What is known about neonatal withdrawal symptoms in the newborn after the use of serotonin uptake i

Fråga: What is known about neonatal withdrawal symptoms in the newborn after the use of serotonin uptake inhibitors during pregnancy?

This is a frequently asked question.

Sammanfattning: Neonatal complications can occur after SSRI exposure in the third trimester. Among the symptoms seen are irritability, constant crying, sleeping- and eating disturbances, hypotonia and tachypnea. Studies have indicated a frequency of 20-30 percent of poor adaptation in SSRI exposed infants compared to under 10 percent for non exposed infants. However, the symptoms are mostly not severe and studies have shown that they gradually subside over the first weeks.

Svar: Several cases of neonatal withdrawal symptoms have been reported for the serotonin uptake inhibitors (SSRIs). Usually the symptoms occur during the first 24 hours after delivery, but sometimes it can take up to 4-5 days before symptoms develop. Characteristic symptoms are irritability, constant crying and sleeping disturbances. In more severe cases hypotonia, jitteriness, eating difficulties or tachypnea can occur. Rarely cyanosis, increased muscular tonus and in the worst cases convulsions have been seen (1).

In one prospective controlled cohort study the perinatal outcome after third trimester paroxetine exposure in 55 children was studied. A control group with children exposed to paroxetine during first and second trimester only (27) or children not exposed to SSRIs at all (27) was used. The control group was matched for maternal age, gravity, parity, social drug use and nonteratogenic drug use. Twelve (22%) of the infants exposed to paroxetine had complications requiring prolonged hospitalisation. The most prevalent symptom was respiratory distress. In the control group only three children (6%) had any neonatal complications requiring hospitalisation (2).

A prospective cohort study compared the neonatal behaviour of 46 infants exposed to either SSRIs alone (paroxetine (33), fluoxetine (9) or sertraline (4)) or together with clonazepam to a control group of 23 non exposed infants. Maternal age and delivery characteristics did not vary significantly between the groups. Overall 14 infants (30%) exposed to SSRIs were found to have symptoms reflecting a poor neonatal adaptation during the first hours of life requiring hospital care. All infants with symptoms had some degree of respiratory distress. Other symptoms included hypotonia, jitteriness, tremor, hypertonia and hypoglycaemia. All symptoms occurred within the first 24 hours after delivery and resolved within 48 hours. In the control group only two infants (9%) had similar symptoms. The presence of neonatal symptoms after SSRI exposure was not related to an altered developmental outcome after assessment at two and eight months (3).

A study based on the Swedish Medical Birth Registry investigated neonatal outcomes in 997 infants exposed to antidepressants, out of which 558 had been exposed to SSRIs. In 70 cases the drug use was stopped before week 24 and in 561 cases drug use started after or continued after week 23 (in 387 cases the pregnancy week when the drug had been used was not stated). There was a statistically significant increase in odds ratio (OR) for respiratory distress (OR=1.97), low Apgar score (OR=2.28) and convulsions (OR=3.6) for the SSRI-group compared to the normal population. Since we do not know if the infants showing poor neonatal adaptation had been exposed to SSRIs during the last trimester these data are hard to evaluate (4).

Another prospective study compared 17 children exposed to SSRIs to 17 non exposed. The infants were studied between 14 and 39 hours of age. The exposed infants showed significantly more irritability and tremulousness, less changes in behavioural state, a more narrow range of states and longer periods of REM-sleep (5). In two other studies an increased risk of poor adaptation in children exposed to SSRIs have been noted (6, 7).

In addition to these studies we have found a total of 14 published case reports of poor neonatal adaptation after SSRI exposure ((paroxetine (10), sertraline (2), fluoxetine (1), and citalopram (1)). The symptoms included respiratory distress, poor feeding, lethargy, tachypnea, increased or decreased tonus, constant crying, irritability, jitteriness and one case of seizures. Symptoms came immediately or a few days after delivery and remained up to four weeks in one case (8-14). One case of adaptation disturbances in an infant exposed to paroxetine in utero is also described in Drugline (15).

Most case reports and studies have concerned the exposure to paroxetine. Whether there is any difference in the frequency of neonatal withdrawal symptoms between the SSRIs is not known.

If poor neonatal adaptation, with quite unspecified symptoms, can be specifically attributed to SSRIs in these cases is not clear. Other factors, such as the mothers underlying disease, age and other drugs, may contribute. However, in one study half of the control group was composed with depressed mothers who had been treated with an SSRI during the first and second trimesters. The children in this group hade better outcomes than those exposed in the third trimester (2).

It has been suggested that SSRI treatment can be discontinued 2-3 weeks prior to delivery. However, nothing has been published showing that discontinuation of treatment prior to delivery is beneficial. Since it is difficult to know the exact date of delivery, discontinuation may instead cause a relapse of the disease, which can be of greater clinical importance. The recommendation today will still be to continue treatment, minimum effective dose should however always be strived for. Spigset O, Hagg S. Nya antidepressiva läkemdel under graviditet och amning. Läkartidningen 2004;101(13):1176-81. Costei AM, Kozer E, Ho T, Ito S, Koren G. Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med 2002;156:1129-32. Oberlander TF, Misri S, Fitzgerald CE, Kostaras X, Rurak D, Riggs W. Pharmacologic factors associated with transient neonatal symtoms following prenatal psychotropic medication exposure. J Clin Psychiatry 2004;65(2):230-7. Kallen B. Neonate characteristic after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med 2004;158(4):312-6. Zeskind PS, Stephens LE. Maternal Selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics 2004;113(2):368-75. Cohen LS, Heller VL, Bailey JW, Grush L, Ablon JS, Bouffard SM. Birth outcomes following prenatal exposure to fluoxetine. Biol Psychiatry 2000;48(10):996-1000. Laine K, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Pediatr Adolesc Med 2003;60:720-6. Nordeng H, Lindemann R, Perminov KV, Reikvam Å. Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr 2001;90(3):288-91. Santos RP, Pergolizzi JJ. Transient neonatal jitteriness due to maternal use of sertraline (Zoloft). J Perinatol 2004 Jun;24(6):392-4. Stiskal JA, Kulin N, Koren G, Ho T, Ito S. Neonatal paroxetine withdrawal syndrome. Arch Dis Child Fetal Neonatal Ed 2001 Mar;84(2):F134-5. Nijhuis IJ, Kok-Van Rooij GW, Bosschaart AN. Withdrawal reactions of a premature neonate after maternal use of paroxetine. Arch Dis Child Fetal Neonatal Ed 2001;84(1):F77. Herbst F, Gortner L. Paroxetine withdrawal syndrome as differential diagnosis of acute neonatal encephalopathy? Z Geburtshilfe Neonatol 2003;207(6):232-4. (abstract) Dahl ML, Olhager E, Ahlner J. Paroxetine withdrawal syndrome in a neonate. Br J Psychiatry 1997;171:391-2. (abstract) Drugline no 17325 (year 2000) Drugline no 13694 (year 1996)