Antidepressants in Pregnancy: Risks to the Fetus and Long-term Health of the Child

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The research literature reveals that antidepressant use in pregnancy poses considerable risks to the fetus and the long-term health of the child. These risks include preterm birth, birth defects, abnormal brain development, and behavioral abnormalities in early childhood.

Adam Urato, an Ob-Gyn, presents an online course on this subject, which can be taken for CEU/CME credits.

 

A. Antidepressant Use In Pregnancy

1.) Cooper WO, Willy ME, Pont SJ, Ray WA.  Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol. 2007 Jun;196(6):544.e1-5.

An examination of pregnant women in the Tennessee Medicaid system between 1999-2003 found that 8.7 percent had been exposed to an antidepressant, 6.2 percent to a SSRI specifically. The percentage of pregnancies that had antidepressant use increased from 5.7 percent (1999) to 13.4 percent (2003).

2.) Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernández-Díaz S; National Birth Defects Prevention Study.  Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008.  Am J Obstet Gynecol. 2011 Jul;205(1):51.e1-8. doi: 10.1016/j.ajog.2011.02.029. Epub 2011 Apr 22.

A large interview-based study of 30,000 women found that the percentage taking antidepressant drugs has increased from less than one percent (1988-90) to 7.5 percent by 2008.

 

B. The role of antidepressants in brain and fetal  development

3.) Bellissima V, Visser GH, Ververs TF, van Bel F, Termote JU, van der Heide M, Florio P, Li Volti G, Gazzolo D.  Antenatal maternal antidepressants drugs affect Activin A concentrations in maternal blood, in amniotic fluid and in fetal cord blood.  J Matern Fetal Neonatal Med. 2011 Oct;24 Suppl 2:31-4. doi: 10.3109/14767058.2011.604931.

The concentrations of a brain fluid protein, Activin A, increased in the fetuses of women taking SSRIs in the third trimester. This increase may play a role in the development of the central nervous system.

4.) Brummelte S, Galea LA, Devlin AM, Oberlander TF.  Antidepressant use during pregnancy and serotonin transporter genotype (SLC6A4) affect newborn serum reelin levels.  Dev Psychobiol. 2013 Jul;55(5):518-29. doi: 10.1002/dev.21056. Epub 2012 Jun 12.

Mothers taking SSRIs during pregnancy had higher levels of reelin fragment while infants prenatally exposed to SSRIs had lower total reelin levels. Lower reelin levels predicted increased irritability and decreased sleep time by the sixth day after birth.

5.) Pawluski JL, Galea LA, Brain U, Papsdorf M, Oberlander TF.  Neonatal S100B protein levels after prenatal exposure to selective serotonin reuptake inhibitors.  Pediatrics. 2009 Oct;124(4):e662-70. doi: 10.1542/peds.2009-0442. Epub 2009 Sep 28.

After controlling for mothers’ mood during pregnancy, SSRI exposure was associated with decreased neonatal serum S100B levels.

6.) Calibuso-Salazar MJ, Ten Eyck GR.  A novel whole-embryo culture model for pharmaceutical and developmental studies.  J Pharmacol Toxicol Methods. 2015 Feb 24.

This study revealed that fluoxetine infiltrated and penetrated embryonic tissue. It was found that altering serotonergic activity during development, via fluoxetine, stunted craniofacial development, and organization.

7.) Sadler TW.  Selective serotonin reuptake inhibitors (SSRIs) and heart defects: potential mechanisms for the observed associations.  Reprod Toxicol. 2011 Dec;32(4):484-9.  Epub 2011 Sep 24. Review.

This analysis suggests mechanisms by which SSRI exposure in utero may lead to congenital heart defects in infants.  They find numerous potential target sites where serotonin could disrupt cardiac development, providing biological plausibility for the origin of heart defects caused by SSRIs.

8.) Berger M, Gray JA, Roth BL.  The expanded biology of serotonin.  Annu Rev Med. 2009;60:355-66. doi: 10.1146/annurev.med.60.042307.110802. Review.

Researchers review the “expanded serotonin biology” related to cardiovascular function and other systems outside of the brain.

9.) Bonnin A, Torii M, Wang L, Rakic P, and Levitt P  (2007) Serotonin modulates the response of embryonic thalamocortical axons to netrin-1. Nat Neurosci 10:588–597

Data indicated that serotonin has a role modulating axons which may disrupt the precision of sensory maps.   

10.) Bonnin A, Levitt P   Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain.  Neuroscience. 2011 Dec 1;197:1-7. doi: 10.1016/j.neuroscience.2011.10.005. Epub 2011 Oct 8. Review.

Research reveals a new, direct role that serotonin may play in altering fetal brain development.

