Obstetric and Fetal Pharmacology

Primer

Obstetric and Fetal Pharmacology is an important clinical issue for physicians and patients because of the potential for teratogenic risk, perinatal syndromes, and effect on neonatal development. This page focuses specifically on (Obstetric and Fetal Psychopharmacology). Decisions regarding treatment should be a shared decision between obstetric and mental health clinicians, and the patient before the pregnancy occurs whenever possible. Untreated psychiatric illness comes with its own risks, including significant impacts on maternal and neonatal health, including suicide and infanticide.

General Principles

  • In general, using the minimum number of psychotropic medications at the lowest effective dose should guide your treatment principles.
  • A single medication at a higher dose should be favoured over multiple medications
  • Changing medications increases the exposure to the offspring
  • Medications with fewer metabolites, higher protein binding (decreases placental passage), and fewer interactions with other medications are preferable
  • During pregnancy, levels of medications may change due to changes in renal clearance or alteration in CYP450 enzyme activities
  • All psychotropic medications will cross the placenta, be present in amniotic fluid, and enter breast milk. The highest risk for teratogenesis is during embryogenesis, from the 3rd to 8th week of gestation.

Don't forget women of child-bearing age!

Although psychotropic use during pregnancy and breastfeeding is an important clinical issue, it is just as important to consider the implications of starting/continuing psychotropic medications in women of child-bearing age. A serum/urine beta hCG should always be done to rule out a pregnancy prior to starting psychotropic medications, especially for mood stabilizers and anti-epileptics, where the risks of fetal anomalies are much greater.

Pre-Conception and Oral Contraceptives (OCPs)

Mood Stabilizers

Mood Stabilizers and Antiepileptics and Effects on Contraception

Adapted from: Williams, D. (2014). Antiepileptic drugs and contraception. US Pharm, 39(1), 39-42.
Medications[1]
No Effect (Safe to use) • Benzodiazepines: diazepam, clonazepam, lorazepam
• Divalproex, valproic acid
• Gabapentin
• Pregabalin
• Lacosamide
• Levetiracetam
Decreased Effectiveness • Carbamazepine
• Clobazam
• Lamotrigine (>300 mg/day may reduce contraceptive efficacy; <150 mg/day does not appear to affect efficacy)
• Oxcarbazepine
• Phenobarbital
• Phenytoin
• Topiramate (>200 mg/day)

During Pregnancy

Antidepressants

  • Recent controversy has come up regarding concerns about the incidence of mental illness (autism, mood disorders, somatoform disorders, and behavioral disorders) in offspring of mothers taking SSRIs. Although animal studies of the neurobehavioral outcomes of fetal antidepressant exposure suggest mechanisms for such effects, most human studies indicate that maternal psychiatric illness account for much (but not all) of this risk. The fraction of cases attributable to antidepressant use (0.5%) is substantially lower than what would be attributable to parental psychiatric illness. Current treatment guidelines advise that antidepressants be used for severely ill mothers and advocate for discontinuation only in those with minimal illness/symptoms.[2][3]
  • SSRI use late in pregnancy has been associated with an increased risk of persistent pulmonary hypertension (PPHN) of the newborn (risk is 3 in 1,000; compared to population risk of 2 in 1,000).[4]

Antidepressant Recommendations

Adapted from ACOG practice bulletin no. 92. Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. 2008;111(4):1001–1020.
Medication Recommendations
Paroxetine Use in pregnant women and women planning pregnancy should be avoided, if possible. Fetal echocardiography should be considered for women who are exposed to paroxetine in early pregnancy.

Antipsychotics

  • Atypical antipsychotics can be used in pregnancy and have a lower rate of teratogenicity compared to mood stabilizers
  • Typical (first generation) antipsychotics are no longer first-line due to lower side effect profiles of second generation antipsychotics

Mood Stabilizers

Antiepileptics Recommendations

Adapted from ACOG practice bulletin no. 92. Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. 2008;111(4):1001–1020.
Effects
Lithium Exposure in pregnancy is associated with a small increase in congenital cardiac malformations (including Ebstein's anomaly) with a risk ratio of 1.2–7.7.
Valproic acid Exposure in pregnancy is associated with an increased risk neural tube defects, fetal valproate syndrome, and long-term adverse neurocognitive effects. It should be avoided in pregnancy, if possible, especially during the first trimester.
Carbamazepine Exposure in pregnancy is associated with fetal carbamazepine syndrome. It should be avoided in pregnancy, if possible, especially during the first trimester.

