Fetal exposure to neurotropic drugs : neonatal effects and long-term outcome

Chronic illness in pregnant women is common. In epilepsy, bipolar disorder (BD) or major depressive disorder (MDD), pharmacotherapy is often necessary. Some neurotropic drugs may have negative effects on children exposed in utero. The aim of this thesis was to describe how neurotropic drugs and/or maternal chronic illness during pregnancy may influence the health of the child, both in the neonatal period and long-term outcome, with emphasis on neurodevelopment. In study I, we investigated school results at age 16 in children born to women with epilepsy (WWE), with or without antiepileptic drugs (AED) during pregnancy. Study II and study III aimed at describing neonatal morbidity in infants prenatally exposed to antidepressant drugs. In study IV we studied neonatal and long-term outcome of children born to mothers with severe mood disorders, mostly BD.

Methods: In study I, national health care and education registers as well as maternal care records were used to compare final grades of children of WWE with the rest of the population. Study II was a retrospective, hospital-based study of patient records of women treated with antidepressants in late pregnancy and their children. Information on neonatal diagnoses, maternal use of antidepressant drugs and scoring according to Neonatal Abstinence Score (NAS) was used. In study III, we used the Medical Birth Register, the Prescribed Drug Register and two neonatal quality registers to obtain data on maternal use of antidepressants, maternal health and infant morbidity (diagnoses, admission to neonatal care unit (NCU) and interventions). In study IV, information on maternal health during and after pregnancy was obtained from patient records and at a structured interview. At age 4 to 5 years, the children were assessed by a psychologist with a cognitive test (WPPSI-III).

Results: In study I, we observed an increased risk of not receiving a final grade from compulsory school for children exposed to ≥ 2 AED during pregnancy, adjusted odds ratio (OR) 2.99 (95 % confidence interval [CI] 2.14–4.17), but no increased risk for children born to mothers with untreated epilepsy or exposed to AED in monotherapy. In study II, 22 % of 205 infants assessed with NAS had signs of mild neonatal abstinence and 3 % of severe abstinence. Among a total of 741 040 infants included in study III, 22 507 (3 %) were exposed to antidepressants during pregnancy. Thirteen percent of exposed infants were admitted to NCU compared to 8 % in the population, adjusted OR 1.5 (95 % CI 1.4-1.6). Respiratory disorders, persistent pulmonary hypertension and hypoglycemia were more common after maternal use of selective serotonin reuptake inhibitors. In study IV, there were no statistically significant differences in IQ between children born to women with mood disorders with lithium use during pregnancy (n=20), children born to mothers with mood disorders but no lithium use during pregnancy (n=8) and children born to mothers with no mood disorders (n=11).

Conclusions: Neurotropic drugs during pregnancy can be associated to adverse outcomes in exposed children. Infants exposed to antidepressants have a moderately increased risk of being admitted to NCU. AED polytherapy during pregnancy may be associated to a worsened neurodevelopmental outcome but a causal connection is not established. Lithium exposure during pregnancy was not associated to adverse cognitive outcome at preschool age in our cohort.

List of scientific papers

I. Forsberg L, Wide K, Kallen B. School performance at age 16 in children exposed to antiepileptic drugs in utero : a population-based study. Epilepsia. 2011;52(2):364-9.
https://doi.org/10.1111/j.1528-1167.2010.02778.x

II Forsberg L, Naver L, Gustafsson LL, Wide K. Neonatal Adaptation in Infants Prenatally Exposed to Antidepressants- Clinical Monitoring Using Neonatal Abstinence Score. PLos One. 2014;9(11):e111327.
https://doi.org/10.1371/journal.pone.0111327

III Nörby U, Forsberg L, Wide K, Sjörs G, Winbladh B, Källén K. Neonatal care after maternal use of antidepressant drugs during pregnancy. [Submitted]

IV Forsberg L, Adler M, Römer Ek I, Ljungdahl M, Navér L, Gustafsson LL, Berglund G, Chotigasatien A, Hammar U, Böhm B, Wide K. Neonatal health and cognitive outcome at preschool age in children with intrauterine exposure to maternal mood disorders and lithium. [Manuscript]