PREGNANCY OUTCOME FOLLOWING FIRST TRIMESTER MATERNAL EXPOSURE TO THE NEWER

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Nathalie A. Kulin

A thesis submitted in conformitv with the requirements

for the degree of Master of Science

Graduate Department of Pharmacology

University of Toronto

O Copyright by Nathalie A. Kulin 1997

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PREGNANCY OUTCOME FOLLOWING FIRST TRIMESTER MATERNAL EXPOSURE TO THE NEWER SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Master of Science, 2997

Nathalie A. Kulin Department of Pharmacology, University of Toronto

The main objective of this study was to determine if first trimester use of the newer

selective serotonin reuptake inhibitors (SSRIs), fluvoxamine, paroxetine and/or

sertraline increases the baseline risk of having a child with a major malformation.

The secondary outcornes of interest were pregnancy outcome, gestational age a n d

birth weight.

Women who called a participating teratogen information service regarding tirst

trimester use of one of the above SSRIs were contacted at a later date to ascertain

pregnancy outcome. These women were compared to a control group consisting of

women not exposed to anv known human teratogen in their pregnancy.

X total of 267 exposed women were followed up: 26 women used fluvoxamine, 97

women used paroxetine, and 147 women used sertraline (1 woman used both

flwoxamine and sertraline, and 2 women used both paroxetine and sertralinei.

There rïere 9 liwborn infants with major malformations in the exposed group and

9 in the control group (p = 0.91). The number of live births in the esposed group

were 227 versus 235 in the control group (p = 0.14). There was no difference in

either birth weights (3439 g in the exposed group, 3145 g in the control group, p =

0.91) or gestational age (39.4 weeks in the exposed group, 39.4 weeks in the control

group, p = 0.71). These results do not suggest an associated increase in risk of major

malformations. Although reassuring, a larger study is required to definitively label

these drugs as safe for use in pregnancy.

I am grateful for the support and guidance of my supervisor, Gidi.

Dr. Ingeborg Radde was an inspiration to me. Her experience was invaluable to the

development of this thesis.

Anne Pastuszak graciously donated much time and effort to aiding me with the

studv design and cvriting of this thesis.

Thank-you to my fellow grad students: Myla, Paul, Cindy, and the honourary grad

student, Gilda. And thanks to my best pal and fellow grad student, Kristen tor

enduring al1 the "Big Adventures" and numerous trips to the Second Cup.

This thesis is dedicated to my parents.

1 . Introduction ...................................................... .. ........................................ 1

1.1. Historv of Modem Teratology ................................................................. 1

1 . 2. Pus t-Marketing Surveillance Methodology ......................................... 4

1.2.1. Case Reports and Case Series ................... .... ..................... 4

1.2.2. Case-Control Studies ................................................................... 6 - 1.2.3. Cohort Studies .............................................................................. 1

1.2.4. Randomized Clinical Trials ...................................................... 7

1.3. Background Information ......................................................................... '1

... 1.3.1. Baseline Risk for Anomalies in the General Population 9

1.3.2. Definition of Malformation ................................................ 11 q q 1 . J J . Prepanc): Outcornes ................................................................. 11

1.3.4. Definition of Teratogen ........................................................... 12

1.3.5. Teratogen Information Services ............................................ 13

1 .4 . Depression .................... .. ......................................................................... 15

1 . 1. 1 . Historv of ht idepressant Medica tions ............................. 15

1.5. Selective Serotonin Reup ta ke Inhib itors ......................................... 17 -

1 .> .I. Mechanism of Action .......................................................... 27 1.5.2. Advantages and Disnd~rantages ........................................... 17 - 1 .J. 3. Pharmacology ............................................................................. 19 -

............................................................................. 1.3.4. Teratogenicity 20

1.6. Hvpothesis ................................................................................................. 2-4

1.7. Objectives ................................................................................................... 24 3- 2 . blethods ..................................................................................................................... 3

- 2.1. Study Design .............................................................................................. 2s

2.2. Pa tient Selection ....................................................................................... 26

7.1.1. Sample Size Calculation .......................................................... 26

2.3. Data Collection .......................................................................................... 28

2.4. Da ta Analysis ............................................................................................. 29

3 . Results ....................................................................................................................... 51

3.1. Data CoIiection .......................................................................................... 31

3.2. Cornbined SSRIs .................................................................................... 35

3 . d.1. Materna1 Demographics ........................................................... 33

3.7.1. Major Structural Malformations ..................... .... .......... 37

3.2.3. Pregnancv Outcome .................................................................. 40

3.2.4. Other Findings ........................................................................... 41

3.3. Fluvoxamine ............................................................................................. 43 7 1 . .............................*............-.....***........ J.J . 1 Ma temal Demographics 43

3.3.2. Major Structural Malformations ........................................ 4-4 3 3 1 J.J.J. Pregnancy Outcome .................................................................. 45

2.4. Paroxetine .................................................................................................. 46

.?.A. 1 . Materna! Demographics ........................................................... 4h

3 - 4 2 Major Structurai Malformations .......................................... 4S

3.4.3. Pregnancv Outcome .................................................................. 49 - .................................................................................................... 3.5. Sertraline 30 . .

............................... ......................... 3.3.1. Materna1 Demographics ... >O m ........................................... 3.3.2. Major Structural Malformations 32

-7 3.5.3 . Pregnancy Outcome ................................................................. 33

........................ Esposed From First Trimester to Third Trimester ... 54

............................... 3.6.1. Ma terna 1 Demographics ......................... ... 34

........................................... 3.6.7. Major Structural Malformations 56 -

3.3.3. Pregnancy Outcome ................................................................ 56

on ................................................................................................................. 58

................. Research Implications - Nul1 Hypothesis Not Rejected 5S ........................................... 4.1.1. Major Structural Malformations 5S

Limitations of the Study ........................................................................ 63

4.2.1. Recall Bias ................................................................................... 63

4.2.2. Loss ot Follow-up ...................................................................... 6-4

4.2.3. Demographic Differences Between Exposed and Control

Croups .................................................................................................... 64

4.2.4. Initial Stuclv .............................................................................. 65

Recommenda tions for F L ~ ture Research ........................................... 66

Recommenda tions for Counselling a t Motherisk ........................... 67

4.4.1. Women Planning Pregnancy and Pregnant Women

Planning t« Use a Newer SSRI ................................................... h7

4.4.2. Women Who Are Currently P r e p a n t and Using a Newer

SSRI ........................................................................................................ h i

Appendix 1 - Figures ................................................................................................. hS

Appendix II - Known Human Teratogens ............................................................ S3

References .................................................................................................................... S-l

LIST OF TABLES

Table 1 - Summarv of Epidemiological Study Types Used for Reproductive Outcome

Studies

Table 1 - Safety and Tolerability of TCAs vs SSRIs

Table 3 - Pharmacokinetics of the Four SSNs

Table 4 - Sample Size Calculations

Table 5 - Matemal Demographics - Motherisk Cases Included vs Lost

Tabk 6 - Cases Contributed bv Centre

Table 7 - Materna1 Demographics - Motherisk vs Other OTIS Centres

Table S - Breakdown by Exposure and Trimester of Exposure

Table 9 - Maternal Demographics: SSRI-Exposed vs BPG

Table 10 - Major Structural Malformations

Table I l - Major Structural Evlalformations - All SSRIs

Table 12 - Major Structural Malformations - All SSRis

Table 13 - Preg-tancy Outcome - Al1 ÇSMs

Table 14 - Birth Weiglit and Gestational Age for Live-Born Children - Al1 SSRIs

Table 15 - Other Findings

Table 16 - Maternal Demographics: Fluvoxamine-Exposed ï s BPG

v i i

Table 17 - Major Structural Malformations - Fluvoxamine

Table 18 - Pregnancv Outcorne - Fluvoxamine

Table 19 - Birth Weight and Gestational Age for Live-Born Children -Fl~i~.oxamine

Table 20 - Rilaterna1 Demographics: Paroxeti~e-Exposed vs BPG

Table 21 - Major Structural Malformations - Paroxetine

Table 22 - Pregnancv Outcome - Paroxetine

Table 23 - Birth GVeight and Gestational Age for Liw-Born Children - Paroxetine

Table 24 - Ma ternal Demographics: Sertraline-Exposed vs BPG

Table 23 - Major Structural Malformations -Sertr a 1' ine

Table 26 - Major Structural bhlformations -Sertr a 1' me

Table 27 - Pregnancy Outcome - Çertraline

Table 2S - Birth Weight and Gestational Age for Live-Born Children - Sertraline

Table 39 - Materna1 Demographics: SSRI-Exposed irom First Trimester to Tliird

Trimester i rs BPG

Tablé 30 - Major Structural Malformations - Exposed from First Trimester to Third

Trimester

Table 31 - Birth Weight and Gestational Age - Exposed from First Trimester to Third

Trimes ter

Table 32 - Birth Weight of SSRI-Exposed Non-Smokers 1-s BPG

Figure 1 - Motherisk Intake Form

Figure 2 - Motherisk Clinic Form

Figure 3 - Chernical Structures of the Selective Serotonin Reuptake Inhibitors

Figure 4 - Motherisk Follow-Up Form

Figure 5 - Motherisk Follorv-Up Letter to Offspring's Health Care Provider

BPG - baseline population group

CYP - cvtochrome P450

LMP - last menstrual period

MAO-I -monoamine oxidase inhibitor

SSRI - selective serotonin reuptake inhibitor

TC A - tricyclic antidepressant

TIS - teratogen information service

1.1. HISTORY OF MODERN TERATOLOGY

Throughout history, there have been many theories as to the causes of birth defects.

These theories ranged from maternai dreams to messages from the gods. Howewr,

it was not until the realization that certain environmental factors such as rnatern~l

rubella infection' could result in birth defects that the science of modern human

teratology emerged. The term teratogen is used tn describe a substance that could

have an adverse effect on the fetus. A more thorough definition is oifered in

section 1.3.4.

In 1958 a German pharrnaceutical Company marketed a d r u g labelled as a safe

sedatitee that kvas found to be an effective anti-emetic in earlv pregnancv. Soon after

thalidomide's introduction, reports of an outbreak of a series of Lincornmon

s tr~ictural malformations in newborns began to appear-r3. Phocornelia (limh

reduction) spontaneouslv occurs at a rate of about 0.14 per 1000 births, but betrveen

September 1960 and August 1961 that rate increased to 1 in 1000 births in Cermanv4.

The mothers of the children born cvith this structural defect took thalidomide

between the 20th to 35th slay post-conception, a time when the limbs are h rming in

the tetus. Thalidomide embryopathy is also associated with defects of interna1

organs, such as the heart, and the eves and earsï.

Until this time the placenta was thought to protect the developing fetus from the

effects of materna1 medication. After the thalidomide tragedy, however, heaith care

professionals and the public began to question the role of drugs in human

malformation and scientists strived to identify teratogens via animal s t~idies and

other experimental models. [n 1962 the United States Food and Drug

Administration introduced the first requirements for preclinical tosicologv testing,

inciuding reproductive studies, for new drug applications.

Today, during preclinical testing, the drug must be tested for teratogenic potential

and other reproductive endpoints such as fertility and matemal function in at least

two animal speciesb. During animal testing confounding variables can be

controlled. A confounder is a variable independently associated with a disease and

exposure which may affect the outcome. Despite the advantages of animal testing,

the extrapolation of i r i i1iil0 animal data to human pregnancy has been questioned

for several reasons. While animal studies have identified almost al1 teratogens

since thalidomide, thev have a high rate of false positives. tn a sample of 350 agents

tested in animais Shepard; found that 55"L of them were positive for being

teratogenic. This would mean that of the 1600 agents tested in animals 880 are

terntogens, yet in humans onlv about 30 agents have been found to be teratogenic.

