SUMMARY  

• SPRAVATO nasal spray is not recommended during pregnancy.¹
• The risks of SPRAVATO use during pregnancy have not been studied. Women who were pregnant, breastfeeding, or planning to become pregnant while enrolled in a study were excluded from the phase 3 clinical program.^2-5
  • For inclusion in the SPRAVATO studies a woman of childbearing potential had to be practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly).^2-5
  • Women of childbearing potential had to agree to use a highly effective method of contraception throughout the study and for at least 6 weeks after the last dose of study drug.^2-5
• There are insufficient data on SPRAVATO use in pregnant women to draw conclusions about any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.¹
• Based on published findings from pregnant animals treated with ketamine, SPRAVATO may cause fetal harm when administered to pregnant women.¹
  • Published studies in pregnant primates demonstrate that the administration of drugs that block N-methyl-D-aspartate (NMDA) receptors during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring.¹
• If a woman becomes pregnant while being treated with SPRAVATO, treatment should be discontinued and the patient should be counseled about the potential risk to the fetus.^1,6
• An analysis of the Johnson and Johnson Global Medical Safety database conducted through 30 September 2024 found 161 cases of maternal exposure prior/during pregnancy and 12 cases of paternal exposure prior to their partners’ pregnancies. There were 8 live births resulting in 10 babies, of which, 3 were normal/healthy babies and 5 babies were premature (2 sets of twins and 1 single delivery), and 2 live births with no information on the babies.⁷
• A case report of SPRAVATO exposure during the first trimester in a 27-year-old female resulted in a birth with no congenital malformations. SPRAVATO was discontinued after two treatment sessions, but other psychiatric medications were taken throughout her pregnancy. The pregnancy was complicated by preeclampsia. The baby was delivered at 37 weeks and was treated in the neonatal intensive care unit for hypoglycemia for 1 day. All development milestones were achieved in the first year of life; however, at 16 months of age, there were observations of gross motor delays and at 20 months, there was a slight delay in language development.⁸
  • The authors stated that the etiology of the developmental delays was unclear and could be attributable to maternal depression during pregnancy and postpartum and/or in utero exposure to psychiatric medications.⁸
• SPRAVATO is not recommended in women who are breastfeeding.¹
  • SPRAVATO is present in human milk.
  • There is no data available to assess the effects of SPRAVATO on human milk production or effects on the breastfed infant.
  • Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment with SPRAVATO.
• The pharmacokinetics of SPRAVATO in patients who were either pregnant or lactating was not studied.

PRODUCT LABELING

Healthcare providers are encouraged to register patients in a pregnancy exposure registry by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and researchprograms/pregnancyregistry/antidepressants/⁹

Outcomes of spravato exposures during pregnancy

A search of the Johnson and Johnson Global Medical Safety database conducted through 30 September 2024 found 173 unique pregnancies, with 161 cases of maternal exposure prior/during pregnancy and 12 cases of paternal exposure prior to their partners’ pregnancies. Of these, 126 cases were from noninterventional clinical studies (solicited), 10 came from interventional studies, and 29 cases were reported spontaneously.⁷ Pregnancy outcomes following maternal exposure are found in Table: Pregnancy Outcomes in Cases of Maternal Exposure to SPRAVATO. Pregnancy outcomes following paternal exposures are found in Table: Pregnancy Outcomes in Cases of Paternal Exposure to SPRAVATO.

There was a total of 8 live births, 5 from maternal exposure (see table above) and 3 following paternal exposure. The 3 live births following paternal exposure resulted in normal/healthy babies with no adverse events reported, and another 3 live births from maternal exposure resulted in 5 premature babies (2 sets of twins and 1 single baby that reported complications). There was no information about the last 2 live births following maternal exposure. One serious adverse event of dyspnea was reported in 1 twin baby. No congenital malformations were reported.⁷

Approximately 8.5% of pregnancies resulted in spontaneous abortion, which is below the range for the estimated background risk of miscarriage in clinically recognized pregnancies (10-20%).^7,10 The risk of spontaneous abortion rises after the age of 30; of the 17 reported cases, 10 were in women 18-35 years and 6 were in those 36-50 years.^7,11

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 14 October 2024. This literature search is restricted to esketamine nasal spray and not other formulations. A case report is presented in the Summary section of this response.