11.) Buznikov GA, Lambert HW, Lauder JM. Serotonin and serotonin-like substances as regulators of early embryogenesis and morphogenesis.  Cell Tissue Res. 2001 Aug;305(2):177-86. Review.

This review of new data indicates that serotonin regulates basic developmental processes.

12.) Gaspar P, Cases O, Maroteaux L.  The developmental role of serotonin: news from mouse molecular genetics.  Nat Rev Neurosci. 2003 Dec;4(12):1002-12. Review.

Serotonin systems can alter human behavior and change the fine wiring of brain connections.

13.) Kelly CR, Sharif NA.  Pharmacological evidence for a functional serotonin-2B receptor in a human uterine smooth muscle cell line.  J Pharmacol Exp Ther. 2006 Jun;317(3):1254-61. Epub 2006 Mar 3.

Researchers investigate the physiological role of serotonin.

14.) Moiseiwitsch JR.  The role of serotonin and neurotransmitters during craniofacial development.  Crit Rev Oral Biol Med. 2000;11(2):230-9. Review.

Researchers investigate the effect of serotonin exposure on craniofacial development. They speculate that children of patients taking SSRIs are at a higher risk for developmental dental defects.

15.) Videman, M., Tokariev, A., Saikkonen, H., Stjerna, S., Heiskala, H., Mantere, O. and Vanhatalo, S., 2016. Newborn Brain Function Is Affected by Fetal Exposure to Maternal Serotonin Reuptake Inhibitors. Cerebral Cortex, p.bhw153.

In a study of 84 mothers (22 on SSRIs and 62 controls), the researchers conducted structured behavioral assessments of their newborns and found only minor affects associated with the drugs. When they carried out neurophysiological testing, however, the researchers found lower levels of “global integration,” “interhemispheric connectivity,” and “local cross frequency integration” in newborns exposed to SSRIs in utero. These effects also appeared to outlast the known period of immediate withdrawal common to such newborns. (MIA Coverage)

 

C. Animal Studies

15.) Bauer S, Monk C, Ansorge M, Gyamfi C, Myers M.  Impact of antenatal selective serotonin reuptake inhibitor exposure on pregnancy outcomes in mice.  Am J Obstet Gynecol. 2010 Oct;203(4):375.e1-4. doi: 10.1016/j.ajog.2010.05.008. Epub 2010 Jun 12.

This study tests the antidepressant fluoxetine on mice and measures for altered gestational length and adverse pregnancy outcomes. Fluoxetine did not change the gestational length but did affect litter size and spontaneous loss in mice.

16.) Borue X, Chen J, Condron BG.  Developmental effects of SSRIs: lessons learned from animal studies.  Int J Dev Neurosci. 2007 Oct;25(6):341-7. Epub 2007 Jul 7. Review.

A review of animal studies on SSRIs effects on pregnancy outcomes finds that the drugs can cause subtle changes in brain circuitry and maladaptive behaviors, including anxiety, aggression, or depression that may not appear until adulthood.

17.) Cray JJ Jr, Weinberg SM, Parsons TE, Howie RN, Elsalanty M, Yu JC. Selective serotonin reuptake inhibitor exposure alters osteoblast gene expression and craniofacial development in mice.  Birth Defects Res A Clin Mol Teratol. 2014 Dec;100(12):912-23.

A study on mice using the SSRI citalopram finds that exposure is associated with cellular and morphological alterations of the craniofacial complex.

18.) da-Silva VA, Altenburg SP, Malheiros LR, Thomaz TG, Lindsey CJ.  Postnatal development of rats exposed to fluoxetine or venlafaxine during the third week of pregnancy.  Braz J Med Biol Res. 1999 Jan;32(1):93-8.

Antidepressants (fluoxetine and venlafaxine) administered to rats in the third week of pregnancy were associated with low birth weight among pups.

19.) Fornaro E, Li D, Pan J, Belik J.  Prenatal exposure to fluoxetine induces fetal pulmonary hypertension in the rat.  Am J Respir Crit Care Med. 2007 Nov 15;176(10):1035-40. Epub 2007 Aug 16.

Pregnant rats were treated with fluoxetine resulting in fetal pulmonary hypertension. Exposed rats had increased postnatal mortality and lower arterial oxygen saturation.

20.) Fraher D, Hodge JM, Collier FM, McMillan JS, Kennedy RL, Ellis M, Nicholson GC, Walder K, Dodd S, Berk M, Pasco JA, Williams LJ, Gibert Y.  Citalopram and sertraline exposure compromises embryonic bone development.  Mol Psychiatry. 2015 Sep 8. doi: 10.1038/mp.2015.135.

Testing the possible effects of SSRI exposure on developing bone, researchers treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram, and sertraline. The researchers suggest that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation.