There are several reasons for the high rate of teratogrnicitv reported in mimai

studies. The dosages tl-iat are given are not comparable to human doses, different

dosing methods such as intraperitoneal injection are often used, and animals have

different embrvonic development, pharmacokinetics, target organ sensitivi ty and

metabolic pathwayss. Thus far, there are no predictive i r i oitro tests availnble for

testing the human teratogeiiicity of drugs since our knowledge of o r s a n

dev elopment is still limited.

There are three phases of premarketing clinical testing. During phase 1, the clrug is

tested in sel.eral healthv volunteers to determine the safe human dosage, Iniman

pharmacokinetics and pharmacodynarnics. I t is onlv in phase II that the medication

is given to a small cohort of patients with the target disease to determine i f there are

anv differences from the phase I findings. Finallv, phase [ I I is an extension o t phase

11, but consists of larger numbers of patients, usually between 500-3001) people. In

this phase, randomized clinical trials are performed to test efficacy, yet rare aclverse

drug reactions mav easilv be missed.

During phase IV the manufacturer is required to monitor for adverse d r u g events

after the drug has been approved. Such events include rare side effects, chronic

toxicity and drug interactions. O f en such events are spontaneously reported to the

drug Company and Health Protection Branch by health care professionals. These

reports may include pregnant women who inadvertently took the medication.

Pregnant women are excluded from the premarketing clinical trials as it is medically

unethical to test drugs in human pregnancy. This results in a lack of d r ~ i g satetv

information tor a large segment of the population - narnelv women of child-benring

age. it is currentiy estimated that over half of al1 pregnancies are unplannedu.

Given that many women will not realize that they are pregnant until about five to

six rveeks after their last menstrual period (LMP), many of them inadvertantlv use

medications during this time whose fetal safety has not yet been determined. Often

the mother is unable to stop the medication because there is no alternative

treatment. For example, seizure disorders must continue to be treated with

medications throughout pregnancy in spite of the risk to the fetus. The mean age o f

Lvomen having children has also increased and this increase in age is paralleleci by

an increase in medical problems and medication uselu.

The raritv of human teratology studies, the increase in medication Lise and the

number of new medications available makes post-marketing surveillance a n

important requirement for determining the safetv of drugs in human pregnnncv.

There are several tvpes of epidemiologic studies that can be used to assess the

relationship between materna1 drug exposure and fetal outcome. Çummarized

below are the different study types aimed to determine the safetv of drugs in

pregnancy in increasing order of validity, validity being the degree to which a

measurement reflects the "true" value of what is being measured. The advantages

and disadvantages of each tvpe of study are summarized in Table 1.

1.2.1. CASE REPORTS AND CASE SERIES

A case report describes a patient with an exposure and a subsequent outcome.

Seïeral such patients mav constitute a case series. A case report studv is simple and

quick to perform since it is often retrospective. As there are no controls in a case

report studv, i t is purelv descriptive and statistical cornparison cannot be performed.

Xnother issue is that often only patients with ~inusual outcornes are noted a n d case

reports d o not include the frequency for the rate of exposure in the general

population. Crise reports or case series, however, are useful for generating

hypotheses for turther evaluation by a study which aims to test the hvpothesis (1.r-,

analvtic s tudy). Most case report findings are not supported by further

epidemiologic studies and are due to chance occurence. In the case of a rare or new

exposure, thouph. it mav be the only study design initially available.

Des pi te tl-ieir limitations, case reports and case series c m be helpful in tera tology.

Thalidomide is the best known esample of a teratogen suspected bv a case series'.

Though not generaliznble to all patients, case reports are an important tool in

assessing the risks of new drugs or drugs to cvhich pregnant women are rnrely

exposed. For esample, if the medication is infrequently iised in women of

childbearing age and causes a rare malformation, a small number of cases can

eçtablish the association. Conversely, if the medication is commonlv used by

pregnant rvomen. a few cases may onlv reflect the b a d i n e risk of malformation (see

Section 1.3.1.) unless a specific pattern of malformation is noted.

Spontaneous reporting to the drug company during phase IV regarding pregnancv

exposures essentially is a case series. There are many limitations to these

spontaneous reporting systems. For example, the cases are a mixture of prospective

and retrospecive reports and the amount of information is often limited and not

well documented regarding the exposure and timing of exposure11. There is a large

potential for bias in retrospective cases, as women having a child with a

malformation are more likelv to be reported to the drug company by their health

care providers than a mother who has a normal outcome. Several driig

manufacturers, however, are now creating prospective registries for women esposed

to their product during pregnancy.

In a case-control studv, the patient's disease status is determined first and for each

case there is at least one control patient without the disease selected for comparis«n.

The investigator then retrospectively determines the patient's e spos~i res bv

interviewing the patient and /or checking the patient's medical records. Case- control studies are inexpensive and quick to perform. Recall bias is the differing

abilities of cases and controls to rernember past events and is a major flaw in this

study type since it is retrospective. Another tlaw is that confounders arc not

controlled. To minimize contounders in this type of studv, two approaches mav bc

taken. If one c m predict the confounders, the controls may be matched bv the

confounder. I f a confounder is suspected after the studv is cornplete, one mav

stratifv the confounders during analvsis. This study torm is ideal for a rare outcorne.

In human reproductive outcome studies, the mother of a child with the suspected

anomaly is interviewed about previous exposures. The controls a r e usually

children with a clifferent tvpe of malformation since mothers of malformed infants

may have better recall of events occurring in their pregnancy than mothers of

normal childrenl2. An example of a confounder associated with pregnancy

outcome studies is materna1 cigarette smoking, rvhich results in an increased rate of

spontaneous abortion and lower birth weight for live-born childrenl? This type ot

study c m be performed to test findings found in case reports or cohort studies (see

below).

Essentiallv in a cohort s tudv information about the risk factor (exposure) is

determined and the patient is followed over time to see whether o r not disease

occurs. It is contrasted to a case-control study in that selection is based upon the

presence or absence of a predefined exposure rather than a disease. Cohort studies

provide information on the incidence of the outcome after exposure. This tvpe ot

study c m be retrospective, but more often is prospective. Recall bias is less likelv in

a prospective cohort when compared to a case-control studv since the exposure of

interest is recorded at the time of initial interview.

In human reproductive outcome studies, exposure is first determined m c l the

woman is then hllowed ~ i p after her expecteci date ot delivery. The baseline risk in

the general population for major birth defects is low (see section 1.3.1) and specific

defects have even lower rates. Neural tube defects such as spina bifida and

anencephaly, for example, occur at a rate of 1.3 per 1000 births. When a drug causes

a defect, it causes a specific type of defect or series of defects. The rarer an outcome,

the larger the sample size required

groups. Statistical power, the ability

two g r o ~ p s , is infl~iencecl bv sample

specific birth defect the sample size

risk is large and often inhibitory from

in order to detect a difference between the

of a studv to detect a true difference between

size. In the case of a rare outcome suc11 as a

required to rule out definitivelv an increased

a time or cost perspective when cornpared to a

case-control studv. This tvpe of study is useful for hypothesis generation for fut~ire

case-control studies and ruling out a large increase in the baseline risk.

The epidemiologic studies mentioned abo1.e have a11 been obsernt ional ( i . r* . the

investigator hes not intervened in patient treatment). A randomized clinical trial is

interventional and is the "gold standard" of epidemiological studies since unknown

or unmeasurable confounders are controlled for as the patients are randomlv

allocated to one of at least two treatment arms in the study. This type of st~ici\? is

often very expensive to perform and time-consuming when compared to the above-

mentioned studv tvpes. As described earlier, medical ethics prevents the testing in

human pregnancv of drugs for the purposes of determining whether or not a rirug is

terri togenic.

The following sections deal with background information needed to pertorm ri

human reproductive outcome epiderniologic study. In the first section various

studies addressing the baseline risk of major malformation are discussed. The

second section defines major structural malformation. The third section

summarizes diffcrent endpoints of pregnancy outcomes. The fourth section details

further the definition ot a teratogen. In the final section a description of a teratogen

information service is given.

1.3.1. BASELINE RISK FOR ANO~IALIES IN THE GENERAL POPULATION

Every pregnant woman has a certain chance of giving birth to a child with a major

structural malformation. This risk is independent of exposure to medications,

radiation and infectious diseases, as well as materna1 age or disease s t a t u during

pregnancy. This risk is termed the baseline rate of major malformation.

There have been several studies examining the rate of malformation in the general

pop~ilation. The results differ for each studv due to dissimilar definitions o t

malformation, methods of ascertaining presence o t malformations and pop~ilations

being studied. These issues will be explored in this section.

Marcien ct.d.l-' performed gross rnorphologic examinations on 1412 Caiicasian

births (including stillbirths) within 4s hours of birth. The infants had tu be n t Ieast

20 iveeks gestational age (from the first day of materna1 LMP) to be included in the

study. Marden s t . d detined a major malformation as one that has adverse effect on

either the function or social acceptability of the individual, and 90 chilclren (7.O1'L)

were diagnosed with a major malformation. Tl-iey defined a minor maliurmatic~n

as one having neither medical nor cosmetic consequences ta the patient. There

were 609 children ( 3 . S ) diagnosed with having one or more minor

malformations without anv major malformation.

A studv with similar design to that of Marden et ni. was published in ls>S71-?

Caucasian live-born singleton infants were randomly selected and had surface

examinations within four davs of birth. Excluded were infants of diabetic mothers

or mothers who used phenytoin in pregnancy. The definitions of major and minor

malformations were the same as those used in the studv - by - Marden rt 111. Unlike

Marden et al., however, malformations found bv additional diagnostic tests ordered

bv the infant's pedia trician were also included for analvsis. OnIv mal formations

diagnosed by 5 davs of age were included. Of the 4305 infants esamined, 162 had

major malformations (3.Sc)L) and 1652 had minor malformations (3S.-L":t).

Due to the dispara te methodologies in the above studies, many potentially

classifiable malformations were missed. A malformation such as an ectopic kidnev

would be missed by a surface examination and also is not likely to be diagnoseci

tvithin two davs ot birth.

The iirst large scale studv included 5330 live-born children and was published in

19541h. The measured outcorne \vas anv type ot anomaly, including mental

deticiencv. The children were followed ~ i p t» one vear of age rvhere possible. Stxen

percent of the children (n = 336) were diagnosed with an anomaly.

Tittelve urban medical centres in the United States participâted in a studv that

included 53,357 children born between 1959 - 1966 making this the largest s t~ idv to

date';. .ksessed were al1 singleton births including lSSl fetal and neonatal deaths.

.A congenital anomal!. was defined as a g r o s physical or anatomic developmental

m o m a l v that WCIS present at birth or detected ciuring the tirst vear of Me.

Malformations that rvere no longer detectable at one year of age rvere not c~tcgorized

ùs a malformation. Assignment as major or minor malformation was arbitrarv and

based on experience and expert advice. Thirteen percent of the births (n = 69 11) ivere

diagnosed with only minor malformations: 6911 (13.0'10) and 4422 tvere diaanosrd

with a major malformation (8.3'%,).

Heinonenlhssessed singleton births, including stillborns at 14 ~iniversitv-affiliated

hospitals in the United States. Children were follorved up for varying lengths of

time ,ind 91% of l i w borns were examined at the one vear mark. Of thc JO,ZS2

singleton births, 1393 (2.8'!:1) were determined to have a major malformation. The

malformations were each assigned as major or minor, although the criteria for this

categoriza tion were not explained.

