17α-hydroxyprogesterone caproate is a synthetic progestogen initially approved in the 1950s to treat gynecologic and obstetrical conditions. Despite continued concerns about safety and short-term efficacy regarding the use of 17α-hydroxyprogesterone caproate for the prevention of preterm birth in pregnant women, little is known about the long-term effects of 17α-hydroxyprogesterone caproate on the health of the offsprings.

To examine the association between in utero exposure to 17α-hydroxyprogesterone caproate and the risk of cancer in the offspring.

The Child Health and Development Studies was a population-based cohort of >18,000 mother-child dyads receiving prenatal care in the Kaiser Foundation Health Plan (Oakland, CA) between 1959 and 1966. Clinical information was abstracted from the mothers’ medical records beginning 6 months before pregnancy through delivery. We identified the number and timing of 17α-hydroxyprogesterone caproate injections during pregnancy. Incident cancers diagnosed in the offspring were ascertained through 2019 by linkage to the California Cancer Registry. We used the Cox proportional hazard models to estimate the adjusted hazard ratios and their 95% confidence intervals, with the follow-up time accrued from the date of birth through the date of cancer diagnosis, death, or last contact.

A total of 1008 offspring were diagnosed with cancer over 730,817 person-years of follow-up. Approximately 1.0% of the offspring (n=234) were exposed in utero to 17α-hydroxyprogesterone caproate. Exposure in the first trimester was associated with an increased risk of any cancer (adjusted hazard ratio, 2.57; 95% confidence interval, 1.59–4.15), and the risk increased with the number of injections (1–2 injections: adjusted hazard ratio, 1.80; 95% confidence interval, 1.12–2.90; ≥3 injections: adjusted hazard ratio, 3.07; 95% confidence interval, 1.34–7.05). Exposure in the second or third trimester conferred an additional risk for the male (adjusted hazard ratio, 2.59; 95% confidence interval, 1.07–6.28) but not for the female (adjusted hazard ratio, 0.30; 95% confidence interval, 0.04–1.11) offspring. The risk of colorectal (adjusted hazard ratio, 5.51; 95% confidence interval, 1.73–17.59), prostate (adjusted hazard ratio, 5.10; 95% confidence interval, 1.24–21.00), and pediatric brain (adjusted hazard ratio, 34.72; 95% confidence interval, 7.29–164.33) cancer was higher in the offspring first exposed to 17α-hydroxyprogesterone caproate in the first trimester than the offspring not exposed.

Caution using 17α-hydroxyprogesterone caproate in early pregnancy is warranted, given the possible link with cancer in the offspring.