Pregnancy & Infant Loss Awareness Month
Benefits of Estradiol to Prevent Miscarriage: A Review of Research
By: Andrew Chambers, DO
Director’s Note: October is the month designated to raise awareness about the significant impact of pregnancy and infant loss on women, couples, families, communities, and medical teams. Our 3-week series on this important topic begins with a retrospective cohort study published by Boyle et al [1] and summarized below by former FACTS elective student, Dr. Andrew Chambers. Published earlier this year, the research explores how restoring serum estradiol levels in pregnancy impacts rates of miscarriage. The series will continue with a case report in which Dr. Boyle applies the principles described below in a clinical setting. Our series concludes with research on a clinically useful grief assessment adapted to identify complicated grief in the setting of reproductive loss. To learn more about Dr. Boyle’s research on miscarriage and other clinical applications of fertility awareness-based methods (FABMs), register for our virtual conference October 18-19, 2024 and/or enroll in our online CME course!
Introduction
The literature has established that lower estrogen levels are associated with increased rates of miscarriage. [2] Lower estrogen levels are also associated with preeclampsia [3] and birth of babies who are small for gestational age. [4] Prior to the study by Boyle et al [1] summarized below, it had not been clearly demonstrated that low estrogen levels in pregnancy represented a deficiency for which supplementation to normal values could result in a clinically significant reduction in rates of pregnancy loss. The retrospective cohort study was designed to determine if supplementation with estrogen or dehydroepiandrosterone (DHEA) could increase estrogen levels and decrease pregnancy loss rates. DHEA was used based on research demonstrating it is a necessary prohormone for estradiol synthesis that can be used to increase estradiol levels. [5]
“Lower estrogen levels are associated with increased rates of miscarriage, … preeclampsia, and birth of babies who are small for gestational age.”
Methodology
The study by Boyle et al [1] was conducted in fertility clinics in Dublin and Galway, Ireland. They studied the clinics’ practice patterns regarding testing and supplementation of estrogen from 2009 to 2017. During the first 6 weeks, they assessed pregnant women’s estrogen levels weekly. Estrogen levels were compared to average estrogen levels for corresponding gestational age as determined by a prior study [6] and to a sample of 104 women from the patient population whose pregnancies resulted in deliveries of healthy babies. From 2009 to 2011, a total of 22 patients with lower estradiol levels were identified, but they were not given supplementation at that time. From 2013 to 2015, a total of 52 women were treated with estradiol if they had <50% of the average estradiol levels. From 2015 to 2017, a total of 40 women were treated with DHEA if they had <50% of the average estradiol levels.
The study used these three cohorts to compare (1) a primary outcome of successful increase in subsequent estradiol levels during pregnancy, (2) rates of miscarriage, and (3) birth weight and gestational age at birth as secondary outcomes. Additionally, there was a 5-7-year follow-up period to ensure children who received supplementation were healthy, particularly regarding signs of abnormal sexual development given their exposure to hormonal supplementation in utero.
Results
Although supplementation with estradiol led to an increase in estradiol levels, this increase was not statistically significant: 32% to 41% (P = 0.14) after 6 weeks. In the DHEA group, however, there was a statistically significant increase in estradiol levels from 33% to 90% (P < 0.0001) after 6 weeks of supplementation with DHEA.
The secondary outcomes revealed a miscarriage rate of 45.5% in the first cohort that did not receive any supplementation. The estradiol supplementation group was associated with a decrease in miscarriage rate at 21.2% (P = 0.067). The DHEA group had a statistically significant association with a decreased miscarriage rate of 17.5% (P = 0.038). There were no sexual deformities or side effects seen at birth or at 5-7 year follow up.
Discussion
The data produced from this study reveal multiple statistically significant associations which have clinical implications in the field of reproductive medicine. Specifically, this study is the first which explores an intervention for the previously established association between low estradiol levels in pregnancy and pregnancy loss. The data from this study showed that in patients with less than 50% of the average estrogen level per gestational age, a significant increase in estradiol levels with DHEA supplementation was associated with a decreased rate of miscarriage compared to patients who did not receive supplementation. Interestingly, there was not a statistically significant increase in estradiol levels with supplementation; serum estradiol levels were more responsive to DHEA supplementation.