In summary, the baseline rate of major malformation in the general population

ranges from 7'1;) to 8.30% depending on the definition of malformation and the

methods emploved in the study.

A mistake commonly encountered is the assurnption that "defect", "anomalv", and

"mal formation" are equivalen t terms, which is no t so. Anomalv encomp'isses al1

structural aberrations of the normal and defect is also a broad term tliat n-iav involve

morphologic, enzymatic. genetic, and/or chromosoma1 anornalieslu. The definition

of a malformation is quite precise. it is a change in form rather than f ~ ~ n c t i o n ~ ~ .

Spranger et ( 1 1 . 3 ) define a malformation as a rnorphologic defect of a n organ, part oi

an organ, or larger region of the body resulting from an intrinsically ( i .c . , inherited)

abnormal deïeloprnental process. I f an anomaly is due to an extrinsic interference

ivith an otherwise normal process, it is ri d i s r ~ p t i o n ~ ~ . It is o f e n impossible t o

determine in the postnatal period if a n anomaly is due to an intrinsic or cstrinsic

factor (or some combina tion o t the tivo) during pregnancv?

One other tvpe of structural anomaly exists. A deformation is an abnormnl form,

shape, or position of a part of the bodv caused by intrinsic or extrinsic meclinnical

to rces?

Pregnancv outcome can be categorized into two main groups: live birth, and ietal

death. Fetal death inclride abortions and stillbirths. Abortions can occur

spontaneouslv (ix., "miscarriage") or by medical intervention. An abortion hv medical intervention is called a therapeutic abortion and can be performed for a

variety of reasons. In the case of an ectopic pregnancy, a therapeutic abortion must

be performed to save the motherfs life. In most western countries a therapeutic

abortion will be performed upon the request of the mother. This ma- be due to

social reasons, materna1 medical conditions or detects detected in the fetus bv one ot

the prenatal tests commoniv administered to preçnant women.

A fetal death can occur an! time in the pregnancv and the terminology used to

describe the death varies with the gestational age when the death occurs. Currently,

the World Health Organization considers a death before 34 weeks ps t -LMP of

pregnancy a spontaneous abortion and one after that time a stillbirth? Prior to thùt

definition, the World Heaith Organization delineated the point between

spontaneous abortion and stillbirth as 30 weeks", a definition still accepted os valid

by many. Warburton r t nl. further divide spontaneous abortions into earlv and

late? An "earlv spontaneous abortion" occurs before 14 weeks post-LMP and a "la te

spontaneous abortion" occurs between 14 and 30 weeks post-LMP. The reason h r

this division is that the majority of spontaneous abortions before the week have

gross chromosoma1 abnormalities. The fetal death rate before 20 weeks wns 15.3'0

'inci c7t 20 cveeks or more was 2.1°0 in a 1971 striciv? There are severai rne~lications

and environmental exposures, such as cigarette smoking", that increase the fetal

death rate.

The term tera togen is clerived from the Gree k words k i n t o s (monster) and , p p i l

(producing). A teratogen is clefined as an environmental influence that has an effect

o n the embrvo o r tetus after fertilization, but beiorc birth and primarilv C~ILISCS

morphologie mnlformations and disruptions? Altliough teratogens c m act at any

time in pregnancy, they act essentially during the first S weeks of embryogenesis.

Schardein'" offers a broader definition of teratogen. I t is an agent that induces

structural mal formation, metabolic or physiological dysfunction, or psychological or

behavioural alterations or deficits in the offspring, detected either at birth or in a

defined postnatal period.

Shepard has m a d e a list of criteria which can be used as a guideline in the

determination of teratogenicity. The fi rst three criteria are considered essential. The

criteria are as follows:

Proven maternal exposure to agent a t critical tirnets) (i .r. , when the structure is

forrning) in prenatal development

Consistent findings by two or more epidemiologic studies of high quality.

a. Control of confounding factors

b. Sufficient numbers

c. Exclusion of positive and negative bias factors

d. Prospective studies if possible

e. Relative risk of six or more (?)

Careful delineation of the clinical cases. A specific defect or svndrome i f present

is very help hil.

Rare enl-ironmental exposure associated with rare defect. Probablv three o r

more cases.

Teratogenicity in animals important but not essential.

The association should make biologic sense.

Proof in esperirnental animals that the agent acts in an unaltered state.

Terntogen information sen-ices (TISs) plav an important role in the postrnarketing

suri-eillance of medication use during pregnancy. These programs ofter risk

âssessment counselling for pregnant women exposed to medications and also a n

opportunity tor prospective collection of d rug exposures in pregnancy.

Collaboration among TIS centres allows for larger sample sizes to be compiled and 7 - 7 y 79 several such studies have successfully been completed-i .-. I- . There are c~irrentlv 50

members of the Organization of Teratogen Information Services in North America,

including the Motherisk Program.

The Motherisk Program in Toronto, Ontario was established in 1985 to provide risk

assessments regarding maternal medication in pregnancy and lactation and the

possible effects on the fetus or baby. Motherisk is a telephone counselling service for

both the public and health care professionals. Currently 750 calls are answered by the Motherisk team in a n average week. Information is documented for each cal1

and callers are required to provide a demographic, medical, and pregnancy history

(Figure 1, ail figures can be found in Appendix 1). Patients concerned about a

knocvn teratogenic exposure or an exposure for which there is not enough evidence

to definitivelv label as non-teratogenic (cg. new medications) are referred to a clinic

for face-to-face counselling with one of the tearn's phvsicians. In the c h i c the

phvsician records a more thorough medical and demographic history (Fig~ire 3.

Subsequent to the clinic visit, a summary letter is sent to the patient's health care

provider regarding the information relayed during session.

Betrveen 5 and 10% of the queries regard medications used to treat depression.

1.4. DEPRESSION

Depression is among the most common disorders in the ivorld today. The

.American Psvchiatric Association's fourth edition ot' the Diagnostic and Statistiçal

Manual of Mental Disorders (DSM-IV)30 defines a major depressive episode as a

period of at least two weeks during which there is either depressed mood o r the loss

of interest o r pleasure in neariy al1 activities. Two terms commonlv used to

quantifv the rate of depression in the population are the one-year prevalence rate

and the lifetime prevalence rate. The first term refers to the

population who suffered t'rom depression in the year prior to

second term reiers to the percentage of people who have

depression in their lifetime.

The one-vear prevalence rate for major depressive disorder by

ttstimated to be 7°0 among rvomen of child-bearing age (1s

percentage of the

interview and the

DSM-III criteria is

to 44 ~ - e a r s ) - ' ~ . A

pop~ilation of Canadian h7omen aged 18 to 64 in Edmonton, Alberta had a lifetime

prer-alence rate O C major depression of 12.3"O". In an Ontario sample of rural and

urban populations, of the people who were diagnosed with depression 63.8":) in the

urban sample and 73.0"0 in the rural sample were womenx. The prei-alence rate ot

depression in Canadian women aged 1s to 71 vears was 1U.S1!L and for women aged

25 to 44 this rate was 8.6'!iJ3-1. A 1995 ltalian d rug prescription monitoring studv

randomly selected Y743 subjects of which 5.4% received a prescription for an

antidepressant within n 30 month period? The ratio of female to male was tnw to

one. In summarv, women of childbearing age have a high rate »f depression and

this is reflected in prescrihing patterns.

The first medication closs found to be effective in treating depression was the

monoamine oxidase inhibitors (MAO-Is), drugs that were initially produced in an

attemp t to find effective anti-tuberculosis treatrnent? They mediate their et'kct bv inhibiting monoamine osidase, an enzyme which destrovs excess amine

neurotransmitters in the presynaptic receptors. This increases the amount of

neurotransmitter available to act upon the postsynaptic receptors and ultimatelv

downregulates these receptors. The MAO-Is, however, are associated with

numerous adverse effects as well as food and drug interactions leading to poor

patient cornpliance and toxicitv. As a result the MAO-1s are not comrnonlv

prescribed today. Since they are not widelv used, information regarding satetv ot

MAO-1s in pregnancy is sparse.

The development of the tricyclic antidepressants (TCAs) was the result of an '~tternpt to improve the antipsvchotic effectiveness of the phenothiazines-;:. Thev inhibit the

reuptake of serotonin and norepinephrine at the presynaptic receptors. By

preventing reuptake, the drugs keep the neurotransmitter in contact with the

postsynaptic receptors and therebv cause postsynaptic receptor downregulation. The

TCXs have not been associated with an increased risk of maior structural

mal formation in p r e g n a n ~ y ~ ~ .

A recent addition to the drug therapies available for the treatment of depression are the selectiïe serotonin reuptake inhibitors (SSRIs). In Januarv 1988 fluoretine

(ProzacG) was marketed in the United States. Since this time several newer SSRIs

have been introduced, namely sertraline (Zoloft'"), fluvoxarnine (Luvox~ '~) , and

paroxetine (Paxil"'). The term "newer SSRI" herein reters to fluvosamine, a me. paroxetine and/or sertr 1'

Dcspite their use bv women of child-bearing age, little is known about the eifects of

the newer SSRls f luvoxamine, paroxetine, and sertraline on human pregnancv

outcome. This stridv dealt cvith the risk of the use of these medications in

pregnancv in regards to major structural malformations and p repancy outcome.

1.5. SELECTIVE SEROTONTN REUPTAKE INHIBITORS

The SSRIs block the serotonin reuptake carrier. Since serotonin reuptake is the

major mechanism of serotonin inactivation after its release into the synaptic cleft

there is an increase in concentrations of serotonin in the synapse available to act

upon the presynaptic autoreceptors and postsynaptic receptors. The constant

stimulation of the autoreceptors eventually results in their desensitization. This

desensitization causes a greater amount of serotonin (Le., enhances serotonergic

neurotransmission) to be released into the synaptic clett per impulse. Initiallv the

rate of firing decreases, but after approximately 14 days the rate has recowred to

baseline. The net result is an increase in the amount of serotonin in the synaptic

cleft. I t has been hypothesized that the time delay of 14 days correlates with the

onset of antidepressant activity.

1.5.2. ADVANTAGES AND DISADVANTAGES

While the SSRIs sl-rare some similarities with the TCAS, therc are also sewra l

clifferences that have made them popular with but11 patients and phvsicians. Prior

to the introduction of the SSRIs, the TCAs were the most commonly prescribed

antidepressants so thev will be used as a comparison drug ciass in the followinp,

sections.

A. Safetv and Tolerability

While the SSRls affect only the serotonin reuptake carrier, the TCAs are relativelv

nonspecific and act upon ri wide range of neuroreceptor systems inclading the

ùcet~lcholine, histamine, u-adrenergic, norepinephrine and serotonin receptorç, of

which only the norepinephrine and serotonin receptors mediate the desired eifect.

Furthermore, the TCAs also directlv stabilize membranes. Due to these additional

effects the sidr effect and toxicitv profiles of the TCAs are quite different irom those

of the SSRls (Table 2).

From Preçkom. l996jS.

Table 2 - Safety and Tolerability of TCAs vs SSRIS

The TCAS are iverv cardio-toxic in an overdose situation due to inhibition ot tlie tast

sodium channels in the heart. It is possible for as little as five times the therapeutic

dose of a TC;\ to be lethal? Given that patients who suffer from depression art.

between 13 t» 30 times more likely to at tempt suicide than the normal

popuIationJ*P41, the combination of the narrow therâpeutic window of the TCAs and depression is very dangerous. Since the SSMs do not affect the fast sodium

channels they are not cardio-toxic and are relatively safe in an overdose.

