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Original Article | ONLINE FIRST

Maternal Use of Selective Serotonin Reuptake Inhibitors, Fetal Growth, and Risk of Adverse Birth Outcomes FREE

Hanan El Marroun, PhD; Vincent W. V. Jaddoe, MD, PhD; James J. Hudziak, MD; Sabine J. Roza, MD, PhD; Eric A. P. Steegers, MD, PhD; Albert Hofman, MD, PhD; Frank C. Verhulst, MD, PhD; Tonya J. H. White, MD, PhD; Bruno H. C. Stricker, MD, PhD; Henning Tiemeier, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Child and Adolescent Psychiatry, Sophia Children's Hospital (Drs El Marroun, Hudziak, Roza, Verhulst, White, and Tiemeier), Departments of Epidemiology (Drs Jaddoe, Hofman, Stricker, and Tiemeier), Pediatrics (Dr Jaddoe), Psychiatry (Drs Roza and Tiemeier), Obstetrics and Gynecology (Dr Steegers), and Radiology (Dr White), and the Generation R Study Group (Drs El Marroun and Jaddoe), Erasmus MC, Rotterdam, the Netherlands; and Department of Psychiatry, College of Medicine, University of Vermont, Burlington (Dr Hudziak).


Arch Gen Psychiatry. 2012;69(7):706-714. doi:10.1001/archgenpsychiatry.2011.2333.
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Context Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed to pregnant women, but knowledge about their unintended effects on child health is scarce.

Objective To examine the effects of maternal SSRI use during pregnancy on fetal growth and birth outcomes.

Design The study was embedded in the Generation R Study, a prospective population-based study from fetal life onward.

Participants Seven thousand six hundred ninety-six pregnant women were included. Selective serotonin reuptake inhibitor use was assessed by questionnaires in each trimester and verified by pharmacy records. Using depressive symptom scores from the Brief Symptom Inventory, 7027 pregnant mothers (91.3%) had no or low depressive symptoms, 570 pregnant mothers (7.4%) had clinically relevant depressive symptoms and used no SSRIs, and 99 pregnant mothers (1.3%) used SSRIs.

Main Outcome Measures Fetal ultrasonography was performed in each trimester. We determined fetal body and head growth with repeated assessments of body and head size. The birth outcomes studied were preterm birth, small for gestational age, and low birth weight.

Results Fetuses from mothers with prenatal depressive symptoms showed reduced body growth (β = −4.4 g/wk; 95% CI: −6.3 to −2.4; P < .001) and head growth (β = −0.08 mm/wk; 95% CI: −0.14 to −0.03; P = .003). Mothers using SSRIs during pregnancy had fewer depressive symptoms than mothers in the clinical symptom range. Prenatal SSRI use was not associated with reduced body growth but was associated with reduced fetal head growth (β = −0.18 mm/wk; 95% CI: −0.32 to −0.07; P = .003). The SSRI-exposed children were at higher risk for preterm birth (odds ratio = 2.14; 95% CI: 1.08 to 4.25; P = .03).

Conclusions Untreated maternal depression was associated with slower rates of fetal body and head growth. Pregnant mothers treated with SSRIs had fewer depressive symptoms and their fetuses had no delay in body growth but had delayed head growth and were at increased risk for preterm birth. Further research on the implications of these findings is needed.

Figures in this Article

The importance of treating maternal depression during pregnancy is well known. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed medications to treat depression1,2 because they have been shown to be both efficacious and safe.3 Selective serotonin reuptake inhibitors are also frequently prescribed to pregnant women, but knowledge about their potential unintended effects on health of the unborn child is scarce.4 Thus, trying to balance the possible negative consequences of untreated maternal depression with the unknown potential negative consequences of SSRIs remains an open debate.

Animal studies demonstrated that serotonin plays an important role during prenatal brain development; serotonin regulates neuronal proliferation, differentiation, migration, and synaptogenesis.5,6 Serotonin modulates its own synthesis and the number of serotonin receptors.7,8 Also, prenatal exposure to SSRIs was related to smaller head size in mice.9 In serotonin transporter (5-HTT) knockout mice, high levels of serotonin lead to abnormal structural organization of the somatosensory cortex and the corticolimbic circuits in the brain.10 These neuroanatomical deficits were also associated with disturbed behavioral functioning later in life.11

Human studies showed that SSRIs pass the placenta; SSRIs and metabolite concentrations up to 72% of the maternal levels have been detected in umbilical cord blood.12,13 Some studies reported malformations at birth, persistent pulmonary hypertension, and long-term effects on neurodevelopment due to prenatal SSRI exposure in children, but results are conflicting.1417 High-quality studies with good controls are sparse, but prenatal exposure to SSRIs has been associated with delayed motor milestone development, albeit a delay that was within the normal range of motor development. This may suggest subtle effects of prenatal SSRI use on offspring brain development.1721 However, none of these studies focused on the development of the brain or head during pregnancy.

Maternal depression during pregnancy can also adversely affect fetal development; it has been associated with an increased risk of poor pregnancy outcomes and neonatal complications.2224 Moreover, prenatal depression has been associated with adverse neurodevelopmental outcomes, such as language delay.2527

In this population-based study, we examined the association of depressive symptoms and maternal SSRI use during pregnancy with fetal body and head growth assessed by repeated ultrasonography and birth outcomes (birth weight, gestational age at birth, and head circumference at birth).

SETTING AND POPULATION

The present study is part of the Generation R Study,28 a population-based prospective cohort study from early fetal life onward in Rotterdam, the Netherlands. The Medical Ethics Committee of the Erasmus Medical Centre Rotterdam reviewed and approved the study. Written informed consent for both maternal and child data was obtained from all mothers.

Briefly, all pregnant women who resided in Rotterdam and whose delivery date was between April 2002 and January 2006 were invited to participate. In total, 9778 mothers were enrolled in Generation R (8880 during pregnancy and 898 after birth of their child).

For the present analyses, only mothers enrolled during pregnancy (8880) were considered. We excluded 104 fetal deaths (1 exposed to SSRIs) and 93 twin pregnancies. Selective serotonin reuptake inhibitor use only before pregnancy was recorded in 188 women; they were excluded from analyses because spillover effects could not be ruled out. The remaining 8495 mothers were eligible. There were 45 mothers lost to follow-up during pregnancy, and in 754 (8.9%) of the eligible mothers, information on SSRI use was unavailable. Thus, 7696 mothers were included in the analyses.

MATERNAL USE OF SSRIs AND MATERNAL DEPRESSION DURING PREGNANCY

To minimize misclassification of maternal SSRI use during pregnancy, we used 2 sources of information: (1) self-reports assessed with questionnaires and (2) prescription records from pharmacies.

In each trimester, participants reported whether they had used any medication (7129 [92.7%] provided information). In the first trimester, the mothers were asked whether they used medications within the past 6 months. The mothers filled out the type of medication and when it was used (during pregnancy, only before pregnancy, or stopped when I knew I was pregnant). In the second and third trimesters, we asked which medications were used in the preceding 3 months. From these questionnaires, we assessed SSRI exposure and timing (before or during pregnancy).

To validate the use of filled prescriptions, we asked women for permission to contact their pharmacy. For the large majority, permission was obtained and data were requested, but prescription records were only available in 56.4% (n = 4870) of our study sample. The records screened for SSRI use provided information on the type of SSRIs, duration, and dose. The agreement between self-reports and prescription records was high; Yule's Y as a measure of agreement was 0.94. Pharmacy records confirmed many self-reports (68.5%) and added 10 exposed participants.

