Prematurity Awareness Month
Progesterone Effects on Preterm Birth in the Setting of Short Cervix: A Review of Research
By: Christy Chan, MD
Director’s Note: While multiple factors contribute to the incidence of preterm birth in the general population, screening for risk factors can be challenging among women with no history of preterm delivery. Through her summary of research by Hassan et al [4] former FACTS elective student, Dr. Christy Chan, offers encouragement about this topic during Prematurity Awareness Month. The promising study published in Ultrasound in Obstetrics & Gynecology addresses the association between the length of the mother’s cervix and preterm birth. It also provides evidence for the effectiveness of vaginal progesterone to reduce the rate of preterm birth and improve neonatal outcomes.
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Introduction
Preterm birth, defined as delivery that occurs between 20 and 37 weeks of gestation, is the leading cause of perinatal morbidity and mortality, with an estimated 13.4 million babies worldwide born preterm in 2020. [1] Complications from preterm birth were responsible for approximately 900,000 deaths in 2019. [2] Whereas a sonographic short cervical length is a strong indicator of preterm delivery, the American College of Obstetricians and Gynecologists (ACOG) currently recommends cervical length screening for individuals with a singleton pregnancy and a prior spontaneous preterm birth. [3] Given the low risk of preterm birth in individuals with a singleton pregnancy and no history of spontaneous preterm delivery, it is difficult to demonstrate the advantages of universal cervical length screening. The study by Hassan et al summarized below explores the effectiveness and safety of vaginal progesterone gel to reduce preterm birth rates before 33 weeks in asymptomatic women — with or without prior preterm birth — diagnosed with a mid-trimester sonographic short cervix. [4]
Progesterone is not only an essential hormone in menstrual cycle regulation and cognitive function, but it also plays a vital role to maintain pregnancy. Produced by the corpus luteum after ovulation, progesterone facilitates the transition from the proliferative to the secretory phase. [6] During pregnancy, the syncytiotrophoblastic cells of the placenta produce human chorionic gonadotropin (hCG), signaling to the corpus luteum to continue producing progesterone. [7] In a healthy pregnancy, the corpus luteum releases progesterone until about 12 weeks, when the placenta takes over to produce adequate amounts to sustain the pregnancy. By preventing premature uterine contractions and regulating the immune response to protect the fetus from rejection, progesterone is essential for a pregnancy to progress successfully.
“Progesterone is not only an essential hormone in menstrual cycle regulation and cognitive function, but it also plays a vital role to maintain pregnancy, … preventing premature uterine contractions and regulating the immune response to protect the fetus from rejection.”
Methodology
The study was a Phase-III, prospective, randomized, placebo-controlled, double-masked, parallel-group, multicenter international trial conducted from March 2008 to November 2010. Women between 19+0 and 23+6 weeks of gestation were eligible for study screening and assessed for cervical length and gestational age (calculated by the participant’s reported last menstrual period and fetal biometry). Inclusion criteria for the study were: (1) singleton gestation, (2) gestational age between 19+0 and 23+6 weeks, (3) transvaginal sonographic cervical length between 10 and 20 mm, and (4) asymptomatic, without signs or symptoms of preterm labor. Participants were randomly assigned to receive vaginal progesterone gel or placebo starting at 20 to 23+6 weeks of gestation. Participant drug kits were numbered independently from treatment assignments and confirmed to have identical appearance as the study drug packaging and contents to maintain allocation concealment.
The primary outcome of the study was preterm birth before 33 weeks of gestation. The secondary outcomes were neonatal complications.
Results
Out of 32,091 women who had cervical length measured between 19+0 and 23+6 weeks of gestation, 2.3% (733/32,091) had a cervical length of 10–20 mm. A total of 465 women agreed to participate and were randomized, with 7 lost to follow-up (vaginal progesterone gel, n=1; placebo, n=6). The intention-to-treat analysis set included 458 women (vaginal progesterone gel, n=235; placebo, n=223), with no significant differences in baseline characteristics or drug adherence between the groups.
Patients who received vaginal progesterone gel had a significantly lower rate of preterm birth before 33 weeks of gestation compared to those who received a placebo (8.9% vs. 16.1%). In women without a history of preterm birth, the administration of vaginal progesterone gel led to a significant reduction in the rate of preterm birth before 33 weeks (7.6% vs. 15.3%). On the other hand, the reduced preterm birth rate was not statistically significant in women with a prior history of preterm birth between 20 and 35 weeks of gestation.
“In women without a history of preterm birth, the administration of vaginal progesterone gel led to a significant reduction in the rate of preterm birth before 33 weeks (7.6% vs. 15.3%).”
Vaginal progesterone gel was also associated with a significant reduction in the rate of preterm birth before 35 weeks (14.5% vs. 23.3%) and before 28 weeks of gestation (5.1% vs. 10.3%). In addition, infants born to women who received vaginal progesterone gel had a lower incidence of respiratory distress syndrome (RDS) compared to those born to women who received a placebo (3.0% vs. 7.6%).
