School of Public Health, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX.
Child Health and Development Studies, Public Health Institute, Berkeley, CA.
Am J Obstet Gynecol. 2022 Jan;226(1):132.e1-132.e14. doi: 10.1016/j.ajog.2021.10.035. Epub 2021 Nov 9.
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.
17α-羟孕酮己酸酯是一种合成孕激素，最初于 20 世纪 50 年代获批用于治疗妇科和产科疾病。尽管人们一直对 17α-羟孕酮己酸酯预防孕妇早产的短期疗效和安全性存在担忧，但对于 17α-羟孕酮己酸酯对后代健康的长期影响知之甚少。
探讨子宫内暴露于 17α-羟孕酮己酸酯与后代癌症风险之间的关系。
儿童健康与发育研究是一项基于人群的队列研究，纳入了 1959 年至 1966 年期间在 Kaiser 基金会健康计划（加利福尼亚州奥克兰）接受产前护理的>18000 对母婴对子。临床信息从怀孕前 6 个月到分娩后从母亲的医疗记录中提取。我们确定了怀孕期间 17α-羟孕酮己酸酯注射的次数和时间。通过与加利福尼亚癌症登记处的链接，确定了子女中确诊的癌症病例。我们使用 Cox 比例风险模型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起至癌症诊断、死亡或最后一次随访日期。
在 730817 人年的随访中，共有 1008 名子女被诊断患有癌症。大约 1.0%的子女（n=234）在子宫内暴露于 17α-羟孕酮己酸酯。第一孕期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）。第二或第三孕期暴露对男性（调整后的风险比，2.59；95%置信区间，1.07-6.28）但对女性（调整后的风险比，0.30；95%置信区间，0.04-1.11）子女的风险没有额外的影响。结直肠癌（调整后的风险比，5.51；95%置信区间，1.73-17.59）、前列腺癌（调整后的风险比，5.10；95%置信区间，1.24-21.00）和儿科脑癌（调整后的风险比，34.72；95%置信区间，7.29-164.33）的风险在第一孕期首次暴露于 17α-羟孕酮己酸酯的子女中高于未暴露的子女。
鉴于 17α-羟孕酮己酸酯与后代癌症之间可能存在关联，在怀孕早期谨慎使用 17α-羟孕酮己酸酯是有必要的。
