Pregnancy and prescribing antipsychotics

Guidelines for prescribing antipsychotics during pregnancy and lactation include the following:

1.  Consider nondrug options
2.  Avoid drugs if possible during weeks 6–10
3.  Use antipsychotics about which most is known during pregnancy
4.  Keep doses low before delivery
5.  Increase dose postpartum
6.  Have patient take medications just before infant’s longest sleep of the day
7.  Consult with pediatrician

Optimal prescription of antipsychotics during pregnancy is complicated by altered pharmacokinetics across the three trimesters, fear of teratogenesis, need to safeguard the smooth progress of labor and delivery,  need to prevent withdrawal effects in the neonate,  and concerns about subtle effects on the infant’s neurodevelopment. The latter concerns are also present during breast-feeding.  Plasma volume increases by about 50% during pregnancy and body fat also increases, expanding the volume of drug distribution. Blood flow to the kidneys rises, as does the glomerular filtration rate, thus speeding renal elimination.  Many liver enzymes are activated during pregnancy,  so drugs are metabolized more quickly, consequently increasing the rate of clearance.

The end result is that plasma drug concentration is lowered during pregnancy. At the same time, because of increasing titers of sex steroids acting on neurotransmitter receptors,  some pregnant women may not require high drug concentrations in order to stay symptom-free. Changes in physiology begin in early gestation and are most pronounced in the third trimester of pregnancy. Further changes occur during labor, with some returning to baseline within 24 hours of delivery, while others remain for up to 12 weeks postpartum (15, 17, 22). There are relatively few specific data on pharmacokinetics/ dynamics in pregnancy, so therapeutic guidelines must be based on observational studies and basic principles.

The use of medications during pregnancy and lactation requires critical attention to the timing of exposure,  the dose and duration of use,  and fetal susceptibility.  Essentially all psychotropic drugs pass through the placenta. The aim of management of women with schizophrenia during pregnancy and the postpartum period is to achieve an optimal balance between minimizing fetal and neonatal exposure to drugs and the deleterious consequences of a psychotic mother. Usually monotherapy with the lowest effective dose of a drug for the shortest period necessary is the best strategy.  If possible, drug exposure during the first trimester is best avoided (19).  The use of low-potency phenothiazines during the first trimester probably increases the risk of congenital abnormalities by an additional four cases per 1,000.

A recent study of over 2,000 births to mothers diagnosed with schizophrenia compared to over a million births to women without schizophrenia found significantly increased risks for stillbirth, infant death, preterm delivery, low birth weight, and small size for gestational age among t he offspring of women with schizophrenia. Women with an episode of schizophrenia during pregnancy had the highest risks. Control for a higher incidence of smoking during pregnancy among the subjects as well as for single motherhood,  maternal age,  parity,  maternal education and country of birth,  and pregnancy-induced hypertensive diseases in a multiple regression model reduced the risk. But even after adjustments, there was a doubled risk for women with an episode of schizophrenia during pregnancy in relation to women in the comparison group.  The risks for preterm delivery and low birth weight were significantly elevated for all subjects. It is impossible to tell from this study how much of the poorer outcome can be attributed to antipsychotic treatment.

Another study of over 2,000 children of women with schizophrenia found that these infants had an increased   risk   of   postneonatal   death   largely explained by an increase in sudden infant death syndrome. They also had a marginally statistically significant increase in the risk of congenital malformations.  The same study found that women with schizophrenia had fewer antenatal care visits than pregnant women in the general population and that their babies tended to have lower Apgar scores. Subjects were at increased risk of interventions such as cesarean section,  assisted vaginal delivery, amniotomy, and pharmacological stimulation of labor. The authors concluded that their findings must be interpreted against a backdrop of presumed differences in socioeconomic status, substance abuse, smoking, and medication use between subjects with schizophrenia and comparison subjects.

Fetal circulation, compared with maternal circulation, contains less protein, leaving more of the drug unbound—i.e., facilitating entry into the brain. Liver enzymes are relatively inactive in the fetus, increasing the possibility of toxic effects. Excretion is relatively prolonged.  In addition,  the blood-brain barrier is incomplete, and the nervous system is immature and, therefore, it is more sensitive to drug effects.

Teratogenic effects are both dose and time dependent,  with organs at the greatest risk during their period of fastest development. Week 6 to week 10 is the most vulnerable period. Besides organ malformation,  potential risks to the fetus are spontaneous abortion, growth retardation, and immediate neonatal effects,  such as extrapyramidal and withdrawal symptoms.  Neurodevelopmental effects of antipsychotic drugs have never been demonstrated in humans but remain a theoretical concern.

Not much is yet known about the newer drugs.

Clozapine poses special potential risks for the fetus: seizure and agranulocytosis.  Thus far,  olanzapine appears relatively safe.  Twenty-three prospectively and 11 retrospectively ascertained pregnancy reports on pregnant women treated with olanzapine were collected in the Lilly Worldwide Pharmacovigilance Safety Database. Spontaneous abortion occurred in 13%, stillbirth in 5%, and prematurity in 5%—all within the range of normal historic control rates. There were no major malformations.

Most experts suggest minimal use—no use,  if possible—of antipsychotics during weeks 6–10 of gestation to prevent teratogenesis and low doses before expected delivery to prevent toxicity and withdrawal in the infant, with immediate resumption of a full dose after delivery because of the high risk of the mother’s decompensation postpartum (12, 13, 16, 20).

Mary V. Seeman, M.D.

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