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.
Key words
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References
- 38 FDA proposes reevaluation of certain progestin drugs; hearing request by 11–9.. 1973; 73 (Available at: https://www.govinfo.gov/app/details/FR-1973-10-10. Accessed March 26, 2021.): 27947
- Cardiovascular birth defects and antenatal exposure to female sex hormones.N Engl J Med. 1977; 296: 67-70
- Progestational drug products for human use; requirements for labeling directed to the patient. Food and Drug Administration, HHS. Final rule.Fed Regist. 1999; : 62110-62112
65 Lilly Research Laboratories et al; Withdrawal of Approval of 28 New Drug Applications 55264 (2000). Available at: https://www.govinfo.gov/app/details/FR-2000-09-13. Accessed March 26, 2021.
- Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.N Engl J Med. 2003; 348: 2379-2385
- Safety signals of 17-OHP-C use in pregnancy and efficacy in the prevention of preterm birth.J Matern Fetal Neonatal Med. 2009; 22: 540-542
- A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.N Engl J Med. 2007; 357: 454-461
- Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial.Obstet Gynecol. 2009; 113: 285-292
- Failure of 17-hydroxyprogesterone to reduce neonatal morbidity or prolong triplet pregnancy: a double-blind, randomized clinical trial.Am J Obstet Gynecol. 2010; 203: 248.e1-248.e9
- 17-Hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial.Am J Obstet Gynecol. 2011; 204: 221.e1-221.e8
- Embryotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate.Teratology. 1987; 35: 129-136
- Evaluation of the teratogenic potential of Delalutin (17 alpha-hydroxyprogesterone caproate) in mice.Teratology. 1983; 28: 201-208
- Embryo-fetal toxicity signals for 17alpha-hydroxyprogesterone caproate in high-risk pregnancies: a review of the non-clinical literature for embryo-fetal toxicity with progestins.J Matern Fetal Neonatal Med. 2007; 20: 89-112
- 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): a multicenter, international, randomized double-blind trial.Am J Perinatol. 2020; 37: 127-136
- Withdrawing approval of Makena - a proposal from the FDA Center for Drug Evaluation and Research.N Engl J Med. 2020; 383: e131
- Evaluating Progestogens for Preventing preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials.Lancet. 2021; 397: 1183-1194
- Preterm birth and 17OHP - why the FDA should not withdraw approval.N Engl J Med. 2020; 383: e130
- Accelerated approval of 17α-hydroxyprogesterone caproate: a cautionary tale.Obstet Gynecol. 2020; 135: 1207-1213
- A chronicle of the 17-alpha hydroxyprogesterone caproate story to prevent recurrent preterm birth.Am J Obstet Gynecol. 2021; 224: 175-186
- New frontiers of developmental endocrinology opened by researchers connecting irreversible effects of sex hormones on developing organs.Differentiation. 2021; 118: 4-23
- Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification.Nat Rev Endocrinol. 2020; 16: 45-57
- Prenatal exposure to diethylstilbestrol (DES).Fertil Steril. 2008; 89: e55-e56
- Adverse health outcomes in women exposed in utero to diethylstilbestrol.N Engl J Med. 2011; 365: 1304-1314
- Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects.Birth Defects Res C Embryo Today. 2013; 99: 134-146
- Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women.N Engl J Med. 1971; 284: 878-881
- Prenatal diethylstilbestrol exposure and risk of diabetes, gallbladder disease, and pancreatic disorders and malignancies.J Dev Orig Health Dis. 2021; 12: 619-626
- Systematic review and meta-analysis of testicular germ cell tumors following in utero exposure to diethylstilbestrol.JNCI Cancer Spectr. 2019; 3: pkz045
- Prenatal diethylstilbestrol exposure and cancer risk in women.Environ Mol Mutagen. 2019; 60: 395-403
- Prenatal exposure to synthetic progestins and estrogens: effects on human development.Arch Sex Behav. 1977; 6: 257-288
- Exposure to the synthetic progestin, 17α-hydroxyprogesterone caproate during development impairs cognitive flexibility in adulthood.Endocrinology. 2016; 157: 77-82
- Implications of prenatal steroid perturbations for neurodevelopment, behavior, and autism.Endocr Rev. 2014; 35: 961-991
- Pharmacology and placental transport of 17-hydroxyprogesterone caproate in singleton gestation.Am J Obstet Gynecol. 2012; 207: 398.e1-398.e8