Depressive symptoms were assessed with the Brief Symptom Inventory at, on average, 20.6 weeks of gestation. The Brief Symptom Inventory is a validated self-report questionnaire with 53 items29,30 and these items define a spectrum of psychiatric symptoms; we used the 6-item Depression Scale. According to the manual, mothers with a score higher than 0.75 were defined to have clinically relevant depressive symptoms.30

Based on the information about depressive symptoms and SSRI use, we classified the pregnant mothers into 3 groups:

  1. Women not using SSRIs with low depressive symptoms (7027 [91.3%]), ie, the control group.

  2. Women with clinically relevant depressive symptoms and not using SSRIs (570 [7.4%]).

  3. Women using SSRIs during pregnancy (99 [1.3%]).

FETAL OUTCOMES

Fetal ultrasonography assessments were performed in the first (median 12.8 weeks [90% range: 11.0-16.6 weeks]), second (median 20.3 weeks [90% range: 19.1-22.0 weeks]), and third (median 30.1 weeks [90% range: 29.0-32.0 weeks]) trimesters.31 The ultrasonography examinations were used for both establishing gestational age and assessing fetal growth characteristics. Crown-rump length, femur length, abdominal circumference, and head circumference were measured using standardized procedures. Fetal weight was then estimated using femur length and head and abdominal circumference in the formula of Hadlock.32 Estimated fetal weight and head circumference were correlated; the correlation coefficients were 0.90 in the first measurement but only 0.72 in the third measurement. The intraobserver and interobserver reliabilities of fetal biometry in early pregnancy within Generation R were excellent, with all intraclass correlation coefficients greater than 0.98.33 Gestational age and weight at birth were extracted from medical records.

PREGNANCY COMPLICATIONS AND BIRTH OUTCOMES

Prematurity was defined as birth before 37.0 weeks of gestation and low birth weight was defined as a birth weight smaller than 2500 g. Small for gestational age was defined as a standard deviation score smaller than −2.0 and based on standard deviation curves derived from the whole Generation R cohort.31 Head circumference after birth was measured directly by the midwife or at child health care centers at the age of 2 weeks (mean postconception age was 42.9 weeks).

COVARIATES

Important covariates were selected based on previous literature and change-in-estimate criteria.34 Maternal body mass index and height were measured during the first visit to the research center. Demographic information such as maternal age, ethnicity, education, and obstetric information were based on self-report. Ethnicity of the parents was defined according to the classification of Statistics Netherlands35; a mother was classified as being non-Dutch if one of her parents was born abroad. If both of her parents were born abroad, the country of birth of the mother's mother determined maternal national origin. Among non-Dutch mothers in this study, we identified persons of Western origin (such as European, American, and Australian) and non-Western origins (Cape Verdean, Dutch Antillean, Indonesian, Moroccan, Surinamese, Turkish, and other non-Western). Educational level was categorized into 3 levels: primary (no or primary education), secondary (lower and intermediate vocational training), and higher (higher vocational education and university) education.36 Family income, defined by the total net monthly income of the household, was categorized as less than [euro]1200 (US $1551) (below social security level), [euro]1200 to [euro]2000 (US $1551-US $2586), and more than [euro]2000 (US $2586) (more than modal income). Maternal prenatal smoking and alcohol use was obtained by questionnaires in each trimester and categorized into “no,” “until pregnancy was known,” and “continued during pregnancy,” as described previously.37 Information on cannabis use during pregnancy was obtained by a questionnaire in early pregnancy and by urine samples and was categorized into “not in pregnancy” and “during pregnancy” and has been described previously.38 Information on maternal benzodiazepine use, like information on maternal SSRI use during pregnancy, was collected with mailed questionnaires in each trimester and prescription records.

STATISTICAL ANALYSES

We determined differences in the demographic data of the 3 groups using the χ2 test, analysis of variance, and the Kruskal-Wallis test.

Based on multiple ultrasonography assessments of body size (estimated fetal weight) and head size (head circumference), we examined fetal growth. Since body size was not measured reliably in the first measurement, the body growth analyses were conducted with the second and third ultrasonography measurements and birth measures (gestational age range: 18.0-43.6 weeks). For head growth, we used head circumference from each measurement in pregnancy (gestational age range: 7.1-39.2 weeks). The associations between maternal depressive symptoms and antidepressant use with fetal weight gain and head growth were analyzed using longitudinal multilevel analyses.39 The multilevel models take between-subject and within-subject changes over time into account. Using the repeated ultrasonography measures in flexible mixed models with polynomials provides a more accurate estimation as compared with a single measurement in the analysis. These analyses involved 2 steps. First, the best-fitting model with the outcome as a function of gestational age was constructed using fractional polynomials.40 Second, maternal depressive symptoms or antidepressant use was brought into the model. The final curve was fitted with random effects for both the intercept and gestational age. The interaction term of depressive symptoms/maternal antidepressant use with gestational age was included in the model to compare the slope of the curves between the different groups defined by depressive symptoms and SSRI use. Using the same strategy, linear models were constructed for standard deviation scores of the growth characteristics.31 All analyses were adjusted for body mass index, educational level, maternal smoking habits, maternal age, ethnicity, fetal sex, parity, and maternal use of benzodiazepines, but not maternal drinking habits and cannabis use because these variables did not change the observed associations.34 These adjustments in the multilevel models were performed for random effects on the intercept. When analyzing the effects of depressive symptoms and SSRI use on head growth, we also corrected the fetal body size measures in the models to test specificity. We also tested whether results changed if we additionally adjusted the model for random effects on the slope using the following interaction terms: depressive symptoms score with gestational age, smoking with gestational age, maternal ethnicity with gestational age, and maternal use of benzodiazepines with gestational age. We added the interaction term maternal ethnicity with gestational age to control for any difference in fetal growth by ethnicity that may be related to SSRI use. We compared the effects of exposure to depressive symptoms with the effects of SSRI exposure using standard methods calculating the difference between the 2 effects and a standard error, which provided a 95% confidence interval with a P value.41,42

We examined the association of depression and SSRI use during pregnancy with birth outcomes using linear and logistic regression analyses. Statistical analyses were performed using SAS version 9.2 (SAS Institute Inc), including the PROCMIXED module for longitudinal multilevel analyses.

NONRESPONSE ANALYSES

We compared the characteristics of the 7694 women included in the analyses with those of 799 mothers without SSRI information or lost to follow-up. Women without information on medication use were somewhat younger (n = 799; mean [SD] age, 28.7 [5.8] years) than those with information (n = 7696; mean [SD] age, 29.7 [5.3] years; t = 5.35; P < .001), tended to be less educated (18.8% higher education vs 40.2%; χ2 = 816.4; P < .001), and smoked more often (18.1% never smoked in pregnancy vs 67.8%; χ2 = 799.0; P < .001). Children of mothers without information on medication use were born with a shorter gestational age (mean [SD] age, 39.6 [2.2] vs 39.8 [1.8] weeks; t = 2.54; P = .01) and had a somewhat lower birth weight (mean [SD], 3348 [595] vs 3416 [558] g; P = .002).

DESCRIPTIVE STATISTICS

Table 1 shows that women with depressive symptoms not using SSRIs in pregnancy were younger, less educated, more often of non-Dutch origin, and more likely to smoke and drink alcohol during pregnancy as compared with the controls. As compared with the control group, women using SSRIs in pregnancy were less educated, more often of Dutch origin, and more likely to smoke and drink alcohol during pregnancy (Table 1). In addition, we compared the SSRI-using group with the group with depressive symptoms; the SSRI-using group was significantly older (t = 5.51; P < .001).

Table Graphic Jump LocationTable 1. Descriptive Characteristics of the Study Populationa

Mean depression scores were 0.10, 1.45, and 0.74 for the control group, the group with depressive symptoms, and the SSRI-using group, respectively (Table 1). The SSRI-using group demonstrated a significantly lower score on the depressive symptoms scale than the group with depressive symptoms not using SSRIs (t = −9.43; P < .001).

Of the 99 women who used SSRIs during pregnancy, 28 had clinically relevant depressive symptoms. Moreover, 47 women used SSRIs in the first trimester only, and 52 pregnant women used SSRIs in the first trimester plus at least 1 additional trimester.

