of months that had elapsed between

clinic visit and follow-up among the two groups.

Details of materna1 self-report of smoking are shown in Table 4. There was no

significant difference in the number of cigarettes smoked per day during pregnancy as reported

at c h i c between the two groups. There was also no significant difference (p4.32) in the

proportion of mothers who at follow-up declared themselves to be non-srnokers (decreased to

zero cigarettes). There was however a statistically significant difference between the two groups

in the change in reporting of cigarette consumption dunng pregnancy in clinic versus at follow-

up after pregnancy. That is, mothers who experienced Fetal Disîress in their babies reported

significantly less smoking during pregnancy at follow-up han during their initial clinic visit.

This difference was categorized and compared as shown in Table 5. The two groups were

significantly different in ternis of the change in the report of number of cigarettes per day at

follow-up with respect to whether it had increased, remained unchanged or decreased. These

results indicate that mothers who had events of fetal distress during delivery were significantly

more likely to decrease their subsequent report of smoking during pregnancy compared to

mothers who had uneventful deliveries, who did not change their reports.

Discussion

The probIem of underreporting in epidemiological research poses a threat to the validity

of a study. Our results suggest that in studies of adverse outcomes during pregnancy, mothers

tend to underreport their smoking which they rnay feel had in some way contributed to the event.

Because the two groups were similar in a large number of materna1 characteristics and

outcome measures, it is highly probable that it is the adverse pregnancy outcome that led to the

reporting bias. Moreover, women who had uneventhl pregnancy outcome did not change their

reported number of cigarettes (median change*), indicating that because of the chronic and

stable nature of smoking, there is no problem of recall per se.( f 3)

Moreover, it is noteworthy that the event of fetal distress may in fact have caused women

to have a better recall of their smoking during pregnancy. In a study looking at bottled water

consumption during pregnancy and pregnancy outcome, it was concluded that wornen who had

spontaneous abortions in fact had a significantly better recall of their water intake when

compared to women with normal outcomes.(l4) Hence, it is not an issue of recall per se, but

rather of recall bias.

The results of our study reinforce the need to obtain biological marken of exposures

during pregnancy as we have demonstrated that in instances of adverse outcomes, matemal self-

report may be unreliable. However, while biological markers such as blood, urine or hair

cotinine can help distinguish smokers from nonsmokers, they may not be adequate for the

detection of changes in pregnancy consurnption, as nicotine undergoes phamacokinetic changes

during pregnancy.( 1 5)

Our study has two major advantages over previous attempts to charactenze this reporting

bias: This was a prospectively collected cohort, and at the time of the initial interview, women

were very open about their smoking habits as they were eager to receive accurate estimates of

their nsk. Secondly, we could assess not just smoking status, but also changes in the number of

reported cigarettes.

Further studies in the area of underreporting should be undertaken in order to determine

if there is some predictive value that can be elucidated. If one can determine a consistent pattern

of underreporting or determinants leading to underreporting, this would be important

information in an attempt to improve the understanding of the materna1 fetal toxicology of

tobacco smoke.

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14. Neutra RR, et al. Potential sources of bias and confounding in environmental

epidemiologic studies of pregnancy outcornes. Epidemioiogy l992;3(2): 1 34-42.

15. Seaton MJ, Vesell ES. Variables affecting nicotine metabolism. Pharmacology &

Therupeutics 1993;60(3):46 1-500.

Additional Information Provided by Mothers Reporting "Fetal Distress"

Comment No. of Occurrences'

Emergency Caesarian Section Perfonned

Baby's Heart Rate Was Low Cord Around Neck Baby's Heart Rate Elevated Induced Labor Baby Adrnitted to MCU No Additional ~ornments. Decreased Oxygen to Fetus Presence of Meconium Baby Aspirated Meconium "Baby Was Blue" Baby Received Oxygen

*-2 women did not elaborate on the circumstances of Fetal Distress a-Not rnutuaIly exclusive

Table 1

Maternal Characteristics at Clinic

Materna1 Age' Gravidityb Parity b

SAb TA^ No. Exposures for Clinicb No. Exposures Teratogeoicb No. Exposures Unknownb

a - Values expressed as mean I S.D.

