How SSRIs Taken During Pregnancy and Lactation Can Affect Newborns - March 2007

Lifetime risk for depression in women is 10-30%, twice the risk for men. The peak risk for women is during the childbearing years. It is estimated that 10-15% of all parturients will have postpartum depression. Pregnant women who have untreated clinical depression do poorly with a greater risk for obstetrical complications, premature delivery and pre-eclampsia. The babies born to these women also do poorly and are at greater risk to be low birth weight, exhibit lower activity and interactive behaviors, have increased irritability, lower Bayley scores, lower growth centiles at one year of age and delayed language and behavioral difficulties.

Half of depressed women will need medication. Currently selective serotonin reuptake inhibitors (SSRIs) are the medication of choice for depressed women who are pregnant or in the postpartum period due to their lower teratogenicity risks and profile for fewer side effects. What risks do these medications pose for her baby?

Effects of SSRIs on the Baby in Utero
The most extensively reported data is on Fluoxetine. Most studies show there is no increase in the incidence of major malformations(1,2) due to the use of SSRIs during pregnancy with the possible exception of Paroxetine. A post-marketing surveillance study done by the manufacturer of this SSRI found a 2.2-fold increase in birth defects if the mother had first trimester exposure(3). The bulk of these defects were cardiac (ASD, VSD). In response to this finding, the FDA issued a warning against using Paroxetine in women who were planning on becoming pregnant or were in the first trimester.

A meta-analysis(4) including nine studies looking at any SSRI use in the third trimester showed an increase risk of premature birth and low birth weight. Wen et al(5) found an increase in low birth weight, premature birth, fetal death and seizures in babies born to 972 pregnant Canadian women who took SSRIs during pregnancy (compared to 3878 controls). Premature birth and low birth weight are also risks for babies born to women with untreated depression. Risk of premature birth and low birth weight was not increased in depressed women treated with tricyclic antidepressants.

Perinatal Effects
Babies born to women taking SSRIs were more likely to have lower Apgar scores, increased need for NICU admission (2-6 fold) and “Poor Neonatal Adaptation Syndrome” (PNAS)(6) or “Neonatal Abstinence Syndrome” (NAS)(7,8). Lower Apgar scores were more likely if there was third trimester use of SSRIs. Admission to the NICU soon after birth was due to the presence of seizures, hypoglycemia, respiratory distress (some needing breathing support) and hypotonia. There has been a preliminary report(9) of a 10 fold increase in the incidence of persistent pulmonary hypertension with SSRI use (1/100 incidence vs. 1/1000).

PNAS/NAS has been described by multiple investigators and consists of symptoms including: nervousness, jitteriness, tremor, abnormal crying, hypertonia, sleep disorder (both insomnia and somnolence) and seizures. These symptoms usually manifest within a few days after birth and are self limited, but can last up to one month. Up to 30% of exposed infants show some symptoms. Paroxetine seemed to be the SSRI that caused PNAS most commonly. It is unclear whether PNAS is a withdrawal or a toxicity effect as symptoms for both conditions are similar. Babies whose mothers were taking shorter-acting SSRIs (Paroxetine, Venlafaxine, Citalopram, Escitalopram, and Fluvoxamine) may be more likely to have withdrawal. It is recommended that drug levels be documented in the baby if there is a strong suspicion of neonatal withdrawal symptoms.

Long-term Effects
There have been no long-term effects on global IQ, language development, temperament, mood or behavior noted(10). However, Casper et al(11) did find a lower PDI (90 vs. 98) in babies whose mothers took SSRIs compared to those whose mothers did not. Both groups of babies had equal MDI scores (91 vs. 94). There was also a recent report that the pain response was blunted at age 2 months in babies born to women taking SSRIs both prenatally and pre- and postnatally(12). These two studies indicate that there may be long term effects from in utero SSRI exposure, and that ongoing investigation is needed.

SSRIs During Lactation
In 2001 the AAP(13) listed a number of SSRIs as “drugs for which effects on nursing infants is unknown, but may be of concern.” There were no reported effects of SSRIs on nursing infants at the time this policy was published. Since this time there have been case reports of babies exhibiting effects presumably from SSRIs transferred via breast milk. An updated AAP policy is expected in the near future.

Two of the SSRIs have had reported effects on nursing babies(14). Colic, irritability, somnolence, unresponsiveness and poor weight gain have been reported with Fluoxetine. Somnolence, weight loss and decreased feeding have been reported with Citalopram. No effects have been reported with studies looking Fluvoxamine, Paroxetine or Sertraline. There is no data on Escitalopram.

Transfer of SSRI into breast milk is variable among the SSRIs. In most cases, the amount of SSRI transferred is small compared to the maternal dose. In general, lactating women should use the lowest effective dose and the SSRI with the shortest half life (Sertraline or Paroxetine). Venlafaxine and Escitalopram also have short half lives, but there is no data reported on breastfeeding babies whose mothers are taking these two drugs. All babies receiving breast milk from women who are taking SSRIs should be watched carefully for symptoms of ill effects.



If a woman needs treatment for depression and wants to breastfeed her baby, she should be informed that her SSRI medication can be transferred to her baby via her breast milk and that the baby could experience effects from the medication and therefore should be watched closely. However, treatment of depression is important and SSRIs are not incompatible with breastfeeding.

References
1. Simon GE et al, Am J Psychiatry, 159:2055, 2002
2. Kulin NA, et al, JAMA 279(8): 609, 1998
3. www.gsk.ca/en/health_info
4. Lattimore KA et al, J Perinatology 25:595, 2005
5. Wen SW, et al, Am J OBGyn, 194: 961, 2006
6. Koren G, et al, Canadian Med Ass J, 172(11): , 2005
7. Levinsin-Castiel R et al, Arch Ped Adol Med, 160: 173, 2006
8. Costei AM, et al, Arch Ped Adol Med, 156: 1129, 2002
9. Chambers CD, et al, NEJM, 354(6): 579, 2006
10. Nulman, I et al, N Eng J Med, 336(4):258, 1997
11. Casper RC et al, J Peds, 142(4):402, 2003
12. Oberlander, TF et al, Pediatrics, 115(2): 411, 2005
13. AAP Committee on Drugs, Pediatrics, 108(3): 776, 2001
14. Gentile S, Drug Safety, 28(2):137, 2005
15. Hale TW, Medications in Mothers’ Milk, 11th ed, Pharmasoft Publishing, Amarillo, TX, 2004

This information provided by David A. Lee, M.D., Division of Neonatology, California Pacific Medical Center Department of Pediatrics.