Download PDF
Am J Perinatol 2023; 40(11): 1158-1162
DOI: 10.1055/a-2081-2573
SMFM Fellowship Series Article

Vaginal Progesterone Is Associated with Intrahepatic Cholestasis of Pregnancy

Abraham Tsur 
1   Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
2   Department of Obstetrics and Gynecology, The Sheba Medical Center, Tel HaShomer, Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
,
Stephanie A. Leonard 
1   Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
,
Peiyi Kan
1   Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
,
Imee A. Datoc
1   Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
,
Anna I. Girsen
1   Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
,
Gary M. Shaw
3   Department of Pediatrics, Stanford University School of Medicine, Stanford, California
,
David K. Stevenson
3   Department of Pediatrics, Stanford University School of Medicine, Stanford, California
,
Yasser Y. El-Sayed
1   Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
,
Maurice L. Druzin
1   Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
,
Yair J. Blumenfeld
1   Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Objective The frequency of intrahepatic cholestasis of pregnancy (ICP) peaks during the third trimester of pregnancy when plasma progesterone levels are the highest. Furthermore, twin pregnancies are characterized by higher progesterone levels than singletons and have a higher frequency of cholestasis. Therefore, we hypothesized that exogenous progestogens administered for reducing the risk of spontaneous preterm birth may increase the risk of cholestasis. Utilizing the large IBM MarketScan Commercial Claims and Encounters Database, we investigated the frequency of cholestasis in patients treated with vaginal progesterone or intramuscular 17α-hydroxyprogesterone caproate for the prevention of preterm birth.

Study Design We identified 1,776,092 live-born singleton pregnancies between 2010 and 2014. We confirmed second and third trimester administration of progestogens by cross-referencing the dates of progesterone prescriptions with the dates of scheduled pregnancy events such as nuchal translucency scan, fetal anatomy scan, glucose challenge test, and Tdap vaccination. We excluded pregnancies with missing data regarding timing of scheduled pregnancy events or progesterone treatment prescribed only during the first trimester. Cholestasis of pregnancy was identified based on prescriptions for ursodeoxycholic acid. We used multivariable logistic regression to estimate adjusted (for maternal age) odds ratios for cholestasis in patients treated with vaginal progesterone, and in patients treated with 17α-hydroxyprogesterone caproate compared with those not treated with any type of progestogen (the reference group).

Results The final cohort consisted of 870,599 pregnancies. Among patients treated with vaginal progesterone during the second and third trimester, the frequency of cholestasis was significantly higher than the reference group (0.75 vs. 0.23%, adjusted odds ratio [aOR]: 3.16, 95% confidence interval [CI]: 2.23–4.49). In contrast, there was no significant association between 17α-hydroxyprogesterone caproate and cholestasis (0.27%, aOR: 1.12, 95% CI: 0.58–2.16)

Conclusion Using a robust dataset, we observed that vaginal progesterone but not intramuscular 17α-hydroxyprogesterone caproate was associated with an increased risk for ICP.

Key Points

  • Previous studies have been underpowered to detect potential association between progesterone and ICP.

  • Vaginal progesterone was significantly associated with ICP.

  • Intramuscular 17α-hydroxyprogesterone was not associated with ICP.

Keywords

preterm birth - 17α-hydroxyprogesterone caproate - micronized progesterone - claims