FETAL GROWTH

Table 2 demonstrates that children in the group with depressive symptoms not using SSRIs showed a slower rate of fetal weight gain of approximately 4.4 g per week (95% CI: −6.3 to −2.4). In contrast, children in the SSRI-using group did not show a reduction in fetal growth as measured by fetal weight gain (slope β = −2.3; 95% CI: −7.0 to 2.3).

Table Graphic Jump LocationTable 2. Associations of Maternal SSRI Use and Depressive Symptoms in Pregnancy With Fetal Growth Characteristicsa

Children of mothers with depressive symptoms not using SSRIs also showed a reduced growth of head circumference (slope β = −0.08; 95% CI: −0.14 to −0.03). Children of mothers using SSRIs, however, had a more pronounced reduced head circumference growth of β = −0.18 mm per week (95% CI: −0.32 to −0.07). A direct comparison of the effect estimates of SSRI use and depressive symptoms showed a trend but it did not reach statistical significance (β = −0.10; 95% CI: −0.24 to 0.04; P = .07). Performing an additional adjustment for the depressive symptom scores, the decreased head growth remained present in the SSRI-using group (β = −0.15; 95% CI: −0.27 to −0.02; P = .02). Taking into account the effects of maternal ethnicity and smoking habits on the slope (interaction terms: ethnicity with gestational age and smoking with gestational age) did not attenuate the effect of SSRI exposure on head growth (β = −0.17; 95% CI: −0.29 to −0.04; P = .008). Moreover, taking into account the effects of maternal use of benzodiazepines on the slope (interaction term: benzodiazepine use with gestational age) did not attenuate the effect of SSRI exposure on head growth (β = −0.19; 95% CI: −0.32 to −0.06; P = .003). Finally, when we excluded the 28 SSRI-using women with high depressive symptoms, the association between maternal SSRI use and fetal head growth (β = −0.17 mm/wk; 95% CI: −0.31 to −0.03; P = .02) remained the same. Supplementary analyses using the standard deviation scores of fetal growth and head growth yielded very similar results (data not shown).

The Figure demonstrates the fetal head growth trajectories; Figure, A shows the absolute growth of head circumference and Figure, B shows the relative fetal head growth (ie, the difference of fetal head circumference growth between the groups). The graph demonstrates that the growth rate of the fetal head was high, varying from 171 mm at 20 weeks of gestation to 345 mm at 40 weeks of gestation. It also demonstrates that the effect of maternal SSRI use on head growth was rather small, up to a 4.0-mm difference in head circumference. The total effect size of SSRI use during pregnancy on fetal head circumference varied from 0.24% (at 20 weeks of gestation) to 1.19% (at 40 weeks of gestation).

Place holder to copy figure label and caption
Graphic Jump Location

Figure. The absolute (A) and relative (B) growth of fetal head circumference in 3 groups: fetuses exposed to selective serotonin reuptake inhibitors (SSRIs) during pregnancy, fetuses exposed to high levels of depressive symptoms during pregnancy, and fetuses in the control group. Estimates were obtained from fitting a fractional polynomial model adjusted for maternal age, maternal body mass index, parity, sex of the child, maternal educational level and ethnicity, and maternal smoking habits and benzodiazepine use.

BIRTH OUTCOMES

Table 3 shows that children of mothers with depressive symptoms not using SSRIs were born after a slightly longer (on average 1 day) gestational duration (β = 0.18; 95% CI: 0.01 to 0.34) compared with the controls. In contrast, children in the SSRI-using group were born with a shorter gestational duration as compared with the controls (β = −0.60; 95% CI: −0.97 to −0.21). Moreover, children in the SSRI-using group were twice as likely to be born preterm (odds ratio = 2.14; 95% CI: 1.08 to 4.25), as compared with the controls. The absolute numbers for preterm birth were 355 (5.1%), 36 (6.3%), and 10 (10.1%) for the control children, children of mothers with depressive symptoms, and children of mothers in the SSRI-using group, respectively.

Table Graphic Jump LocationTable 3. Association Between SSRI Exposure in Pregnancy and Birth Outcomesa

Also, Table 3 demonstrates that the low birth weight of children of mothers using SSRIs during pregnancy (unadjusted in Table 1) was explained by the shorter gestational duration and other covariates. There was no evidence for a relationship between SSRI use and being small for gestational age (odds ratio = 0.89; 95% CI: 0.28 to 2.87).

Table 4 demonstrates that children of mothers who had depressive symptoms during pregnancy but did not use SSRIs had no reduced head circumference at birth (β = 0.05; 95% CI: −3.48 to 4.43), while SSRI-exposed children did have a smaller head circumference at birth (β = −5.88; 95% CI; −11.45 to −0.30) compared with children in the control group.

Table Graphic Jump LocationTable 4. Association Between SSRI Exposure in Pregnancy and Head Circumference at Birtha

In this prospective population-based study, we examined the association of maternal depression and SSRI use during pregnancy with fetal growth. Untreated depressive symptoms were associated with a reduction in total body growth, including the fetal head, during pregnancy. In contrast, prenatal SSRI use was related to a reduced growth of the fetal head, whereas prenatal SSRI use did not affect growth of the fetal body. Our results indicate a rather specific effect of SSRI use during pregnancy, which differs from depressive symptoms on the fetus.

Although our findings add to current knowledge about the consequences of SSRI use (or nonuse) in women with depressive symptoms during pregnancy, they are not conclusive. Most importantly, untreated women with depressive symptoms also have children with reduced growth of the fetal head, albeit less prominently. Nevertheless, our findings are of important value because there is a paucity of data regarding safety of SSRI use during pregnancy and possible consequences on fetal health. Importantly, a recent review characterized the unwanted effects of prenatal SSRI exposure as the prenatal antidepressant exposure syndrome, which included pregnancy complications and negative neurological, gastrointestinal, metabolic, respiratory, and cardiac symptoms at birth.21 However, this syndrome does not include decreased fetal head growth.

Several possible explanations for our results are conceivable. First, SSRIs are prescribed to treat depression; thus, the association between prenatal SSRI exposure and fetal head growth could be explained by these residual depressive symptoms. We tried to account for confounding by indication with a contrast group of women not pharmacologically treated for their depressive symptoms. However, confounding by severity of the disease might still be present, because women treated with antidepressants during pregnancy might have initially had more severe depression. On the other hand, women taking SSRIs have lower depression scores during pregnancy as compared with the women not treated pharmacologically, which possibly is consistent with the intended antidepressant effect (Table 1), and adjusting for depressive symptoms in the SSRI-using group did not attenuate the association between SSRI exposure and fetal head growth. Although most women started SSRI use well before pregnancy and had lower depressive symptom scores during pregnancy, it is possible that past depression affects maternal physiology lastingly and thus could also affect fetal development.

Second, serotonin is known to play an important role in prenatal brain development,5,6 and manipulation of serotonin levels with SSRIs in utero may directly affect fetal brain growth. Pharmacological animal studies demonstrated decreased brain maturation; animals exposed to SSRIs had fewer dendritic branches, shorter dendritic length, and a smaller dendritic field in the somatosensory barrel cortex.11,4345 Also, Rayburn et al9 demonstrated that newborn mice exposed to paroxetine were more likely to have narrower heads. In that study, therapeutic doses were used to mimic the human levels in the fetal mouse brain.9

A third potential mechanism to explain the association between maternal SSRI use and fetal head growth is the presence of epiphenomena of SSRI use, eg, smoking or drinking during pregnancy and low socioeconomic status. These risk factors have been shown to affect fetal growth.37,46 We attempted to adjust for these epiphenomena in our analyses, but unmeasured residual confounding (eg, use of other medication or illicit drugs in pregnancy, malnutrition, genetic susceptibility, family stress) could still be present. However, such epiphenomena are less likely to explain a specific effect on head size. If fetal growth is compromised, head growth is typically impaired last; this is termed the brain-sparing effect.47

Our results demonstrated that children of mothers with depressive symptoms not using SSRIs were born after a slightly longer gestational duration (1 day) but within normal range of childbirth. In addition, we found no association between depressive symptoms and low birth weight. These results are in agreement with the meta-analytic study of Grote and coworkers48 demonstrating no increased risk for preterm birth when using a continuous measure of depression and no increased risk of low birth weight in European countries. Interestingly, the meta-analyses showed that in the United States antenatal depression was associated with an increased risk for low birth weight. One potential explanation for this discrepancy is that mental health care in Western Europe, including nonpharmacological depression treatment, is more accessible.

