eTable 1. Distributions of offspring age at diagnosis in the cohort.
eTable 2. Mean (SD) age of children at diagnosis by outcome group.
eTable 3. Frequencies and percentages of children with speech/language, scholastic, and motor disorders by exposure group.
eTable 4. Maternal SSRI use and maternal diagnosis of psychiatric disorders without medication in relation to risk of speech/language, scholastic, and motor disorders among offspring by sex.
eTable 5. Comparisons between the exposure groups for offspring speech/language disorders after exposure to 2 or more purchases of SSRI monotherapy and adjusted for maternal suicidal behavior.
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Brown AS, Gyllenberg D, Malm H, et al. Association of Selective Serotonin Reuptake Inhibitor Exposure During Pregnancy With Speech, Scholastic, and Motor Disorders in Offspring. JAMA Psychiatry. 2016;73(11):1163–1170. doi:10.1001/jamapsychiatry.2016.2594
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Is exposure to selective serotonin reuptake inhibitors during pregnancy associated with an increased risk of adverse speech, scholastic, or motor outcomes in offspring?
In this cohort study, offspring of mothers who purchased at least 2 selective serotonin reuptake inhibitors prescriptions during pregnancy had a significantly increased risk of speech/language disorders compared with offspring of mothers diagnosed as having psychiatric disorders who did not take medication during pregnancy.
The findings suggest that use of selective serotonin reuptake inhibitors during pregnancy increases the risk of speech/language disorders in offspring.
Speech/language, scholastic, and motor disorders are common in children. It is unknown whether exposure to selective serotonin reuptake inhibitors (SSRIs) during pregnancy influences susceptibility to these disorders.
To examine whether SSRI exposure during pregnancy is associated with speech/language, scholastic, and motor disorders in offspring up to early adolescence.
Design, Setting, and Participants
This prospective birth cohort study examined national population-based register data in Finland from 1996 to 2010. The sampling frame includes 845 345 pregnant women and their singleton offspring with data on maternal use of antidepressants and depression-related psychiatric disorders during pregnancy.
There were 3 groups of offspring: 15 596 were in the SSRI-exposed group, ie, had mothers diagnosed as having depression-related psychiatric disorders with a history of purchasing SSRIs during pregnancy; 9537 were in the unmedicated group, ie, had mothers diagnosed as having depression-related psychiatric disorders without a history of purchasing SSRIs during pregnancy; and 31 207 were in the unexposed group, ie, had mothers without a psychiatric diagnosis or a history of purchasing SSRIs.
Main Outcomes and Measures
Cumulative incidence of speech/language, scholastic, or motor disorders (829, 187, and 285 instances, respectively) from birth to 14 years. All hypotheses tested were formulated before data collection.
Of the 56 340 infants included in the final cohort, 28 684 (50.9%) were male and 48 782 (86.6%) were 9 years or younger. The mean (SD) ages of children at diagnosis were 4.43 (1.67), 3.55 (2.67), and 7.73 (2.38) for speech/language, scholastic, and motor disorders, respectively. Offspring of mothers who purchased SSRIs at least twice during pregnancy had a significant 37% increased risk of speech/language disorders compared with offspring in the unmedicated group. The cumulative hazard of speech/language disorders was 0.0087 in the SSRI-exposed group vs 0.0061 in the unmedicated group (hazard ratio, 1.37; 95% CI, 1.11-1.70; P = .004). There was a significantly increased risk of these disorders in offspring in the SSRI-exposed and unmedicated groups compared with offspring in the unexposed group. For scholastic and motor disorders, there were no differences between offspring in the SSRI-exposed group and in the unmedicated group.
Conclusions and Relevance
Exposure to SSRIs during pregnancy was associated with an increased risk of speech/language disorders. This finding may have implications for understanding associations between SSRIs and child development.
Use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy is increasing, with recent prevalence estimates of 4% to 10%.1,2 Selective serotonin reuptake inhibitors cross the placenta and enter the fetal circulation.3 Exposure to SSRIs during pregnancy has been associated with an increased risk of autism in some studies4-6 (although many studies have not replicated these findings7,8) and to neonatal adaptation syndrome.9
The question of fetal SSRI exposure on these parameters has biologic plausibility. Mice with elevated serotonin signaling from genetic mutations exhibit motor deficits.10 Mice exposed to SSRIs during a sensitive period of development overlapping with fetal brain development exhibit cognitive impairments.11
Speech/language, scholastic, and motor disorders without intellectual disability are prevalent in the population, with estimates as high as 10%.12 Several studies have investigated SSRI exposure during pregnancy and outcomes in offspring. While these investigations have generally shown no associations, Casper et al13 demonstrated associations between length of SSRI exposure and diminished scores on psychomotor function and motor quality tests during infancy, and Simon et al14 and Casper et al15 have shown psychomotor delay after in utero SSRI exposure.