SSRIs

1 O ttr

low

low

1 O

low

high

Consideration

Safe ty

overdose lethalitv risk

alcoliol potentiation

Toterability

anticholinergic adverse eïents

antihistarnine adverse events anti-ul adrenergic adverse events

serotonin adverse events

Drug interactions are a n important factor to consider when prescribing ai-itidepressants since &en they are used on a long-term basis. The TCAS Iiaw a

great potential for pharrnacodynamic drug interactions. Anxietv is otten ,issociated

with depression and patients may be prescribed a sedative to counter the symptoms.

This can be problematic with concomitant TCA use, because TCAs potentiatt.

ethanol and sedatives due to their antihistaminergic effects. Another example of a

pharmacodvnamic drug interaction is with p-blockers and other antihvpertensive

medications. The TCAs block a-adrenergic receptors thus lowering peripherd

resistance which can have an additive effect with p-blockers. Inhibition of the tast

sodium channels also po ten tia tes P-blockers.

TCAs

high

high

higl-i

high

high

locv

Common side effects associa ted with TC .As include dizziness, tremors, swea ting,

constipation, drowsiness and dry mouth. Side effects commonly encountered with

the SSRis are sweating, nausea, nervousness and drowsiness. The side effects of the

SSRIs are more tolerable to the patient than those of the TCAs resulting in increased

patient c ~ m p l i a n c e ~ ~ .

B. Efficacv A meta-analvsis of the literature found that there was no significant difference in

effectiveness between the TCAs and the SSRIsq?

C . Sim~licity

Due to the side effects and narrow therapeutic index of TCAs, they are often started

at a sub-therapeutic dosage to allow the patient ta adapt to the side etfects and for the

phvsician to titrate the dose upward to avoid toxicity. Conversely, patients can be

started on a therapeutic dose oi their SSRI immediately thus obtaining a therapeutic

effect more quickly.

The chernical structures of the four SSRIs differ (Figure 3). The pharmacokinetics

between the cirugs also Vary (Table 3) . For example, fluoxetine has a l-idf-lifc of S4

hours and the half-life of it's active metabolite, norfluoxetine, is 146 hours. The

tl-iree newer SSRIs have half-lives of 24 hours, though the half-life of sertraline's

active metabolite, desmethylsertraline, is 66 hours. Desmethylsertraline is a much

less potent inhibitor of serotonin reuptake than the parent compound, so its

contribution to the clinical efficacy of the drug is minimal.

Table 3 - Pharrnacokinetics of the Four SSRIs

parameter FLLJO FLUV PAR0 SERT

extent of absorption (%) 80 94 64 >44

time to ~ e a k concentration (h) 4-8 2-8 2-8 6-10

volume of distribution (L) 25 20 17 N A

pro tein binding ("4)) 95 77 95 97

elimination half Me (h) parent compound 84 -- 7 ? 24 26

active metabolite 146 n o n e none 66

FLUO = ftuoxetine; FLUV = fluvosamine; NA = not available; PARO = paro~etinc;

SERT = sertraline. From Finley, 199-L4-'.

Each of the SSRIs is metabolized bv different enzymes'" Cytochrome P450 (CYP)

ID6 is partiallv responsible for the metabolism of' fluoxetine, thouoh the rernainder

has not been established. Paroxetine is metabolized by CYP I D 6 a t lou

concentrations and at higher concentrations is metabolized by a n unidentifieci low-

affinity enzyme. The enzyme responsible for the metabolism of fluvoxamine is

unknown, but is thought to be CYP 1A2. Sertraline is demethylated by CYP 3A3/4.

A, Fluoxetine

In pregnant rots treated with ~ i p to 7.4 mg/kg fluoxetine prior to and throughout

gestation no effects were noted in either fetal morphology or pregnancy outcorne.".

In pregnant rats and rabbits given oral fluoxetine during organogenesis at doses up to 40 mg/kg/day and 15 mg/kg/day respectively, there were no changes in eitl-ier

pregnancv outcorne or rate of major malformations in the p u p d h .

The company that produces fluoxetine, Eli Lilly, has prospectively followed up 544

fluoxetine-exposed pregnancies-'? Of these pregnancies 91 were terminated, 7 2

resulted in spontaneous abortion and two were stillbirths. The remainder were l i w

births with thirteen major malformations reported in this group. Additiondly

there were 2s major malformations reported to the company retrospectively. There

was no pattern to the malformations in either the prospective or the retrospective

group.

In 1993 Pastuszak c t al? published the results of a prospective multi-centre cohort

on pregnancv outcome of 128 women exposed to fluoxetine in their first trimester

compared to two age-matched control groups. The first control group consisted of

women who had taken a tricyclic antidepressant in their first trimester (74 women)

and the second group of women who had not been exposed to a human teratogen

(12s women). No statistical difference was found between the three groups in either

the rate of major malformations or pregnancy outcome.

Another s t u d v ~ ~ r o s p e c t i v e l y followed 228 p r e p a n t women who used fluoxetine

at some time in their pregnancy. Of the 173 pregnancies that ended in a live-birth,

162 women wed fluoxetine in the first trimester. There was no signif iant

ciifference in the rate of major structural malformations and deformations between

164 liïeborn children (this includos two twin pregnancies) exposed to fluoxetine in

the first trimester and 226 livebom children in the control group.

Finâilv, a recent meta-analvsis summarized al1 the available prospective st~idies

regarding iirst trimester exposure to fluoxetine? Of the 367 pregnancies, there [vas

no associated increased risk in the rate of major structural malformations.

B. Fluvoxamine

In pregnant rats and rabbits given fluvoxamine during organogenesis in doses of up

to SO mg/kg/dav and 40 mg/kg/day respectively, neither pregnancy outcome nor

fetal morphology were affected-?O.

Prescription-event monitoring in Britain revealed 31 cases of women exposed in

pregnancy to the SSRI fluvoxamine? The outcornes for 21 of these pregnancies are

known. One of these women was exposed in the second/third trimester and

subsequently had a non-malformed child. Three women had unknown exposure

times in their pregnancy. One of these women had a non-malformed child, one

terminated the pregnancy and the third had a spontaneous abortion. The

remainder of the women were exposed to fluvoxamine in the first trimester. Of

these there were five spontaneous abortions, one ectopic pregnancy and tour

terminations. One of the terminations was due to detection of a chromosomal

abnormality (matemal age = 40). There were eight live births including a set of

twins. No malformations were recorded in this group. There is one case report in

the literature of a mother who took the dmg throughout her pregnancy who had a

non-rnalforrned child52.

C . Paroxetine

Pregnant rats and rabbitç dosed with up to 5.1 mg/kg/day and 43 mg/kg/day of

paroxetine during organogenenesis did not differ from their controls in either

pregnancy outcome or fetal morphology-;j. The dose given was SU times the

recommended human dose. Another s tudv performed on rats and rabbits

administered up to 8.3 (rat) and 1.7 (rabbit) times the maximum recommended

human dose vielded similar re~ul ts - '~ .

The British prescription-event monitoring system recorded 71 paroxetine esposed pregnancies and their outcornes'? Of these, 63 women were exposed in the first

trimester. Exposure times for the remaining 8 pregnancies were unknown. For the

62 known pregnancy outcomes, there were 12 elective abortions, 9 spontaneous

abortions and 43 live births. There were three sets of twins among the live births

and one twin rvas stillborn (cause unknown). There were no malformations

reported for anv of the live births.

Spontaneous reports to the company have not shown any pattern of malformations

due to paroxetine use in pregnancy5".

D. SertraIine

Teratology studies performed in pregnant rats and rabbits at up to 80 mg/kg/dav did

not show sertraline to affect fetal morphology" (Zoloft product monograph, 1994).

The therapeutic human concentration is about 3 mg/ kg/day.

The company that produces sertraline, Pfizer, has nine reports of patients who

received the medication while pregnant. There were 5 non-malformed children

born, one elective termination and 3 spontaneous abortionsYs.

In summarv, none of the SSRIs have been shown to be teratogenic in mimals .

With the exception of fluoxetine, there are no controlled epidemiologic studies

regarding the teratogenic potential of the SSRIs in human pregnancy. Since each of

the SSRIs has a similar mechanism of action, it is possible for them to be studied

together in regards to teratogenic potential.

Matemal exposure to the newer SSRIs fluvoxamine, paroxetine, and/or sertraline

in the first trimester rvill not increase the baseline rate of major structural

malformations.

Primarv Obiective: To record and compare the rates of major structural malformations between the

esposed studv group and a control group rcpresenting the baseline population of

pregnnnt women.

Secondarv Obiectives:

To record and compare the distribution ot pregnancy outcome, gestational nge

and weight of livebom infants at delivery, hetween the exposed and the baseline

population control groups.

This was a prospective cohort design with one control group consisting of ivomen

who were not exposed to anv known teratogen at any time in their pregnancy and

who represented the baseline population group (BPG) of pregnant women. Botl i the

exposed and the control groups were ivomen who voluntarily contacted a teratogen

in torma tion service.

The sample consisted of women who contacted either Motherisk or another of the

teratogen information services (TE) participating in this studv. Al1 women wh»

met the inclusion criteria were included in the s t~ idv . The control group miisistd

of women randomly selected from pregnancies tollowed u p bv the Motherisk

Program. One control rvoman was selected for each SSRI-exposed woman.

Inclusion Criteria - Exposed Grouv

pregnant women who voluntarily contacted one of nine TISs for counstilling

about exposure to either to Ruvoxamine, paroxetine, and/or sertraline in rveeks

two to thirteen post-LMP

Inclusion Criteria - Baseline Population Control Grouv

pregnant rvomen not exposed io any knorvn human teratogen (see Appendis I I )

Exclusion Criteria

exposure to a known human teratogen anvtime during pregnancv (both groups)

esposure to any of the drugs of interest in secondhhird trimester onlv (exposed

groupl

Table -L outlines the nurnber of live births in each group required to cietect an

increase of a specific magnitude in the observed proportion of major structural

malformations. The svmbol Pi represents the baseline risk of major structural

malformations in the control group ( i . ~ . , BPG) and for this study is considered to be

5% in liïeborn children (sec section 1.3.1.). The svrnbol Pl represents the observeci

proportion oi major structural malformations in the esposecl group detectable in the

studv sample size. Relative risk (RR) is the ratio of the incidence of major structural

malformations in exposed women to the incidence of major structural

malformations in the BPG. The final colun-in in Table 4 indicates the nurnber ot

liveborn children in each group that is needed to rule out this speciiied relative risk.

Based on these values a total of 227 liveborn infants exposed t» a newer S R I in the

first trimester of pregnancy would allow a relative risk of 2.3 to be rulecl out i f LI

difference does exist.

Table 4 - Sample Size Calculations'

pl RR n

Each of the newer SSRIs were separatelv compared to the control group, ancl post-

hoc analvsis was performed to determine the relative risk that was detectable by their respective sample sizes with SOCXI power and an alpha of 0.05. Additionally,

pregnancies o t rvomen who used a newer SSRI through three trimesters iïere

separately analvzed in the same way.

2.3. DATA COLLECTION

Women or their health care providers who contacted the Motherisk program for

counselling about fluvoxamine, paroxetine, and/or sertraline between February -1st' 1992 and Xpril ~ 1 s t ' 1995 were followed-up. I f the caller to Motherisk was a

health care provider, he/she was asked to obtain permission for Motherisk to contact the mother regarding pregnancy outcome. These women were interviewed

by phone using the standard Motherisk follow-up form (Figure 4). The

q~~est ionnaire covered a variety of topics regarding pregnancy and pregnancy

outcome. These included obstetrical history, maternal disease, drug and

environmental exposures during pregnancy, delivery information, and neonatal

health. A11 mothers of live-born children were also asked permission to contact thc

child's doctor so as to corroborate the medical details of the follow-up. Letters were

sent to the child's doctor requesting maternal obstrical records and medicai details about the child's health (Figure 5). 1f a response was not received within two

months, the letter was fased, and if a response was still not receiveci, the doctor was

telep honed.