21.) Haskell SE, Hermann GM, Reinking BE, Volk KA, Peotta VA, Zhu V, Roghair RD.  Sertraline exposure leads to small left heart syndrome in adult mice.  Pediatr Res. 2013 Mar;73(3):286-93. doi: 10.1038/pr.2012.183. Epub 2012 Dec 11.

Exposure to the antidepressant sertraline causes long-term changes in cardiac morphology and physiology. The researchers speculate that early-life SSRI exposure impairs cardiomyocyte growth and central serotonin signaling, leading to a small left heart syndrome in adult mice.

22.) Lee LJ.  Neonatal fluoxetine exposure affects the neuronal structure in the somatosensory cortex and somatosensory-related behaviors in adolescent rats.  Neurotox Res. 2009 Apr;15(3):212-23. doi: 10.1007/s12640-009-9022-4. Epub 2009 Mar 4.

This study examined the effects of early exposure of the SSRI fluoxetine on the developing somatosensory system of neonatal rats. Results indicate that neonatal fluoxetine exposure has long-lasting effects on the function and structure in the somatosensory system.

23.) 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 Jul 23;3(7):e2782. doi: 10.1371/journal.pone.0002782. Erratum in: PLoS One. 2009;4(9). doi: 10.1371/annotation/71abed9d-9ee9-4be0-a663-0d469750e13a.

This study examined how fluoxetine and fluvoxamine cross the placental barrier and then tracked the effects.  Results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner.

24.) Simpson K. L., Weaver K. J., de Villers-Sidani E., Lu J. Y., Cai Z., Pang Y., et al. (2011). Perinatal antidepressant exposure alters cortical network function in rodents. Proc. Natl. Acad. Sci. U.S.A. 108, 18465–18470 10.1073/pnas.1109353108.

Perinatal rats were given the SSRI citalopram, and their serotonin levels were tracked. Drug-exposed rat pups exhibited neophobia and disrupted juvenile play behavior.

25.) Van den Hove DL, Blanco CE, Scheepens A, Desbonnet L, Myint AM, Leonard BE, Prickaerts J, Steinbusch HW.  Prenatal maternal paroxetine treatment and neonatal mortality in the rat: a preliminary study.  Neonatology. 2008;93(1):52-5. Epub 2007 Jul 25.

Paroxetine was given to pregnant rats to counteract daily restraint stress. Drug was given during the last week of gestation. Paroxetine led to shortened gestational length, reduced birth weight and a 10-fold rise in neonatal mortality in both stressed and non-stressed litters.

26.) Vorhees CV, Acuff-Smith KD, Schilling MA, Fisher JE, Moran MS, Buelke-Sam J.  A developmental neurotoxicity evaluation of the effects of prenatal exposure to fluoxetine in rats. Fundam Appl Toxicol. 1994 Aug;23(2):194-205.

Rats were treated on days 7-20 of gestation with fluoxetine. At the highest dose, fluoxetine caused maternal weight loss during pregnancy, reduced litter sizes at birth, and increased neonatal mortality.  The researchers conclude that that fluoxetine is not developmentally neurotoxic in the rat.

27.) Xu Y., Sari Y., Zhou F. C. (2004). Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development. Brain Res. Dev. Brain Res. 150, 151–161 10.1016/j.devbrainres.2003.02.001.

Paroxetine was administered to rat pups for the first eight days after birth. The development of neural circuitry in the rodent somatosensory cortex was affected by exposure to a SSRI during synaptic development.

28.) Morrison JL, Chien C, Riggs KW, Gruber N, Rurak D.  Effect of maternal fluoxetine administration on uterine blood flow, fetal blood gas status, and growth.  Pediatr Res. 2002 Apr;51(4):433-42.

A study assessed the impact of fluoxetine on a fetus in late-gestation pregnant sheep finding transient effects that may affect development with repeat exposures.

 

D. Miscarriage

29.) Hemels ME, Einarson A, Koren G, Lanctôt KL, Einarson TR.  Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis.  Ann Pharmacother. 2005 May;39(5):803-9. Epub 2005 Mar 22. Review.

In a meta-analysis, maternal use of antidepressants significantly increased the rate of spontaneous abortions.

30.) Nikfar S, Rahimi R, Hendoiee N, Abdollahi M.  Increasing the risk of spontaneous abortion and major malformations in newborns following use of serotonin reuptake inhibitors during pregnancy: A systematic review and updated meta-analysis.  Daru. 2012 Nov 1;20(1):75. doi: 10.1186/2008-2231-20-75.

The results of a meta-analysis of studies conducted between 1990 and 2012 demonstrate that maternal use of SSRIs increased the risk of spontaneous abortions, but did not find an increase in cardiovascular malformations.

