Neurodevelopment of Children Exposed in Utero to Antidepressant Drugs
Irena Nulman, M.D., Joanne Rovet, Ph.D., Donna E. Stewart, M.D., Jacob Wolpin, Ph.D., H. Allan Gardner, M.D., Jochen G.W. Theis, M.D., Nathalie Kulin, B.Sc., and Gideon Koren, M.D.
Background Many women of reproductive age have depression, necessitatingtherapy with either a tricyclic antidepressant drug or a drug,such as fluoxetine, that inhibits the reuptake of serotonin.Whether these drugs affect fetal neurodevelopment is not known.
Methods We studied the children of 80 mothers who had receiveda tricyclic antidepressant drug during pregnancy, 55 childrenwhose mothers had received fluoxetine during pregnancy, and84 children whose mothers had not been exposed during pregnancyto any agent known to affect the fetus adversely. The children'sglobal IQ and language development were assessed between 16and 86 months of postnatal age by age-appropriate Bayley Scalesof Infant Development or the McCarthy Scales of Children's Abilities(for IQ) and the Reynell Developmental Language Scales.
Results The mean (±SD) global IQ scores were 118±17in the children of mothers who received a tricyclic antidepressantdrug, 117±17 in those whose mothers received fluoxetine,and 115±14 in those in the control group. The languagescores were similar in all three groups. The results were similarin children exposed to a tricyclic antidepressant drug or fluoxetineduring the first trimester and those exposed throughout pregnancy.There were also no significant differences in temperament, mood,arousability, activity level, distractibility, or behavior problemsin the three groups of children.
Conclusions In utero exposure to either tricyclic antidepressantdrugs or fluoxetine does not affect global IQ, language development,or behavioral development in preschool children.
An estimated 8 to 20 percent of women have depression at sometime in their lives, most commonly during childbearing yearsand often requiring drug therapy.1,2 The decision to continueor initiate pharmacotherapy for depression during pregnancyis complicated by the need to balance maternal well-being withfetal safety. Although the first trimester of pregnancy, inparticular weeks 2 to 8 after conception, is the most criticalperiod for drug-induced malformations, the brain develops throughoutpregnancy, and injury may occur after the first trimester.3
There is ample evidence that discontinuation of antidepressant-drugtherapy in patients with medication-responsive illness may bedetrimental, with high relapse rates.4 The main drugs currentlyused in treating major depression are tricyclic antidepressantdrugs and agents that selectively inhibit the reuptake of serotonin.The latter have fewer anticholinergic and cardioarrhythmic effects,5but cause anxiety, nausea, and insomnia in a substantial proportionof patients.6,7,8
Both tricyclic antidepressant drugs and fluoxetine cross theplacental barrier. In studies of these drugs in animals, dosesmuch larger than those used in humans did not induce malformations.9,10,11Several small studies in humans have suggested that tricyclicantidepressant drugs are not teratogenic,12,13,14,15,16,17 butthe studies were not controlled for various confounders, suchas coexisting diseases and maternal lifestyle, that may affectthe outcome of pregnancy. In a comparison of 74 children exposedin utero to tricyclic antidepressant drugs, 128 exposed to fluoxetine,and 128 matched children who were not exposed to such medications,exposure to drugs during the first trimester was not associatedwith an increased risk of major malformations.18 More recently,Chambers and colleagues reported similar rates of major malformationsamong children exposed in utero to fluoxetine and unexposedinfants; however, the offspring of women who took fluoxetinein the third trimester were at increased risk for perinatalcomplications.19 The study did not control for coexisting diseasesand did not correct for the more severe nature of depressionamong women who needed the drug throughout pregnancy.
Despite the wide use of tricyclic antidepressant drugs and fluoxetineby women of reproductive age, the paucity of information onfetal effects has not allowed physicians to reassure women thateither exposure during the first trimester or continuous therapythroughout gestation is safe. This lack of data has createdanxiety among women planning pregnancies and pregnant women,as well as among their families and physicians. Although neithertricyclic antidepressant drugs nor fluoxetine causes major malformations,the possibility of long-term damage to the developing centralnervous system may deter women from taking these drugs, evenwhen clinically indicated.20 This study was designed to assessprospectively cognitive and language development and behaviorin children exposed in utero to tricyclic antidepressant drugsor fluoxetine.
Methods
The Motherisk Program
The Motherisk Program is an information and consultation servicefor women, their families, and health professionals regardingexposure to drugs, chemicals, radiation, and infectious agentsduring pregnancy and lactation. Women with major depressionwho contact the program are invited to visit the clinic to becounseled by a physician.