Other TISs were contacted and asked to send follow-up information about women

who Iiad ïoluntarilv contacted their centre for counselling about fluwsarnine,

paroxetine, and /or sertraline use in pregnancï.

2.4. DATA ANALYSIS

Analysis was performed primarily using the Statview Program? Fisher's exact

tests, relative risks and confidence intervals were generated by the Epi Info

Programho.

Continuous variables (materna1 age at conception, gestational age a t live birth, birth

rveight), expressed herein as mean 2 standard cieviation, were analvzed using an

unpaireci Çt~icient's t-test for parametric data and Wilcoxon rank-sum test for non-

parametric data. Nominal data variables (gravidity, parity, previous spontaneous

abortion/stilIt?irth, previous therapeutic abortion/ectopic pregnancy, alcohol

exposure, tobacco exposure, pregnancv outcorne, major structural mnlfornintions)

were analyzed using a ~2 test. I f there was a small espected frequency in the

nominal data, a Fisher's exact test was performed. X small espected frequency was

defined as one that \vas Iess than five. The reiative risk and 95% confidence

inter1.d~ were calculated for major struct~iral malformations.

Several TISs in the United States and Canada collaberated on this study. Since each

centre serves a different patient population it is possible that the demographics of

patients differed. To discern if this was the case, demographic characteristics

(gravidity, paritv, previous spontaneous abortion/stillbirth, previo~is therapeutic

abortion/ectopic pregnancy, alcohol exposure, tobacco exposure, materna1 age at

conception) were statistically compared between Motherisk and a cohort CI' al1 the

other centres.

Firs tlv, all the exposed pregnancies were analyzed together. Secondly, first trimester

exposures to each of the newer SSRIs, namely fluvoxamine, paroxetine and

sertraline, were nnalyzed separatelv as were women exposed to any of the newer

SSRIs through three trimesters O t pregnancy.

The primarv outcome of interest in this work was the rate of major structural

malformations. It is thus important that "malformation" and what was considered

"major" in this work be defined.

In the posrnatal period it is often impossible to determine if an anomalv is due to an

intrinsic or extrinsic factor iri rltrro (or some combination of the two)'u, therefore

this work did not make anv attempt to differentiate between the two in statistical

analvsis and simplv referred to both as a "structural malformation". An exception

#as made in cases where i t was clearly a chromosomal anomalv trisomv 3).

These cases were excluded from the analysis of major structural maltormntions.

De formations were reported as "other findingsrr but were not statisticallv annlvzed.

The definitions of H e i n o n e d b e r e used to differentiate major from minor

malformations, because this reference offers the most thorough List of

malformations ilassified as major o r minor. Al1 case information and

malformation classification were reviewed bv a geneticist a t the Hospital tor Sick

Children.

The secondnry outcomes of interest were the pregnancy outcome and the gestational

age and weight of liwborn infants at delivery. Pregnancy outcome was categorized

as: live birth, stillbirth (fetal death 230 weeks post-LMP), therapeutic abortion.

ectopic pregnancv, earlv spontaneous abortion (fetal death 51-1 weeks post-LM'), and

late spontaneous abortion (fetal death >14 weeks, but c30 weeks post-LMP).

Gestational age was recorded a s number ot iveeks post-LMP, and birth weii$~t ivas

recordeci in grams.

3.1. DATA COLLECTION

X total of 207 women or their health care providers contacted Motherisk between

February P t , 1992 and ApriI ~ l s t , 1995 regarding exposure to either Au~msnrnine,

paroxetine, and/or sertraline. Of these, 150 were followed up and the remaining 57 women were lost to follow-up. Of the 150 women interviewed, only 93 rvere

included in the study. The other 5s women were excluded for a varietv of reasons.

Twentv-five of the wornen contacted Motherisk when they were planning a

pregnancy and had not become pregnant by the time follow-up was attempteci, 16 of

the women did not use the medication at al1 in pregnancy, 6 women or their l-iealth

care professionals refused to participate, 6 women were esposed to a known human

teratogen during their pregnancies, 3 women used the medication after the first

trimester, one patient could not speak English, and one womnn hnd committcd

suicicie.

X cornparison ot demographic variables between the Motherisk cases included (n =

92) in the study and those lost to follow-up (n = 57) did not show any significant ciifferences between the groups for any of the variables except for alcol-iol

consumption (Table 5). Women who rvere included in the study reported more

alcohol intake than the women who rvere lost to follow-up.

Table 5 - Matemal Demographics - Mothensk Cases Included vs Lost

variable included lost p-value

-- - -

previous spontaneous abortion (SA) SA = O

SA = l+

previous therapeutic abortion (TA)

TA=O

TA = 1+

tobacco consumption

Y- no

alcohol consumption

Yes no

age (yrs)

'Sornt. ot' the lcist c'ascs were ivomen plmning pregnancv at the timc ot initial inter\'ieiv i~~l-io

Iiad never been prt.gncmt.

In total, 267 ivomen who met the study inclusion criteria were tollowed up by

Motherisk and other OTIS centres (Table 6 ) . The demographics of women collectecl

by Motherisk (n = 92) were not statistically different when compared to those

collected from al1 the other centres combined (n = 175) (Table 7).

Table 6 - Cases Contributed by Centre

centre n %

Toronto O N 92 34.5

Tampa FL

Farmington, CT 32 12.0

Salt Lake Citv, UT 11 4.1

London O N 6 -. 3 - 7

Table 7 - Matemal Demographics - Motherisk vs Other OTIS Centres

variable Motherisk O ther* p-value

gravidity (g) g = l 23 34 t i . 3

g = 2+ 69 130

parity (p) p = O 36 59 0.9s

p = l + 36 96

previous spontaneous abortion (ÇA)

SA = O 68 S2 0.30

SA = l+ 24 19

previous therapeutic abortion (TA) TA = O 76 78

TA = l+ 16 23

tobacco consump tion

Yes no

alcohol consumption

Y- no

materna1 age at conception

' Sts.crnl centres ticici missins information ior various parameters.

-411 the women used a newer SSRI in the first trimester, but most stopped use in the

first trimester (Table 8). Some women, however, used the medication beyond the

first trimester and into the second or third trimester. There were 49 wcnmen who

used a newer SSRI through three trimesters ot pregnancy.

Table 8 - Breakdown by Exposure and Trimester of Exposure trimes ter total ('/O) fluvoxamine paroxetine sertraline

Sc\.cral ccntre-; had cases ot tiVorncn tvlio iaLlcd after :ising CI nc\\.t.r SSRI in the first

trinw,ter, but ivcrc ~mable to pro\.idc accuratc information regarding stop dates u t rncciicationc;.

Clne t\.ornnn iiscd paroxetine in the first trimester .and sertraline in the third trimester. Slic

ic; tiieretore classified under first trimester paroxetine use.

$ Four Lvornen used more than one of the newer SSRIs, therefore the totals for tlic indi \ . id~i~i l

SSNs d u not add rip to 267.

Four of the women used two different SSRIs in their pregnancy. One ot these

wnmen usecl sertraline through three trimesters and f luwwmine for one week in

the first trimester. Two women used paroxetine in the first trimester and switched

to sertraline at 10 weeks post-LiMP. Both of these women used sertraline t» term.

Finallv, one cvoman used paroxetine in the first trimester and sertraline in he r third . .

trimes ter.

Tl-iere were signif ican t differences between the SSRI-exposed group

several variables (Table 9). Women in the SSRI-exposed group l-iad

and the BPG for

higher graviditv

and higher numbers ot prelrious therapeuetic abortion, and thev reported a higher

rate of smoking.

Table 9 - Matemal Dernographics: SSRI-Exposed vs BPG

variable* SSRI- BPG p-value exposed

gravidity (g) g = 1 er = 2+

previous spontaneous abortion (SA) SA=O 157 205 0.91

SA = 1+ 49 61

previous therapeutic abortion (TA) TA = O 166

TA = 1+ 40 -

tobacco consumption

Yes no

- -

alcohol consumption

Yes no

matemal age at conception

* Sarrral centres had missing iniormation for various parameters.

The cases of children born tvith structurai malformations are described in Table IO

on the following page. For the SSRI-exposed women, the medication, dose and

time-frame of use are also outlined.

3 -fi r; u w

A CI

3 > . C.

Y

c; - 3

5 J 1 - -n f i J

C L

.n y: 0 /

Cc,

u

CZ

13 TL, -4

-5

-5 - -4

l- II

u . . . - - 2 C t: f - a r c L

Ln summarv, there were 7 confirrned cases o i major structural malformations in the

children of women exposed to a newer SSM in the first trimester. Adclitionallv,

there were trvo children with unconfirmed diagnosis. Due to these, statistical

analvsis was performed twice, once excluding (Table 11) and once including (Table

12) these two cases as major structural malformations. In the control group, 9 of the

children were born with a major structural malformation. Note that major

structural malformations were only assessed for live-bom children, so that the totâls

reflect the number of live births and not the total cohort. The number ot [ive-Lwrn

children in the SÇRI-expose group was 222, and the number in the BPG [vas 233.

Table Il - Major Structural Malformations - Al1 SSRls

major structural SSRI-exposed BPG p-value

malformation

ves 7 9 0.S9

-- - - . - . -- . -. -. .

relative risk (95% confidence interval) = 0.82 (0.31-2-17)

Table 12 - Major Structural Malformations - All SSRIs

major structural SSRI-exposed BPG p-value

malformation

total 333 335

relative risk (95% confidence intervail = 1.06 (0.43-2.62)

When pregnancy outcome was compared, there were no significant differences

betiveen the groups (Table 13). Trvo neonrital deaths occurred in the BPG. Both

children died shortly al'ter delivery. No defects were observecl in the tirst cliild, but

the second child had a venticular-septal defect. In the SSRI-exposed & - qroup, «ne

child died at three weeks of age after an operation to repair an unspecitieci heart

defect.

Table 13 - Pregnancy Outcome - Al1 SSRIs

pregnancy outcome SSRI-exposed BPG p-value

live birth --- 377 -33 O. 24 31-

- -

early spontaneous abortion 24 16 0.25

6 -

late spontaneous abortion 3 1 .O

therapeutic abortion 15 9 t1.30

ectopic pregnancy 0 O

s tillbirth O 7 O .50

X cornparison cif hirth weight and gestational age for live-born children between the

two jiroups did not reveal nnv statisticallv significant difterences (Table 14). Eight O t

the live-born children in the SSRI-exposed group were of low birth weight (i-s.. less

thnn 2500 g), and 15 of the live-born children in the BPG were of Iow birth weight.

Sixteen children in the SSRI-exposeci group were premature (i.tV., born at less than 37

weeks post-LMP), and 13 children in the BPG were premat~ire.

Table 14 - Birth Weight and Gestational Age for Live-Born Children

- AI1 SSRIs

variable SSRI-exposed fn) BPG (n) p-value

birth weight (g) 3439 + 505 (218) 3445 I 610 (235) 0.92

gestational age 39.4 + 1.7 (204) 39.4 11: 1.9 (235) 0.72

(wks)

Table 15 on the following page lists the other findings, including minor

maiformations, genetic svndromes and deformations.

A total of 26 tvomen used fluvoxamine in the iirst trimester. When materna1

demographics were compared between the Cluvoxamine-exposed and the BPG (Table 16), onlv tobacco consumption was significantlv different. Women in the

iluvoxamine-exposed group smoked more than ivomen in the control group.

