14th August 2020, Dr Chee L Khoo
Most women would prefer not to take any medications during the pregnancy for fear of any potential teratogenic effects on the foetus. However, for some women, the use of anti-depressants is necessary. Managing these mental disorders during pregnancy and the post-partum period can be challenging (1-2) but effective management can maintain maternal and infant health (3), improve maternal prenatal health care practices (4) and improve maternal-infant attachment (5). However, concerns remain about the adverse associations of antidepressants with foetal and infant health (6-7) including birth defect risk after early pregnancy exposure (8-9) Thus, if you have to use an antidepressant during pregnancy, which ones will be the safest?
There have been numerous reports linking anti-depressants (mainly SSRIs) to increased risk for birth defects or congenital heart defects but the findings are occasionally conflicting. The clinical usefulness of the research is limited by the inability to account for associations between the underlying condition and birth defects, which may confound associations between early pregnancy antidepressant use and birth defect risk (10-11). In other words, are those birth or heart defects the result of the underlying mental illness or the result of the drugs?
The National Birth Defects Prevention Study (NBDPS) was a US population-based, multisite case-control study that examined risk factors for major structural birth defects (12). Cases with selected birth defects were identified from surveillance systems using standard case definitions and included live births, stillbirths and terminations. Clinical data were abstracted from medical records and classified by clinician geneticists and other clinicians. Controls were randomly sampled live-born infants without major birth defects identified via vital records or hospital birth logs.
Mothers were asked about the use of citalopram, fluoxetine, paroxetine, sertraline, venlafaxine, and bupropion during the 3 months before conception or during pregnancy. Other antidepressants could be reported when women were asked to report any medications used as well as any disease and subsequent medication treatment in the 3 months before or during pregnancy.
They categorised exposure into:
- Early pregnancy exposure – maternal report of using 1 or more anti-depressants in any dose, duration, or frequency from the month before conception through the third pregnancy month.
- Exposed only outside of early pregnancy – exposure to any antidepressant, but solely during the 2 to 3 months before conception and/or pregnancy months 4 to 9.
- Unexposed – no antidepressant use during the 3 months before conception through their pregnancy end.
They used two comparison models:
- Mothers exposed to each antidepressant during early pregnancy compared with mothers unexposed to an antidepressant before or during pregnancy and
- Mothers who were exposed to each antidepressant during early pregnancy compared with mothers only exposed to an antidepressant(s) outside of early pregnancy.
The approach used in model 2 was intended to account partially for confounding by the underlying condition. That is, women exposed only outside of early pregnancy may have had similar conditions, as well as other factors associated with these conditions, during and around the time of pregnancy but did not take antidepressants during the birth defect critical period. This may answer the question on whether the underlying (mental) condition is the cause of any birth defects uncovered.
What did they find?
Although there were several previously reported associations between individual antidepressants and specific birth defects, when they compared women in the early pregnancy exposed group to women exposed only outside early pregnancy, those associations of specific antidepressants with heart defects were attenuated (reduced). Venlafaxine had the highest proportion of associations with specific birth defects; escitalopram had the lowest proportion. For example, fluoxetine and anomalous pulmonary venous return (odds ratio: 2.56; 95%CI, 1.10-5.93). This association was attenuated after partially accounting for underlying conditions (odds ratio: 1.89; 95%CI, 0.56-6.42). This pattern was observed for many SSRI-Congenital Heart Defects combinations.
The findings suggest that the elevated associations between heart defects and antidepressants may be confounded by the underlying condition. Other work examining SSRI use and the risk of any heart defect has also concluded that associations between antidepressants and heart defects may be attributable to the underlying condition (11).
For each SSRI (except escitalopram), there were some degree of higher risk for some non-heart defects among women taking antidepressants who were exposed during early pregnancy compared with those exposed outside of early pregnancy. Among the non-SSRI antidepressants examined, venlafaxine had meaningfully elevated associations with many specific birth defects. After accounting at least partially for the underlying condition, bupropion was only associated with diaphragmatic hernia.
For women who require antidepressants during pregnancy, relative differences in the safety of specific medications maybe useful to consider in risk-benefit decision-making. Fully informed decision-making requires balancing the risks and benefits of any proposed intervention against the maternal and foetal risks of untreated depression or anxiety, mindful that with every pregnancy an underlying risk of a birth defect exists regardless of antidepressant treatment.
- American College of Obstetrics and Gynecology. ACOG practice bulletin: clinical management guidelines for obstetrician-gynecologists, number 92, use of psychiatric medications during pregnancy and lactation. https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Bulletins-List
- Pearlstein T. Depression during pregnancy. Best Pract Res Clin Obstet Gynaecol. 2015;29(5):754-764. doi:10.1016/j.bpobgyn.2015.04.004
- Berard A, Sheehy O, Zhao J-P, et al; Mother To Baby Collaborative Research Committee. Impact of antidepressant use, discontinuation, and dosage modification on maternal depression during pregnancy. Eur Neuropsychopharmacol. 2019;29 (7):803-812. doi:10.1016/j.euroneuro.2019.06.007
- Lindgren K. Relationships among maternal-fetal attachment, prenatal depression, and health practices in pregnancy. Res Nurs Health. 2001;24 (3):203-217. doi:10.1002/nur.1023
- Flykt M, Kanninen K, Sinkkonen J, Punamaki R-L. Maternal depression and dyadic interaction: the role of maternal attachment style. Inf Child Dev. 2010;19:530–550. doi:10.1002/icd.679
- Eke AC, Saccone G, Berghella V. Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and risk of preterm birth: a systematic review and meta-analysis. BJOG. 2016;123(12):1900-1907. doi:10.1111/1471-0528.14144
- Masarwa R, Bar-Oz B, Gorelik E, Reif S, Perlman A, Matok I. Prenatal exposure to selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors and risk for persistent pulmonary hypertension of the newborn: a systematic review,meta-analysis, and network meta-analysis. Am J Obstet Gynecol. 2019;220(1):57.e1-57.e13. doi:10.1016/j.ajog.2018.08.030
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- Louik C, Kerr S, Mitchell AA. First-trimester exposure to bupropion and risk of cardiac malformations. Pharmacoepidemiol Drug Saf. 2014; 23(10):1066-1075. doi:10.1002/pds.3661
- Louik C, Lin AE,Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007;356(26):2675-2683. doi:10.1056/NEJMoa067407
- Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014;370(25):2397-2407. doi:10.1056/NEJMoa1312828
- Reefhuis J, Gilboa SM, AnderkaM, et al; National Birth Defects Prevention Study. The national birth defects prevention study: a review of the methods. Birth Defects Res A Clin Mol Teratol. 2015;103(8):656-669. doi:10.1002/bdra.23384
- Anderson KN, Lind JN, Simeone RM, et al. Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects. JAMA Psychiatry. 2020;10.1001/jamapsychiatry.2020.2453. doi:10.1001/jamapsychiatry.2020.2453