No. Exposures Nonteratogenicb Use of Illicit Drugs Use of Alcohol Materna1 IUness Psyc hiatric Iiiness Prev. "Fetal Distressn

b - Values expressed as median with range

P value

0.09' O. 16' O. 12' 0.82' 0.852 0.6 1 *

Uneventful Deliver y

n=95 29.lk4.9

&Fetal Distress" n=25

3 1 .Ok4.9 1 :1-61 O ;O-51 O :O-2:

1 - Student's t-test 2 - Mann-Whitney Rank S m Test 3 - Chi-squared

2 1 O O 1

O 2

O

1 10-71 1 1 (1 1.6%) 37 (38.9%) 72 (75.8%) 27 (28.4%) O (0%)

Table 2

r1-71 :O41 10-6: :0-2: il-71

10-2:. :1-8:

O [O-II O [O-21

10- 11 0.9g2 0.65' O :O-31

1 [O-81 3 (12%) 14 (56%) 18 (72%) 6 (24%) 1 (4%)

0.8 1' 0.773 O. 1g3 0.903 0.8S3 0.473

Foiiow-up Characteristics

a - Values expressed as mean + S.D.

Major Malformations Gestational Age ( ~ k ) ~ Birth Weight (g)' Time to Follow-up (rnoslb

b - Values expressed as median with range 1 - Student's t-test 2 - Mann-Whitney Rank Sum Test 3 - Chi-squared

Table 3

P value

0.863 0.50' 0.86' 0.3 l2

Uneventful Delivery n=95

3 (3.2%) 40 l35-421 327 1+546 16 17-35.51

&Fetal Distress" n=25

O (0%) 40 t34-421 325W565 20 12-36.51

Materna1 Self-Report of Smoking

1 ( Uneventful Delivery

1 Clinic' 1 No. Cig/d reported at

n=93 1 O [O401

Wetal Distress" 1 P value 1

No. Cig/d reported at ~ollow-upb Difference in No. Cig/d reported at FoUow-up vs. Clinic'

10 [O-401

O [-24-+30]

b - Values expressed as median with range 2 - Mann-Whitney Rank Sum Test

Table 4

Changes in Self-Report of Materna1 Smoking

Table 5

Change in No. Cig/d Reported at Follow-up vs. Clinic Increased Same Decreased

Uneventful Delivery n=95

24 (?5.3%) 34 (35.8%) 37 (38.9%)

"Fetal Distress" n=25

5 (20%) . 3 (12%) 17 (68%)

P value

0.02'

--

0 Pdornaki G, a aï. R i s k - b d prenatai screcnll\g for tnsomy 18 using alpha-fetoprokin, unconjugated oatnol and human duorionic gonadotropin. R a u t Diagn 1995;15:7ï3-23.

0 Philiips O, et al. h4aterml saum sanning for ktal Down syndrome in women l a s than 35 yeus of age using aipha fetoprotein, hCG and unconjugated estnol: a prospective 2-year study. Obstet Gynecol 1992;80334.

0 Piggott M, et al. hphentation of an antexutai unmi screning progrunme for Down's syndrome in two districts (Brighton and Eastboume). J Med Screcn 1994;1:4549- Spencer K, et al. Free-&hCG as first-trimester marker for fetal trisomy. Lancet 19!32~1W.

O StapIes AJ, et al. A mitenul serum scriéen for trisomy 18: an extension of matenul senun saeaiing for Down syndrome. Am J Hum Genet 1991,49102133.

0 Tafas T, et al. An automated image anaiysis method for the measurement of neutrophil alkaline phosphatase in the prenatal saeening of Down syndrome. Fetal Diagn 'Iher 1%1129-259. Van Lith J, et al. First-trimester mateml semm immunoreactive inhibin in dvomosomally mm1 and abnorrml prpgruncies. Obstet Cynecol 1994;83:661a64.

0 Wald NJ, et al. Mateml secum scmming for Down's syndrome in earl y pregnancy. Br4 1988,297S83-887.

0 Wald NJ, George L, Smith D, Densem JW, Petterson K. Semm screening for Down syndrome between 8 and 14 weeks of pregnancy. Br J Obstet Gynaecol1996;11)3:407-412.