However, prior studies have several limitations. First, sample sizes of participants exposed and unexposed to SSRIs have been small to modest, limiting statistical power. Second, the follow-up periods frequently did not include children older than 3 years. Third, to our knowledge, previous studies have not examined clinical disorders of speech, language, scholastic, and motor function. Fourth, most studies have included samples derived from clinics rather than from populations.
Therefore, we evaluated whether prenatal exposure to SSRIs is associated with speech/language, scholastic, and motor disorders. This was conducted in a large population-based study of a national birth cohort in Finland. We improved on previous studies by including larger sample sizes, conducting follow-up to 14 years, assessing clinical disorders, and using a sample derived from a population. To address the possible confounding effect of maternal depression, we included a comparison group of offspring from pregnancies of women diagnosed as having depression and other psychiatric disorders but not treated with SSRIs during pregnancy.
The study derives from a population-based, prospective cohort design. All data were obtained from national registries, which were linked by a unique personal identification number assigned to all citizens and permanent residents of Finland. The register administrators and the data protection authority approved the use of health registry data for scientific research and data linkages. The institutional ethical review boards at the National Institute for Health and Welfare and the Social Insurance Institution of Finland and the Institutional Review Board of the New York State Psychiatric Institute approved the study protocol. Because the individuals were not contacted, informed consent was not required.
The sampling frame consisted of 845 345 singleton live births in Finland between January 1996 and December 2010. Most children were 9 years or younger (eTable 1 in the Supplement). Of the 56 340 infants included in the final cohort, 28 684 (50.9%) were male and 27 656 (49.1%) were female. The mean (SD) ages of children at diagnosis were 4.43 (1.67), 3.55 (2.67), and 7.73 (2.38) for speech/language, scholastic, and motor disorders, respectively (eTable 2 in the Supplement). The age distribution at time of diagnosis and the average ages at time of diagnosis for each developmental outcome are provided in eTables 1 and 2 in the Supplement. The Finnish Medical Birth Register was used to identify mother-child dyads. The registry includes comprehensive data on maternal demographic information, diagnoses during pregnancy and delivery, and neonatal outcomes. Data on diagnoses were derived from the Finnish Hospital Discharge Register (FHDR), which contains person-level information on all treatments in inpatient clinics since 1969 and in all public outpatient clinics since 1998. These data were based on contact with Finnish specialized health services for developmental disorders but not from primary care. Diagnoses were based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coding.
The group exposed to SSRIs and the comparison groups were obtained from the drug reimbursement register, which has been maintained since 1995. This register contains data on all reimbursed prescription drug purchases throughout Finland and covers virtually all prescription drug purchases (99% in 2007). The Anatomical Therapeutic Chemical (ATC) Classification System was used to categorize drug purchases that were recorded at pharmacies.
There were 15 596 offspring included in the SSRI-exposed group, ie, with mothers diagnosed as having depression or another psychiatric disorder associated with SSRI use who made 1 or more purchases of SSRIs (ie, fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, and escitalopram) by prescription between 30 days before pregnancy and delivery. The date of purchase was designated as the beginning date of each prescription. The onset of gestation corresponding to the last menstrual period was calculated from the best clinical estimate of gestational age at birth, primarily from ultrasonography and Finnish Medical Birth Register registration. Information on diagnosis of depression or depression-related diagnoses was available in the FHDR for 4765 mothers (30.6%) in this group (ie, for those who had been treated in inpatient care or outpatient specialized care centers).
There were 9537 offspring included in the unmedicated group, ie, with mothers diagnosed as having depression or another psychiatric disorder associated with SSRI use with no history of SSRI purchase during pregnancy. Data on diagnoses of depression or other psychiatric disorders associated with depression or SSRI use were obtained from the FHDR (ICD-9 codes 295-298 and 300 and ICD-10 codes F20-F48) between 1 year before pregnancy and hospital discharge after delivery (3 weeks or less), as were data on antidepressant purchases (ATC codes N06A and N06CA) or antipsychotics (N05A) between 3 months before pregnancy and delivery.
There were 31 207 offspring included in the unexposed group, ie, with mothers without a psychiatric diagnosis associated with SSRI use or a history of purchasing antidepressants or antipsychotics any time prior to or during pregnancy. Each child in the SSRI-exposed group was matched with 2 children in the unexposed group on date of birth (within 6 months).