- Metabolism of 17alpha-hydroxyprogesterone caproate, an agent for preventing preterm birth, by fetal hepatocytes.Drug Metab Dispos. 2010; 38: 723-727
- Metabolism of 17-alpha-hydroxyprogesterone caproate by human placental mitochondria.Reprod Sci. 2012; 19: 290-297
- EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals.Endocr Rev. 2015; 36: E1-E150
- The California child health and development studies.Handbook of longitudinal research. 1984; 1 (Available at: https://www.google.com/books/edition/Handbook_of_Longitudinal_Research_Birth/s4AoAAAAYAAJ?hl=en&gbpv=0. Accessed March 26, 2021.): 166-179
- The California child health and development studies of the School of Public Health, University of California at Berkeley.Paediatr Perinat Epidemiol. 1988; 2: 265-282
- The early determinants of adult health study.J Dev Orig Health Dis. 2011; 2: 311-321
- Cancer in California, 1998–2015. 2018.(Available at:) (Accessed March 26, 2021)
- Cancer reporting in California. 2021.(Available at:) (Accessed March 26, 2021)
- Modeling and variable selection in epidemiologic analysis.Am J Public Health. 1989; 79: 340-349
- Methods of covariate selection: directed acyclic graphs and the change-in-estimate procedure.Am J Epidemiol. 2009; 169: 1182-1190
- Time-to-event analysis of longitudinal follow-up of a survey: choice of the time-scale.Am J Epidemiol. 1997; 145: 72-80
- Applying quantitative bias analysis to epidemiologic data.Springer Science and Business Media, 2011 (Available at: https://link.springer.com/book/10.1007/978-0-387-87959-8. Accessed March 26, 2021.)
- A method to automate probabilistic sensitivity analyses of misclassified binary variables.Int J Epidemiol. 2005; 34: 1370-1376
- Multiple imputation by fully conditional specification for dealing with missing data in a large epidemiologic study.Int J Stat Med Res. 2015; 4: 287-295
- Emerging cancer trends among young adults in the USA: analysis of a population-based cancer registry.Lancet Public Health. 2019; 4: e137-e147
- Decrease in incidence of colorectal cancer among individuals 50 years or older after recommendations for population-based screening.Clin Gastroenterol Hepatol. 2017; 15: 903-909.e6
- Age-specific trends in incidence of noncardia gastric cancer in US adults.JAMA. 2010; 303: 1723-1728
- Decrease in incidence of young-onset colorectal cancer before recent increase.Gastroenterology. 2018; 155: 1716-1719.e4
- Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations.Semin Perinatol. 2014; 38: 516-522
- Challenges and opportunities in research on early-life events/exposures and cancer development later in life.Cancer Causes Control. 2012; 23: 983-990
- Increased incidence of gestational diabetes in women receiving prophylactic 17alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery.Diabetes Care. 2007; 30: 2277-2280
- Effect of 17alpha-hydroxyprogesterone caproate on glucose intolerance in pregnancy.Obstet Gynecol. 2009; 114: 45-49
- The risk of fetal anomalies as a result of progesterone therapy during pregnancy.Fertil Steril. 1986; 45: 575-577
- Prospective study of suspected associations between certain drugs administered during early pregnancy and congenital malformations.Teratology. 1983; 27: 57-64
- Congenital malformations among offspring exposed in utero to progestins, Olmsted County, Minnesota, 1936-1974.Fertil Steril. 1985; 43: 514-519
- Teratogenicity of progestogens given during the first trimester of pregnancy.Obstet Gynecol. 1985; 65: 775-780
- Effects of prenatally administered 17 alpha-hydroxyprogesterone caproate on adolescent males.Arch Sex Behav. 1984; 13: 441-455
- Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo.Obstet Gynecol. 2007; 110: 865-872
- Does the administration of diethylstilbestrol during pregnancy have therapeutic value?.Am J Obstet Gynecol. 1953; 66: 1062-1081
- Selected item from the FDA drug bulletin-November 1971: diethylstilbestrol contraindicated in pregnancy.Calif Med. 1972; 116: 85-86
- Vaginal epithelial changes in young women enrolled in the National Cooperative diethylstilbestrol Adenosis (DESAD) project.Obstet Gynecol. 1979; 53: 300-308
- Pathologic findings in young women enrolled in the National Cooperative diethylstilbestrol Adenosis (DESAD) Project.Obstet Gynecol. 1979; 53: 309-317
- Cancer risk in women prenatally exposed to diethylstilbestrol.Int J Cancer. 2007; 121: 356-360
- Utilization of hydroxyprogesterone caproate among pregnancies with live birth deliveries in the sentinel distributed database.J Matern Fetal Neonatal Med. 2021; ([Epub ahead of print])