Benzodiazepines

  • Maternal benzodiazepine use should be strongly avoided.
  • First trimester use is linked to oral cleft malformations, while third trimester use linked to floppy infant syndrome (hypotonia, lethargy, sucking difficulties) and withdrawal syndrome (tremors, irritability, hypertonicity, diarrhea, vomiting, vigorous sucking).

Lower Risk Medications

  • Lamotrigine (Lamictal) is a potential maintenance therapy option for pregnant women with bipolar disorder because of its protective effects against bipolar depression, general tolerability, and a growing reproductive safety profile relative to alternative mood stabilizers.

Summary Table

Management Issues Associated With Medication Use During Pregnancy and Lactation

Adapted from ACOG practice bulletin no. 92. Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. 2008;111(4):1001–1020.
Medication Class Birth Defects Pregnancy Delivery Neonatal Lactation Treatment Options
Benzodiazepines Possible increased incidence of cleft lip or palate Ultrasonography for facial morphology Floppy infant syndrome Neonatal withdrawal syndrome Infant sedation reported Clonazepam, lorazepam, alprazolam
SSRIs, SNRIs, TCAs None confirmed Decreased serum concentrations across pregnancy None Neonatal withdrawal syndrome None Fluoxetine, sertraline, paroxetine, citalopram, nortriptyline
Lithium Increased incidence of heart defects (Ebstein's anomaly) Ultrasonography or fetal echocardiography for heart development or both. Decreased serum concentrations across pregnancy Intravenous fluids. Increased risk for lithium toxicity in mother Increased risk for lithium toxicity in infant. Risk of birth increased weight. Monitor infant CBC, TSH, and lithium levels Sustained release lithium
Antiepileptics Increased incidence of birth defects Decreased serum concentrations across pregnancy. Need folate supplementation, Vitamin K for some antiepileptic drugs None Neonatal symptoms, need to give Vitamin K for some anti-epileptic drugs Monitor infant CBC, liver enzymes, and antiepileptic drug levels Lamotrigine, carbemazepine
Antipsychotics None Confirmed Avoid anticholinergic medications for side effects. None Possible risk for neuroleptic malignant syndrome and intestinal obstruction None Haloperidol

Lactation and Breastfeeding

Antipsychotics

  • In general, quetiapine and olanzapine are preferred choices for breast-feeding because they have the lowest amount of excretion into breast milk.
  • Mothers on clozapine should continue during pregnancy, but consider tapering/discontinuing during breastfeeding due to risk of sedation and agranulocytosis in nursing infants.[5]

Mood Stabilizers

  • The use of lithium is discouraged during lactation, because dehydration can increase the vulnerability to lithium toxicity.[6] The hydration status of nursing infants of mothers taking lithium should be carefully monitored if lithium is being taken.

Clinical Pearls

  • Quetiapine can be safely used in postpartum depression
  • Hyperprolactinemia is common in aripiprazole
  • Atypical antipsychotics are mostly compatible with breastfeeding
  • Women of childbearing age using valproic acid should have folic acid supplementation, regardless of intention to have pregnancy

Guidelines

Perinatal Mental Health Guidelines

Guideline Location Year PDF Website
BC Best Practice Guidelines for Mental Health in the Perinatal Period Canada 2014 PDF Link
American College of Obstetricians and Gynecologists (ACOG) Psychotropic Medication Guidelines USA 2008 PDF • Link (AAFP)
• Link (ACOG)
American Psychiatric Association (APA) and ACOG Depression Guidelines USA 2009 - Link
National Institute for Health and Care Excellence (NICE) UK 2014, 2020 - Link
British Association for Psychopharmacology (BAP) UK 2017 PDF Link
The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) Australia, New Zealand 2018 PDF Link

Resources

For Providers
For Patients

References

1) Williams, D. (2014). Antiepileptic drugs and contraception. US Pharm, 39(1), 39-42.
2) Rapid Response: Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study
3) NEJM Journal Watch: Antidepressant Use During Pregnancy May Raise Risk for Psychiatric Illness in Offspring
4) Huybrechts, K. F., Bateman, B. T., Palmsten, K., Desai, R. J., Patorno, E., Gopalakrishnan, C., ... & Hernandez-Diaz, S. (2015). Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. Jama, 313(21), 2142-2151.
5) Mehta, T. M., & Van Lieshout, R. J. (2017). A review of the safety of clozapine during pregnancy and lactation. Archives of women's mental health, 20(1), 1-9.
6) American Academy of Pediatrics Committee on Drugs. (2001). Transfer of drugs and other chemicals into human milk. Pediatrics, 108(3), 776.