31.) Nakhai-Pour HR, Broy P, Bérard A.  Use of antidepressants during pregnancy and the risk of spontaneous abortion.  CMAJ. 2010 Jul 13;182(10):1031-7. doi: 10.1503/cmaj.091208. Epub 2010 May 31.

Data from the Quebec Pregnancy Registry revealed an increased risk for spontaneous abortion when women had a prescription for at least one antidepressant.

 

E. Pre-term Birth and Other Complications

32.) Huang H, Coleman S, Bridge JA, Yonkers K, Katon W.  A meta-analysis of the relationship between antidepressant use in pregnancy and the risk of preterm birth and low birth weight.  Gen Hosp Psychiatry. 2014 Jan-Feb;36(1):13-8. doi: 10.1016/j.genhosppsych.2013.08.002. Epub 2013 Oct 2.

Maternal antidepressant use significantly increases the risk for low birth weight and preterm birth, according to a meta-analysis of 28 English and non-English language articles.

33.) Huybrechts KF, Sanghani RS, Avorn J, Urato AC.  Preterm birth and antidepressant medication use during pregnancy: a systematic review and meta-analysis.  PLoS One. 2014 Mar 26;9(3):e92778. doi: 10.1371/journal.pone.0092778. eCollection 2014.

A review of 41 studies found that maternal use of antidepressants in the second and third trimesters is consistent with a risk for preterm birth.

34.) Simon GE, Cunningham ML, Davis RL.  Outcomes of prenatal antidepressant exposure. Am J Psychiatry 2002; 159:2055–61.

SSRI use during pregnancy was found to be associated with early delivery and lower birth weight, and use during the third trimester was associated with lower Apgar scores.

35.) Suri R, Altshuler L, Hellemann G, Burt VK, Aquino A, et al. (2007) Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry 164: 1206–1213. doi: 10.1176/appi.ajp.2007.06071172.

In a prospective naturalistic study of ninety women, researchers found that prenatal use of antidepressants was associated with an increased risk for preterm birth while the presence of depressive symptoms alone was not associated with this risk.

36.) Costei AM, Kozer E, Ho T, Ito S, Koren G (2002) Perinatal outcome following third-trimester exposure to paroxetine. Arch Pediatr Adolesc Med 156: 1129–1132. doi: 10.1001/archpedi.156.11.1129.

Maternal use of paroxetine was found to be associated with a high rate of neonatal complications. Researchers speculate that this is caused by discontinuation syndrome.

37.) Hayes RM, Wu P, Shelton RC, Cooper WO, Dupont WD, Mitchel E, Hartert TV.  Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies.  Am J Obstet Gynecol. 2012 Jul;207(1):49.e1-9. doi: 10.1016/j.ajog.2012.04.028. Epub 2012 Apr 30. Erratum in: Am J Obstet Gynecol. 2013 Apr;208(4):326.

An examination of Medicaid data in Tennessee between 1995 and 2007 found that use of antidepressants in the second trimester was associated with preterm birth and use in the third trimester was associated with infant convulsions.

38.) Eke, A., Saccone, G. and Berghella, V., 2016. Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and risk of preterm birth: a systematic review and meta‐analysis. BJOG: An International Journal of Obstetrics & Gynaecology

Dr. A Eke from Johns Hopkins University, completed a meta-analysis of eight prior studies, including data on over one million women, evaluating the effect of SSRI exposure on pregnancy outcomes. The review showed that women who received SSRIs during pregnancy had a significantly higher risk of preterm birth. (MIA Coverage)

 

F. Birth Defects

38.) Colvin L, Slack-Smith L, Stanley FJ, Bower C.  Dispensing patterns and pregnancy outcomes for women dispensed selective serotonin reuptake inhibitors in pregnancy.  Birth Defects Res A Clin Mol Teratol. 2011 Mar;91(3):142-52. doi: 10.1002/bdra.20773. Epub 2011 Mar 4. Erratum in: Birth Defects Res A Clin Mol Teratol. 2011 Apr;91(4):268.

Examining health system data and pharmaceutical claims in Western Australia, researchers confirmed earlier findings connecting SSRI exposure in pregnancy and preterm birth and cardiovascular defects.

39.) FDA advising of risk of birth defects with Paxil. News release of the Food and Drug Administration, December 8, 2005 (http://www.fda.gov.ezproxy.library.tufts.edu/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108527.htm).

The FDA issued a warning that taking Paxil (paroxetine) during the first trimester increases the risk of birth defects, particularly heart defects.

40.) Grigoriadis S, VonderPorten EH, Mamisashvili L, Roerecke M, Rehm J, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A, Ross LE.  Antidepressant exposure during pregnancy and congenital malformations: is there an association? A systematic review and meta-analysis of the best evidence.  J Clin Psychiatry. 2013 Apr;74(4):e293-308. doi: 10.4088/JCP.12r07966. Review.