Table 16 - Materna1 Demographics: Fluvoxamine-Exposed vs BPG

variable* fluvoxamine BPG p-value

gravidity (g)

g = 1

g = 2+

previous spontaneous abortion (SA)

SA = O

SA = 1+

previous therapeutic abortion (TA)

TA=O TA = 1+

tobacco consumption

Yes no

alcohol consump tion

Yes no

materna1 age at conception

---- - - -

* Se\.craI centres h.id missing information for various parameters.

Most of the fluvoxamine-exposed women were using the drug at the time tiiet-

conceived (n=17, data available for 24 women). The mode for dailv dose was 50 mg

(n=ii , data available for 23 women). The highest reported daily dose was 200 mg.

There were no major structural malformations in the liveborn children of wornen

who used fluvoxamine in the first trimester (Table 17). This tvas nat ~tatistica11v

different from the control group.

Table 17 - Major Stmctural Malformations - Fluvoxamine

major structural fluvoxamine- BPG malformation exposed

p-value

ves 0 9 1 .O

total O- 37 235

relative risk (95% confidence interval) = 1.00 (0.83-1.21)

There was a ratio of 10.7:l for non-exposed women to fluvoxamine-exposed wornen

whose pregnancies ended in a live birth. The relative risk detectable by the wmple

size, using the same parameters as the sample size calculâtion in Table 4 h.., CL =

0.05, a = 0.80, and a baseline risk of 0.05 in the general population for major

structural malformation), was 5.6. This altows a 38% risk of major structural

malformation due to flwoxamine use in the first trirnester of pregnancy to he ruled

c'iut.

Tables 18 and 19 outline the pregnancy o~itcomes of the fluvoxamine-esposed

women and the BPG. There was no signifiant differences between the trvo groups

in anv of the outcornes. There were no differences in either the birth tveight or the

gestational age of Iive-barn children. One child was premature and was oi loti- birth

weight in the fluvoxamine-exposed group.

Table 18 - Pregnancy Outcome - Fluvoxamine

pregnancy outcome fluvoxamine- BPG p-value exvosed

live birth - 77 235 0.54 -

earlv spontaneous abortion - 7 16 0.67 -

O -

late spontaneous abortion 3 1 .O

theraveutic abortion - 3 9 0.25

ectopic pregnancy O O

stillbirth O - 7 1 .O

Table 19 - Birth Weight and Gestational Age for Live-Born Children

- Fluvoxamine

variable - -

fluvoxamine- BPG (n)

exposed (n) p-value

- - - - - -

birth weight (g ) 3434 + 529 (22) 3445 I 6 10 (235) 0.93

gestational age 39.3 F 1.8 (21) 39.4 -t 1.9 (235) 0.77

A total of 97 women were exposed to paroxetine in the first trimester. When

demographics of these women were compared to those of the BPG (Table

paroxetine-exposed women were found to smoke more than their controls but were

similar in al1 other variables measured.

Of the cases cvith information on the medication start date (n=72), most of the

women started paroxetine before thev were pregnant (n = 63). The dailv close rangeci

t'rom 10 to 61) mg (information amilable for 69 rvomen) and the mode t ïas dosage

kvas 30 mg od (n=39).

Table 20 - Materna1 Demographics: Paroxetine-Exposed vs BPG

variable paroxe tine- BPG p-value

exposed* . - - -. . - - - -

gravidity (g) g = 1 24 90 O. IS

g = 2+ 70 177

parity (p) p = O 38 125 0.51

p = l+ 53 142

previous spontaneous abortion (SA) SA=O

SA = l+ - - - - - - - - - - - -

previous therapeutic abortion (TA) TA = O 54 235 0.23

TA = 1+ 12 31 - -

tobacco consumption

Yes no

- -

alcohol consumption

Yes no

materna1 age at conception

* Seirerd centres h.id missing intorrnation ior i-arious parameters.

Five of the offspring born to ivomen exposed to paroxetine had a major structural

malformation (reier to Table 10). When statisticallv compared, the rates between the

two groups were not significantly different (Table I l ) .

Table 21 - Major Structural Malformations - Paroxetine

maj or structural paroxetine- BPG p-value

malformation exposed -

Yes 3 9 0.34

total 76 235

relative risk (95% confidence intemal) = 0.57 (0.20-1.68)

The ratio of non-exposed women in the BPG to parosetine-exposed women u-ho

had live-born children tvas 3.1:l. This allows a relative risk of 3.1 (17%) to be ruled

out for an increased risk of major structural maiformation due to paroxetine.

Tables 22 and 23 outline the pregnancy outcomes of the paroxetine-exposeci women

and the BPG. When the rate of live birth was compared to al1 other outcomes

between the two groups, women in the paroxetine-exposed group had a significantly

lower rate. Neither birth weight nor gestational age were statisticallv difterent

between the two groups. Eight children born to mothers who used parosetine in

pregnancy were premature and five were of low birth rveight.

Table 22 - Pregnancy Outcorne - Paroxetine

pregnancy outcome paroxe tine- BPG p-value

exposed

Iive birth 76 235 0.03

early spontaneous abortion 12 16 0.07

Iate spontaneous abortion 3 5 0.44

therapeutic abortion 6 9 0.24

ectopic pregnancy O O - s tillbirth O 3 1.0

o n e child in thc BPG m d onc child in the paroretinr-exposed group clicri in the nronotal

periocl

Table 23 - Birth Weight and Gestational Age for Live-Born Children - Paroxe tine

variable paroxe tine- BPG (n) p-value

exposed (n)

birth weight (g) 3424 _+ 600 (74) 3443 k 610 (235) 0.79

gestational age 39.2 i 1.9 (66) 39.4 k 1.9 (235) 0.29

A total of 147 women used sertraline in the first trimester. The maternai

demographics for these women and their controls are described in Table 24. The

women in the control group had a lower gravidity then the sertraline-eposeci

women. CVomen in the sertraline-exposed group smoked more than the women in

the BPG.

The majoritv of the sertraline-exposed women were using the drug at the time of

conception (n= 102, information available for 115 women). Dosage da ta were

available for 93 women. The dailv dosage mode was 50 mg ( n = 3 ) , and the daiiy

close ranged from 23 mg to 150 mg.

Table 24 - Matemal Demographics: Sertraline-Exposed vs BPG

variable* sertraline- BPG p-value

gravidity (g)

g = 1

-- - - - - -

previous spontaneous abortion (SA)

SA = O

SA = 1+ - - -

previous therapeutic abortion (TA) TA = O

TA = 1+

tobacco consumption

yes

no

alcohol consumption

Yes no

materna1 age at conception

* Sc\.crûl ccntrcs Iiad missing intorrnation for various parameters.

There were two children with confirmed major structural malformations in the

offspring of women who used sertraline in the first trimester ( T d d e 10).

Additionallv, there rvere two other anomalies reported without enough

information to label ciefinitively as major structural malformations. Due t» these

two cases, cornparison of major structural malformations between the two groups

was performed excluding these cases (Table 25) and including them (Table 26). The

two groups did not differ in either analysis.

Table 25 - Major Structural Malformations - sertraline

major structural sertraline- BPG p-value

malformation exposed

ves 7 - 9 O. 34

relative risk (95% confidence interval) = 0.51 (0.14-1.80)

Table 26 - Major Structural Malformations - Sertraiine

major structural sertraline- BPG p-value

malformation exposed

total 127 235

relative risk (9SoA confidence interval) = 0.82 (0.26-2.62)

There was a ratio of 1.9:l of women in the BPG to sertraline-exposed women whose

pregnancies resulted in a live birth. Post-hoc analysis reveals that the relative risk

of major structural malformation d u e to sertraline that may be ruled out h y this

shidv was 2.9, or 14.5'%.

The pregnancv outcornes of the women who used sertraline in the Cirst trimester

and their controls are summarized in Tables 27 and 28. There ivere no significrint

differences between the two groups for any of the variables measured. Tivo oi the

children in the sertraline-exposed group had low birth weight and 7 r w r e

prematurely born.

Table 27 - Pregnancy Outcome - Sertraline

pregnancy outcome sertraline- BPG p-value exposed

Iive birth 127 235 0.75

early spontaneous abortion 10 16 0. 9 1

3 - late spontaneous abortion 3 1 .O

therapeutic abortion 7 9 0.66

ectopic pregnancy O 0 - s tillbirth O - 7 0.54

one child in the BPG died in the neonatal prriod

Table 28 - Birth Weight and Gestational Age for Live-Born Children - Sertraline

variable sertraline- exposed (n)

BPG (n) p-value

- - - - -

birth weight (g) 3440 f 339 (125) 3445 I 610 (235) 0.93

gestational age 39.5 + 1.6 (120) 39.4 k 1.9 (235) 0.86

iwks)

3.6. EXPOSED FROM FIRST TRIMESTER TO THIRD TRIMESTER

A total of 49 women used one or more of the newer SSRIs through three trimesters

o t pregnancv. Al1 of these pregnancies resulted in a live birth. There were no

statistical differences betrveen the exposed and control groups for anv of the

Jemographic variables, except for increased use of tobacco in the esposecl g o u p (Table 29).

Table 29 - Materna1 Demographics: SSRI-Exposed from First Trimester to

Third Trimester vs BPG

variable' SSRI- BPG p-value exposed

gravidity (g) g = 1

previous spontaneous abortion (SA)

SA=O

SA = 1+

previous therapeutic abortion (TA) TA=O TA = 1+

tobacco consumption

alcohol consump tion

Yes no

materna1 age at conception

* Several ccntres h.id rnissing inionnation for various p.iranietcrs.

In the group of women exposed to a newer SSRI from the first trimester into the

third trimester of pregnancv, there were three major structural malformations (cases

#18S, #205 and #170). This did not statisticallv differ from the proportion of major

structural malformations in the control group (Table 30).

Table 30 - Major Structural Malformations - SSRI-Exposed From First Trimester

to Third Trimester

major structural SSRI-exposed BPG malformation

p-value

ves 9 0.44

- . -

total 49 235

relative risk (95% confidence interval) = 1.60 (0.45-5.69)

There was a ratio of -1.8 control pregnancies to each pregnancv exposed to a newer

SSRI through three trimesters of pregnancy. This ratio and the sample size oi 49

pregnancies nllows a relative risk of 4 to be ruled out.

The birth weights and the gestational ages oi the children were not different

between the tivo groups (Table 31). Since the women who were exposed to a newer

SSRI ~int i l the third trimester al1 had live born children, nominal pregnrincv

outcornes were not compared to the BPG. Three of the 49 cl-iildren born in the

SSRI-exposed group had low birth weight and 4 were premature.

Table 31 - Birth Weight and Gestational Age - SSRI-Exposed From First Trimester to Third Trimester

variable SSRI-exposed (n) BPG (n) p-value

birth weight (g) 3333 k 569 (48) 3445 k 610 (235) 0.24

gestational age 39.0 + 1.9 (48) 39.4 + 1.9 (235) 0.14

4.1. RESEARCH IMPLICATIONS - NULL HYPOTHESIS NOT RETECTED

First trimester exposure to the necver SSRIs did not increase the rate of major

structural malformations when compared to a control group of women rvho were not exposed to anv known teratogen in pregnancy. When each drug was ânalvzed

separately, results were similar.