Selective serotonin reuptake inhibitor exposure during pregnancy was associated with a shorter gestational age at birth, which was in line with previous studies.4952 These studies were based on hospital, health insurance, or patient data and demonstrated consistently that SSRI use is associated with preterm birth or a shorter gestational duration.4952 The effect of SSRI use during pregnancy on birth weight in the present study was explained by the shorter gestational duration, consistent with the observations of Simon and colleagues.51

To place the magnitude of the observed effects of prenatal SSRI use on fetal head circumference in perspective, we compared our results with 2 previous studies of head growth. These studies showed that prenatal tobacco (−0.13 mm/wk) and prenatal cannabis (−0.21 mm/wk) exposure negatively affected growth of fetal head circumference.37,53

The strengths of our study include the large population recruited prospectively and precise and sensitive measure of fetal growth obtained with repeated ultrasonography measurements. Furthermore, we used both self-reported information and prescription records to determine prenatal SSRI use. Moreover, we contrasted the effects of SSRIs and depressive symptoms on fetal growth. Thus, the current study meets the methodological criteria proposed for studies on the effects of prenatal antidepressant exposure, ie, the distinction of different exposed and unexposed groups.54 However, 1 group, the women treated with SSRIs who failed to achieve remission (n = 28), was too small to study separately. We could only exclude these women in additional analyses to rule out that this group, in particular, explained the observed effect of SSRI use. Nevertheless, several limitations must be discussed. For example, it would be useful to have pretreatment or preconception depression scores to better match the SSRI and depressive symptom groups. Such data would only be available in preconception cohorts. Moreover, because of small numbers, we could not study period-specific effects of SSRI use and were not able to assess prenatal effects related to exposure to specific SSRIs. Furthermore, this small sample could be the reason why the reduction in fetal weight in the SSRI-using group did not reach significance. Because of logistical reasons, pharmacy records were not available in many participants. This was most likely random, but further information could have reduced any misclassification of SSRI exposure. Finally, we cannot rule out selection bias because the nonresponse analyses demonstrated that nonresponders were younger, tended to be less educated, and smoked more often. Their children were more likely to be born with a shorter gestational duration and had a somewhat lower birth weight.

Prescribing antidepressant medication to pregnant women is a major controversy in current psychiatry.55 Whereas the use of SSRIs among pregnant women has increased from 1.5% in 1996 to 6.2% in 2005,56 studies using detailed measures of fetal and child developmental outcomes to examine potential long-term consequences are sparse. Our study shows a rather specific effect of maternal SSRI use on fetal head growth, one of the best prenatal markers of brain volume. Fetal head circumference in early life has been shown to be an accurate indicator of brain weight.57,58 Small head size in neonates predicts behavioral problems and psychiatric disorders, such as internalizing problems, anxiety and attention-deficit/hyperactivity disorder, and poorer cognitive performance later in life.5962 Importantly, a recent study demonstrated that prenatal exposure to SSRIs might increase the risk of autism spectrum disorders.63 Nonetheless, we must be careful not to infer an association of SSRI use in pregnancy with future developmental problems. Therefore, more long-term drug safety studies are needed before evidence-based recommendations can be derived.

Our findings further raise the question whether maternal SSRI treatment during pregnancy is better or worse for the fetus than untreated maternal depression. Clinicians must carefully weigh the known risks of untreated depression during pregnancy and the possible adverse effects of SSRIs. Ideally, preconception health promotion and prevention programs should be developed to improve health of pregnant women and to reduce the risk of developing prenatal depression. However, these programs will doubtless be ineffective for some women with prenatal depression in whom the benefits of antidepressant treatment with SSRIs probably outweigh the risks.

Correspondence: Henning Tiemeier, MD, PhD, The Department of Child and Adolescent Psychiatry, Erasmus MC, Sophia Children's Hospital, 3000 CB Rotterdam, the Netherlands (h.tiemeier@erasmusmc.nl).

Submitted for Publication: September 26, 2011; final revision received December 7, 2011; accepted December 29, 2011.

Published Online: March 5, 2012. doi:10.1001/archgenpsychiatry.2011.2333

Author Contributions: Drs El Marroun and Tiemeier had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: The first phase of the Generation R Study was made possible by financial support from the Erasmus Medical Centre Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (grant ZonMW Geestkracht 10.000.1003), and the Netherlands Organization for Scientific Research (NWO Brain & Cognition Program, grant 433-09-311 and VIDI Grant 017.106.370). The present study was supported by an additional grant from the Sophia Children's Hospital Foundation, project number 616. The Generation R Study is conducted by the Erasmus Medical Centre Rotterdam in collaboration with the Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond, Rotterdam.

Role of the Sponsors: The funding agencies (Netherlands Organization for Health Research and Development [grant ZonMW Geestkracht 10.000.1003, NWO Brain & Cognition grant 433-09-311, and VIDI Grant 017.106.370] and the Sophia Children's Hospital [project number 616]) had no role in the design and conduct of the study; the collection, management, analyses, and interpretation of the data; or the preparation, review, and approval of the manuscript.

Additional Contributions: We gratefully acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam.

