Case 1: A newborn in distress

A newborn boy presented to the emergency room at 24 h of life with respiratory distress and jitteriness.

He was born at term to a G1P0 mother who had an unremarkable pregnancy, protective serologies and no diabetes. She tested negative for group B streptococcus, and had no history of maternal herpes simplex virus infection. She denied smoking, alcohol and recreational drug use during pregnancy. The baby was born at home following an uncomplicated vaginal delivery. At 24 h of life, the baby was still grunting and jittery, and was brought to the emergency department.

In the emergency department, he was in moderate respiratory distress. His respiratory rate was 76 breaths/min, with visible subcostal indrawing and nasal flaring. His heart rate was 150 beats/min, O₂ saturation was 92% on room air and his rectal temperature was 36.8°C. The infant was alert, appeared warm and pink, but demonstrated fine tremor in all four limbs, which was suppressed by holding his limbs firmly. There were no dysmorphic features, fontanelles were flat, and the infant’s cardiorespiratory examination was normal. Neurological examination revealed normal primitive reflexes, but significantly increased tone to all four limbs.

The infant’s bedside glucose level measured 0.34 g/L, which was normalized with a bolus of 10% dextrose in water. Jittery movements and hypertonia persisted despite correction of hypoglycemia. Full septic work-up was performed, and the infant was started on broad-spectrum antibiotics and admitted to the neonatal intensive care unit.

Additional information from the mother provided the diagnosis.

CASE 1 DIAGNOSIS: POOR NEONATAL ADAPTATION SYNDROME

On admission to the neonatal intensive care unit, the infant was stabilized using continuous positive airway pressure. The infant’s cultures were negative at 48 h; therefore, antibiotics were discontinued. His respiratory distress, jitteriness and hypertonia gradually resolved, and the infant was discharged home after three days in hospital.

The infant’s mother later reported that she was taking citalopram (40 mg daily) throughout the pregnancy for depression. There was no other illicit or prescribed drug exposure. At six months of age, the infant is developing appropriately.

After a negative work-up and, with relatively rapid improvement with supportive care, the infant was diagnosed with poor neonatal adaptation syndrome – a group of maladaptive symptoms associated with maternal exposure to selective serotonin reuptake inhibitors (SSRIs) in late pregnancy. Also known as neonatal behaviour syndrome, this condition is comprised of a spectrum of symptoms including irritability, respiratory distress, jitteriness, hypotonia or hypertonia, hypoglycemia, feeding difficulties, seizures, hypothermia, sleep disturbance and jaundice (1,2).

Depression is common among pregnant women, with an estimated prevalence of 7% to 16%. Adverse perinatal effects associated with untreated or poorly managed depression include prematurity, low birth weight, growth retardation and increased risk of fetal death. Maternal-infant bonding and postpartum infant care may also be adversely affected (2,3).

Poor neonatal adaptation syndrome has been associated with a variety of SSRIs and serotonin noradrenaline reuptake inhibitors. The mechanism is not well understood; it has been proposed by some to be a discontinuation reaction similar to that seen in adults (2). However, a form of toxicity or serotonergic syndrome as the causative mechanism cannot be ruled out. Moreover, depression itself has been shown to adversely impact the neonate and, therefore, the mechanism is likely to be multifactorial (1).

Management of poor neonatal adaptation syndrome primarily consists of supportive care. Identification of at-risk infants and education of parents and health professionals is critical to effective counselling and early management. Admission may be required for stabilization; symptoms generally self-resolve within a few days to a maximum of four weeks. More severe presentations of the syndrome are relatively rare (approximately 0.3%), and no reported deaths have been attributed to antenatal SSRI exposure (1).

Apart from poor neonatal adaptation, the data describing other potential adverse fetal effects associated with in utero SSRI exposure are conflicting. While many studies have shown SSRIs to be free of teratogenic effects, some studies (4) have reported a small elevation in the risk of congenital defects, including septal heart defects and omphalocele. When implicated, the absolute risk of congenital defects was small (4). Paroxetine has been shown, in a limited number of studies, to increase the risk of congenital heart defects 1.5-fold to 2-fold, but the possibility of detection bias related to increased rates of both fetal ultrasound and infant echocardiography has been suggested (5). Regardless, paroxetine’s Food and Drug Administration pregnancy category was changed from C (risk cannot be ruled out) to D (positive evidence of risk) as a result of this potential risk. Guidelines from the American Congress of Obstetrics and Gynecology (Washington, USA) state that paroxetine use in pregnant women should be avoided, if possible, and fetal echocardiography should be considered for women who are exposed to paroxetine in early pregnancy (level B) (3).

Finally, neurodevelopmental outcomes of children exposed to SSRIs in utero have been examined in a limited number of studies. While these studies demonstrated normal neurodevelopment through childhood, additional investigation and long-term follow-up are warranted to further elucidate the long-term sequelae of in utero SSRI exposure.

Considerable debate exists regarding the specific effects of newer SSRIs and serotonin noradrenaline reuptake inhibitors, and further investigation is required to characterize these effects.

Given the prevalence of depression in pregnant women, the well-established adverse effects of untreated depression on maternal and fetal health, and the conflicting data surrounding safety of SSRIs in pregnancy, clinicians are presented with a considerable challenge in counselling pregnant women with depression. The potential risks associated with SSRI use in pregnancy must be balanced with the risks associated with depression to both mother and fetus, as well as the risk of depression relapse if treatment is discontinued. Motherisk (www.motherisk.org) – a valuable Canadian resource for safety issues surrounding pregnancy – currently recommends that in addition to weighing the risks and benefits of discontinuing antidepressant medication during pregnancy, infants born to mothers taking SSRIs during late pregnancy be closely monitored for longer than the typical 24 h to 48 h after birth.

CLINICAL PEARLS

• When presented with a neonate in distress, it is critical to obtain a detailed maternal medication history.

• Poor neonatal adaptation is a syndrome of maladaptive symptoms in neonates exposed to SSRIs in the third trimester of pregnancy; it is generally mild and self-limited, and primarily requires supportive management.

• Identification of at-risk infants and the education of parents and health professionals are critical to effective counselling and early management of poor neonatal adaptation syndrome.