Selection of Patients
We recruited three groups of mother–child pairs for thisstudy. Two of the groups included the children of all womencounseled by the program during the first trimester of pregnancyregarding therapy with either a tricyclic antidepressant drugor fluoxetine. We excluded from the study women in whom antidepressant-drugtherapy had been discontinued before conception, those who tookmore than one antidepressant drug or were exposed to known teratogensduring the pregnancy, and those who were unwilling to participatein our follow-up program. We also studied a group of mothersnot exposed to any drug, chemical, radiation, or infection knownto affect the fetus adversely. This group, also assembled prospectively,consisted of women who had taken innocuous drugs such as acetaminophenor oral penicillin or who had had dental x-ray films obtainedduring pregnancy. The control mothers were chosen from thislist of women whose clinic appointments were closest (withintwo months) to those in the other two groups. The study wasapproved by the hospital's research ethics board, and informedconsent was provided by all women.
Assessments
Antenatal Assessment
During the initial assessment, at the diagnosis of pregnancyor within several weeks thereafter, we obtained a medical historyof each woman, including data on alcohol ingestion, use of medicinaland recreational drugs, smoking status, lifestyle, medical andnutritional status, and sexually transmitted diseases. A detailedgenetic and obstetrical history was also obtained. Informationconcerning the time of drug therapy was recorded, as were thedoses of tricyclic antidepressant drugs or fluoxetine and ofany concomitantly administered drugs.
Postnatal Assessment
The first postnatal assessment occurred six to nine months afterdelivery. During this interview the mother was questioned aboutthe course of her pregnancy after the initial meeting and wasasked to verify the duration of treatment with tricyclic antidepressantdrugs or fluoxetine during gestation, the dose of the drug,illnesses during pregnancy, and perinatal and postnatal complications.Details about the type of delivery, the perinatal period, andthe times at which her child reached developmental milestoneswere also collected. This assessment also included a writtenreport from the physician caring for the child.
Neurobehavioral Testing
All children were assessed by a psychometrician who did notknow the nature of the intrauterine exposure. To assess neurocognitivedevelopment, children between 16 and 30 months of age were testedwith the Bayley Scales of Infant Development21 and older childrenwere tested with the McCarthy Scales of Children's Abilities.22The temperament and behavior of children up to 24 months ofage were evaluated with age-appropriate Carey Temperament Scales,23,24and in children older than 24 months, the age-appropriate AchenbachBehavior Checklist25 was used. Language skills were assessedin all children with the Reynell Developmental Language Scales.26Maternal IQ was assessed with the Wechsler Adult IntelligenceScale–Revised,27 and socioeconomic status with the HollingsheadFour Factor Index.28
The mother's level of depression and function from the birthof the infant to the time of the neurobehavioral assessmentwere evaluated with the Global Assessment Scale, which ratesa subject's lowest level of functioning by selecting the lowestrange that describes his or her functioning on a continuum ofmental illness29; the Center for Epidemiologic Studies DepressedMood Scale, a 20-item scale that measures symptoms of depressionfor both epidemiologic research and clinical purposes30; andthe Index of Parental Attitudes, a 25-item scale designed tomeasure the extent, severity, or magnitude of problems in theparent–child relationship as seen and reported by a parent.31As part of these assessments we recorded whether the mothercontinued drug therapy in the postpartum period, and if so,for how long.
Statistical Analysis
The outcome measures in each of the three groups were comparedby one-way analysis of variance and Tukey's multiple-range test.All statistical tests were two-tailed. Subsequently, multipleregression analysis was conducted to determine the effects ofpotential confounders on the outcome measures. Differences inproportions among the groups were compared by the chi-squaretest.
Results
A total of 129 pregnant women who were taking a tricyclic antidepressantdrug have been counseled by the Motherisk Clinic since 1985.Twenty-four were lost to follow-up, 8 declined to participate,3 were exposed to known teratogens, 12 had spontaneous abortions,and 2 had therapeutic abortions. Thus, the group comprised 80women and 80 infants. Of the 80 women, 62 were treated for depressionand 18 for other indications, including migraine (9 women),pain (6 women), and bladder control (3 women). Forty women tooka tricyclic antidepressant drug during the first trimester,36 throughout pregnancy, 2 during the first and second trimesters,and 2 during the first and third trimesters. Twenty-nine womentook amitriptyline, 20 imipramine, 10 clomipramine, 9 desipramine,8 nortriptyline, and 1 each maprotiline, doxepin, amoxapine,and trimipramine.
Eighty-eight pregnant women who were taking fluoxetine havebeen counseled since the introduction of the drug in Canadain 1988. Six were lost to follow-up, 8 declined to participate,12 had spontaneous abortions, and 7 had therapeutic abortions.This group therefore consisted of 55 women and 55 infants —37 whose mothers had taken fluoxetine during the first trimesterand 18 whose mothers had taken the drug throughout pregnancy.The control group consisted of 84 pairs of mothers and children.
The characteristics of the women in the three groups are shownin Table 1. As compared with the other two groups, the womenin the fluoxetine group had had more pregnancies and more previoustherapeutic abortions and were of lower socioeconomic status.The women in both drug groups consumed more alcohol and smokedmore cigarettes during the index pregnancy than the women inthe control group. The women treated for depression in the twodrug groups had similar scores on the three tests used to quantifytheir levels of depression and function after the birth of theindex child (Table 1).