.A structural malformation c m be associated with a d rus if exposure occurred a t the

time of structure formation. For example, thalidomide caused phocornelia onlv if

taken when the limbs were forming. Therefore, major structural malformations in

the SSRI-exposed group are individually assessed for overlap between timing of

drug exposure and organ formation in the foliowing paragraphs.

du pli catin^ renal svstems

Duplex ureters are cornmon (the approximate rate is 1/150), often inherited anomalies that rire frequentlv a s ~ m p t o m a t i c ' ~ ~ ~ C I t riras not possible to determine i f

cases #9 and #12 were inherited, so thev were classified as major structural

malformations rather than genetic anomalies in this study. This tvpe of

malformation is thought to occur when the pelvic end of the ureteric b ~ i d is expanding and dividing, approximateiy between 8 to 13 rveeks post-LMPh3. The

mather had stopped the medication before the 8 week point in both cases. therefore

neither case is likelv to be associated with the use of sertraline.

aeenesis of the corpus cailosum

Xgenesis of the corpus callosum is a complete M u r e of the allosal commissural

fibers to cross the midline and form the corpus callosum. The rate of this defect

ranges from 1 /1670 to 3 /1000f~~ , though it is likely higher since i t often goes

~indiagnosed when not associated with a syndrome"? Though the corpus callosum

forms between weeks 13-22 post-LMP, Barkovich and Norman (53) be1it.w that

agenesis of the corpus callosum is due to damage a t about 10 weeks post-LMP, before

the structure develops. Materna1 exposure to paroxetine (case #77) occurred

between 6 and 14 weeks post-LMP, so an association with the drug cannot be ruled

out.

ovarian cvsts

Neonatal ovarian cvsts are primarily of follicular origin and likelv develop et about

30 weeks post-LMP during folliculogenesis~~~. Thev mav form in response to

excessive stimulation of the fetal ovary by both placental and maternai hormones.

Neonatal cysts tend to occur more frequently in the offspring of mothers who had

diabetes, toxemia, or rhesus immunization during pregnancv. These comp l i a tions

a re hvpothesized to either increase placental secretion of human chorionic

gonadotropin or increase placental permeabilitv to human chorionic gonadotropin.

Case #170 did not suffer from anv of these complications and used parosetine

throughout her pregnancy; thus,the drug might be associated with the defect. The

ovarian cvsts were diagnosed at 7 months of pregnancy by ultrasound. Thev were

surgically removed in the neonatai period, along with an ovary and a fallopien tube.

bilateral clubfoot

Tho~igh clubfoot occurs rela tively frequentlv ( 3 . W 1000) 1" the etiology ot this defect

is ~ inknorvd~? Orthopedic surgeons hâve tounci clubfoot in products of conception

as early as 12 weeks post-LMPhY. Clubfoot can occur with varyinç degrees of severity,

and though tliere is currentlv no svstem for defining the severitv, the bilateral

clubfoot of the child in the SSRI-exposed group was corrected surgicallv so i t c m be

essumed that i t tuas CI seiverer forrn. As the mother of the child with c lubhot had

used parosetine tintil 31 weeks post-LMP, it is possible that the drug rvas associated

with the defect.

cardiac defects

The h a r t forms t'rom week 5 to week 11 post-LMP. Cardiac malformations occur in

about 5 to 8 of every 1000 live births? There were two cases of a child born with a

cardiac malformation. In one case (#197) the mother used sertraline until S weeks

post-LMP and in the other case (#222) the mother used paroxetine in the first

trimester for an unspecified arnount of time. In case #197, the drug exposure and

time of heart formation overlap. In case #222, while it is known that the mother

ujed paroxetine in the first trimester, a stop date (if any) is unknown, so rvhether

drug use and heart formation overlap is undetermined. In both cases the

underlying structural malformation was not recorded by the teratogen information

service. however case #272 needed an operation to repair the malformation at threr

weeks postnntally, thus i t can be assumed that this was a major structural

malformation. There was not an exact diagnosis for case #197, which ma)- have

been a minor cardiac malformation such as a left vena cava. Since there was no!

enough information to label definitively the anomaly as either major o r minor,

sensitivity analvsis was performed including and excluding case #197 as a major

structural malïormation. Given the Lack of information in both cases, it is difficult

to assess whether the drug could have been associated with either defect.

external auditorv cana1 stenosis

This defect is normally associated with a genetic syndrome or microtia (hypoplasia

of the auricle) and isolated external auditory canal stenosis is quite rare (2/100,000)3'.

The child of case #200 was awaiting testing to confirm diagnosis of estemal auditor!.

canal stenosis without microtia when the family moved and the teratosen

information service lost touch with the farnily. This child may have subsequently

been tested and found to have one of the several genetic syndromes associated with

this defect. but as this \vas unknown the case was included as a major structural

malformation. Since diagnosis was not cont'irmed a sensitivitv analvsis was

performed. The external car forms from 7 1 / 2 weeks to 24 weeks post-LM? As the

mother stopped using sertraline at 6 weeks post-LMP, this defect is not likely

attributable to use of sertr a 1- me.

pvloric stenosis

Pvloric stenosis is the hvpertrophv of the muscular pyloric canal, leading to a

thickening of the pvloric wall and a reduction in the size of the lumen? It is a

relativelv cornmon defect (3,4000) and usuallv arises in the late perinatal period or

early postnatal life? Rollins" performed ultrasound examination in the neonatal

period on 1400 consecutive infants which were al1 negative for pyloric stenosis, yet

nine children later developed pyloric stenosis. However, pyloric stenosis can occur

in early embryogenesis. I t can also be a familial trait or associated kvith genetic

svnctromes (70). Since the rnother ~ised paroxetine throughout her pregnancv and i t

is ~inknown if the pvloric stenosis was present at birth, the defect mav be associated

with the drug.

In summarv, of the nine major structural malformations reported in the SSRI-

exposecl group, an association between the newer SSRI and the defect mav not be

ruled out for six of them.

4.1.2. PREGNANCY OUTCOME

There were no differences between the SSRI-exposed women and the BPG in any of

the measured pregnancv outcome variables. When each SSRI was analyzed

separa tely, paroxetine-exposed rvomen had a significan tlv lower rate of li\-e birth

than the BPG. I t must be remembered that a large number of cornparisons were

performed in this study, and this finding may be due to chance (type I error). I f the

lorver lil-e birth rate in the paroxetine-exposed group was clinically significant, ive

~ v o u l d espect to see a corresponding increase in another nominal pregiiancy

uutcome variable, such as rate of early spontaneous abortion. Since this was not

seen, likelv this finding is not clinically significant, though further studies rïit1.i

larger sample sizes ma y chri- this.

Children born to mothers who smoke have been tound to have a significantl>r lower

birth weight than the offspring of non-smoking womenï3. Therefore, it is curious

that although there was a higher rate of tobacco consumption in the SSRI-esposed

group, there was no difference in the birth weight of live-born children wlien

compared to the control group. Children exposed to one of the newer SSRIs i i i

i r t~v-o may have a higher birth weight. To determine if this is so, post-hoc analysis

compared the birth weights of liveborn children born to SSRI-exposed mothers who

did not smoke to the birth weights of the liveborn chiidren in the control group

(Table 32). Nci s ta tistical difference was seen.

Table 32 - Birth Weight of SSRI-Exposed Non-Smokers vs BPG

SSRI-exposed BPG p-value

There are se~*eral possible explanations. In this study, a woman was considered a

smoker if she reported tobacco consurnption at anv time during pregnancy. If the

woman reported smoking at the time of initial interview, but quit a t 10 cveeks oi

gestation, she was still categorized as a smoker. It is known that if a woman quits

smoking earlv in pregnancy, the effect of smoking on birth weight is negated?

Additionallv, there is a dose-response seen between the amount of cigaret tes

smoked per dav and the decrease in birth weight, the higher the number of

cigarettes, the lower the birth weight? [f a woman in the SSRI-exposed group rvas

smoking one cigarette a day, the birth weight may not have changed to an\ -

significant extent. Since the amount of cigarettes smoked per day and exactlv when

in pregnancy the cvoman smoked were not recorded in this study, it is not possible

to take the above factors into account when analyzing birth weight and tobacco

consump tion.

4.2. LIMITATIONS OF THE STUDY

Recall bias is a potential in any retrospective studv. In this study mothers were

interviewed earlv in pregancv about their current esposure historv, hcnvever,

follow-up required maternai recall of events occurring in pregnancy after the initial

interview. These could not have changed, however, either the primarv outcome

measure (major structural malformations) or the primary independant variable

(esposure to a newer SSRI), however, recall bias mav have affected two ot the

secondary outcome measures of interest, namely birth weight and gestational age.

A recent studv found that there was a high correlation between maternal recall and

medical records for gestational age and birth weight7K However, there was a poor

correlation for post-deliverv complications/problems and pregnancy complications.

These results did not significantlv differ when the time between delil-erv and

maternal interview \vas taken into consideration. Additionallv, a l tho~igh

klotherisk routinelv requests the labour and delivery forms t'rom the child's

plivsician, otten the phvsician does not have these forms because either he/shc is

iiot the mother's physician or he/she simply did not receive a copv. From my

experience interviewing patients. though questions regarding pregnancy and

delivery complications are asked, the rnothers a re uncertain of the mecliccil

definitions. For cxample, when asked about k ta l distress they mav recall that "the

heart-rate went up, so yes, there was fetal distress", but wlien the deliverv report is

received, this \vas not defined as fetal distress. Therefore, this thesis did not ~7naIvze

ma ternal pregnancv complications and post-delivery complications.

A patient was considered lost in the following events:

phone nurnber not in service/wrong phone number, no new listing in phone

book/directorv assistance

no answer after contact attempted over a period of two months a i least 10

tirnes/phone number on different days, at different times

no longer at work place, no forwarding phone number

patient deceased

The concern with follow-up loss is if there is a difference in pregnancv outcome in

the women included in the study and those who were iost to follow-up. A s there is

no way to determine whether or not this is the case, baseline maternal

demographics were compared between women included in the s t ~ i d v and tl-iose who

were lost to follow-up.

When the Motherisk cases that were successfullv followed up were compared to

those that were lost to follow-up (Table 3, almost none of the variables differed

statistically between the two groups, except for ethanol consumption. The ~vornen

who were interviewed after pregnancy reported a higher rate ot ethanol

consumption. Though Motherisk records ethanol and tobacco use on intakc and

clinic forms, it is a report about the mother's current habits. During follon--up, the

motlwr is asked about exposures throughout the pregnancy. This mav account for

the difference in ethanol reporting between the two groups.

4.2-3. DEMOGRAPHIC DIFFERENCES BETWEEN EXPOSED AND CONTROL GROUPS

I f there are differences in the maternal baseline demographic variables, it may

indicate that women from two different populations are being observed. I f this is

truc, the groups mav not be comparable due to confounding variables.

Wumen in the SSRI-exposed group smoked more than those in the BPG (Table 9).

This is not surprising as it is well documented that tobacco consumption is

associated with depression;;t's? This pattern was also seen when each of the

SSRIs were analvzed separately. Women in the SSRI-exposed group had a

significantlv higher graviditv and number of previous therapeutic abortions when

compared to the control group. The higher number of previous therapeutic

abortions is likelv associated to the higher gravidity. When each drug was analvzed

separatelv, hoivever, onlv sertraline-exposed mothers had a higher rate of graviditv

compared to the control group. Post-partum depression occurs in about 1>"1, of

women after the birth of a child". Additionally, depression commonlv occurs after

a spontaneous abortion"' S. If women were treated by an antidepressant due to

post-partum depression or depression following a fetal death, this mav esplain the

finding of higher gravidity in the SSRI-exposed group.

This studv could only rule out a 2.5-fold increase in baseline risk. However, many

known teratogens cause an increase in baseline risk below this level. Valproic acid

for example, increases the risk of neural tube defects from about 0.13":, to 1-2%"'.