Discussion
Preterm birth is associated with neonatal morbidity, including RDS, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and sepsis. [5] Prioritizing the prevention of preterm birth is imperative to avoid such complications and improve infant outcomes.
For low-risk pregnancies, women with a cervical length below 25 mm (10th percentile) at 24 weeks face a six-fold higher likelihood of a spontaneous preterm birth before 35 weeks compared to those with measurements surpassing 40 mm (75th percentile). [8] This study demonstrates that using transvaginal sonographic cervical length to identify such at-risk patients and administering vaginal progesterone gel from mid second trimester until term can decrease preterm birth rates before 33 weeks and reduce RDS in preterm infants. Vaginal progesterone gel shows additional benefits, including decreased rates of low-birth-weight infants (<1500 g), reduced infant morbidity and mortality rates, and improved neonatal outcomes based on composite scores. Vaginal progesterone gel is well tolerated, with adherence rates exceeding 90%.
“This study demonstrates that using transvaginal sonographic cervical length to identify … at-risk patients and administering vaginal progesterone gel from mid second trimester until term can decrease preterm birth rates before 33 weeks and reduce respiratory distress syndrome in preterm infants.”
This study’s strengths lie in its design as a multicenter, placebo-controlled, double-masked, randomized trial, ensuring treatment allocation and concealment. A sensitivity analysis within the intention-to-treat analysis set reinforced the significant positive impact of vaginal progesterone to reduce preterm births before 33 weeks of gestation, even when considering the worst-case scenario. The multinational representation among participants with substantial diversity across ethnic groups added to the study’s broader applicability.
A notable limitation of the study is the use of a surrogate endpoint (preterm birth before 33 weeks of gestation) for infant outcomes, as the primary endpoint may not directly translate to infant wellbeing. Additionally, the study was not powered to detect variations in outcomes based on different risk factors, such as a history of preterm birth.
Further research is needed to determine the efficacy of early second-trimester treatment in women with a short cervix to reduce preterm delivery rates. Inclusion criteria for this trial specified a short cervix identified between 19+0 and 23+6 weeks of gestation. Moreover, this study focused solely on singleton pregnancies, emphasizing the need to explore the benefits of vaginal progesterone for twin pregnancies with a short cervix. Study participants were limited to those with cervix length between 10 and 20 mm, given the management challenges associated with cervical length below 10 mm; further research is needed in this area. Additionally, investigating the interaction between vaginal progesterone and cerclage effectiveness is crucial to enhance treatment approaches.
This study by Hassan et al supports universal sonographic cervical length screening of women in the mid-trimester to identify patients at risk, as the use of vaginal progesterone gel in these women can significantly reduce preterm birth rates and improve neonatal outcomes. A cost-effectiveness analysis should be conducted before implementing this universal risk assessment. Other questions remain, including the ideal time to start screening as well as benefits and potential drawbacks of monitoring cervical length throughout pregnancy. Assessing the benefits of screening once versus at intervals is also important, and determining the cost-effectiveness of periodic screening is an additional consideration. As a future obstetrician considering the findings of this study, I am more inclined to propose sonographic cervical length screening for all first-time mothers rather than multiparous women with no history of preterm birth.
References
[1] Ohuma EO, Moller AB, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, Okwaraji YB, Mahanani WR, Johansson EW, Lavin T, Fernandez DE. National, regional, and worldwide estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023;402(10409):1261-1271. doi:10.1016/S0140-6736(23)00878-4
[2] Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, Prieto-Merino D, Cousens S, Black RE, Liu L. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health 2022;6(2):106-15. doi:10.1016/S2352-4642(21)00311-4
[3] Committee on Practice Bulletins—Obstetrics, the American College of Obstetricians and Gynecologists. Practice bulletin No. 234: Prediction and prevention of spontaneous preterm birth. Obstet. Gynecol. 2021;138(2):e65-e90. doi:10.1097/AOG.0000000000004479
[4] Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O’Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW. PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38(1):18-31. doi: 10.1002/uog.9017
[5] Cleveland Clinic. Premature birth (https://my.clevelandclinic.org/health/diseases/21479-premature-birth). Accessed 2/25/2024.
[6] Taraborrelli S. Physiology, production and action of progesterone. Acta obstetricia et gynecologica Scandinavica. 2015;94:8-16. doi: 10.1111/aogs.12771
[7] Betz D, Fane K. Human Chorionic Gonadotropin. [Updated 2023 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532950/
[8] Lee HJ, Park TC, Norwitz ER. Management of pregnancies with cervical shortening: a very short cervix is a very big problem. Reviews in Obstetrics and Gynecology. 2009;2(2):107. PMID: 19609405; PMCID: PMC2709324
ABOUT THE AUTHOR
Christy Chan, MD
Christy Chan, MD is a first-year resident in obstetrics and gynecology at the Renaissance School of Medicine at Stony Brook University in Stony Brook, NY. She graduated from the Renaissance School of Medicine and completed undergraduate education at Trinity College in Hartford, CT. Dr. Chan has a special interest in reproductive justice and advocacy. She enrolled in the FACTS elective to learn more about fertility awareness-based methods, understanding their potential to empower patients and enhance patient care.
