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

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.