Outcomes were derived from the FHDR, which is based on medical examinations by physicians in units of specialized health care. All schoolchildren in Finland receive annual examinations; those requiring specialized health care are referred to experts in the designated conditions. All these clinics are universal, and expenses are covered by the national health care system.
The outcomes were coded using ICD-10 and categorized as specific developmental disorders of speech and language (F80), specific developmental disorders of scholastic skills (F81), and specific developmental disorder of motor function (F82). To separately examine each of the categories, participants diagnosed as having combinations of disorders were excluded from the analyses.
Covariates were selected based on their plausibility and prior associations with SSRI exposure and outcomes. Data on covariates were obtained from Finnish national registries. The registry data were nearly complete for most covariates, except for socioeconomic status, which was recorded less extensively. Accordingly, we based the socioeconomic status classification on maternal occupation. Information on parental psychiatric diagnoses was coded using ICD-8 codes from 1969 to 1986, ICD-9 codes from 1987 to 1995, and ICD-10 codes from 1996 to 2010.
Children born from 1996 to 2010 were 14 years or younger at the end of the follow-up in 2010. To account for loss to follow-up, we used survival analysis methods, with the time to event of interest being the age at first diagnosis of speech/language, scholastic, and motor disorders. Separate analyses were conducted for each of the 3 outcomes. Events occurring after migration, death, or the end of the follow-up on December 31, 2010, were treated as right-censored. Cox proportional hazards models were used to compare offspring developmental diagnoses between the 3 groups, and models were compared using hazard ratios (HRs) and 95% CIs. To account for the correlation between time to event outcomes in the same family (clusters), robust sandwich estimates of the standard errors of the estimated Cox regression parameters were used. Each outcome was analyzed separately by fitting it to 2 models: a crude model adjusted only for sex and a model adjusted for sex, previous births, marital status, socioeconomic status, gestational age, exposure to antiepileptic drugs, mother’s country of birth, parental death, smoking, maternal substance abuse, paternal age, maternal age, place of residence, exposure to anxiolytics/sedatives, entitlement to chronic diseases, maternal history of psychiatric diagnoses, and paternal history of psychiatric diagnoses. The extent of SSRI exposure was greater for mothers with more than 1 purchase of SSRI prescriptions during pregnancy, so we also examined exposure by number of purchases (1 vs 2 or more). Separate analyses were also conducted by sex of offspring. All analyses were performed with SAS version 9.4 (SAS Institute). Statistical significance was set at P < .05.
Maternal, neonatal, and family characteristics by exposure group are shown in Table 1. The frequencies and percentages of children with each outcome by exposure group are presented in eTable 3 in the Supplement.
The results of analyses from the Cox proportional hazards models are presented in Table 2. For brevity, we report only the results of analyses adjusted for the covariates. In summary, offspring in the SSRI-exposed group and the unmedicated group were at a significantly increased risk of speech/language disorders compared with offspring in the unexposed group. There were no significant differences in any of the outcomes between offspring in the SSRI-exposed group and in the unmedicated group, although a statistical trend (HR, 1.20; 95% CI, 0.97-1.49; P = .10) was found for speech/language disorders in the adjusted model (Table 2).
We next conducted analyses of the association between offspring disorders and the number of SSRI purchases during pregnancy (Table 3). Among mothers with at least 2 SSRI purchases, there was a significant increase in risk of speech/language disorders in offspring in the SSRI-exposed group compared with the unmedicated and unexposed groups in the adjusted analyses (2 or more purchases vs unmedicated: HR, 1.37; 95% CI, 1.11-1.70; P = .004; 2 or more purchases vs unexposed: HR, 1.63; 95% CI, 1.37-2.01; P < .001). Moreover, there was a statistical trend toward an increased risk of motor disorders for offspring of mothers with at least 2 SSRI purchases compared with offspring in the unexposed group (HR, 1.39; 95% CI, 0.98-1.96; P = .06). There were no significant differences in the risk of the other disorders between offspring in the SSRI-exposed group and the unmedicated group.
The findings of the Cox regression analyses by sex are presented in eTable 4 in the Supplement. Among males, there was a significant increase in the risk of speech/language disorders in offspring in the SSRI-exposed group vs the unexposed group and offspring in the unmedicated group vs the unexposed group. There was no increase in risk of any disorder in offspring of either sex in the SSRI-exposed group compared with the unmedicated group, although there was a statistical trend for increased speech/language disorders among females (HR, 1.40; 95% CI, 0.96-2.03; P = .08) (eTable 4 in the Supplement).
