Why the Maternal Medication List Matters: Neonatal Toxicity From Combined Serotonergic Exposures

A 34-week gestation male infant was delivered via caesarian for breech positioning, partial placental abruption, and preeclampsia without severe features. Maternal history was notable for bipolar disorder and posttraumatic stress disorder, for which she was taking venlafaxine 150 mg daily, bupropion hydrochloride 300 mg daily, quetiapine 200 mg daily, and gabapentin 1200 mg 3 times daily. Maternal urine toxicology result was negative except for 3,4-methyl​enedioxy​methamphetamine, suspected to be a false-positive attributable to bupropion.¹¹ 

Apgar scores were 5 and 8 at 1 and 5 minutes, and the infant was resuscitated with continuous positive airway pressure. At the time of delivery, he was hypotonic, but, at ∼10 minutes of life, while in the delivery room, he was noted to have nonsuppressible spells of bilateral arm internal rotation with wrist flexion and bilateral leg extension, alternating with generalized hypotonia. He demonstrated sustained ankle clonus and significant hyperreflexia with bilateral knee extension elicited by a unilateral patellar stimulus. His movements were not associated with vital sign changes.

A neonatal seizure evaluation was initiated, and empirical antimicrobial therapy with ampicillin, gentamicin, and acyclovir was started. Cord-blood gas was negative for acidosis. Cerebrospinal fluid testing revealed 2592 red blood cells and 19 white blood cells; results of herpes simplex virus testing, meningitis and encephalitis panel, and bacterial cultures of the cerebrospinal fluid were ultimately negative. Head ultrasound was normal. Two 0.1 mg/kg doses of intravenous lorazepam were given, with transient improvement in abnormal movements, and he was transferred to a quaternary care center. Neurologic examination remained notable for mild encephalopathy, jitteriness, 3+ tendon reflexes throughout, and generalized hypotonia alternating with extensor posturing. Continuous EEG revealed excessive left temporal sharp waves and mildly prolonged interburst intervals with decreased voltages between the bursts, indicating mild cerebral dysfunction and potential risk for seizures. Numerous episodes of abnormal movements were captured and were nonepileptic. Cord and meconium toxicology results were negative. MRI of the brain on the day of birth revealed an immature gyral folding pattern with no evidence of stroke, ischemia, hemorrhage, or structural abnormalities. Because of concern that hypoxic-ischemic injury may not yet have been detectable, repeat MRI was obtained on the third day of life. Diffusion-weighted imaging and apparent diffusion coefficient sequences showed no restricted diffusion; therefore, spectroscopy was not obtained. Serum amino acids, ammonia, thyroxine, and newborn screen were normal. The infant’s encephalopathy, hypertonicity, and hyperreflexia gradually improved over several days. He was discharged from the hospital with a normal neurologic examination at 14 days, and has had appropriate development and normal neurologic examination up to 15 months.

This is the first case reported of poor neonatal adaptation from psychotropic medications presenting within the first 10 minutes of life. The severity of neurologic abnormalities in this case, leading to an extensive workup and transfer of care, stands out among previously reported cases. We propose that the severity and rapidity of symptoms were caused by interactions between psychotropic medications.

In adults, venlafaxine is extensively metabolized, with only 1% to 10% eliminated unchanged in the urine. It is metabolized primarily by cytochrome P450 2D6 (CYP2D6) to the active metabolite O-desmethylvenlafaxine (ODV), which is further metabolized via cytochrome P450 2C19 and cytochrome P450 3A4 (CYP3A4) to inactive metabolites.¹²  Venlafaxine is metabolized to a lesser extent by CYP3A4 directly to an inactive metabolite.¹²  Bupropion inhibits CYP2D6, thus increasing venlafaxine serum concentrations.¹²  Quetiapine is metabolized by CYP3A4 and thus may competitively interfere with venlafaxine metabolism.¹³  Because both venlafaxine and ODV readily cross the placenta, the mother and fetus in our case likely experienced elevated concentrations of the active drug and metabolite.¹⁴ 

After birth, the neonate can no longer rely on the mother for the metabolism and excretion of venlafaxine and ODV. This is problematic because neonates have minimal CYP2D6, cytochrome P450 2C19, and CYP3A4 activity and decreased renal function, particularly if premature.^15,16  This leads to long elimination half-lives suggesting toxicity rather than withdrawal as the cause of symptoms within the first hours to days of life.

Given that our patient’s abnormal movements were determined to be nonepileptic and attributable to pharmacotoxicity, we retrospectively evaluated the appropriateness of the treatment and workup. Psychotropic medications more often cause nonepileptic abnormal movements than true seizure; however, bupropion and quetiapine can lower the seizure threshold, increasing the possibility of true seizure.^17,18  Seizures in infants are rarely tonic-clonic and are more often characterized by generalized stiffening or focal, asymmetric movements. The absence of vital sign changes is reassuring but may not be sufficient to rule-out seizure.¹⁹ 

Although patients with known in utero exposure to psychotropic medications should be recognized as at risk for drug-induced abnormal movements, the provider must first evaluate for potentially life-threatening conditions such as infection, metabolic derangements, or hypoxic-ischemic encephalopathy. Infants should undergo appropriate evaluation and empirical treatment until EEG can be performed. In cases of uncertainty, a benzodiazepine with a short half-life may be considered rather than an agent with a longer half-life such as phenobarbital. Additional evaluation such as early MRI, metabolic testing, and genetics consultation may not be necessary.

Review of the maternal drug list is an essential component of neonatal care. This is particularly important in cases of multiple medication use where there is a higher probability of pharmacologic interactions. Infants exposed to serotonergic medications should have emergent evaluation and treatment of possible seizures congruent with nonexposed infants. If symptoms persist with an otherwise negative evaluation, providers should consider serotonin toxicity as an etiology, recognizing that persistent but ultimately self-resolving abnormal movements may continue for up to 2 weeks.

CYP2D6

cytochrome P450 2D6

CYP3A4

cytochrome P450 3A4

ODV

O-desmethylvenlafaxine

SNRI

serotonin-norepinephrine reuptake inhibitor

SSRI

selective serotonin reuptake inhibitor