Publication History

Received: 20 June 2022

Accepted: 24 April 2023

Accepted Manuscript online:
26 April 2023

Article published online:
31 May 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Wikström Shemer E, Marschall HU, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 2013; 120 (06) 717-723
    CrossrefPubMedSearch in Google Scholar
  • 2 Lee RH, Mara Greenberg Metz TD, Pettker CM. Society for Maternal-Fetal Medicine (SMFM). Electronic address: pubs@smfm.org. Society for Maternal-Fetal Medicine Consult Series #53: intrahepatic cholestasis of pregnancy: replaces Consult #13, April 2011. Am J Obstet Gynecol 2021; 224 (02) B2-B9
    CrossrefPubMedSearch in Google Scholar
  • 3 Batra S, Sjöberg NO, Aberg A. Human placental lactogen, estradiol-17beta, and progesterone levels in the third trimester and their respective values for detecting twin pregnancy. Am J Obstet Gynecol 1978; 131 (01) 69-72
    CrossrefPubMedSearch in Google Scholar
  • 4 Abu-Hayyeh S, Papacleovoulou G, Lövgren-Sandblom A. et al. Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. Hepatology 2013; 57 (02) 716-726
    CrossrefPubMedSearch in Google Scholar
  • 5 Vallejo M, Briz O, Serrano MA, Monte MJ, Marin JJ. Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol 2006; 44 (06) 1150-1157
    CrossrefPubMedSearch in Google Scholar
  • 6 Romero R, Conde-Agudelo A, Da Fonseca E. et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol 2018; 218 (02) 161-180
    CrossrefPubMedSearch in Google Scholar
  • 7 Meis PJ, Klebanoff M, Thom E. et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348 (24) 2379-2385
    CrossrefPubMedSearch in Google Scholar
  • 8 Blackwell SC, Gyamfi-Bannerman C, Biggio Jr. JR. et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): a multicenter, international, randomized double-blind trial. Am J Perinatol 2020; 37 (02) 127-136
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Society for Maternal-Fetal Medicine (SMFM) Publications Committee. SMFM statement: use of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth. Am J Obstet Gynecol 2020; 223 (01) B16-B18
    CrossrefPubMedSearch in Google Scholar
  • 10 Romero R, Stanczyk FZ. Progesterone is not the same as 17α-hydroxyprogesterone caproate: implications for obstetrical practice. Am J Obstet Gynecol 2013; 208 (06) 421-426
    CrossrefPubMedSearch in Google Scholar
  • 11 Dormuth CR, Winquist B, Fisher A. et al; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Comparison of pregnancy outcomes of patients treated with ondansetron vs alternative antiemetic medications in a multinational, population-based cohort. JAMA Netw Open 2021; 4 (04) e215329
    CrossrefPubMedSearch in Google Scholar
  • 12 Schuster M, Ananth CV, Gomez D. et al. 17-alpha hydroxyprogesterone caproate and risk for venous thromboembolism during pregnancy. J Matern Fetal Neonatal Med 2022; 35 (25) 6336-6337
    CrossrefPubMedSearch in Google Scholar
  • 13 Venkatesh KK, Chiang CW, Castillo WC. et al. Changing patterns in medication prescription for gestational diabetes during a time of guideline change in the USA: a cross-sectional study. BJOG 2021; 129 (03) 473-483
    CrossrefPubMedSearch in Google Scholar
  • 14 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371 (9606): 75-84
    CrossrefPubMedSearch in Google Scholar
  • 15 American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. Prediction and prevention of spontaneous preterm birth: ACOG Practice Bulletin, Number 234. Obstet Gynecol 2021; 138 (02) e65-e90
    CrossrefPubMedSearch in Google Scholar
  • 16 Serra V, Perales A, Meseguer J. et al. Increased doses of vaginal progesterone for the prevention of preterm birth in twin pregnancies: a randomised controlled double-blind multicentre trial. BJOG 2013; 120 (01) 50-57
    CrossrefPubMedSearch in Google Scholar
  • 17 El-Refaie W, Abdelhafez MS, Badawy A. Vaginal progesterone for prevention of preterm labor in asymptomatic twin pregnancies with sonographic short cervix: a randomized clinical trial of efficacy and safety. Arch Gynecol Obstet 2016; 293 (01) 61-67
    CrossrefPubMedSearch in Google Scholar
  • 18 Group E. EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet 2021; 397 (10280): 1183-1194
    CrossrefPubMedSearch in Google Scholar
  • 19 Zipori Y, Bachar G, Farago N. et al. Vaginal progesterone treatment for the prevention of preterm birth and intrahepatic cholestasis of pregnancy: a case-control study. Eur J Obstet Gynecol Reprod Biol 2020; 253: 117-120
    CrossrefPubMedSearch in Google Scholar
  • 20 Liu L, Oza S, Hogan D. et al. Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet 2015; 385 (9966): 430-440
    CrossrefPubMedSearch in Google Scholar
  • 21 Boelig RC, Schoen CN, Frey H. et al. Vaginal progesterone vs intramuscular 17-hydroxyprogesterone caproate for prevention of recurrent preterm birth: a randomized controlled trial. Am J Obstet Gynecol 2022; 226 (05) 722.e1-722.e12
    CrossrefPubMedSearch in Google Scholar
  • 22 Florey RC. Hydroxyprogesterone caproate. Analytical Profiles of Drug Substances. Academic Press; 1975: 208-224
    Search in Google Scholar
  • 23 Attardi BJ, Zeleznik A, Simhan H, Chiao JP, Mattison DR, Caritis SN. Obstetric-Fetal Pharmacology Research Unit Network. Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins. Am J Obstet Gynecol 2007; 197 (06) 599.e1-599.e7
    CrossrefPubMedSearch in Google Scholar
  • 24 Beardon PH, McGilchrist MM, McKendrick AD, McDevitt DG, MacDonald TM. Primary non-compliance with prescribed medication in primary care. BMJ 1993; 307 (6908): 846-848
    CrossrefPubMedSearch in Google Scholar