We conducted 2 supplemental analyses to address whether the associations between maternal SSRI use (2 or more purchases) and risk of speech/language disorders in offspring were confounded by severity of depression (eTable 5 in the Supplement). We first restricted SSRI use to monotherapy during pregnancy and compared the risk of speech/language disorders between all 3 groups. The rationale for limiting these mothers to those with monotherapy is that those with more severe depression are likely treated with more than 1 antidepressant. Second, we adjusted for diagnoses associated with suicidal behavior (suicide attempt or self-harm; eTable 5 in the Supplement), one proxy of depression severity, in the model of maternal SSRI use and speech/ language disorders. In both analyses, the HRs did not change appreciably, and the results remained statistically significant.
Using a large, national birth cohort observed from birth to 14 years, we have provided novel evidence of an association between speech/language disorders in offspring and SSRI use during pregnancy while accounting for maternal depression and other psychiatric disorders. The finding was observed only in offspring of mothers who purchased at least 2 SSRI prescriptions during pregnancy. This finding is particularly noteworthy because these women were more likely to have taken these medications and were exposed for a longer period and to larger amounts of SSRIs during pregnancy compared with women who filled only 1 prescription. In the whole sample, irrespective of the number of purchases, the risk of speech/language disorders was increased among offspring of mothers who used SSRIs during pregnancy as well as offspring of mothers diagnosed as having depression or other psychiatric disorders who did not take SSRIs compared with offspring of mothers with neither SSRI use nor psychiatric diagnoses.
To our knowledge, no previous study examined associations between maternal SSRI use and clinical speech/language, scholastic, or motor disorders in offspring. Most studies that used rating scales of cognitive and motor outcomes showed no significant associations with maternal antidepressant use.16 In a study of venlafaxine therapy during pregnancy, no associations with cognitive outcomes were found in children aged 3 to 7 years.17 Moreover, 2 earlier studies18,19 from that group did not show associations between SSRI and tricyclic antidepressant use during pregnancy on global intelligence and language development in offspring aged 15 to 86 months18 and showed no differences on the Bayley Scales of Infant Development at 6 months between offspring of mothers exposed to SSRIs and unexposed infants. These findings are similar to findings by Johnson et al,19 who showed no associations between antidepressant use during pregnancy and scores on the Infant Neurologic International Battery. However, Casper et al13 found that a longer duration of SSRI exposure during pregnancy among women with major depressive disorder was associated with a lower psychomotor development index score on the Bayley Scales of Infant Development–II in offspring aged 12 to 40 months. A second study by this research group15 also found significantly lower scores on the Bayley psychomotor development test and motor quality factor test, suggesting a subtle effect on motor development. A study in the Danish National Birth Cohort found a small developmental delay in gross motor function in children exposed to SSRIs.20 In a study of speech and language outcomes, Weikum et al21 found that infants exposed to SSRIs demonstrated a failure to discriminate nonnative vowel and visual language changes that persisted at 10 months, suggesting that these medications led to an accelerated timing of perceptual attunement. In summary, most studies of SSRI exposure and offspring cognitive and motor outcomes did not report significant associations. However, comparisons of the prior findings with those of the present study are limited by the facts that the children in the previous studies were often evaluated at younger mean ages, graded on rating scales rather than clinical outcomes, and taken from generally small sample sizes.
Strengths of the present study include the use of a large and population-based birth cohort, the prospective collection of data on SSRI purchases during pregnancy, the inclusion of a comparison group of mothers diagnosed as having depression who were not taking antidepressants, and the use of an extensive national register database that included other known confounders. Consequently, ascertainment and recall bias are unlikely, and confounding by indication or other covariates is less likely to have occurred.
Despite these advantages, there were notable limitations. First, although we included a comparison group of mothers diagnosed as having depression and other psychiatric disorders who were not treated with antidepressants, severity of maternal depression cannot be ruled out as an explanation for the increased childhood speech and language disorders among mothers who filled more than 1 SSRI prescription. However, it should be noted that in a prior study,22 indicators of severity of maternal psychiatric symptoms were not associated with the choice to continue or discontinue SSRIs during pregnancy. These indicators included age at onset, duration of illness, number and duration of prior episodes, time since most recent episode, history of suicide attempts, and comorbidities. Furthermore, the findings in our sample persisted in analyses incorporating proxies of depression severity (ie, adjusted for mothers treated with SSRI monotherapy and for previous diagnoses associated with suicidal behavior).