0 Wald NJ, Kennard A: Prenatal biodiemial xreening for Down's syndrome and neuat tube defects. Curr Opin Obstet Gynecol 1992,4:302-307. Wald Nj, Kennard A, Densem JW, CuckJe HS, Chard T, Butler L Antenatal maternal senun m g for Down's syndrome: resuits of a demonstration pmpct. BMJ 1992,3û5391-394. Watt H, Wald N, Huttly W. The pattern of materna1 senun inhibin-A concentrations in the second trimester of pregnancy. Prenat Diagn 1998;18â46-848. Yankowitz J, Fulton A, W i n R, Grant S, Budelier W. Prospective waluation of prenatal matemal serum screening for trisorny 18. Am J Obstet CynecoL1998;1fs:44645û.

Dr. Rosalinde Snijders

ABSTRACTS FROM THE TORONTO FETAL CENTRE

Prospective Non-Invasive Monitoring Of Pngnancies Complicated By Red Cell Alloimmunüation. iskaros J, Kin dom J, Morrison J, Rodeck C. Ultrnsound O%SM Gynecol lW?;ll:62-7

Our objective was to evaluate the impact of non-invasive assessrnent of fetal anemia and anti-D antibody quantification on the timing and frequency of invasive procedures in pregnanaes complicated by rhesus alloimrnuniza tion

Ninetwn consecutive non-hydropic pregnanaes referred to the fetal mediane center were assigneci a pnor risk category (none/mild, moderate, or severe) and monitored by: (1) serial fetal measurernents of umbilical vein maximal flow velocity (UVV-), liver length and spleen perimeter measurernents; and (2) serial anti-D antibody concentration.

Invasive tests for fetal anernia (amniocentesis or fetal blood sampling) were deferred in the absene of abnormal ultrasound findings and/or rishg antibody levels. In six

@FETAL CENTRE NEWSlEïER cases, serial non-invasive tests were normal with stable antibody levels, and no invasive tests were performed; four infurts were mildly affected, one was unaffeded and one required pastnatai exchange transfusion.

in the remaining 13 affecteci cases, amniocentesis was performed in 9 cases for: elwated UVV- alone (n=3), elevated UVV- and an increased antibody lwel (n=2), or normd UVV- with an increased antibody lwel(>15 IU /mL) and severe prior risk ca tegory (n=4). Six fetuses undemrent fetal blood sampüng (initial hematocrit 9 to 2%), and five of these had an elevated UVV-. Liver length and spleen perimeter meammmmrS were increased in only one anemic khrs (hematocrit 13%). Of 17 infants bom alive, an elwated W- prior to delivery was predictive of the need for exchange transfusion (six of seven cases with an elwated UVV- versus one of ten with a normal UW-- chi- square=5.73, pd.017 with Yates' correction).

These preliminary data suggest that pregnanaes with a mild or no history of fetal anemia may be monitored by a combination of serial antibody quantification and Doppler m o n i t o ~ g of UVV-.

John Kingdom, M B Dept. of Obstetncs & Gynaecology, Mount Sinai Hospital

Pnrrrited at the Canadian Bioethics Society Meetin& Oct. ï9!M

Proposcd Non-Consensual Research to Avoid Potential Iatrogtnic Parental Guilt: An Example in Hypoxic- ischemic Encephalopathy (HIE) Badcground: The loss of a baby d u ~ g childbirth is a dwastating event associated with feelings of extreme grief, disappointment, helpfessness, and self-blame. Perhaps wen more tragic and emotionaliy cornplex is an event during childbirth that may tesult in the child having a lifdong disability. One such outcome occurs in babies who develop a perinatal condition known as hypoxic-ischemic encephalopathy or HIE In HIE, the oxygen supply to the fetus is decreased during delivery resulting in temporary or permanent brain damage. Although many obstetncal rkk factors have been identifieci, approximately 40% of cases present no obvious cause. Because of the baseline decrease in oxygenation and vascular changes that occur during smoking, our group wishes to investigate the hypothesis that maternai smoking is a risk hctor for HIE.