A meta-analysis of SSRI treatment during pregnancy found statistical significance for an increased risk of cardiovascular congenital malformations but pooled relative risks did not meet clinical significance.

41.) Knickmeyer RC, Meltzer-Brody S, Woolson S, Hamer RM, Smith JK, Lury K, Gilmore JH.  Rate of Chiari I Malformation in Children of Mothers with Depression with and without Prenatal SSRI Exposure.  Neuropsychopharmacology. 2014 Oct;39(11):2611-21. doi: 10.1038/npp.2014.114. Epub 2014 May 20.

In a retrospective two-cohort study researchers found an increased risk for Chiari I malformations, where a part of the skull is abnormally small or misshapen, in children exposed to SSRIs in pregnancy. Children exposed to maternal depression only did not differ in risk from children of mothers with no depression.

42.) Louik C, Lin AE, Werler MM, Hernández-Díaz S, Mitchell AA.  First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects.  N Engl J Med. 2007 Jun 28;356(26):2675-83.

First-trimester use of SSRI antidepressants suggests increased risks for some specific defects, including associations between sertraline and omphalocele and septal defects, and between paroxetine and specific cardiovascular defects.

43.) Munch TN, Rasmussen ML, Wohlfahrt J, Juhler M, Melbye M.  Risk factors for congenital hydrocephalus: a nationwide, register-based, cohort study.  J Neurol Neurosurg Psychiatry. 2014 Mar 25. doi: 10.1136/jnnp-2013-306941.

In a retrospective nationwide study, the use of antidepressants in the first trimester was associated with a significantly increased risk for congenital hydrocephalus, a buildup of excessive fluid in the brain at birth.

44.) Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ 2009;339:b3569-b3569.

An increased prevalence of septal heart defects was observed for mothers who had been prescribed an antidepressant early in pregnancy. An increased risk for found for women prescribed more than one type of antidepressant.

45.) Wemakor A, Casson K, Garne E, Bakker M, Addor MC, Arriola L, Gatt M, Khoshnood B, Klungsoyr K, Nelen V, O’Mahoney M, Pierini A, Rissmann A, Tucker D, Boyle B, de Jong-van den Berg L, Dolk H.  Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study.  Eur J Epidemiol. 2015 Jul 7.

A population study of over 2 million births found a teratogenic effect of SSRIs during pregnancy for certain congenital anomalies. An association between SSRI use in pregnancy and heart defects, Ebstein’s anomaly, ano-rectal atresia/stenosis, gastroschisis, renal dysplasia, and clubfoot.

46.) Yazdy MM, Mitchell AA, Louik C, Werler MM.  Use of Selective Serotonin-Reuptake Inhibitors During Pregnancy and the Risk of Clubfoot.  Epidemiology. 2014 Aug 28.

This study of 622 clubfoot cases found an increased risk for clubfoot when SSRIs were used during pregnancy.

 

G. Smaller Head Size

47.) Davidson S, Prokonov D, Taler M, Maayan R, Harell D, Gil-Ad I, Weizman A.  Effect of exposure to selective serotonin reuptake inhibitors in utero on fetal growth: potential role for the IGF-I and HPA axes.  Pediatr Res. 2009 Feb;65(2):236-41

SSRI exposure in utero was associated with a higher percentage of infants with birth weight, birth length, and head circumference below the 10th percentile.

48.) Dubnov-Raz G, Hemilä H, Vurembrand Y, Kuint J, Maayan-Metzger A.  Maternal use of selective serotonin reuptake inhibitors during pregnancy and neonatal bone density.  Early Hum Dev. 2012 Mar;88(3):191-4. doi: 10.1016/j.earlhumdev.2011.08.005. Epub 2011 Sep 3.

Infants with SSRI exposure had a marginally smaller head circumference and shorter length.

49.) El Marroun H, Jaddoe VW, Hudziak JJ, et al. 2012. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomesArch Gen Psychiatry 69:706–714.

Fetuses exposed to SSRIs had delayed head growth and were more likely to be born preterm.

H. Newborn Behavioral Syndrome and Other Issues

50.) Grigoriadis S, VonderPorten EH, Mamisashvili L, Eady A, Tomlinson G, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A, Ross LE.  The effect of prenatal antidepressant exposure on neonatal adaptation: a systematic review and meta-analysis.  J Clin Psychiatry. 2013 Apr;74(4):e309-20. doi: 10.4088/JCP.12r07967. Review.

A meta-analysis found a significant association between antidepressant exposure and poor neonatal adaptation syndrome (PNAS), respiratory distress, and tremors.

