A preterm infant with abnormal movements

CASE PRESENTATION

A preterm female neonate is born to a 31-year-old gravida 1 para 0 mother at 33 + 4/7 weeks of gestation via spontaneous vaginal delivery at a community hospital. Her mother received routine antenatal care, with protective serologies and normal prenatal ultrasounds. The pregnancy was complicated by an antepartum hemorrhage at 28 weeks of gestation, and she received a course of steroids. The mother’s medical history includes fibromyalgia treated with 60 mg of duloxetine daily for the duration of the pregnancy.

At birth, the newborn had hypotonia of all four limbs and poor respiratory effort. Positive pressure ventilation was given for 2 min. The infant was then placed on continuous positive airway pressure (CPAP) of 5 cmH₂O at an FiO₂ of 90% which was weaned to 40% after stabilization with an SpO₂ of 92%. Apgar scores were 2, 5, and 9 at 1, 5, and 10 min, respectively. At 10 min of life, she had bilateral extension and internal rotation of both arms, apnea with desaturations, cycling movements of the lower limbs, and episodes of jitteriness. Cord arterial blood gas showed pH 7.09, pCO₂ 73, bicarbonate 16, and base excess of −9. Cord venous blood gas showed pH 7.14, pCO2 59, bicarbonate 16, and base excess −10.

Although stable on CPAP of 5 cmH₂O, the infant was intubated with fentanyl 2 mcg/kg, atropine 0.01 mg/kg and succinylcholine 2 mg/kg. Because of persistent abnormal movements, the infant received two doses of lorazepam (0.1 mg/kg), 40 mg/kg of phenobarbital, and levetiracetam (60 mg/kg). Persistent and recurring apnea necessitated ongoing ventilation and a transport call was initiated for transfer to a tertiary centre.

DISCUSSION

Due to persistent abnormal movements unresponsive to several classes of antiepileptic drugs (AED) and ensuing respiratory failure, a comprehensive investigation including a full workup to rule out sepsis, cerebral imaging, and amplitude integrated electroencephalogram was done. At the time of admission, EEG monitoring was remarkable for burst-suppression with no evidence of seizure activity. A head ultrasound on day one of life showed a small left-sided subependymal hemorrhage. An MRI was remarkable for focal areas of caudothalamic groove hemorrhage, minimal intraventricular hemorrhage, no hydrocephalus, no diffusion restriction, and no punctate white matter injury. Septic workup including complete blood count and lumbar puncture was within normal limits, and a cerebrospinal culture was negative for bacterial growth. Polymerase chain reaction (PCR) for herpes simplex virus was not tested. Blood glucose and ionized calcium were normal. After a 5-day admission at the tertiary care centre, the infant was transferred to a level II centre off respiratory support and tolerating oral and gavage feeds. Her initial workup was unremarkable and she had no recurrence of abnormal movements; her EEG and neurological exam normalized. Thus, the most likely diagnosis was abnormal movements secondary to maternal serotonin norepinephrine reuptake inhibitor (SNRI) use during pregnancy. Persistent apnea was likely secondary to cumulative doses of AED, causing respiratory failure.

A constellation of symptoms, collectively known as neonatal behavioural syndrome, has been linked to prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and SNRIs. Symptoms may include respiratory distress with tachypnea and cyanosis; neurological dysfunction including jitters, convulsions, hypertonia, extensor posturing of upper extremities with internal rotation; feeding difficulties; and jaundice (1). Factors that influence the length and severity of the symptoms include the type of SSRI/SNRI, the dose, half-life, and duration of exposure and maternal and neonatal hepatic cytochrome P450 isoenzyme genotype (2).

Duloxetine is an SNRI commonly used in the treatment of chronic pain syndromes including fibromyalgia, as seen in this case. SNRIs exert their effects by blocking the reuptake of both serotonin and norepinephrine, therefore increasing serum and cerebrospinal fluid concentrations of these monoamines. During development, serotonin plays a crucial role in organ development, including fetal lungs and brain (1). The placenta acts as the primary source of serotonin production for the fetus and likely produces the only source of serotonin for the developing fetal brain (3). Consequently, a disruption in placental serotonin levels may interrupt this process and result in the neurological symptoms seen at birth (3). Serotonin, via its interaction with 5-HT2 receptors on motor neurons of the ventral horn in the spinal cord, increases neuronal excitability. Therefore, increased serotonin levels at these synapses induced by SSRI/SNRI may cause the abnormal movements seen at birth, which would be unresponsive to anti-epileptics (4). In newborn rabbit kits, intrathecal injections of serotonin increased hypertonicity (5).

A lack of awareness of the abnormal movements induced by prenatal exposure to SSRI/SNRI resulted in significant morbidity. Despite the movements being unresponsive to anticonvulsants, multiple AEDs were administered prior to initiating a call for transfer to a tertiary centre. Phenobarbitone levels were not done, but we anticipate that her level was ~ 40 mcg/mL since she received 40 mg/kg. Tolerance does develop with resolution of the respiratory depression, but this usually occurs over days (6). Thus, overtreatment led to respiratory failure requiring intubation, mechanical ventilation, and transfer. If the abnormal movements or suspected seizures do not respond to benzodiazepines, we suggest that EEG monitoring be performed before the escalation of AED management. Moreover, a careful history of maternal drug exposures is key to the diagnosis, and physicians should be aware of the early presentation of the characteristic abnormal movements associated with SSRI/SNRI exposure which typically present with extensor posturing with or without jitteriness, sometimes immediately after birth. Other characteristic features can include dilated pupils.(7) Enhanced awareness of these abnormal movements in neonates with prenatal exposure to SSRI/SNRIs will decrease over treatment with anti-epileptics and extensive neurological workup. Treatment is supportive and the movements usually resolve within 48–72 h.

CLINICAL PEARLS

1. Abnormal movements: jitteriness, seizure-like activity, hypertonia, posturing, and apnea occurring shortly after birth can occur in infants exposed to SSRI or SNRI during pregnancy.

2. Increased serotonin levels at birth may act at the level of the spinal cord and cause the persistent abnormal movements.

3. Early recognition and awareness of the abnormal movements can help us to alleviate disease burden by ensuring that appropriate supportive management is in place, thereby avoiding excessive exposure to AEDs.