Is sertraline (Zoloft) safe to use during pregnancy?

Fråga: Is sertraline (Zoloft) safe to use during pregnancy?

Sammanfattning: On the basis of a significant number of observations, there is no indication that SSRI, such as sertraline, are harmful to the fetus. There is one study indicating that that these drugs could harm the human fetus but this study is small and controversial. There are some case reports indicating that SSRIs, including sertraline, could cause a transient withdrawal syndrome (as tricyclic antidepressants can do) in the neonate.

Svar: This question has previously been answered in Drugline (1-4). It was then concluded that selective serotonin reuptake inhibitors (SSRI), such as sertraline, have not been proven to cause major malformations. However, data is limited and SSRIs should only be used in pregnant women after special considerations. A tricyclic antidepressant drug is the drug of choice during pregnancy because more experience is gained with that group of drugs.

In studies in mice of two SSRIs (sertraline and fluoxetine) and a tricyclic antidepressant (amitryptiline), craniofacial malformations were seen at concentrations considerably higher than achieved in patients receiving the drug (probably due to a direct effect at 5-HT receptor sites) (5). In other studies of sertraline no teratogenicicty was seen at maternally toxic doses in rats and rabbits but decreased neonatal survival and growth were seen (6, 2).

In one study of 228 pregnant women taking fluoxetine during pregnancy (7) it was concluded that there was no increase of major fetal anomalies or spontaneous pregnancy loss. The control group consisted of 254 women who had contacted California Teratogen Information Service because they had taken drugs that were not considered teratogenic. However the women taking fluoxetine during the third trimester compared with those taking fluoxetine first or second trimester had significantly higher incidence of three or more minor malformations (15.5 per cent versus 6.5 per cent, p=0.03), premature delivery (relative risk, 4.8; 95 per cent confidence interval, 1.1 to 20.8), admissions to special care nurseries (relative risk, 2.6; 95 per cent confidence interval, 1.1 to 6.9) and poor neonatal adaptation, including respiratory difficulty, cyanosis on feeding and jitteriness (relative risk, 8.7; 95 per cent confidence interval, 2.9 to 26.6). Birth weight was also lower in infants exposed to fluoxetine late in gestation compared to those exposed earlier. This study has been debated (8). There was no description of the minor malformations and it is hard to understand why they should occur. The data from the study was nonrandomized and the design did not allow depressive illness to be excluded as a confounding factor. One can speculate that the women taking fluoxetine during the third trimester were more depressed than those taking it during the first and second trimesters. As prematurity, admissions to special care nurseries, poor neonatal adaptation, low birth weight are associated with psychiatric disorders, the differences seen in this study could be due to the illness and not the drug. As the study was open, bias could affect the differences seen and the higher age in the control group could also influence the result. Finally, 30 per cent in the fluoxetine group also took other psychoactive drugs.

One the other hand there exists several studies not showing any teratogenic effect. In one study 128 women (9) exposed to fluoxetine during first trimester were compared with matched groups of women exposed to tricyclic antidepressants or nonteratogenic drugs. No difference in the incidence of major birth defects compared to both control groups was found. Both fluoxetine and tricyclic antidepressant group had a tendency (but not significant) of higher reported miscarriage rate which suggests that this tendency may be associated with the depression and not the medication. This tendency might also be explained by the women opted to report miscarriage when they in fact had chosen to terminate the pregnacy. In another study 267 women exposed to three different SSRIs (fluvoxamine, paroxetine and sertraline) were compared with 267 controls (10). No difference in the incidence of major malformations, miscarriages, stillbirths prematurity or mean birth weight and mean gestational ages were found. This study also has been debated (11,12,13). Ely Lilly has two prospective studies, one with 723 and one with 112 (14, 5) women exposed to fluoxetine. No specific pattern of the malformations was found. Further evaluation cannot be done due to methodological problems as no control group existed and there was probably reporting bias. One should though point out that in the study of 112 women the frequency of postnatal complications was not higher than expected.

There is one case of sertraline withdrawal syndrom in a neonate (15). The mother´s dose of sertraline during pregnancy was 200 mg per day. One day after delivery the baby became agitated, restless, fed poorly, cried constantly, did not sleep and had an enhanced startle reaction. These symptoms were intense for 48 hours and then subsided over the next few days. Two case reports of neonate transient fluoxetine toxicity (16, 17) and one of neonate paroxetine withdrawal syndrome (18) exist. Adaption disturbancies in neonates have also been reported for tricyclic antidepressants (19)

In one study (20) 55 children whose mothers had received fluoxetine were compared with 80 children whose mothers had received tricyclic antidepressants and 84 children whose mother had not been exposed to any drug known to affect the fetus adversely. Global IQ, language development and behavioural development were followed between 16 and 86 months of postnatal age and no affect of prenatal exposure to fluoxetine or tricyclic antidepressant was found.

The swedish birthdefect register contains about 500 women exposed to SSRI (mostly citalopram) during pregnancy and finds SSRIs, as a group, to be safe (21).

However, the manufacturer of Zoloft (sertraline), does not recommend sertraline use in pregnancy (22). 1 Drugline no 14992 (year 1998)

2 Drugline no 13551 (year 1996)
3 Drugline no 13471 (year 1998)
4 Drugline no 13411 (year 1998)
5 Nulman I, Koren G: The safety of fluoxetine during pregnancy and lactation. Teratology 1996; 53: 304-308

6 Davies TS, Klowe WM: Preclinical toxicological evaluation of sertraline hydrochloride. Drug Chem Toxicol 1998; 21: 163-179 7 Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL: Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996; 335: 1010-1015 8 Robert E: Treating depression in pregnancy. N Engl J Med 1996; 335:1056-1058 9 Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, Donnenfeld A, McCormack M, Leen. Mitchell M, Woodland C, Gardner A, Horn M, Koren G: Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA 1993; 269: 2246-2248 10 Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldkamp M, Ormond K, Matsui D, Stein-Schechman AK, Cook L, Brochu J, Rieder M, Koren G: Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors. A prospective controlled multicenter study. JAMA 1998; 79: 609-610 11 Grush L: Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. Letter. JAMA 1998; 279: 1873 12 Witlin AG: Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. Letter. JAMA 1998; 279: 1873 13 Koren G: Risk of fetal anomalies with exposure to selective serotonin reuptake inhibitors. Letter. JAMA 1998; 279: 1873 14 Goldstein DJ: Effects of third trimester fluoxetine exposure on the newborn. J Clin Psychopharmacol 1995; 15; 417-420 15 Kent LSW, Laidlaw JDD: Suspected congenital sertraline dependenceBr J Psychiatry 1995; 167: 412-413 16 Mhanna MJ, Bennet JB II, Izatt SD: Potential fluoxetine chloride (Prozac) toxicity in a newborn. Letter. Pediatrics 1997; 100: 158-159

17 Spencer MJ: Fluoxetine hydrochloride (Prozac) toxicity in a neonate. Pediatrics 1993; 92: 721-722
18 Dahl ML, Olhager E, Ahlner J: Paroxetine withdrawal syndrome in a neonate. Br J Psychiatry 1997; 171: 391-392
19 Drugline no 13252 (year 1998)

20 Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, Theis JGW, Kulin N, Koren G: Neurodevelopment of children exposed in utero to antidepressant drugs.