51.) Jensen HM, Grøn R, Lidegaard Ø, Pedersen LH, Andersen PK, Kessing LV.  Maternal depression, antidepressant use in pregnancy and Apgar scores in infants.  Br J Psychiatry. 2013 May;202(5):347-51. doi: 10.1192/bjp.bp.112.115931. Epub 2013 Feb 21.

In an examination of all pregnant women in Denmark between 1996 and 2006 found that prenatal exposure to antidepressants increased the risk of low Apgar scores independent of maternal depression.

52.) Källén B.  Neonate characteristics after maternal use of antidepressants in late pregnancy.  Arch Pediatr Adolesc Med. 2004 Apr;158(4):312-6.

Antidepressant exposure during pregnancy was associated with preterm birth, low birth weight, low Apgar scores, respiratory distress, neonatal convulsions, and hypoglycemia.

53.) Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G.  Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants.  Arch Pediatr Adolesc Med. 2006 Feb;160(2):173-6.

This cohort study found that 30% of newborns exposed to SSRIs in pregnancy experience neonatal abstinence syndrome.

 

I. Autism and other adverse developmental outcomes

54.) Boukhris T, Sheehy O, Mottron L, Bérard A.  Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatr. 2015 Dec 14:1-8. doi: 10.1001/jamapediatrics.2015.3356. [Epub ahead of print.]

Researchers examined the Québec Pregnancy/Children Cohort through 2009. They found that the use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of autism spectrum disorder (ASD) in children, even after considering maternal depression.

55.) Casper R. C., Fleisher B. E., Lee-Ancajas J. C., Gilles A., Gaylor E., DeBattista A., et al. (2003). Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J. Pediatr. 142, 402–408 10.1067/mpd.2003.139

Children whose mothers were diagnosed with major depressive disorder in pregnancy and elected not to take medication were compared with children of depressed mothers treated with SSRIs. Children exposed to SSRIs during pregnancy had lower APGAR scores and developmental scores than children whose mothers did not take SSRIs.

56.) Croen L. A., Grether J. K., Yoshida C. K., Odouli R., Hendrick V. (2011). Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch. Gen. Psychiatry 68, 1104–1112 10.1001/archgenpsychiatry.2011.73.

In a population based control study, researchers found a 2-fold increased risk of ASD when the mother used SSRIs in the year before pregnancy. The strongest effect existed for those who took SSRIs during the first trimester. No increased risk was observed for mothers that had a history of mental health treatment who did not take SSRIs.

57.) El Marroun H, White TJ, van der Knaap NJ, Homberg JR, Fernández G, Schoemaker NK, Jaddoe VW, Hofman A, Verhulst FC, Hudziak JJ, Stricker BH, Tiemeier H.  Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children.  Br J Psychiatry. 2014 Aug;205(2):95-102.

This population-based study finds that children exposed to SSRIs prenatally had more autistic traits than those whose mothers had depressive symptoms but who did not take SSRIs during pregnancy. Both those exposed to SSRIs and those exposed to maternal depression had a higher risk for pervasive developmental problems.

58.) Harrington RA, Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I.  Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay.  Pediatrics. 2014 Apr 14. [Epub ahead of print.]

Using data from the Childhood Autism Risks from Genetics and Environment (CHARGE) study, researchers investigated 996 mother-child pairs to test the association between SSRIs and the odds of autism spectrum disorders (ASDs) and developmental delays (DDs). The strongest finding was that prenatal exposure to SSRIs increased susceptibility to ASD and DD in boys and that risk increased with third trimester use.

59.) Klinger G, Frankenthal D, Merlob P, Diamond G, Sirota L, Levinson-Castiel R, Linder N, Stahl B, Inbar D.  Long-term outcome following selective serotonin reuptake inhibitor induced neonatal abstinence syndrome.  J Perinatol. 2011 Sep;31(9):615-20. doi: 10.1038/jp.2010.211. Epub 2011 Feb 10.

This study looked at the long-term development of children exposed in utero to SSRIs, who developed neonatal abstinence syndrome (NAS). They found that while these children had average cognitive abilities that there appeared to be at an increased risk for social-behavioral abnormalities by age six.

60.) Man KK, Tong HH, Wong LY, Chan EW, Simonoff E, Wong IC.  Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: A systematic review and meta-analysis of observational studies.  Neurosci Biobehav Rev. 2015 Feb;49C:82-89.

In this meta-analysis of studies on the association between SSRI exposure during pregnancy and autism spectrum disorder (ASD) risk, the researchers find an increased risk for ASD in children exposed to SSRIs in utero.

61.) Mortensen J. T., Olsen J., Larsen H., Bendsen J., Obel C., Sorensen H. T. (2003). Psychomotor development in children exposed in utero to benzodiazepines, antidepressants, neuroleptics, and anti-epileptics. Eur. J. Epidemiol. 18, 769–771.