Expectant mothers who smoke are generally aware of at least =me of the risis of smoking during pregnancy induding dmeased birth weight, increased chance of mixamage, and inaeased chance of stillbirth. In addition, some cigarette wamïngs indude statements indicating some potentîaî for other wents. One example is "May cause fetal harm". It is assumeci that these women may not envision a potential N k for a condition such as HIE which if moderate or severe may result in a number of outcornes including cerebral palsy, cognitive defiab or death. In a study exarnining maternal reaction to the birth of an infant who suffered h m a long- terrn disability (of genetic or perinatal cause), üuee types of causal attributions have been documented that were not mutually exclusive (AffIeck 1984):

The behaviour of others (includes obstetrician - 22G%) Materna1 behaviour (self-blame) - 26% No behavioral causes (chance, Act of God, "fate") - 57%

Page 5

Although the hirul a- does not d i d y attriôute the outcome to a particuiar persan, the author states that it may lead to self-blame as some mothers developed the idea tht somehow they "deserveci it'. This category is alsa believed to be associated with depression and low self-esteern both of which have been associatd with smoking populations. In light of this psychologidy vulnerable study p u p , we felt that seeking consent would represent a potential risk for psychologicai hm. Simply stating that there was a possibility of a mother k i n g responsible for this outcome might convert al1 of the smokers to the self-blame category. In addition, any underlying paranoia of the non-smoking mothers might be exacerbateci by thoughts of any exposure to second hand smoke. We therefore sought to do an anonymous study using discardeci meconium (a baby's first bowel rnovement) as an indicator of materna1 smoking status. Given the importance of this project and in light of this fragile population, we consequently requested that ouf Research Ethi- b a r d REB) / Interna1 Rwiew Board (IRE) allow us to carry out this research without consent as it would be anonymous and cornpletely non-invasive.

Our request was subsequently denied and we were required to fully inform parents and obtain consent in this study. ï h e ethics cornmittee felt that in the interests of planning future

0 FETAL CENTRE N E W S L ~ R ' orrnnuries ~ u e n t s should be inforniod of the h l e link &een smdcing uid HIE. In addition, because'mokikïng carmot be pmed h m this study to cause HIE (only a risk factor) Uiey felt that it would not represent an ethical fraud to indude -mlcing as a possible risk factor in a study deigned to examine HIE risk factors in g e n d thereby diffusing the accusation of smoking. It was also requested that counseling be available to any mothem who were experiencing any foms of self-blarne and that the results of this study be provided to families with personalùed comments where appropriate.

in accordance with the decision of the ethics cornmittee, we decidd to comply with th& reqwsts- As fuiiy informeci consent would be sought, the REB/IRB agreed with our desire to obtain complete obstetrical details of these patients and additional biological samples to improve the quality of the study.

Matthew Won& BSc, gduatc studmt, U of T Cideon Koren, MD, Director, Dept. Pharmacology, HSC

Christine Harrison, PhD, Director, Dept. Biocthics, HSC

O CASE MANAGEMENT in THE TORONTO FETAL CENTRE

Antenatal Dirgnorh Of Uhl'r Anomily

Uhl's anomaly of the heart is a rare congenital cardiac malformation characterized by aplasia or hypoplasia of the myocardium of the right ventride, such that the free wall of the right ventride is paper thin. The pathogenesis is undear, but could be explaineci on the basis of 'apoptosis'(cell death) in a developing human heart (1). We report a case of Uhl's anornaly identifid at 24wks gestation.

A 3û-year old primi gravida healthy caucasian woman was re fend at 24 weeks of gestation given the finding of an enlarged fetal heart on a level II obstetrical ultrasound. She had an wiremarkable early pregnancy. The general fetal ultrasound revealed a single fetus with severe hydrops (ascites and pleural effusion). A biparietal diameter consistent with 24-25 weeks of gestation ïhe placenta was normal and the amniotic fluid volume was adequate. There was massive cardiac enlargement such that the heart nearly fUed both the right and leH chest. The right atrium and ventride were severely dilated and Ebstein's anornaly of the tricuspid valve was suspected. There was no obvious extra-cardiac abnorrnality. A genetic amniocentesis was performed that showed a normal 46XY.