We also emphasize that because our study was observational and not based on a randomized clinical trial, there is the potential for residual confounding. We note that the HRs for the comparison of speech/language disorders between offspring in the SSRI-exposed group and the unmedicated group remained significant and increased to 1.37 (95% CI, 1.11-1.70), adjusting for all 17 covariates in Table 1 associated with SSRI use. Although these covariates included use of anxiolytics/sedatives, we also compared the mean number of purchases of benzodiazepines between the groups, given the possibility of group differences in duration of use. However, there were no differences in the number of benzodiazepine purchases between mothers in the SSRI and unmedicated groups (data available on request). Moreover, maternal alcohol use is a potential confounder, although we did not have available data on this variable. However, the frequencies of substance abuse, including alcohol, were very similar between the SSRI and unmedicated groups (Table 1). In addition, we were not able to adjust for many variables affecting child development. However, these variables would need to be associated with maternal SSRI use to have potential confounding effects.
Because the diagnostic data were based on Finnish specialized health services rather than primary care, some proportion of children with mild cognitive and motor dysfunction may have been missed. However, the universal care and comprehensive registers provided considerably better coverage of developmental disorders, including those in the present study, than those of most prior investigations.
It is possible that increased care-seeking in mothers treated with SSRIs may have accounted for greater ascertainment of the observed conditions in this group compared with those with no SSRI use. However, we have previously reported no increases in the risk of autism and attention-deficit/hyperactivity disorder among offspring of mothers using SSRIs during pregnancy compared with those diagnosed as having psychiatric disorders but no SSRI use.23 This provides evidence that ascertainment bias owing to maternal care-seeking tendencies among those treated with SSRIs may not have explained the association.
Similar to other studies based on population registries, we were not able to confirm that the purchased medications were taken. However, the association between maternal SSRI purchase and clinical speech and language disorders was present only among mothers with more than 1 SSRI purchase during pregnancy. Moreover, prior studies have also shown positive correlations between data from prescription registries and self-reported use of antidepressants.24
Finally, the effect sizes in the present study were small. Consequently, it should be emphasized that if maternal SSRI use is a true risk factor for childhood speech and language outcomes, one must take into account many additional contributory environmental exposures and genetic factors.25,26 In addition, replication of the findings in independent cohorts is essential.
We found a significant increase in the risk of speech/language disorders among offspring of mothers who purchased SSRIs at least twice during pregnancy compared with mothers diagnosed as having depression or other psychiatric disorders not treated with antidepressants. Further studies are necessary to replicate these findings and to address the possibility of confounding by additional covariates before conclusions regarding the clinical implications of the results can be drawn.
Corresponding Author: Alan S. Brown, MD, MPH, New York State Psychiatric Institute, 1051 Riverside Dr, Unit 23, New York, NY 10032 (email@example.com).
Accepted for Publication: August 21, 2016.
Published Online: October 12, 2016. doi:10.1001/jamapsychiatry.2016.2594
Author Contributions: Dr Sourander had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Brown, Malm, Hinkka-Yli-Salomäki, Artama, Gissler, Gingrich, Sourander.
Acquisition, analysis, or interpretation of data: Brown, Gyllenberg, Malm, McKeague, Hinkka-Yli-Salomäki, Gissler, Weissman, Sourander.
Drafting of the manuscript: Brown, Malm, Artama, Sourander.
Critical revision of the manuscript for important intellectual content: Brown, Gyllenberg, Malm, McKeague, Hinkka-Yli-Salomäki, Gissler, Weissman, Gingrich.
Statistical analysis: Malm, McKeague, Hinkka-Yli-Salomäki, Gissler.
Obtained funding: Brown, Malm, Weissman, Gingrich, Sourander.
Administrative, technical, or material support: Brown, Gyllenberg, Hinkka-Yli-Salomäki, Gissler, Gingrich.
Study supervision: Brown, Sourander.
Conflict of Interest Disclosures: Dr Gyllenberg has received research grants from the Sigrid Juselius Foundation, the Foundation for Pediatric Research in Finland, and the Finnish Medical Foundation. Dr McKeague was partially funded by grant 2R01 GM095722-05 from the National Institutes of Health. No other disclosures were reported.
Funding/Support: This study was funded by grant P50MH090966 by the National Institutes of Health, the Sackler Foundation of Columbia University, and Turku University. Dr Brown received funding from grant 5R01 ES019004 from the National Institute of Environmental Health Sciences.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We wish to acknowledge Juha-Pekka Virtanen, BS (Department of Child Psychiatry, University of Turku, Turku, Finland), for data management as well as Jacky Chow, BS (Columbia University Medical Center, New York, New York), Megan Carreiro, BS (Columbia University Medical Center, New York, New York), and Jukka Huttunen, BM (Department of Child Psychiatry, University of Turku, Turku, Finland), for administrative support. None of the contributors received compensation for their work.
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