Using a regional prescription register in Denmark, researchers looked at women who had filled a prescription for a CNS drug (sedatives and tranquilizers) during pregnancy and found that abnormal test results from children occurred more frequently in those exposed (16%) than those unexposed (4%).

62.) Oberlander T. F., Reebye P., Misri S., Papsdorf M., Kim J., Grunau R. E. (2007). Externalizing and attentional behaviors in children of depressed mothers treated with a selective serotonin reuptake inhibitor antidepressant during pregnancy. Arch. Pediatr. Adolesc. Med. 161, 22–29 10.1001/archpedi.161.1.22.

Researchers assessed the attentional and activity behaviors of 4-year olds that had been exposed to SSRIs during pregnancy. While the persistence score for exposed children was significantly lower in the exposed group, the best predictors of externalizing behaviors were found to be current maternal mood and parental stress.

63.) Pedersen LH, Henriksen TB, Olsen J.  Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age.  Pediatrics. 2010 Mar;125(3):e600-8. doi: 10.1542/peds.2008-3655. Epub 2010 Feb 22.

Researchers investigated the association between prenatal antidepressant exposure and developmental milestones in early childhood. Checking milestones at six and nineteen months, they found that exposed children were able to sit and walk later than unexposed children and that fewer exposed children were able to sit without support or occupy themselves.

64.) Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C.  Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study.  BMJ. 2013 Apr 19;346:f2059. doi: 10.1136/bmj.f2059.

 In this population-based study in Sweden, researchers found that in utero exposure to antidepressants was associated with an increased risk for autism spectrum disorders (ASDs), particularly in cases of ASD without intellectual disability.

 

J. Persistent Pulmonary Hypertension of the Newborn

65.) Adams JM, Stark AR.  Persistent Pulmonary Hypertension of the Newborn.  UpToDate. Accessed September 29, 2014.

66.) Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA.  Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn.  N Engl J Med. 2006 Feb 9;354(6):579-87.

Interviews with 377 women whose infants had persistent pulmonary hypertension of the newborn (PPHN) support an association between the use of SSRIs late in pregnancy and PPHN in the newborns.

67.) Delaney C, Gien J, Grover TR, Roe G, Abman SH. Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus. Am J Physiol Lung Cell Mol Physiol. 2011 Dec;301(6):L937-44.

This study hypothesizes that prolonged exposure to SSRIs has direct effects on fetal pulmonary circulation, leading to hypertension.

68.) Eriksen V, Nielsen LH, Klokker M, Greisen G.  Follow-up of 5- to 11-year-old children treated for persistent pulmonary hypertension of the newborn.  Acta Paediatr. 2009 Feb;98(2):304-9. doi: 10.1111/j.1651-2227.2008.01065.x. Epub 2008 Oct 11.

Children with persistent pulmonary hypertension (PPHN) are at a high risk for sensorineural hearing loss (SNHL) and a high incidence of chronic health problems and remedial education.

69.) Grigoriadis S, Vonderporten EH, Mamisashvili L, Tomlinson G, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A, Ross LE.  Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis.  BMJ. 2014 Jan 14;348:f6932. doi: 10.1136/bmj.f6932. Review.

A systematic review and meta-analysis found an increased risk for pulmonary hypertension of the newborn (PPHN) in infants exposed to SSRIs late in the pregnancy. This association was independent of the potential moderator variables examined.

70.) Kieler H, Artama M, Engeland A, Ericsson Ö, Furu K, Gissler M, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ 2012;344:d8012

A large-scale population-based cohort study of the national health registers in Denmark, Finland, Iceland, Norway and Sweden between 1996 and 2007 found that the use of SSRIs in late pregnancy doubled the risk for persistent pulmonary hypertension of the newborn (PPHN).

 

K. Reviews and meta-analyses

71.) Bourke CH, Stowe ZN, Owens MJ.  Prenatal antidepressant exposure: clinical and preclinical findings.  Pharmacol Rev. 2014 Feb 24;66(2):435-65. doi: 10.1124/pr.111.005207. Print 2014 Apr.

This review is critical of the existing literature on SSRI use in pregnancy, pointing out that the existing literature fails to distinguish between statistical significance and clinical significance.

72.) Olivier JD, Akerud H, Kaihola H, Pawluski JL, Skalkidou A, Högberg U, Sundström-Poromaa I.  The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on offspring.  Front Cell Neurosci. 2013 May 21;7:73.

This review addresses the effects of antidepressants during pregnancy versus the effects of maternal depression and suggests that animal studies be conducted to unravel these effects.

73.) Ross LE, Grigoriadis S, Mamisashvili L, Vonderporten EH, Roerecke M, Rehm J, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A.  Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis.  JAMA Psychiatry. 2013 Apr;70(4):436-43. doi: 10.1001/jamapsychiatry.2013.684. Review.