Paulose-Ram R, Safran MA, Jonas BS, Gu Q, Orwig D. Trends in psychotropic medication use among U.S. adults.  Pharmacoepidemiol Drug Saf. 2007;16(5):560-570
PubMed   |  Link to Article
Ravera S, Visser ST, de Gier JJ, de Jong-van den Berg LT. Prevalence, cumulative incidence, monotherapy and combination therapy, and treatment duration of frequently prescribed psychoactive medications in the Netherlands: retrospective database analysis for the years 2000 to 2005.  Clin Ther. 2010;32(14):2457-2466
PubMed   |  Link to Article
Barbey JT, Roose SP. SSRI safety in overdose.  J Clin Psychiatry. 1998;59:(suppl 15)  42-48
PubMed
Bakker MK, Kölling P, van den Berg PB, de Walle HE, de Jong van den Berg LT. Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from the Netherlands.  Br J Clin Pharmacol. 2008;65(4):600-606
PubMed   |  Link to Article
Gaspar P, Cases O, Maroteaux L. The developmental role of serotonin: news from mouse molecular genetics.  Nat Rev Neurosci. 2003;4(12):1002-1012
PubMed   |  Link to Article
Mercado R, Floran B, Hernandez J. Regulated release of serotonin from axonal growth cones isolated from the fetal rat brain.  Neurochem Int. 1998;32(1):103-106
PubMed   |  Link to Article
Fillion MP, Hernandez RJ, Bauguen C, Fillion G. Postnatal development of high affinity neuronal recognition sites for 3H-5-HT in rat brain.  Dev Neurosci. 1982;5(5-6):484-491
PubMed   |  Link to Article
Nebigil CG, Etienne N, Schaerlinger B, Hickel P, Launay JM, Maroteaux L. Developmentally regulated serotonin 5-HT2B receptors.  Int J Dev Neurosci. 2001;19(4):365-372
PubMed   |  Link to Article
Rayburn WF, Gonzalez CL, Christensen HD, Kupiec TC, Jacobsen JA, Stewart JD. Effect of antenatal exposure to paroxetine (Paxil) on growth and physical maturation of mice offspring.  J Matern Fetal Med. 2000;9(2):136-141
PubMed   |  Link to Article
Homberg JR, Schubert D, Gaspar P. New perspectives on the neurodevelopmental effects of SSRIs.  Trends Pharmacol Sci. 2010;31(2):60-65
PubMed   |  Link to Article
Lee LJ. Neonatal fluoxetine exposure affects the neuronal structure in the somatosensory cortex and somatosensory-related behaviors in adolescent rats.  Neurotox Res. 2009;15(3):212-223
PubMed   |  Link to Article
Heikkine T, Ekblad U, Laine K. Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta.  BJOG. 2002;109(9):1003-1008
PubMed   |  Link to Article
Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D. Placental passage of antidepressant medications.  Am J Psychiatry. 2003;160(5):993-996
PubMed   |  Link to Article
Andrade SE, McPhillips H, Loren D, Raebel MA, Lane K, Livingston J, Boudreau DM, Smith DH, Davis RL, Willy ME, Platt R. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn.  Pharmacoepidemiol Drug Saf. 2009;18(3):246-252
PubMed   |  Link to Article
Campagne DM. Fact: antidepressants and anxiolytics are not safe during pregnancy.  Eur J Obstet Gynecol Reprod Biol. 2007;135(2):145-148
PubMed   |  Link to Article
Noorlander CW, Ververs FF, Nikkels PG, van Echteld CJ, Visser GH, Smidt MP. Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities.  PLoS One. 2008;3(7):e2782
PubMed   |  Link to Article
Mulder EJ, Ververs FF, de Heus R, Visser GH. Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus.  Neuropsychopharmacology. 2011;36(10):1961-1971
PubMed   |  Link to Article
Pedersen LH, Henriksen TB, Olsen J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age.  Pediatrics. 2010;125(3):e600-e608
PubMed   |  Link to Article
Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy.  J Pediatr. 2003;142(4):402-408
PubMed   |  Link to Article
Nordeng H, Lindemann R, Perminov KV, Reikvam A. Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors.  Acta Paediatr. 2001;90(3):288-291
PubMed   |  Link to Article
Gentile S. On categorizing gestational, birth, and neonatal complications following late pregnancy exposure to antidepressants: the prenatal antidepressant exposure syndrome.  CNS Spectr. 2010;15(3):167-185
PubMed
Bonari L, Pinto N, Ahn E, Einarson A, Steiner M, Koren G. Perinatal risks of untreated depression during pregnancy.  Can J Psychiatry. 2004;49(11):726-735
PubMed
Jablensky AV, Morgan V, Zubrick SR, Bower C, Yellachich LA. Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders.  Am J Psychiatry. 2005;162(1):79-91
PubMed   |  Link to Article
Wisner KL, Sit DK, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, Perel JM, Jones-Ivy S, Bodnar LM, Singer LT. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes.  Am J Psychiatry. 2009;166(5):557-566
PubMed   |  Link to Article
Deave T, Heron J, Evans J, Emond A. The impact of maternal depression in pregnancy on early child development.  BJOG. 2008;115(8):1043-1051
PubMed   |  Link to Article
Hay DF, Pawlby S, Waters CS, Sharp D. Antepartum and postpartum exposure to maternal depression: different effects on different adolescent outcomes.  J Child Psychol Psychiatry. 2008;49(10):1079-1088
PubMed   |  Link to Article
Paulson JF, Keefe HA, Leiferman JA. Early parental depression and child language development.  J Child Psychol Psychiatry. 2009;50(3):254-262
PubMed   |  Link to Article
Jaddoe VW, van Duijn CM, van der Heijden AJ, Mackenbach JP, Moll HA, Steegers EA, Tiemeier H, Uitterlinden AG, Verhulst FC, Hofman A. The Generation R Study: design and cohort update 2010.  Eur J Epidemiol. 2010;25(11):823-841
PubMed   |  Link to Article
Derogatis LR, Melisaratos N. The Brief Symptom Inventory: an introductory report.  Psychol Med. 1983;13(3):595-605
PubMed   |  Link to Article
de Beurs E. Brief Symptom Inventory, Handleiding. Leiden, the Netherlands: PITS; 2004
Verburg BO, Steegers EA, De Ridder M, Snijders RJ, Smith E, Hofman A, Moll HA, Jaddoe VW, Witteman JC. New charts for ultrasound dating of pregnancy and assessment of fetal growth: longitudinal data from a population-based cohort study.  Ultrasound Obstet Gynecol. 2008;31(4):388-396
PubMed   |  Link to Article
Hadlock FP, Harrist RB, Carpenter RJ, Deter RL, Park SK. Sonographic estimation of fetal weight: the value of femur length in addition to head and abdomen measurements.  Radiology. 1984;150(2):535-540
PubMed
Verburg BO, Mulder PG, Hofman A, Jaddoe VW, Witteman JC, Steegers EA. Intra- and interobserver reproducibility study of early fetal growth parameters.  Prenat Diagn. 2008;28(4):323-331
PubMed   |  Link to Article
Mickey RM, Greenland S. The impact of confounder selection criteria on effect estimation.  Am J Epidemiol. 1989;129(1):125-137
PubMed
 Migrants in the Netherlands 2004. Statistics Netherlands website. http://www.cbs.nl. Accessed November 18, 2010
 Standard classification of education 2003. Statistics Netherlands website. http://www.cbs.nl. Accessed November 18, 2010
Roza SJ, Verburg BO, Jaddoe VW, Hofman A, Mackenbach JP, Steegers EA, Witteman JC, Verhulst FC, Tiemeier H. Effects of maternal smoking in pregnancy on prenatal brain development: the Generation R Study.  Eur J Neurosci. 2007;25(3):611-617
PubMed   |  Link to Article
El Marroun H, Tiemeier H, Jaddoe VW, Hofman A, Verhulst FC, van den Brink W, Huizink AC. Agreement between maternal cannabis use during pregnancy according to self-report and urinalysis in a population-based cohort: the Generation R Study.  Eur Addict Res. 2011;17(1):37-43
PubMed   |  Link to Article
Twisk JWR. Applied Multilevel Analysis: A Practical Guide for Medical Researchers. Cambridge, England: Cambridge University Press; 2006
Royston P, Ambler G, Sauerbrei W. The use of fractional polynomials to model continuous risk variables in epidemiology.  Int J Epidemiol. 1999;28(5):964-974
PubMed   |  Link to Article
Matthews JN, Altman DG. Interaction 3: how to examine heterogeneity.  BMJ. 1996;313(7061):862
PubMed   |  Link to Article
Matthews JN, Altman DG. Statistics notes, interaction 2: compare effect sizes not P values.  BMJ. 1996;313(7060):808
PubMed   |  Link to Article
Young-Davies CL, Bennett-Clarke CA, Lane RD, Rhoades RW. Selective facilitation of the serotonin(1B) receptor causes disorganization of thalamic afferents and barrels in somatosensory cortex of rat.  J Comp Neurol. 2000;425(1):130-138
PubMed   |  Link to Article
Xu Y, Sari Y, Zhou FC. Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development.  Brain Res Dev Brain Res. 2004;150(2):151-161
PubMed   |  Link to Article
Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA. Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry.  Neuropsychopharmacology. 2006;31(1):47-57
PubMed
Silva LM, Jansen PW, Steegers EA, Jaddoe VW, Arends LR, Tiemeier H, Verhulst FC, Moll HA, Hofman A, Mackenbach JP, Raat H. Mother's educational level and fetal growth: the genesis of health inequalities.  Int J Epidemiol. 2010;39(5):1250-1261
PubMed   |  Link to Article
Baschat AA. Fetal responses to placental insufficiency: an update.  BJOG. 2004;111(10):1031-1041
PubMed   |  Link to Article
Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction.  Arch Gen Psychiatry. 2010;67(10):1012-1024
PubMed   |  Link to Article
Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data.  Arch Gen Psychiatry. 2006;63(8):898-906
PubMed   |  Link to Article
Lund N, Pedersen LH, Henriksen TB. Selective serotonin reuptake inhibitor exposure in utero and pregnancy outcomes.  Arch Pediatr Adolesc Med. 2009;163(10):949-954
PubMed   |  Link to Article
Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure.  Am J Psychiatry. 2002;159(12):2055-2061
PubMed   |  Link to Article
Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine.  N Engl J Med. 1996;335(14):1010-1015
PubMed   |  Link to Article
El Marroun H, Tiemeier H, Steegers EA, Jaddoe VW, Hofman A, Verhulst FC, van den Brink W, Huizink AC. Intrauterine cannabis exposure affects fetal growth trajectories: the Generation R Study.  J Am Acad Child Adolesc Psychiatry. 2009;48(12):1173-1181
PubMed   |  Link to Article
Gentile S. Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of birth defects.  Acta Psychiatr Scand. 2011;123(4):266-275
PubMed   |  Link to Article
Austin MP. To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects.  Psychol Med. 2006;36(12):1663-1670
PubMed   |  Link to Article
Andrade SE, Raebel MA, Brown J, Lane K, Livingston J, Boudreau D, Rolnick SJ, Roblin D, Smith DH, Willy ME, Staffa JA, Platt R. Use of antidepressant medications during pregnancy: a multisite study.  Am J Obstet Gynecol. 2008;198(2):194-195, e1-e5
PubMed   |  Link to Article
Cooke RW, Lucas A, Yudkin PL, Pryse-Davies J. Head circumference as an index of brain weight in the fetus and newborn.  Early Hum Dev. 1977;1(2):145-149
PubMed   |  Link to Article
Epstein HT, Epstein EB. The relationship between brain weight and head circumference from birth to age 18 years.  Am J Phys Anthropol. 1978;48(4):471-473
PubMed   |  Link to Article
Herba CM, Roza SJ, Govaert P, van Rossum J, Hofman A, Jaddoe V, Verhulst FC, Tiemeier H. Infant brain development and vulnerability to later internalizing difficulties: the Generation R study.  J Am Acad Child Adolesc Psychiatry. 2010;49(10):1053-1063
PubMed   |  Link to Article
Whitaker AH, Van Rossem R, Feldman JF, Schonfeld IS, Pinto-Martin JA, Tore C, Shaffer D, Paneth N. Psychiatric outcomes in low-birth-weight children at age 6 years: relation to neonatal cranial ultrasound abnormalities.  Arch Gen Psychiatry. 1997;54(9):847-856
PubMed   |  Link to Article
Peterson BS, Anderson AW, Ehrenkranz R, Staib LH, Tageldin M, Colson E, Gore JC, Duncan CC, Makuch R, Ment LR. Regional brain volumes and their later neurodevelopmental correlates in term and preterm infants.  Pediatrics. 2003;111(5, pt 1):939-948
PubMed   |  Link to Article
Peterson BS, Vohr B, Staib LH, Cannistraci CJ, Dolberg A, Schneider KC, Katz KH, Westerveld M, Sparrow S, Anderson AW, Duncan CC, Makuch RW, Gore JC, Ment LR. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants.  JAMA. 2000;284(15):1939-1947
PubMed   |  Link to Article
Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders.  Arch Gen Psychiatry. 2011;68(11):1104-1112
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure. The absolute (A) and relative (B) growth of fetal head circumference in 3 groups: fetuses exposed to selective serotonin reuptake inhibitors (SSRIs) during pregnancy, fetuses exposed to high levels of depressive symptoms during pregnancy, and fetuses in the control group. Estimates were obtained from fitting a fractional polynomial model adjusted for maternal age, maternal body mass index, parity, sex of the child, maternal educational level and ethnicity, and maternal smoking habits and benzodiazepine use.