- Timing of environmental exposures as a critical element in breast cancer risk.J Clin Endocrinol Metab. 2015; 100: 3245-3250
- DDT and breast cancer in young women: new data on the significance of age at exposure.Environ Health Perspect. 2007; 115: 1406-1414
- Cancer and developmental exposure to endocrine disruptors.Environ Health Perspect. 2003; 111: 389-394
- Development of the genital ducts and external genitalia in the early human embryo.J Obstet Gynaecol Res. 2010; 36: 929-937
- Progesterone is not the same as 17α-hydroxyprogesterone caproate: implications for obstetrical practice.Am J Obstet Gynecol. 2013; 208: 421-426
- The pharmacodynamics and safety of progesterone.Best Pract Res Clin Obstet Gynaecol. 2020; 69: 13-29
- The relationship between hormonal pregnancy tests and congenital anomalies: a prospective study.Am J Epidemiol. 1981; 113: 563-574
- Transplacental carcinogenesis (adrenocortical carcinoma) associated with hydroxyprogesterone hexanoate.Lancet. 1983; 2: 580
- Overall evaluations of carcinogenicity: an updating of IARC monographs Volumes 1 to 42.International Agency for Research on Cancer, 1987 (Available at: https://www.ncbi.nlm.nih.gov/books/NBK533500/. Accessed March 26, 2021.)
- [Stimulating effect of pregnancy on the growth of cervical cancer].Akush Ginekol (Mosk). 1981; 1: 53-55
Cancer I. AfRo. IARC Monogr Eval Carcinog Risk Chem Hum Vol 21 Sex hormones (II) 1979;21. Sex hormones (II). Available at: https://pubmed.ncbi.nlm.nih.gov/296128/. Accessed March 26, 2021.
- Hormonal contraception and post-menopausal hormonal therapy.International Agency for Research on Cancer, 1999 (Available at: https://www.ncbi.nlm.nih.gov/books/NBK396191/. Accessed March 26, 2021.)
- Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.Endocr Rev. 2013; 34: 171-208
- Systemic distribution of progesterone receptor subtypes in human tissues.J Steroid Biochem Mol Biol. 2020; 199: 105599
- Progestogen metabolism.J Reprod Med. 1999; 44: 148-152
- Prenatal diethylstilbestrol exposure and cancer risk in males.Cancer Epidemiol Biomarkers Prev. 2021; 30: 1826-1833
- Sexual dimorphism in environmental epigenetic programming.Mol Cell Endocrinol. 2009; 304: 8-18
- Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics.Biol Sex Differ. 2013; 4: 5
- Impairment of male reproduction in adult rats exposed to hydroxyprogesterone caproate in utero.Naturwissenschaften. 2004; 91: 242-244
- Gestational exposure to hydroxyprogesterone caproate suppresses reproductive potential in male rats.Naturwissenschaften. 2005; 92: 385-388
- Effect of prenatal exposure to hydroxyprogesterone on steroidogenic enzymes in male rats.Naturwissenschaften. 2003; 90: 40-43
- Alterations in hepatic metabolism of adult male rats following exposure to hydroxyprogesterone during embryonic development.Asian J Androl. 2006; 8: 463-467
- Perinatal sex hormones and risk of breast and prostate cancers in adulthood.Epidemiol Rev. 2000; 22: 239-248
- Development of the human prostate.Differentiation. 2018; 103: 24-45
Article info
Publication history
Published online: November 08, 2021
Accepted:
October 28,
2021
Received in revised form:
October 15,
2021
Received:
July 14,
2021
Footnotes
C.C.M. reports consulting for Freenome. The other authors report no conflict of interest.
This work was supported by the National Cancer Institute at the National Institutes of Health (NIH) under award number R01CA242558 (C.C.M.) and by the National Institute of Child Health and Development at the NIH under contract number HHSN275201100020C (B.A.C.). The sponsor had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
The collection of the cancer data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program under contract number HHSN261201000140C (awarded to the Cancer Prevention Institute of California), contract number HHSN261201000035C (awarded to the University of Southern California), and contract number HHSN261201000034C (awarded to the Public Health Institute); and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement U58DP003862-01 (awarded to the California Department of Public Health).
Cite this article as: Murphy CC, Cirillo PM, Krigbaum NY, et al. In utero exposure to 17α-hydroxyprogesterone caproate and risk of cancer in offspring. Am J Obstet Gynecol 2022;226:132.e1-14.
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