A meta-analysis of 23 studies found statistically significant association between prenatal antidepressant exposure and delivery outcomes such as preterm delivery.

74.) Udechuku A, Nguyen T, Hill R, Szego K.  Antidepressants in pregnancy: a systematic review.  Aust N Z J Psychiatry. 2010 Nov;44(11):978-96. doi: 10.3109/00048674.2010.507543. Review.

A critical review of the literature on adverse effects of antidepressant use in pregnancy found a higher risk of preterm birth, neonatal adaptation difficulties, and congenital cardiac malformations.

75. Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, et al (2009) The Management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol 114: 703–713. doi: 10.1016/j.genhosppsych.2009.04.003

This review criticizes the inability of the existing literature to control for other factors that may lead to adverse birth outcomes from infants exposed to antidepressants prenatally.

 

L. Miscellaneous

76.) Engle WA, Tomashek KM, Wallman C (2007) “Late-preterm” infants: a population at risk. Pediatrics 120: 1390–1401.

This report recommends a change in terminology from “near-term” to “late preterm,” in light if the higher risks for morbidity and mortality than term infants.

 77.) Goyal N, Fiks A, Lorch S (2011) Association of late-preterm birth with asthma in young children: practice-based study. Pediatrics 128: e830–838.

 Late preterm birth may increase the risk for the development of asthma in early childhood.

 78.) Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, et al. (2010) A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry 67: 1012–1024.

Maternal depression during pregnancy was found to increase the risk for preterm birth and low birth weight.

78.) Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes; Behrman RE, Butler AS, editors. Preterm Birth: Causes, Consequences, and Prevention. Washington (DC): National Academies Press (US); 2007.

 A review recommending improved research on the problem of preterm birth.

79.) Kramer MS, Demissie K, Yang H, Platt RW, Sauve R, et al. (2000) The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System. JAMA 284: 843–849.

Preterm births have high relative risks for death during infancy.

 80.) Leone A, Ersfeld P, Adams M, Schiffer PM, Bucher HU, et al. (2012) Neonatal morbidity in singleton late preterm infants compared with full-term infants. Acta Paediatr 101: e6–10.

Singleton preterm infants have a considerably higher rate of medical problems and prolonged hospital stays.

 81.) Mangham LJ, Petrou S, Doyle LW, Draper ES, Marlow N (2009) The cost of preterm birth throughout childhood in England and Wales. Pediatrics 123: e312–327.

The adverse effects of preterm birth represent an economic burden on public sector resources, primarily driven by inpatient visit expenses after birth.

82.) Mizrahi EM.  Etiology and Prognosis of Neonatal Seizures.  UpToDate. Accessed September 28, 2014.

83.) Pacher P, Kohegyi E, Kecskemeti V, Furst S.  Current trends in the development of new antidepressants.  Curr Med Chem. 2001 Feb;8(2):89-100. Review.

Noting that approximately 30% of patients do not respond to antidepressants, researchers suggest that new drugs need to be developed to treat depression.

84.) Palmsten K, Hernandez-Diaz S (2012) Can nonrandomized studies on the safety of antidepressants during pregnancy convincingly beat confounding, chance, and prior beliefs? Epidemiology 23: 686–688. doi: 10.1097/ede.0b013e318258fbb2.

This study suggests that research assessing the connection between preterm delivery and antidepressants should control not only for the presence of depression, but also for its severity, consider differing types of prematurity, and be sufficiently large.

85.) Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, Barfield W, Nannini A, et al. (2008) Effect of late-preterm birth and maternal medical conditions on newborn morbidity risk. Pediatrics 121: e223–232.

When late preterm delivery is combined with a maternal medical condition the risk for newborn morbidity is greatly increased.

86.) Slattery MM, Morrison JJ (2002) Preterm delivery. The Lancet 360: 1489–1497.

This review of preterm delivery highlights the seriousness of the problem as it relates to mortality, disability, and cost to society.

87.) Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N.  Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation.  Proc Natl Acad Sci U S A. 2009 May 26;106(21):8573-8. doi: 10.1073/pnas.0901505106. Epub 2009 May 11.

The researchers investigate the mechanisms by which thalidomide leads to a number of serious birth defects, including through the loss of immature blood vessels.

88.) Yonkers KA, Gotman N, Smith MV, Forray A, Belanger K, Brunetto WL, Lin H, Burkman RT, Zelop CM, Lockwood CJ.  Does antidepressant use attenuate the risk of a major depressive episode in pregnancy?  Epidemiology. 2011 Nov;22(6):848-54. doi: 10.1097/EDE.0b013e3182306847.

In a study of 778 women with a history of depression, researchers found that the discontinuation of antidepressants during pregnancy did not have a strong effect on the development of a major depressive episode.