Tables

Table Graphic Jump LocationTable 1. Descriptive Characteristics of the Study Populationa
Table Graphic Jump LocationTable 2. Associations of Maternal SSRI Use and Depressive Symptoms in Pregnancy With Fetal Growth Characteristicsa
Table Graphic Jump LocationTable 3. Association Between SSRI Exposure in Pregnancy and Birth Outcomesa
Table Graphic Jump LocationTable 4. Association Between SSRI Exposure in Pregnancy and Head Circumference at Birtha

References

Paulose-Ram R, Safran MA, Jonas BS, Gu Q, Orwig D. Trends in psychotropic medication use among U.S. adults.  Pharmacoepidemiol Drug Saf. 2007;16(5):560-570
PubMed   |  Link to Article
Ravera S, Visser ST, de Gier JJ, de Jong-van den Berg LT. Prevalence, cumulative incidence, monotherapy and combination therapy, and treatment duration of frequently prescribed psychoactive medications in the Netherlands: retrospective database analysis for the years 2000 to 2005.  Clin Ther. 2010;32(14):2457-2466
PubMed   |  Link to Article
Barbey JT, Roose SP. SSRI safety in overdose.  J Clin Psychiatry. 1998;59:(suppl 15)  42-48
PubMed
Bakker MK, Kölling P, van den Berg PB, de Walle HE, de Jong van den Berg LT. Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from the Netherlands.  Br J Clin Pharmacol. 2008;65(4):600-606
PubMed   |  Link to Article
Gaspar P, Cases O, Maroteaux L. The developmental role of serotonin: news from mouse molecular genetics.  Nat Rev Neurosci. 2003;4(12):1002-1012
PubMed   |  Link to Article
Mercado R, Floran B, Hernandez J. Regulated release of serotonin from axonal growth cones isolated from the fetal rat brain.  Neurochem Int. 1998;32(1):103-106
PubMed   |  Link to Article
Fillion MP, Hernandez RJ, Bauguen C, Fillion G. Postnatal development of high affinity neuronal recognition sites for 3H-5-HT in rat brain.  Dev Neurosci. 1982;5(5-6):484-491
PubMed   |  Link to Article
Nebigil CG, Etienne N, Schaerlinger B, Hickel P, Launay JM, Maroteaux L. Developmentally regulated serotonin 5-HT2B receptors.  Int J Dev Neurosci. 2001;19(4):365-372
PubMed   |  Link to Article
Rayburn WF, Gonzalez CL, Christensen HD, Kupiec TC, Jacobsen JA, Stewart JD. Effect of antenatal exposure to paroxetine (Paxil) on growth and physical maturation of mice offspring.  J Matern Fetal Med. 2000;9(2):136-141
PubMed   |  Link to Article
Homberg JR, Schubert D, Gaspar P. New perspectives on the neurodevelopmental effects of SSRIs.  Trends Pharmacol Sci. 2010;31(2):60-65
PubMed   |  Link to Article
Lee LJ. Neonatal fluoxetine exposure affects the neuronal structure in the somatosensory cortex and somatosensory-related behaviors in adolescent rats.  Neurotox Res. 2009;15(3):212-223
PubMed   |  Link to Article
Heikkine T, Ekblad U, Laine K. Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta.  BJOG. 2002;109(9):1003-1008
PubMed   |  Link to Article
Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D. Placental passage of antidepressant medications.  Am J Psychiatry. 2003;160(5):993-996
PubMed   |  Link to Article
Andrade SE, McPhillips H, Loren D, Raebel MA, Lane K, Livingston J, Boudreau DM, Smith DH, Davis RL, Willy ME, Platt R. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn.  Pharmacoepidemiol Drug Saf. 2009;18(3):246-252
PubMed   |  Link to Article
Campagne DM. Fact: antidepressants and anxiolytics are not safe during pregnancy.  Eur J Obstet Gynecol Reprod Biol. 2007;135(2):145-148
PubMed   |  Link to Article
Noorlander CW, Ververs FF, Nikkels PG, van Echteld CJ, Visser GH, Smidt MP. Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities.  PLoS One. 2008;3(7):e2782
PubMed   |  Link to Article
Mulder EJ, Ververs FF, de Heus R, Visser GH. Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus.  Neuropsychopharmacology. 2011;36(10):1961-1971
PubMed   |  Link to Article
Pedersen LH, Henriksen TB, Olsen J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age.  Pediatrics. 2010;125(3):e600-e608
PubMed   |  Link to Article
Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy.  J Pediatr. 2003;142(4):402-408
PubMed   |  Link to Article
Nordeng H, Lindemann R, Perminov KV, Reikvam A. Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors.  Acta Paediatr. 2001;90(3):288-291
PubMed   |  Link to Article
Gentile S. On categorizing gestational, birth, and neonatal complications following late pregnancy exposure to antidepressants: the prenatal antidepressant exposure syndrome.  CNS Spectr. 2010;15(3):167-185
PubMed
Bonari L, Pinto N, Ahn E, Einarson A, Steiner M, Koren G. Perinatal risks of untreated depression during pregnancy.  Can J Psychiatry. 2004;49(11):726-735
PubMed
Jablensky AV, Morgan V, Zubrick SR, Bower C, Yellachich LA. Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders.  Am J Psychiatry. 2005;162(1):79-91
PubMed   |  Link to Article
Wisner KL, Sit DK, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, Perel JM, Jones-Ivy S, Bodnar LM, Singer LT. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes.  Am J Psychiatry. 2009;166(5):557-566
PubMed   |  Link to Article
Deave T, Heron J, Evans J, Emond A. The impact of maternal depression in pregnancy on early child development.  BJOG. 2008;115(8):1043-1051
PubMed   |  Link to Article
Hay DF, Pawlby S, Waters CS, Sharp D. Antepartum and postpartum exposure to maternal depression: different effects on different adolescent outcomes.  J Child Psychol Psychiatry. 2008;49(10):1079-1088
PubMed   |  Link to Article
Paulson JF, Keefe HA, Leiferman JA. Early parental depression and child language development.  J Child Psychol Psychiatry. 2009;50(3):254-262
PubMed   |  Link to Article
Jaddoe VW, van Duijn CM, van der Heijden AJ, Mackenbach JP, Moll HA, Steegers EA, Tiemeier H, Uitterlinden AG, Verhulst FC, Hofman A. The Generation R Study: design and cohort update 2010.  Eur J Epidemiol. 2010;25(11):823-841
PubMed   |  Link to Article
Derogatis LR, Melisaratos N. The Brief Symptom Inventory: an introductory report.  Psychol Med. 1983;13(3):595-605
PubMed   |  Link to Article
de Beurs E. Brief Symptom Inventory, Handleiding. Leiden, the Netherlands: PITS; 2004
Verburg BO, Steegers EA, De Ridder M, Snijders RJ, Smith E, Hofman A, Moll HA, Jaddoe VW, Witteman JC. New charts for ultrasound dating of pregnancy and assessment of fetal growth: longitudinal data from a population-based cohort study.  Ultrasound Obstet Gynecol. 2008;31(4):388-396