Table 1. Characteristics of Women Who Were Taking Tricyclic Antidepressant Drugs or Fluoxetine during Pregnancy and Pregnant Control Subjects.
At birth and at the time of testing the percentiles of weight,height, and head circumference of the children in the threegroups were similar (Table 2), and there were no significantdifferences in the rates of perinatal complications. The incidenceof major malformations among the three groups was also similar:three among the children exposed to tricyclic antidepressantdrugs in utero (ventricular septal defect, hypospadias, andpyloric stenosis), two among those exposed to fluoxetine (ventricularseptal defect and patent ductus arteriosus), and two among thecontrol group (cyanotic heart disease and ventricular septaldefect).
Table 2. Physical Characteristics of Infants at Birth and at the Time of Testing, According to Whether They were Exposed in Utero to Antidepressant Drugs.
The mean global IQ values in the three groups of children weresimilar, for both younger children (tested with the Bayley Scalesof Infant Development) and older ones (tested with the McCarthyScales of Children's Abilities) (Table 3). After adjustmentfor independent variables that may affect language development,the scores on the Verbal Comprehension and Expressive Languageportions of the Reynell scales were similar in the three groups.
Table 3. Results of Neurobehavioral Tests in Infants According to Whether They Were Exposed in Utero to Antidepressant Drugs.
There was no significant difference in temperament in eitherdrug group as compared with the control group. Similarly, therewere no significant differences in scores of mood, arousability,activity level, distractibility, or behavior problems. Multipleregression analysis of the effect of the duration of antidepressant-drugtherapy (first trimester vs. the entire pregnancy) revealedno significant differences on any of the neurobehavioral testsin either group of children exposed to antidepressant drugs,as compared with the control children. Eighteen women took tricyclicantidepressant drugs during pregnancy for conditions other thandepression. Their children's IQ scores, Reynell scores, andscores for temperament, mood, arousability, activity level,and distractibility were not different from those of the restof the group (data not shown).
Discussion
In planning our study we wished to address potential confoundersthat may affect a child's achievement on standard neurocognitivedevelopment and behavioral tests regardless of the type of therapythe mother received during pregnancy, including maternal IQand socioeconomic class. Because the mother usually raises thechild, the child's emotional, cognitive, and behavioral developmentmay be adversely affected as a result of postnatal interactionswith a mother who is depressed. For example, disturbances inthe regulation of affect, attachment, and temperament; depression;and inferior development of cognitive and other skills haveall been described in the children of depressed mothers.32 Toaddress these potential confounders, we quantified the mother'sdepression and her resulting function with widely used researchtools.29,30,31 Despite wide variability in the degree of depression,the mean scores of the women receiving tricyclic antidepressantdrugs and those receiving fluoxetine were similar on the threetests. In a similar manner, we quantified other maternal factorsknown to affect a child's scores on standard cognitive tests,including socioeconomic status and maternal IQ.
We found no significant differences in cognitive, language,and behavioral development among the children who were exposedto antidepressant drugs in utero and those who were not. Becausehalf the pregnancies in North America are unplanned, many womentake a tricyclic antidepressant drug or fluoxetine during thefirst few weeks of pregnancy. However, reassuring women thatexposure to these drugs in the first trimester will not affectbrain development in their unborn babies is not likely to reassurethose who need continuous therapy throughout pregnancy. Whenmaternal depression is not optimally controlled, there is ampleevidence of adverse outcomes in infants and young children ina variety of domains, including cognitive, language, and behavioral,as well as higher rates of perinatal risks.33
In our study one third of the women taking fluoxetine and almosthalf of those taking a tricyclic antidepressant drug continuedthe drug throughout pregnancy, allowing us to compare the effectsof first-trimester exposure to these drugs with those of exposureduring the entire pregnancy. We found that exposure to eithertype of drug throughout gestation did not affect the IQ or languageand behavioral development of the offspring, as measured duringthe preschool years. In summary, in utero exposure to eithertricyclic antidepressant drugs or fluoxetine does not adverselyaffect the neurodevelopment of preschool children.
Supported by the Motherisk Research Fund, Ciba Geigy Canada,Toronto, and a grant from the Medical Research Council and thePharmaceutical Manufacturers Association of Canada.
We are indebted to Deborah Altmann for testing and to JelenaPavlovic and Heather Rovet for scoring and analysis.
Source Information
From the Motherisk Program (I.N., J.W., J.G.W.T., N.K., G.K.), the Division of Clinical Pharmacology and Toxicology (I.N., J.G.W.T., N.K., G.K.), the Department of Pediatrics (I.N., J.R., J.G.W.T., G.K.), Research Institute (J.R., G.K.), and the Department of Psychology (J.R.), Hospital for Sick Children and University of Toronto, Toronto; Women's Health Program, Toronto Hospital and University of Toronto, Toronto (D.E.S.); and Oshawa General Hospital, Oshawa, Ont., Canada (H.A.G.).
Address reprint requests to Dr. Koren at the Division of Clinical Pharmacology, the Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
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