Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy

doi:10.1067/mpd.2003.139

The Journal of Pediatrics

Volume 142, Issue 4, April 2003, Pages 402-408

Presented in part at the First International Conference on Women's Mental Health held in March 2001 in Berlin, Germany.

https://doi.org/10.1067/mpd.2003.139 Get rights and content

Abstract

Objective To compare the structural growth and developmental outcome of children born to mothers diagnosed with major depressive disorder during pregnancy who were exposed or not exposed to selective serotonin reuptake inhibitors (SSRIs) in utero. Study design Children whose mothers were diagnosed with major depressive disorder in pregnancy and elected not to take medication (n = 13) were compared with children of depressed mothers treated with SSRIs (n = 31) on birth outcomes and postnatal neurodevelopmental functioning between ages 6 and 40 months. Children underwent blinded standardized pediatric and dysmorphology examinations and evaluations of their mental and psychomotor development with the use of the Bayley Scales of Infant Development (BSID II). Results The Bayley mental developmental indexes were similar in both groups. Children exposed to SSRIs during pregnancy had lower APGAR scores and scored lower on the Bayley psychomotor development indexes and the motor quality factor of the Bayley Behavioral Rating Scale than unexposed children. Conclusions The findings that SSRIs during fetal development might have subtle effects on motor development and motor control are consistent with the pharmacologic properties of the drugs. (J Pediatr 2003;142:402-8).

Section snippets

Methods

Women who were in treatment in the Women's Wellness Clinic or with other clinicians and who met DSM-IV criteria¹⁷ for Major Depressive Disorder during pregnancy were invited to participate in the follow-up study. They were recruited before or during pregnancy (71%) or after delivery (29%). The study was approved by the Panel on Human Subjects in Medical Research at Stanford University. All women signed consent forms that contained a description of the content and purpose of the study, with one

Results

The proportion of prospectively/retrospectively recruited women was similar in both experimental groups (χ² =.59; P =.44 ). There were no differences between prospectively and retrospectively studied patients on any of the demographic or outcome variables.

Discussion

The current study found that children exposed to SSRI antidepressant drugs in utero did not differ on most birth outcome and follow-up measures from children of depressed mothers who elected not to take medication during pregnancy. Drug-exposed newborn infants were found to have lower APGAR scores. At follow-up examination, the mental development of drug-exposed children was similar to that of unexposed children. However, we found evidence that prenatal SSRI exposure may have subtle effects on

Acknowledgements

We thank the women who participated in this study.