PubMed   |  Link to Article
Hadlock FP, Harrist RB, Carpenter RJ, Deter RL, Park SK. Sonographic estimation of fetal weight: the value of femur length in addition to head and abdomen measurements.  Radiology. 1984;150(2):535-540
PubMed
Verburg BO, Mulder PG, Hofman A, Jaddoe VW, Witteman JC, Steegers EA. Intra- and interobserver reproducibility study of early fetal growth parameters.  Prenat Diagn. 2008;28(4):323-331
PubMed   |  Link to Article
Mickey RM, Greenland S. The impact of confounder selection criteria on effect estimation.  Am J Epidemiol. 1989;129(1):125-137
PubMed
 Migrants in the Netherlands 2004. Statistics Netherlands website. http://www.cbs.nl. Accessed November 18, 2010
 Standard classification of education 2003. Statistics Netherlands website. http://www.cbs.nl. Accessed November 18, 2010
Roza SJ, Verburg BO, Jaddoe VW, Hofman A, Mackenbach JP, Steegers EA, Witteman JC, Verhulst FC, Tiemeier H. Effects of maternal smoking in pregnancy on prenatal brain development: the Generation R Study.  Eur J Neurosci. 2007;25(3):611-617
PubMed   |  Link to Article
El Marroun H, Tiemeier H, Jaddoe VW, Hofman A, Verhulst FC, van den Brink W, Huizink AC. Agreement between maternal cannabis use during pregnancy according to self-report and urinalysis in a population-based cohort: the Generation R Study.  Eur Addict Res. 2011;17(1):37-43
PubMed   |  Link to Article
Twisk JWR. Applied Multilevel Analysis: A Practical Guide for Medical Researchers. Cambridge, England: Cambridge University Press; 2006
Royston P, Ambler G, Sauerbrei W. The use of fractional polynomials to model continuous risk variables in epidemiology.  Int J Epidemiol. 1999;28(5):964-974
PubMed   |  Link to Article
Matthews JN, Altman DG. Interaction 3: how to examine heterogeneity.  BMJ. 1996;313(7061):862
PubMed   |  Link to Article
Matthews JN, Altman DG. Statistics notes, interaction 2: compare effect sizes not P values.  BMJ. 1996;313(7060):808
PubMed   |  Link to Article
Young-Davies CL, Bennett-Clarke CA, Lane RD, Rhoades RW. Selective facilitation of the serotonin(1B) receptor causes disorganization of thalamic afferents and barrels in somatosensory cortex of rat.  J Comp Neurol. 2000;425(1):130-138
PubMed   |  Link to Article
Xu Y, Sari Y, Zhou FC. Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development.  Brain Res Dev Brain Res. 2004;150(2):151-161
PubMed   |  Link to Article
Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA. Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry.  Neuropsychopharmacology. 2006;31(1):47-57
PubMed
Silva LM, Jansen PW, Steegers EA, Jaddoe VW, Arends LR, Tiemeier H, Verhulst FC, Moll HA, Hofman A, Mackenbach JP, Raat H. Mother's educational level and fetal growth: the genesis of health inequalities.  Int J Epidemiol. 2010;39(5):1250-1261
PubMed   |  Link to Article
Baschat AA. Fetal responses to placental insufficiency: an update.  BJOG. 2004;111(10):1031-1041
PubMed   |  Link to Article
Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction.  Arch Gen Psychiatry. 2010;67(10):1012-1024
PubMed   |  Link to Article
Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data.  Arch Gen Psychiatry. 2006;63(8):898-906
PubMed   |  Link to Article
Lund N, Pedersen LH, Henriksen TB. Selective serotonin reuptake inhibitor exposure in utero and pregnancy outcomes.  Arch Pediatr Adolesc Med. 2009;163(10):949-954
PubMed   |  Link to Article
Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure.  Am J Psychiatry. 2002;159(12):2055-2061
PubMed   |  Link to Article
Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine.  N Engl J Med. 1996;335(14):1010-1015
PubMed   |  Link to Article
El Marroun H, Tiemeier H, Steegers EA, Jaddoe VW, Hofman A, Verhulst FC, van den Brink W, Huizink AC. Intrauterine cannabis exposure affects fetal growth trajectories: the Generation R Study.  J Am Acad Child Adolesc Psychiatry. 2009;48(12):1173-1181
PubMed   |  Link to Article
Gentile S. Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of birth defects.  Acta Psychiatr Scand. 2011;123(4):266-275
PubMed   |  Link to Article
Austin MP. To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects.  Psychol Med. 2006;36(12):1663-1670
PubMed   |  Link to Article
Andrade SE, Raebel MA, Brown J, Lane K, Livingston J, Boudreau D, Rolnick SJ, Roblin D, Smith DH, Willy ME, Staffa JA, Platt R. Use of antidepressant medications during pregnancy: a multisite study.  Am J Obstet Gynecol. 2008;198(2):194-195, e1-e5
PubMed   |  Link to Article
Cooke RW, Lucas A, Yudkin PL, Pryse-Davies J. Head circumference as an index of brain weight in the fetus and newborn.  Early Hum Dev. 1977;1(2):145-149
PubMed   |  Link to Article
Epstein HT, Epstein EB. The relationship between brain weight and head circumference from birth to age 18 years.  Am J Phys Anthropol. 1978;48(4):471-473
PubMed   |  Link to Article
Herba CM, Roza SJ, Govaert P, van Rossum J, Hofman A, Jaddoe V, Verhulst FC, Tiemeier H. Infant brain development and vulnerability to later internalizing difficulties: the Generation R study.  J Am Acad Child Adolesc Psychiatry. 2010;49(10):1053-1063
PubMed   |  Link to Article
Whitaker AH, Van Rossem R, Feldman JF, Schonfeld IS, Pinto-Martin JA, Tore C, Shaffer D, Paneth N. Psychiatric outcomes in low-birth-weight children at age 6 years: relation to neonatal cranial ultrasound abnormalities.  Arch Gen Psychiatry. 1997;54(9):847-856
PubMed   |  Link to Article
Peterson BS, Anderson AW, Ehrenkranz R, Staib LH, Tageldin M, Colson E, Gore JC, Duncan CC, Makuch R, Ment LR. Regional brain volumes and their later neurodevelopmental correlates in term and preterm infants.  Pediatrics. 2003;111(5, pt 1):939-948
PubMed   |  Link to Article
Peterson BS, Vohr B, Staib LH, Cannistraci CJ, Dolberg A, Schneider KC, Katz KH, Westerveld M, Sparrow S, Anderson AW, Duncan CC, Makuch RW, Gore JC, Ment LR. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants.  JAMA. 2000;284(15):1939-1947
PubMed   |  Link to Article
Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders.  Arch Gen Psychiatry. 2011;68(11):1104-1112
PubMed   |  Link to Article