“The data from this study showed that in patients with less than 50% of the average estrogen level per gestational age, a significant increase in estradiol levels with DHEA supplementation was associated with a decreased rate of miscarriage compared to patients who did not receive supplementation.”
Limitations of this study include its retrospective cohort design, though the nature of this topic makes it exceedingly difficult to orchestrate a randomized clinical trial. Additionally, the sample size was low in each group (22, 52, and 40), but this suggests these associations are strong, as they were able to demonstrate statistically significant differences despite small samples. Also, the fact that the three groups were not contemporaneous causes a degree of synergy due to changes in the protocols at the fertility clinic during that time. Specifically, during the DHEA supplementation period, more of the study participants were taking aspirin, selenium, naltrexone, and prednisolone. The study did note the odds ratios for miscarriage were similar when analysis accounted for naltrexone and prednisolone use, but the results were no longer statistically significant.
A final interesting question this study raises is its generalizability to the population of pregnant women. In low-risk women with no abnormal obstetric history, it is not currently standard of care to check estradiol levels or monitor them weekly for 6 weeks. Initiating this protocol in all pregnant women as a screening tool to prevent miscarriages would likely be burdensome to patients and clinics and not cost effective. Yet, the data from this study suggest that if we are able to identify the subset of patients with lower estrogen levels compared to averages at the same gestational age, there could be a meaningful opportunity to intervene and reduce the likelihood of a serious negative outcome for these patients and their families.
“[This study suggests] that if we are able to identify the subset of patients with lower estrogen levels compared to averages at the same gestational age, there could be a meaningful opportunity to intervene and reduce the likelihood of a serious negative outcome for these patients and their families.”
References
[1] Boyle, Phil, et al. “Restoration of serum estradiol and reduced incidence of miscarriage in patients with low serum estradiol during pregnancy: A retrospective cohort study using a multifactorial protocol including DHEA.” Frontiers in Reproductive Health, vol. 5, 4 Jan. 2024, https://doi.org/10.3389/frph.2023.1321284
[2] Simpson E, Santen RJ. Celebrating 75 years of oestradiol. J Mol Endocrinol. (2015) 55(3): T1–20. doi: 10.1530/JME-15-0128
[3] Wan J, Hu Z, Zeng K, Yin Y, Zhao M, Chen M, et al. The reduction in circulating levels of estrogen and progesterone in women with preeclampsia. Pregnancy Hypertens. (2018) 11:18–25. doi: 10.1016/j.preghy.2017.12.003
[4] Salas SP, Marshall G, Gutierrez BL, Rosso P. Time course of maternal plasma volume and hormonal changes in women with preeclampsia or fetal growth restriction. Hypertension. (2006) 47(2):203–8. doi: 10.1161/01.HYP.0000200042.64517.19
[5] Zhu Y, Qiu L, Jiang F, Găman MA, Abudoraehem OS, Okunade KS, et al. The effect of dehydroepiandrosterone (DHEA) supplementation on estradiol levels in women: a dose-response and meta-analysis of randomized clinical trials. Steroids. (2021) 173:108889. doi: 10.1016/j.steroids.2021.108889
[6] Check JH, Lurie D, Davies E, Vetter B. Comparison of first trimester serum estradiol levels in aborters versus nonaborters during maintenance of normal progesterone levels. Gynecol Obstet Invest. (1992) 34(4):206–10. doi: 10.1159/000292762
ABOUT THE AUTHOR
Andrew Chambers, DO
Dr. Andrew Chambers is a family medicine resident at Trinity Health Livingston Family Medicine Residency in Brighton, Michigan. He has a special interest in fertility awareness-based methods (FABMs). Dr. Chambers participated in the FACTS elective as a resident to gain additional knowledge and experience about FABMs and intends to pursue further training to be a medical consultant. He appreciates the cooperative nature of FABMs with natural and healthy human physiology and is passionate about educating residents and other physicians about their efficacy and benefits.