Segmental approach to cardiovascular system revealed: A regular heart rate of approximately 140bpm with an atrial rhythm, lwocardia (apex pointing to the left), s ihs solitus, A-V and V-A concordance, marked cardiomegaly with the heart occupying an estimated 90% of the thoaac cavity (Figure l), severely dilated right atrium and nght ventride with normal position of the tricuspid valve but with an extremely thin right ventricular free wall/myocardium, and moderate tricuspid inmffiaency. The right ventricular function was severely depresseci. The right ventricular outflow tract and pulmonary arteries were difficult to visualize. ïhere was compression of the left atrium and ventride which appeared to have nonnal morphology, and there was a normal aortic outflow tract with antegrade flow. Both urnbilical vein and artery flows were normal.

At 28 weeks there was spontaneous intrauterine demise. Autopsy was dedineci. To our knowledge, this is the third reported antenatal diagnosis of Uhl's anornaly (2-3).

The differential diagnosis of Uhl's anornaly indudes anomalies of the tricuspid valve: Ebstein's anomaly, unguarded N orifice, and TV dysplasia. In Ebstein's anomaly the W is abnormal in position with displacement of the leafleb(septa1 and postenor)into the right ventricular sinus and atrialization of the proximal right ventricular chamber. However, in unguarded N, there is no identifiable tricuspid leaflet tissue visualized at the tricuspid valve annulus along the ventricular septum or posterior free wall. Rudimentary leaflets rnay be seen within the RV cavity at poshnortem. In N dysplasia, the N leaflets are thick and hequentiy redundant or hypoplastic and usually fail to coapt properly such that there is significant tricuspid regurgi ta tion.

The prognosis for fetuses diagnosed with any of t h e lesions, particularly with significant tricuspid regurgitation or RV dysfunction is very poor, with as much as a 48% antenatal mortality (due to congestive heart failure/hydrops or dysrhythmias) and 38% mortality in the neonatal period (due to heart hilure, dysrhythmias or lung hypoplasia) based on one

The 10th CBS Conference: Reflections on a Decade of Bioethics/

Le 10e Colloque annuel de la SCB: Réflexions sur une décennie de bioéthique

October 15th to 18th. 1998 Delto Chelsea Inn, Toronto, Ontario/

1 5 - 18 octobre 1 998 Hôtel Delta Chelsea, Toronto, Ontario

Conference hosted by the University of Toronto Joint Centre for Bioethics/ Organisé pa le Centre conjoint de bioéthique de runivenité de Toronto

3 - 1225 1 Austen 5 - 1 145 1 Duchesse

115 111

' McLeod, Carolyn W. 1 16 Octobcr

Moore, Aideen M. , Munden, L. Martina . Nathoo, AbNoor . Nisker, Jeff

, McNally. Mary 1 6 October Morgan, Kathryn Pauly Morin, Benoit

3 - 1545 5 - 1225 3 - 1625 3 - 1 105 3 - 1 105 5 - 1630 3 - 1545 1 - 1505 i - 1505 .a 1 - t 145 1- 1625

-

16 Octobcr 17 October 17 October 16 October

1 7 October 1151 16 October i l 1 5

- - Rossetti James Duchesse Windsor i

Duchesse I

Windsor Newton James Rossetti Churchill Courryud James J ~ C S

4

155 1 03 1 03 150

Robinson. D.

151 143

, Page, Staccy A f 17 October

, Rosenberg, Zahava R. S.

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Rock, Melanie 17 October 1110- 1145 Duchesse 1

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1030 - 1 105

16 October 17 October 16 October 17 October 16 October

17 Octoôer 1 143

Newton

Russell, M.L. 1030- 1100

16 Octobcr 16 ûctober 16 October 17 October

-- --

Windsor Duchesse

Trevor-Deutsch, Burleigh 1 17 October ( 1 150 - 1225

16 0ct0ber 16 October 16 O c t o k

16 October ' ChurchiliBallfoom

1510- 1545 .

1 550 - 1 625 Poster 1550 - 1625 Poster 1 churchill Courtyard .

, Weijcr, Charles

Pos 11 1 155

Duchesse ,

Churchill Ballroom Churchill Cowtyud ,

Austen

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Poster 1430 - 1505 1030 - 1 105 1510-1545

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Duchesse Austen Rossetti

16 October

17 October 16 October

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1430 - 1 SOS 16 October 16 October 17 October 1 7 October 16 Octobcr

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Windsor

Poster Churchill Courtyard . Poster 1 550 - 1625 11 50 - 1225 1 1 50 - 1225

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