INTRODUCTION

Pregnant women are at an increased risk for depression. The prevalence of depression during pregnancy is between 10 and 20%.^1,2 Its treatment poses a challenge to clinicians since it requires maximizing maternal treatment while minimizing fetal and neonatal adverse reactions.

Selective serotonin reuptake inhibitors (SSRIs) are one class of antidepressants being prescribed for depression during pregnancy. There are published reports suggesting increased neonatal intensive care (NICU) admissions from poor adaptation of newborns exposed to these medications in utero.³

We report the occurrence of marked jitteriness and an enhanced startle response in a term infant after being exposed to sertraline throughout pregnancy documented with cord and neonatal plasma levels.

CASE REPORT

A 4505-g male infant was born at 38 weeks gestation to a 30-year-old gravida 2 para 1 woman with good prenatal care. She was rubella immune and both her gonococcal and chlamydia tests were negative. Her serologic screens were negative for VDRL, HBs Ag, and HIV. She denied smoking, alcoholic beverages and illicit drugs. Her diabetic screen was negative. Her pregnancy was uncomplicated except for positive group B streptococcus vaginal colonization and depression for which she was prescribed sertraline (50 mg total daily dose) throughout pregnancy. Her last dose of sertraline was 3 hours prior to delivery. Her spinal anesthesia medications included morphine sulfate 0.1 mg, fentanyl 15 microgram and bupivacaine 12 mg. She received cefotetan 2 g intravenously during delivery.

The infant was delivered by elective repeat cesarian section with clear fluid noted and Apgar scores of 8 at 1 minute and 9 at 5 minutes. Birth weight was 4505 g (>90th percentile), length of 54.5 cm (>90th percentile) and head circumference of 35 cm (80th percentile).

His initial vital signs were normal except for tachypnea with intercostal retractions, no grunting and oxygen saturation remained at >95%. This prompted further evaluation in the NICU. The chest radiograph was consistent with transient tachypnea of the newborn. He had a transient oxygen requirement, normal arterial blood gases, and a rapidly resolved respiratory status.

His initial blood glucose level was 17 mg/dL for which he was given 2 mL/kg intravenous 10% dextrose. His subsequent blood glucose level, serum electrolytes including calcium and magnesium remained normal while on maintenance intravenous fluid. No antibiotics were started and his blood culture was negative. Urine toxicology screen was negative. Standard formula feeding was well tolerated.

Physical examination normalized, except the neurological component. He demonstrated marked jitteriness, which was generalized, symmetrical and both stimuli-sensitive and responsive. A Moro response was exaggerated and deep tendon reflexes were brisk (+3 on all extremities). There was marked progression of his jitteriness and startle response over the first 3 days becoming less pronounced by the fourth day and completely resolved on the fifth day. No medication was given since his neurological signs resolved spontaneously.

A neonatal drug withdrawal scoring system⁴ was used and revealed that his manifestations are consistent with withdrawal signs. This was confirmed by his sertraline cord blood level which was <10 ng/mL. On the third day, his sertraline plasma concentration (while at the height of his jitteriness) remained <10 ng/mL and his serotonin level was 6 ng/mL (reference range 50 to 220 ng/mL). The hospital's designated core laboratory noted that no therapeutic range exists for sertraline; however, dosing of 50 to 200 mg/day gives serum values of 30 to 200 ng/mL in adults.⁵

DISCUSSION

Transient neonatal jitteriness and marked startle response due to sertraline exposure in utero has not been previously documented with cord and neonatal plasma samples consistent with withdrawal signs.

Sertraline belongs to the class of SSRIs whose antidepressant action is associated with its inhibition of neuronal uptake of serotonin in the central nervous system. Its mean peak plasma concentrations (C_max) occurs from 6 to 8 hours after dosing. Its half-life (t_1/2) is 25 hours, while its major metabolite (N-desmethylsertraline) has a longer t_1/2 of 66 hours but is significantly less active. Both are subsequently metabolized and excreted in the urine and feces.⁶

Jitteriness and a marked startle response are nonspecific signs in neonates. Common etiologies include asphyxia, hypocalcemia, hypoglycemia, narcotic drug withdrawal, and seizure⁷ were ruled out in this patient. Although spinal anesthesia may cause neonatal acidemia, this was not seen in this patient. The safety profile of the spinal anesthetics used during the delivery of our patient has been discussed elsewhere.⁸ Cefotetan may increase the risk of bilirubin encephalopathy;⁹ however, serial bilirubin level determinations in this patient did not require intervention.

Withdrawal signs from abrupt discontinuation of sertraline have been described in adults.¹⁰ Two other cases describe transient neonatal withdrawal signs from maternal use of sertraline.^11,12 Both reports noted that the withdrawal symptoms may be explained with prenatal exposure to sertraline and its short half-life temporally correlates with the symptoms. However, neither case reports documented the cord blood or the neonatal plasma level of sertraline.