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Response to Maternal use of selective serotonin reuptake inhibitors and fetal outcomes
Posted on July 2, 2012
Sunil Gupta, Subodh BN, Sandeep Grover
Department of Psychiatry, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India
Conflict of Interest: None Declared

We read with interest the study by Marroun et al1 on the impact of Selective Serotonin Reuptake Inhibitors (SSRIs) on fetal growth and adverse birth outcomes. It is a well conducted study which included a large sample, studied prospectively at regular intervals with cross-checking of information from the prescription records. The authors addressed many potential confounders and biases. However, there are some limitations which have to be considered which can significantly affect the veracity of their conclusions.

The authors are silent about the specific SSRIs, doses used and the duration of intake. This information is important as the existing evidence suggest that the effect of SSRIs on the fetus is dose related and Infants exposed to SSRIs continuously throughout the gestation are more likely to be born preterm than infants with partial or no exposure (2). Further, there is differential effect of various SSRIs on the fetal growth, with some like paroxetine known to have more adverse effects than other SSRIs (2). The authors also did not provide any information about use of antidepressants other than SSRIs in those with depression (3). Similarly, it is possible that in some cases SSRIs may have been used for disorder other than depression, for example anxiety disorders, which itself can influence the pregnancy outcome (4), as shown in the data based on the same cohort (5). Further, the authors have assessed depression only once at 20.6 weeks of gestation using the Brief Symptom Inventory (BSI), which is not a diagnostic questionnaire. This could have led to underreporting of depression occuring in the third trimester (6). Hence the findings of prevalence of depression may not be a true reflection of actual prevalence and the impact of depression on pregnancy reported in the study cannot be generalized.

Head circumference was measured at mean post-conception age of 42.9 weeks whereas mean gestational age was 39.2- 39.9 weeks. This gives a difference of more than three weeks after birth when head circumference was measured rather than the two weeks as reported by the authors. Also, gestational age was established using ultrasonography measurements and not the first day of last menstrual period which doesn’t take into account inter subject growth variability. Moreover, even the best fetal weight prediction methods show errors as high as ±15 percent which can adversely impact the analysis of the results (7).

The authors are silent on how numbers of 5431 in control group (against 7027) and 425 in group with depressive symptoms not using SSRIs (against 570) was reached. Although the authors have included many covariates in the analysis, still majority of them were not considered including genetic inheritance, maternal weight, interval since last pregnancy, marital status, unemployment, heavy workload, maternal distress, chronic illnesses, maternal cannabis, alcohol, caffeine consumption during pregnancy, previous intra-uterine growth retardation, anaemia, pregnancy induced hypertension, utero-placental insufficiency, congenital infections, placenta praevia, first trimester hemorrhage, and periconception nutrients supplementation. All these factors have been shown to affect the fetal outcome; some of which have been reported in the studies published based on the same cohort (5,8-13).

Hence, although the findings of the study add to the knowledge, these must be interpreted by taking all these mentioned limitations into consideration.

References:

1. El Marroun H, Jaddoe VW, Hudziak JJ, Roza SJ, Steegers EA, Hofman A, Verhulst FC, White TJ, Stricker BH, Henning Tiemeier H. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry 2012.

2. Wisner KL, Sit DK, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, Perel JM, Sonya Jones-Ivy S, Bodnar LM, Singer LT. Major Depression and antidepressant treatment: Impact on pregnancy and neonatal outcomes. Am J Psychiatry. 2009; 166:557-566.

3. Udechuku A, Nguyen T, Hill R, Szego K. Antidepressants in pregnancy: a systematic review. Aust NZ J Psychiatry 2010; 44:978-996.

4. Gold KJ, Marcus SM. Effect of maternal mental illness on pregnancy outcomes. Exp Rev Obstet Gynecol 2008; 3:391-401.

5. Henrichs J, Schenk JJ, Roza SJ, van den Berg MP, Schmidt HG, Steegers EA, Hofman A, Jaddoe VW, Verhulst FC, Tiemeier H. Maternal psychological distress and fetal growth trajectories: the Generation R Study. Psychol Med 2010; 40:633-643.

6. Bennett, H. A., Einarson, A., Taddio A, Koren G, Einarson TR. Prevalence of depression during pregnancy: systematic review. Obstet Gynecol 2004; 103:698–709.

7. ACR-ACOG-AIUM Practice Guideline for the performance of obstetrical ultrasound. American College of Radiology, Reston, VA, 2007.

8. Newcombe RG. Nonnutritional factors affecting fetal growth. Am J Clin Nutr 1981; 34:732-737.

9. Cetin I, Alvino G, Radaelli T, Pardi G. Fetal nutrition: A review. Acta Paediatrica 2005; 94:7–13.

10. Bakker R, Steegers EA, Obradov A, Raat H, Hofman A, Jaddoe VW. Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: the Generation R Study. Am J Clin Nutr 2010; 91:1691–1698.

11. Bakker R, Pluimgraaff LE, Steegers EA, Raat H, Tiemeier H, Hofman A, et al. Associations of light and moderate maternal alcohol consumption with fetal growth characteristics in different periods of pregnancy: the Generation R Study. Int J Epidemiol 2010; 39:777–789.

12. El Marroun H, Tiemeier H, Steegers EA, Jaddoe VW, Hofman A, Verhulst FC, van den Brink W, Huizink AC. Intrauterine Cannabis exposure affects fetal growth trajectories: the Generation R Study. J Am Acad Child Adolesc Psychiatry 2009; 48:1173-1181.

13. Timmermans S, Jaddoe VW, Hofman A, Steegers-Theunissen RP, Steegers EA. Peri-conception folic acid supplementation, fetal growth and the risks of low birth weight and preterm birth: the Generation R Study. Br J Nutr 2009;102:777-785.

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