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Interactions between maternal fluoxetine exposure, the maternal gut microbiome and fetal neurodevelopment in mice
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Selective serotonin reuptake inhibitors (SSRIs) are the most widely used treatment by women experiencing depression during pregnancy. However, the effects of maternal SSRI use on early offspring development remain poorly understood. Recent studies suggest that SSRIs can modify the gut microbiota and interact directly with particular gut bacteria, raising the question of whether the gut microbiome impacts host responses to SSRIs. In this study, we investigate effects of prenatal SSRI exposure on fetal neurodevelopment and further evaluate potential modulatory influences of the maternal gut microbiome. We demonstrate that maternal treatment with the SSRI fluoxetine induces widespread alterations in the fetal brain transcriptome during midgestation, including increases in the expression of genes relevant to synaptic organization and neuronal signaling and decreases in the expression of genes related to DNA replication and mitosis. Notably, maternal fluoxetine treatment from E7.5 to E14.5 has no overt effects on the composition of the maternal gut microbiota. However, maternal pretreatment with antibiotics to deplete the gut microbiome substantially modifies transcriptional responses of the fetal brain to maternal fluoxetine treatment. In particular, maternal fluoxetine treatment elevates localized expression of the opioid binding protein/cell adhesion molecule like gene Opcml in the fetal thalamus and lateral ganglionic eminence, which is prevented by maternal antibiotic treatment. Together, these findings reveal that maternal fluoxetine treatment alters gene expression in the fetal brain through pathways that are impacted, at least in part, by the presence of the maternal gut microbiota.
Long-term effects of pre-gestational stress and perinatal venlafaxine treatment on neurobehavioral development of female offspring
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Preclinical studies suggest that stress-related disorders even prior gestation can cause long-term changes at the level of neurobehavioral adaptations. Therefore, it is critical to consider undergoing antidepressant therapy which could reverse the negative consequences in the offspring. Venlafaxine is widely used in clinical practice; however insufficient amount of well-controlled studies verified the safety of venlafaxine therapy during gestation and lactation. The aim of this work was to investigate the effects of perinatal venlafaxine therapy on selected neurobehavioral variables in mothers and their female offspring using a model of maternal adversity. Pre-gestational stressed and non-stressed Wistar rat dams were treated with either venlafaxine (10 mg/kg/day) or vehicle during pregnancy and lactation. We have shown that pre-gestational stress decreased the number of pups with a significant reduction in the number of males but not females. Furthermore, we found that offspring of stressed and treated mothers exhibited anxiogenic behavior in juvenile and adolescent age. However, during adulthood pre-gestational stress significantly increased anxiety-like behavior of female, with venlafaxine treatment normalizing the state to control levels. Additionally, we found that even maternal stress prior gestation can have long-term impact on adult number of hippocampal immature neurons of the female offspring. A number of questions related to the best treatment options for maternal depression still remains, however present data may provide greater insight into the possible outcomes associated with perinatal venlafaxine therapy.
Maternal use of antidepressants during pregnancy and risks for adverse perinatal outcomes: a meta-analysis
2020, Journal of Psychosomatic Research
Citation Excerpt :
Second, our study is limited by the quality of the original data. Unfortunately, several studies did not control for any potential confounding factor [17,28,34,39,41,43,50,56,57,60,63], although nearly 60% of the studies (32/54 studies) included more than one potential confounding factor. Of note, we undertook subgroup analyses of whether the confounding factors were adjusted and/or matched to investigate the effect of confounders that can be extracted from the included studies on adverse perinatal outcomes.
Objective: To perform an updated and comprehensive meta-analysis on the risks of adverse perinatal outcomes in children whose mothers received antidepressants during pregnancy.
Methods: A systematic literature search of several databases was conducted through December 2018 to identify relevant studies. Risk estimates and their corresponding 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Subgroup and sensitivity analyses were performed to explore the source of heterogeneity and test the robustness.
Results: Forty-eight cohort and 6 case-control studies were included. In cohort studies, children whose mothers received antidepressants during pregnancy had higher risks of preterm birth (RR = 1.62, 95% CI: 1.37, 1.90), low birth weight (RR = 1.37, 95% CI: 1.04, 1.80), and admissions to neonatal intensive care unit (RR = 1.60, 95% CI: 1.38, 1.85) when compared with children born by depressed but untreated pregnant women. The risks of spontaneous abortions (RR = 1.49, 95% CI: 1.29, 1.73), large for gestational age (RR = 1.11, 95% CI: 1.03, 1.20), stillbirths (RR = 1.16, 95% CI: 1.02, 1.32), low Apgar score at 5 min (RR = 1.91, 95% CI: 1.42, 2.56), and neonatal convulsions (RR = 1.97, 95% CI: 1.56, 2.48) increased in children whose mothers received antidepressants during pregnancy when compared with children born by healthy pregnant women.
Conclusion: Compared with children whose mothers did not receive antidepressants during pregnancy, children whose mothers received antidepressants during pregnancy had increased risks of adverse perinatal outcomes. Further research on the dose of antidepressants is needed.
Intra-uterine exposure to selective serotonin reuptake inhibitors (SSRIs), maternal psychopathology, and neurodevelopment at age 2.5years — Results from the prospective cohort SMOK study
2020, Early Human Development
Citation Excerpt :
Of note, the severity of maternal depression did not influence the association in our cohort. In contrast to our findings, most studies in the past reported no differences in cognitive outcome between children exposed to antidepressant drugs and comparison groups or general population norms [17–19]. Several of these studies had methodological shortcomings as they were either not specifically designed to assess children's intelligence, lacked appropriate comparison groups, were underpowered, included other antidepressant medication like tricyclic antidepressants, or had a follow-up at very different ages using various neurodevelopmental tests.
Selective serotonin reuptake inhibitors (SSRIs) are prescribed in 2–8% during pregnancy. Whether prenatal exposure to SSRIs has long-term effects on the children's development is unknown.
The aim of this study was to determine the effect of prenatal exposure to SSRIs on children's cognitive, motor, and behavioral outcomes at 2.5 years, adjusted for maternal depression and anxiety.
In a prospective, longitudinal cohort-study we included 111 pregnant women treated either or not with an SSRI. We examined cognitive and motor development of their children at 2.5 years, using the Bayley Scale of Infant and Toddler Development, 3rd Edition, and measured emotional and behavioral problems using the parent-rated Child Behavior Checklist (CBCL). Maternal depression and anxiety was determined during pregnancy and at the children's assessment. Differences of normed cognitive, motor, and behavioral scores between SSRI-exposed and non-SSRI-exposed children were tested using multiple linear regression analyses.
We examined 102 children. SSRI-exposed children had lower scaled scores on cognition and gross motor development than non-SSRI-exposed children: 9.0 ± 1.4 (mean ± SD) versus 9.9 ± 1.7 [P = 0.004], and 7.9 ± 2.2 versus 9.0 ± 2.5 [P = 0.01], respectively. Differences remained significant after adjusting for maternal depression and anxiety and other confounders in various models (mean difference for cognition 0.8 to 0.9 points, for gross motor 1.1 to 1.2 points). Only after adjusting for severity of maternal anxiety, differences in gross motor scores lost significance.
Prenatal exposure to SSRIs is associated with poorer cognitive and gross motor development of the children at 2.5 years. Effects on gross motor development disappeared after correction for severity of maternal anxiety.

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^*: Reprint requests: Regina C. Casper, MD, Stanford University, Department of Psychiatry and Behavioral Sciences, 401 Quarry Rd, Room 2365, Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, Stanford, CA 94305-5723. E-mail: [email protected]

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Original ArticlesFollow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy*

Abstract

Section snippets

Methods

Results

Discussion

Acknowledgements

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Advances in psychiatric epidemiology: rates and risks for major depression

Am J Public Health

Risk-benefit decision making for treatment of depression during pregnancy

Am J Psychiatry

Interpersonal psychotherapy for depressed antepartum women: a pilot study

Am J Psychiatry

Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk

Transplacental transfer of amitriptyline and nortriptyline in isolated perfused human placenta

Psychopharmacology

Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac)

JAMA

Birth outcomes in pregnant women taking fluoxetine

N Engl J Med

Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study

JAMA

Delivery outcome after the use of antidepressants in early pregnancy

Eur J Clin Pharmacol

Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study

Am J Psychiatry

Birth outcomes in pregnant women taking fluoxetine

N Engl J Med

Neurodevelopment of children exposed in utero to antidepressant drugs

N Engl J Med

Neurobehavioral follow-up of children prenatally exposed to fluoxetine [abstract]

Teratology

Maternal depressive symptoms and the risk of poor pregnancy outcome

Epidemiol Rev

Original Articles
Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy*