Clinical Perinatal/Neonatal Case Presentation ⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢ Association of Maternal Sertraline (Zoloft) Therapy and Transient Neonatal Nystagmus

Melisa J. Oca, MD had completely resolved. On further questioning, the mother revealed Steven M. Donn, MD that she had been treated with sertraline hydrochloride (Zoloft), 50 mg/day, for 2 weeks before delivery for anxiety and depression. The infant was discharged at 1 week of age on nasal cannula CASE REPORT oxygen at 0.5 LPM but with an otherwise normal physical examina- A 2520-gm infant girl was born at 35 weeks’ gestation to a 29- tion. At 1 month of age, she was growing well with no evidence of year-old primigravida who had reported her as entirely nystagmus or other neurologic deficits, and she had been weaned normal until spontaneous rupture of membranes 18 hours before from the supplemental oxygen. delivery. The mother received intrapartum penicillin because of an unknown group B streptococcus status. Labor was augmented with oxytocin, and an epidural catheter was placed with morphine DISCUSSION administered for analgesia. The infant was delivered vaginally. A Sertraline hydrochloride belongs to the class of selective serotonin tight nuchal cord was clamped and cut after delivery of the head. reuptake inhibitors (SSRIs), which are widely prescribed for the treat- The baby was initially depressed and received bag and mask venti- ment of depression. Other agents currently available in the United lation with 100% oxygen for 15 seconds. Apgar scores were 5 and 8 States include fluoxetine (Prozac), paroxetine (Paxil), and fluvoxam- at 1 and 5 minutes, respectively. On physical examination the ine (Luvox). The mechanism of action is presumed to be linked to the baby was hypotonic; she was noted to have horizontal nystagmus inhibition of the neuronal uptake of serotonin (5-hydroxytryptamine) with an intermittent rotary component in both eyes. She was ad- into the presynaptic terminal. The drug is absorbed in the gastrointes- mitted to the neonatal intensive care unit for further observation. tinal tract and metabolized in the liver to N-desmethylsertraline.

Within an hour, she was noted to have marked improvement Sertraline hydrochloride has an elimination half-life (t1/2)of26 in her neuromuscular tone, but persistence of the nystagmus. The hours; its metabolite N-desmethylsertraline has a t1/2 of 62 to 104 remainder of her physical examination was unremarkable. Evalu- hours and is substantially less active than sertraline. Fluoxetine has ation of venous blood gases revealed a pH of 7.31, PCO2 of 37 torr, the longest t1/2 (1 to 4 days), and its primary metabolite, norfluox- Ϫ 1 PO2 of 36 torr, and HCO3 of 19 meq/liter while breathing room etine, is as potent an inhibitor of serotonin as its parent compound. air. She was treated with ampicillin, gentamicin, and intravenous Both paroxetine and fluvoxamine have a t1/2 similar to sertraline (24 fluids. Enteral feeds were initiated subsequently and tolerated at 24 hours), and their primary metabolites appear to be inactive.1 Com- hours of age. Antibiotics were discontinued at 36 hours following a mon side effects of SSRIs include gastrointestinal problems (nausea, negative blood culture. She required a small amount of nasal vomiting, and diarrhea) and central nervous system dysfunction cannula oxygen to maintain adequate arterial oxygen saturation. (agitation, disinhibition, headache, insomnia, and tremors). Infre- She fed well, maintained adequate urine output, and had no sys- quent adverse effects reported by individuals that have been adminis- temic signs of hypoxic-ischemic dysfunction. Her neurologic eval- tered multiple doses of sertraline (as well as fluoxetine and parox- uation included normal brainstem audiometric-evoked responses, etine) have included nystagmus and, rarely, .2 Two cases of a structurally normal cranial sonogram, and normal fundoscopy. neonatal neurologic side effects of maternally administered fluoxetine A multichannel sleep study was performed on day 5 of life; this hydrochloride (Prozac) have been published. In the first, an infant study showed disorganized breathing with arterial oxygen desatu- exhibited central nervous system problems, including temperature ration, especially with feeds, which improved with the administra- instability, jitteriness, tremors, irritability, , and laterally tion of oxygen. The nystagmus was observed intermittently over roving eyes. Cord blood sampling revealed a fluoxetine concentration the first 24 hours of life but became less frequent; by 72 hours, it below the therapeutic adult level (40 to 350 ng/ml); the norfluoxetine level was within the therapeutic range (30 to 325 ng/ml).3 The second Department of , Division of Neonatal-Perinatal Medicine, University of Michigan case described extreme jitteriness, hypertonia, and petechiae in an Health System, Ann Arbor, MI. infant exposed to fluoxetine throughout pregnancy. Serum concen- Address correspondence and reprint requests to Steven M. Donn, MD, Division of Neonatal- Perinatal Medicine, F5790 C. S. Mott Children’s Hospital, Box 0254, 200 East Hospital Drive, trations for both fluoxetine and its metabolite were within the adult 4 Ann Arbor, MI 48109-0254. therapeutic range at birth. In both cases, signs resolved within 96

Journal of Perinatology (1999) 19(6) 460–461 © 1999 Stockton Press. All rights reserved. 0743–8346/99 $12 460 http://www.stockton-press.co.uk Maternal Sertraline Therapy and Neonatal Nystagmus Oca and Donn

hours, consistent with the t of fluoxetine. To date, there are no such 1/2 Table 1 Pathologic Causes of Congenital Nystagmus descriptions for sertraline. Although we were unable to document the plasma concentration of sertraline (cord blood was not drawn, and Ocular causes the positive history was not obtained until well past the elimination Optic nerve hypoplasia or atrophy Macular scars t1/2), the clinical course of the infant suggests that the etiology of her Retinal disorders nystagmus might well be explained by prenatal exposure to sertraline. Cataracts The t1/2 of 26 hours temporally correlates with the resolution of her Aniridia nystagmus. The mother also discontinued the medication after deliv- Albinism ery, and she did not breastfeed the infant for 72 hours. Neurologic Posterior fossa lesions Many women develop or have a recurrence of psychiatric illness Defective gaze mechanism during pregnancy; the may be vulnerable for the Cerebellar dysfunction development of mood disorders while breastfeeding. Recent studies Brainstem dysfunction show that up to 35% of pregnant women may be using psychoactive Diencephalic lesions 5 Vestibular defects: Familial drugs. Despite increasing prevalence of the use of SSRIs, there is little Autosomal dominant in the literature describing the safety of these drugs in pregnancy and Autosomal recessive lactation. Several studies have examined in utero exposure to SSRIs in X-linked both animals and humans; all have involved fluoxetine. Fluoxetine and its metabolite have been shown to easily cross the placenta in rats.6 Animal studies using up to 11 times the maximum daily dose of fluoxetine for humans have demonstrated no teratogenic effect on With the increasing use of SSRIs and their potential use during exposed .6 The rates of major fetal malformations among flu- pregnancy, it is important for care providers to be aware of potential oxetine-treated mothers during the first and third trimester do not side effects in the newborn, particularly nystagmus. This unusual vary from those expected in the general population (1% to 3%); the clinical finding calls for a detailed prenatal history and a thorough rate of was higher than nondepressed control patients physical examination. Differentiating transient drug-induced nystag- treated with nonteratogens but was considered similar to the general mus from a more serious disorder may obviate the need for invasive population rate of 15%.6 or ionizing diagnostic studies. It is well established that all psychotropic agents are secreted into human milk in varying concentrations. Various studies have found References that 3.3% to 10.8% of the maternal dose of fluoxetine is ingested by 1. Leonard HL, March J, Rickler KC, Allen AJ. Pharmacology of the selective seroto- breastfed infants; there have been no reports of serious side effects in nin reuptake inhibitors in children and adolescents. J Am Acad Child Adolesc infants exposed to SSRIs from human milk, and their use is not pres- Psychiatry 1997;36:725–36. 7 ently a contraindication to breastfeeding. 2. Physicians Desk Reference. Montvale, NJ: Medical Economics; 1996. p. 918–23, Nystagmus can be described as pendular (to-and-fro eye move- 2217–20, 2505–8, 2544–8. ments of equal amplitude in both directions) or jerky (slow compo- nent in one direction and a fast component in the opposite direction). 3. Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicity in a neonate. Pediatrics 1993;92:721–2. Physiological nystagmus can be elicited by the optokinetic phenome- non of a target moving past the eyes, resulting in a jerky nystagmus. 4. Mhanna MJ, Bennet JB, Izatt SD. Potential fluoxetine chloride (Prozac) toxicity Vestibular nystagmus can occur with rotation of the body or irrigation in a newborn. Pediatrics 1997;100:158–9. of the ear canal and is caused by movement of the fluid within the 5. Nulman I, Koren G. The safety of fluoxetine during pregnancy and lactation. semicircular canals. It results in jerky nystagmus that is horizontal Teratology 1996;53:304–8. 8 and torsional. Positional nystagmus may be seen in extreme gaze 6. Baum AL, Misrl S. Selective serotonin-reuptake inhibitors in pregnancy and and is usually in the horizontal direction. Ocular, neurologic, or lactation. Harv Rev Psychiatry 1996;4:117–25. vestibular defects can result in pathologic nystagmus (Table 1). Optic 7. Stokes PE, Holtz A. Fluoxetine tenth anniversary update: the progress continues. nerve hypoplasia or atrophy, macular scars, retinal disorders, cata- Clin Ther 1997;19:1200–5. racts, aniridia, and albinism are ocular defects that can result in congenital pendular nystagmus. Underlying neurologic conditions 8. Fenichel GM. Clinical Pediatric Neurology: A Approach. such as posterior fossa lesions or defects in the gaze mechanism Philadelphia: WB Saunders; 1988. p. 316–9. caused by brainstem or cerebellar abnormalities can also result in 9. Hamming NA, Miller MT. The eye. In: Fanaroff AA, Martin RJ, editors. Neonatal- nystagmus. Central or peripheral defects in the vestibular system Perinatal Medicine: Diseases of the and Infant. 6th ed. St. Louis: CV Mosby; usually cause jerky nystagmus.9 Congenital jerky nystagmus is famil- 1997. p.1671–708. ial and can be diagnosed early in life. Its inheritance is either autoso- 10. Volpe JJ. Neurology of the Newborn. 3rd ed. Philadelphia: WB Saunders; 1995. mal dominant, recessive, or X-linked.10 p. 112.

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