Though this is a 17-fold increase in the risk for neural tube defects, i t is onlv a 1.4-

M d increase in the baseline risk for major structural malformation. The sample

size of this strtdv would not have been able to detect an increase of that size. Future

studies with larger sample sizes would increase the power to detect a smaller

increase in the baseline risk of major structural malformation.

4.3. RECOMMENDATIONS FOR FUTURE RESEARCH

Although this studv has provided initial results on the safetv of the newer SSRis in prepancy, future study is required. While each of the drugs studied beiong to the

same drug class, thev are distinct in their structure, pharmacokinetics ancl

metabolism. For these reasons, each d rug should be studied indiviiluallv. Concurrently, the sample sizes couid be increased. As mentioned above, an increase

in sarnple size is necessary to rule out a smaller relative risk. Future cohort studies

are thus needed.

It is becoming evident that not only structure c m be affected by drug exposures, but

brain tunction as well. In the case of medications such as antidepressants and

antiseizure drugs with their primary site of action on the brain, this concern mav be

well-fo~~nded. For example, children exposed to pheny toin in trtrro haci lower

global intelligence quotients (IQs) thân a control g r o u p u . Rejiarding

antidepressants, ri recent study exarnined the neurodevelopment of pre-school

children whose mothers hâd used fluoxetine or tricyclic antidepressants in the first

trimester of pregancy? Of the children assessed, 55 had been exposed to fluoxetine

and ranged in age from 16 to S6 months (mean, 33 f 14). The global intelligence

quotient (LQ) of these children (117 + 17) did not differ t'rom the two control groups

consistirtg of children esposed to tricyclic antidepressants (n = 80, IQ = 11s + L7, and

children not exposed to anv known teratogen (n = 8-4, IQ = 113 k 14). A s « testecl and

not iound to differ were language and behavioural development. This stuciv was

onlv able to identify structural abnormalities, yet the full picture of fetal drug safety

includes exploration of functional abnormalities. Future studies on the cl-iildren

esposed to the newer SSRis i l i iriero followed-up by Motherisk are therefore

warranteci.

4.4. RECOMMENDATIONS FOR COUNSELLING AT MOTHERISK

4.4.1. WOMEN PLANNING PREGNANCY AND PREGNANT WOMEN PLANNING TO U S E A

NEWER SSRI

Though the results of this study are reassuring, the sample size (POWER) was too

small to draw definitive conclusions (see section 4.3.5). As there are manv other

antidepressants such as fluosetine and the TCAS" currently aïailable fur which

more data regarding pregnancy exist, counselling should direct the woman or her

health care provider towards a different antidepressant medication. Further, since

Çluoxetine and the tricvclic antidepressants have been found to be also safe in

neurodevelopmental studies", they should be the cirugs of choice. If the woman is

unable to use u different anti-depressant (Le.. when previous trials with fluoxetine

and tricvclic antidepressants have been unsuccessful), a clinic appointment with one

ut the Motherisk team phvsicians should be arranged to ensure that the intorrnation

is clearly understood by both the patient and the patient's health care provider.

4.4.2. WOMEN WHO ARE CL'RRENTLY PREGNANT AND USING A NEWER SSRI

Although the newer SSRIs did not cause a large increase in the baseline risk t'or

major structural malformations, a smaller increase cannot yet be ruied out due to

the sample size. The patient and/or health care provider, therefore, sl-iould be

counselled that a n initial study did not demonstrate an increased risk, but thùt therc

are other antidepressant medications for which there is more experience with use in

pregnancy. Separate analysis of each of the newer SSRIs did not suggest an increased

risk of major structural malformations, however, the sample size varied between

the drugs. While both sertraline and paroxetine had a relativelv large sample size (n =147 and n=97 respectively), for an initial prospective cohort studv, the sample size

available for t'lu\-oxamine kvas quite small (n=26). Based on these sample sizes,

women usin): fluvoxamine should be offered a c h i c visit to thoroughly review the

information xailable with a team physician. Women using either paroxetine or

sertraline may be counselled over the phone regarding the results of the s t~ idy , and

i f she is anxious, a clinic visit should be suggested.

Figure I - Mothensk Intake Form

~ O C I

mmpldcd O pasrd ln rJIow0 -pCPrv 0VK;OWG:

aiicofbinh h o ? YQ ~ 0 0 ~ v i s e d O lun~:

oooiplacd by: R c r d by: > Hdrh cnrd P

G P S A TA- & ï ~ i a p r * i a n ~ ? k o ~ a

Gdncy N o 0 Y u

H u n N o 0 Ya

Hypprnisioa N o 0 Ya

Diabcia N o 0 Yes

Rcspirztory N o 0 .Yu

Thymid N o 0 Y u

Fsychiairic N o 0 Ya

Epilepq N o 0 Yu

Viumin suppIerncnutian? N o 0 Ycs:

O<her

Cilnlc date: bring transhtor O

Refend ha& ta MD for suqqesfi~n of medications 5 1

Figure 2 - Motherisk Clinic Fonn

1 MOTHERISK PROGRAM ANTENATAL CLlNlC FOR DRUGICHEMICAL RlSK COUNSULING THE OlVlSlON OF CLlNlCAL PHARMACOLOGY. HOSPiTAl FOR

SlGK CHILDREN. TORONTO, ONTARIO

MOTHERISK NUMBER CONSULTATION DATE (dmily)

MATERNAL DATA

NAME: Biological fethcr's name:

Addrmss: Address: crme as mocher [ ]

Ikte of b l m (m) ~ i t e of blrlh (-1 HOm tdophoru: ( ) Homa Ukphono: rrns [ 1 [ 1

Work tikphonm: ( ) Wark toiophoru : ( )

Contraception

Last Menstrual Period (w ~ y d r -y - days r - days bleeü-ü~

Expected Dellvery Date (-1 Cunent Gestational Age - wk [ j ,-th [ 1 b v : & a a + I l u-[l

Regnancy dlagnosd at wks [ ] manths [ 1 By whkb rnthod? [ 1 bbod tasi [ 1 urina lm [ ] uttrasaund

PRlMARY E X P O S U INFORMATfON

A. Over-ihe-counter and PmscripUon Medicallons OR Radbtlon

B. Chernical Exposures

Ocaipation Tik: matemalD ~aternatu

STAR7 DATE of oxposum STOP DA= of exposrar

Siart date 1 1 1

, Additional Room on page 8

3

ADDKIONAL MATERNAL EXPOSURES & HlSTORY

Genetic Disease or Malformations ND ~a Relative of mother Condition ReMk of

biokfflcal father Condttkn

PAST MATERNAL MEDICAL HISTORY

Cancer NO YU Cardiovascular NO YU mntrai nemous systarn NO Y O Diabetes ND YU Epitepsy NR YU Hematology NU Yu Hypertension NO YU Rena t disease NU YU Thyroid disesse NU YU

BlOLOGlCAL F ATHER DATA

ORUG NAME

Indication for meâht iun kbnc &tails &bout madical wnditiùn

Tobacco NU Y a cgarsnss per day (1 wsek [ ] rvsdrend [ j manth [ ]

Cocaine NO YU duringpiqnancy p e r d a y [ ~ w e e k [ ~ ~ ~ [ l Marijuana NO Y U d n p w o p n y p c r d a ~ [ l - k [ l - - j [ l mmI1 LSD N Y a during pragnancy p e r d a ~ [ l w - k [ I ~ ~ [ l m~mil

A. Tendency to continue / terminate pregnancy

B. Patient's perception of rfsk of major birth defects In the fetus

1 I I NONE f4MC

no diSnce baby w3i definite@ be ttiaibabywüfbe barn wüh a bhfh defect h m wilh brilh

defed

CI Petient's perception of basellne risk for birth defects in the general population

Figure 3 - Chernical Structures of the Selective Serotonin Reuptake Inhibitors

Fiaure 4 - Motherisk Follow-Up Form

Pregnancy Follow Up Form MOTHERISK PROGRAM

Clinic Number

Date of lntewiew lntem-ewer

A. GENERAL

B. PREGNANCY OUTCOME

C. OISEASES COMPUCATlNG PREGNANCY

D. MPOSURES DURING PREGNANCY

Did you u s any zhing for ilkglu, mxkty, -16, c o i r d l p d o ~ dqwudon. dlirrhu, hudich., haartburn, pal% mlght

Ouupauon during prcgnuicy *job da4iption (WWT W U SHE DO?) stanrd smppcd Rclsan

QCPOSURES? c)icmid 0"" OP: wmpuœr o n 0 O F &n O F noidvibracion ana

E. TESTS DURlNG PREGNANCY

Chononic villus nmpling Alpha-fcco prorcin üitnsound

F. DELIVERY INFORMATION

Matemal Neonatal

We*r prc-prcg-cy - Ib k g HospiuJ/City

For wr own documentation, which wll help aher women expasad 10 the same dnigs ttrat you were exposed to. wuild yw d w e wiih os wtiether ywr chi@ was bom with any birth defeds?

G, NEONATAL HEALTH

OTHER

H. MILESTONES

Darc lerta s a i t Dace lccrer rcccivcd

1. CONSENT -

Wo wlouid Iiki to wnd a kttn to your chlWa doctorto conilnn mrdW chtalh of t h im tolbwup. Mey m hnn your wibil p.nnl#lon to wnd thb?

OBTAlNEO COUSEKT 0 no O p*

Fieure 5 - Motherisk Follow-Up Letter to Offspring's Health Care Provider

5 5 5 UNIVERSITY A M N U E TOROKïO. OhTANO CWAD.4 M5C 1- THE HOSPITAL FOR SICK CHILDREN PHONE (416) 813-I5O<)

Dr.

b Dr. :

Re: D.O.B.

On I W X X G . your patient's rnother was counselled by rhc Motherisk Program at

the Hospital For Sick Children. During a telephone interview to ascertain pregnancy

outcorne. we were given verbal consent to contact you to corrobonte the medical

details of XXX's health.

If available, would you send us a copy of the hospiral's labour and delivcry f o m

and a copy of the hospital's neonatd assessrnent r o m ? In addition. would you

pl- cornplere the attached form and return it to us ar the hlotherisk Program?

Thrink you for your anticipated CO-openrion.

Yours sincerely .

NathaIie A. Kulin BSc /Or Gideon Koren. MD. ABMT. FRCP(C).

Direcior. Morherisk h o p m

Mother's Name: Chiid's Name:

Original: patient number: Return forms to: Nathalie A. Kulin

Regarding the development of this child:

A. Major anomalies [ 1 no [ ] yes Description:

B. ,Minor anomalies [ ] no [ 1 yes Descriprion:

C. This child was 1st examined on (dd.mrn.yyl. At that m i l :

wcight

height 1 lengrh

head circurnference

D, Hosprtal labour & delivery fomts are included

Hospital nconatal assessrnent forms are included

Signaturc of physician:

Alcohol

Androgens

ACE inhibitors

Carbarnazepine

Coumarin

Cvclophosp hamide

Diethylstilbestrol

Dipheny lhydantoin

Etretinate

Iso tre tinoin

Lithium

Me thvlmercury

Misoprostol

Propylthiouracil

Radiation (fetal dose of 10 radsi)

Thalidomide

Valproic Xcid

Gregg NkI. Congenitâl cataract follorving yerman measles in the rnother.

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lMACjt LVALUATION TEST TARGET (QA-3)

APPLIED INIAGE . lnc - = 1653 East Main Street - -. , , Rochester. NY 14609 USA -- --= Phone: 7 t 61482-0300 -- -- - - Fax: 7 1 6/288-5989

O 1993. Applled Image. lnc.. Ail Rlghis Resewed