The diagnosis was initially supported using the neonatal drug withdrawal scoring system⁴ in our patient. Although the scoring system is traditionally used among newborns of narcotic-addicted mothers, the diagnosis can be confirmed by maternal intake of sertraline during pregnancy, a negative neonatal urine toxicology screen and by a cord blood and plasma sertraline level consistent with withdrawal signs.

Determination of sertraline cord blood and plasma levels of neonates exposed in utero may confirm whether these adverse neonatal reactions are withdrawal symptoms (if concentration is less than the usual reference range). In the case presented here, plasma level of sertraline from cord blood was low (<10 ng/mL), which may be consistent with the placental studies in which the maternal dose correlates significantly with the cord blood level although in lower concentrations.¹³ However, since the mother's last intake of sertraline was 3 hours prior to delivery, it is unlikely to have been absorbed systemically (C_max 6 to 8 hours)⁶ and having a relatively short t_1/2 may explain the marked increase in the patient's jitteriness and startle response on the second and third day. The sertraline plasma level of this patient while at the peak (third day) of his neurologic symptoms remained below (<10 ng/mL) the reference range. It would be more helpful if the exact sertraline plasma levels have been determined to correlate the decreasing level of sertraline with the increasing symptoms of the patient. This would provide a more plausible explanation for the withdrawal signs. However, the core laboratory to which the blood specimen was sent does not report the exact concentration if less than 10 ng/mL.

Serotonin level, being the surrogate marker of serotonin transporter, has been described to be low with chronic SSRI use.¹⁴ In this patient, the serotonin level was less than the reference range consistent with chronic exposure to sertraline prenatally. However, it is unclear whether the serotonin level or its enhanced neurotransmission with chronic exposure to sertraline contributes to the patient's symptoms.

Recently, the use of SSRI (particularly sertraline) have increased among pregnant women.² Despite it being neither the preferred nor the alternative antidepressant recommended during pregnancy.¹⁵ It is important that neonatal care providers be aware of the potential adverse effects or withdrawal signs in their patients. Although not life threatening, this report suggests a temporal relationship between neonatal exposure to sertraline in utero and the occurrence of marked jitteriness and an enhanced startle response.

References

1. Koren G. SSRIs in pregnancy — are they safe? Pediatr Res 2002;51:424–425. | PubMed |
2. Kulin NA, Pastuszak A, Koren G. Are the new SSRIs safe for pregnant women? Can Fam Physician 1998;44:2081, 2083. | PubMed |
3. Nordeng H, Lindemann R, Perminov KV, Reikvam A. Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr 2001;90:288–291. | Article | PubMed | ISI | ChemPort |
4. Lipsitz PJ. A proposed narcotic withdrawal score for use with newborn infants: A pragmatic evaluation of its efficacy. Clin Pediatr 1975;14:592–594. | ISI | ChemPort |
5. Associate Regional and University Pathologist. The hospital's designated core laboratory website: http://www.aruplab.com.
6. Doogan DP, Caillard V. Sertraline: A new antidepressant. J Clin Psychiatry 1988;49(Suppl):46–51. | PubMed |
7. Volpe JJ. Neurology of the newborn. Philadelphia, PA: WB Saunders Co; 1995, p. 118, 181–182.
8. Miller RD. Anesthesia. Philadelphia, PA: Churchill Livingstone; 2000 p 2047–2050.
9. Micromedex (R) Healthcare Series. Cefotetan — Adverse Reactions, Central Nervous System, Kernicterus: Thomson Micromedex Series, Vol. 119; 2004 (Online quick links — State University of New York, Upstate Medical University, Health Science Library: http://www.upstate.edu/library/).
10. Louie AK, Lannon RA, Ajari LJ. Withdrawal reaction after sertraline discontinuation. Am J Psychiatry 1994;151:450–451. | PubMed |
11. Kent LSW, Laidlaw JDD. Suspected congenital sertraline dependence. Br J Psychiatry 1995;167:412–413. | PubMed |
12. Oca MJ, Donn SM. Association of maternal sertraline (Zoloft) therapy and transient neonatal nystagmus. J Perinatol 1999;19:460–461. | Article | PubMed |
13. Hendrick V, Stowe ZN, Altschuler LL, Hwang S, Lee E, Haynes D. Placental passage of antidepressant medications. Am J Psychiatry 2003;160:993–996. | Article | PubMed |
14. Benmansour S, Owens WA, Cecchi M, Morilak DA, Frazer A. Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter. J Neurosci 2002;22:6766–6772. | PubMed | ISI | ChemPort |
15. Committee on Drugs — American Academy of Pediatrics. Use of psychoactive medication during pregnancy and possible effects on the fetus and newborn. Pediatrics 2000;105:880–887.