Psychotropic drug treatment during pregnancy and lactation : effects on mother and child

The common major depressive disorder and anxiety disorders are often treated with antidepressants. Treatment with mood-stabilizers and antipsychotics are important for pregnant women with bipolar and psychotic disorders, as these women are at risk of postpartum psychosis and even suicide if not treated. The aim of this thesis was to elucidate the risks of psychotropic drug treatment in the perinatal period. Study I aimed at studying sertraline plasma concentrations in pregnant women and their infants and the clinical effects on the infants. Studies II and III focused on antipsychotic treatment during pregnancy and complications for the mother and the infant, respectively. In study IV, we studied infant health and serum lithium concentrations after exposure to lithium through breastmilk.

Study I was a part of a randomized controlled trial where women with moderately severe depression in early pregnancy were randomized to treatment with sertraline or placebo together with internet-based cognitive behaviour therapy. Plasma sertraline concentrations were measured in 9 women during and after pregnancy and in 7 of their infants. In study II we extracted data on 1.3 million pregnancies from the Medical Birth Register and the Prescribed Drug Register to study the effects of antipsychotic treatment on pregnancy complications. For study III, these registers were combined with two neonatal quality registers to study the neonatal morbidity in the exposed infants. For study IV, data was extracted retrospectively from the medical records of 30 infant-mother pairs where the infant was exposed to lithium through breastmilk.

In study I, the inter-individual variation between the maternal plasma sertraline concentrations measured during pregnancy was tenfold, but the median sertraline concentration was 25-40% lower during pregnancy than postpartum. The medians of the sertraline concentrations measured in cord blood and infant serum at 48 hours of age were 33 and 25% of the median of the maternal concentrations at delivery, and the effects on the infants were mild and transient. In study II, the risk for gestational diabetes was increased after use of olanzapine, quetiapine and clozapine, adjusted risk ratio [RR] 1.8 (95% confidence interval [CI]1.3-2.4). In study III, the 2677 infants exposed to antipsychotics had an increased risk of being admitted to neonatal care, adjusted RR 1.7, (95% CI 1.6-1.8). In study IV, the lithium concentrations in infant serum were low, ≤0.2mmol/l, after one month of age, with the median concentration around 10% of the mothers. In the first month of life, serum lithium concentrations varied more, and two infants had therapeutic lithium concentrations, the highest being 1.2 mmol/l. A third of the infants had poor weight gain in the first month and two were described tired, but no other effects on the infants were found.

Psychotropic drug treatment in the peripartal period is associated with some adverse outcomes, but none of the studies in this thesis found any reason to advise against treatment with the included drugs during pregnancy or while breastfeeding. A thorough risk-benefit analysis is required when drug therapy is considered in the peripartal period, as well as increased monitoring of the exposed pregnant women and their infants.

List of scientific papers

I. Heinonen E, Blennow M, Blomdahl-Wetterholm M, Hovstadius M, Nasiell J, Pohanka A, Gustafsson LL, Wide K. Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low. European Journal of Clinical Pharmacology. 2021;77(9):1323-31.
https://doi.org/10.1007/s00228-021-03122-z

II. Heinonen E, Forsberg L, Nörby U, Wide K, Källén K. Antipsychotic use during pregnancy and risk for gestational diabetes: a national register-based cohort study in Sweden. CNS Drugs. 2022
https://doi.org/10.1007/s40263-022-00908-2

III. Heinonen E, Forsberg L, Nörby U, Wide K, Källén K. Neonatal morbidity after foetal exposure to antipsychotics – a national register-based study. [Submitted]

IV. Heinonen E, Tötterman K, Bäck K, Sarman I, Svedenkrans J, Forsberg L. Lithium and breastfeeding – drug concentrations and morbidity in exposed infants. [Submitted]