Background

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.

Objective

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

Study Design

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.

Results

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.

Conclusion

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

中文翻译：

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子宫内接触 17α-羟基孕酮己酸酯与后代患癌症的风险

 背景

17α-羟基孕酮己酸酯是一种合成孕激素，最初于 20 世纪 50 年代被批准用于治疗妇科和产科疾病。尽管人们持续关注使用 17α-羟基孕酮己酸酯预防孕妇早产的安全性和短期疗效，但人们对 17α-羟基孕酮己酸酯对后代健康的长期影响知之甚少。

 客观的

研究子宫内暴露于 17α-羟基孕酮己酸酯与后代患癌症风险之间的关系。

 研究设计

儿童健康与发展研究是一个以人群为基础的队列，其中包括 1959 年至 1966 年间在凯撒基金会健康计划（加利福尼亚州奥克兰）中接受产前护理的 >18,000 名母子。临床信息摘自母亲的医疗记录从怀孕前 6 个月开始直至分娩。我们确定了怀孕期间注射 17α-羟基孕酮己酸酯的次数和时间。 2019 年，通过与加州癌症登记处联系，确定了后代诊断出的癌症事件。我们使用 Cox 比例风险模型来估计调整后的风险比及其 95% 置信区间，随访时间从出生日期到癌症诊断日期、死亡日期或最后一次接触日期。

 结果

经过 730,817 人年的随访，共有 1008 名后代被诊断患有癌症。大约 1.0% 的后代 (n=234) 在子宫内暴露于 17α-羟基孕酮己酸酯。妊娠早期的暴露与任何癌症的风险增加相关（调整后的风险比，2.57；95％置信区间，1.59-4.15），并且风险随着注射次数的增加而增加（1-2次注射：调整后的风险比， 1.80；95% 置信区间，1.12–2.90；≥3 次注射：调整后的风险比，3.07；95% 置信区间，1.34–7.05）。妊娠中期或晚期的暴露会给男性带来额外的风险（调整后的风险比，2.59；95% 置信区间，1.07–6.28），但不会给女性带来额外的风险（调整后的风险比，0.30；95% 置信区间，0.04–1.11） ）后代。结直肠癌（调整后的风险比，5.51；95% 置信区间，1.73–17.59）、前列腺（调整后的风险比，5.10；95% 置信区间，1.24–21.00）和儿童脑部（调整后的风险比，34.72；95）的风险% 置信区间，7.29–164.33）在妊娠早期首次接触 17α-羟基孕酮己酸酯的后代的癌症发病率高于未接触的后代。

 结论

鉴于 17α-羟基孕酮己酸酯可能与后代癌症有关，因此在妊娠早期使用 17α-羟基孕酮己酸酯时应谨慎。