Introduction
Preterm birth is a birth that occurs before 37 weeks, or 259 days, of gestation. It complicates 9 to 12 percent of births worldwide and is the main contributor to infant morbidity and mortality. The occurrence of spontaneous preterm labor is a common cause of preterm birth. Since tocolysis (a procedure used to delay delivery in preterm contractions using medications) has largely failed to delay delivery in patients with spontaneous preterm labor, attention has turned to preventive measures like progesterone supplementation. Although progesterone supplementation may help some high-risk patients avoid spontaneous preterm labor and delivery, it is not a complete remedy.
As per research work, in women with a history of spontaneous preterm birth who received progesterone prophylaxis, it has been estimated that spontaneous preterm birth would be reduced by no more than 20 percent, and the absolute preterm birth rate would be reduced by no more than 0.01 percent because the majority of spontaneous preterm births are not recurrences. Considering efficacy, an additional 0.02 percent reduction in risk would be achieved if patients with a short cervix were also identified and treated.
What Is the Rationale Behind Using Progesterone Supplementation?
The idea behind progesterone supplementation is that, since endogenous progesterone assists in maintaining pregnancy in several ways, exogenous progesterone supplementation may strengthen these effects. Effects of progesterone during pregnancy include:
- Progesterone production in the corpus luteum is essential for preserving the pregnancy until the placenta takes over at seven to nine weeks of gestation. Abortion can be easily induced before seven weeks (49 days) of gestation by removing the corpus luteum or giving a progesterone receptor antagonist.
- Uterine inactivity is maintained by placental progesterone production. With no change in serum progesterone levels in the weeks before labor, functional withdrawal of progesterone activity at the uterus level seems to take place right before the start of labor in both term and preterm infants.
- Preterm labor and delivery are prevented by progesterone-related immune modulation that works to inhibit pro-inflammatory pathways that are both systemic and intrinsic to the uterus.
Who Are the Best Candidates for Vaginal Progesterone Supplementation?
Vaginal progesterone supplementation is most effective and seems to lower the rate of spontaneous preterm birth in patients carrying singletons, particularly in those with a history of spontaneous preterm birth and cervical shortening (defined as 25 millimeters at 16 to 24 weeks). According to a study, in patients who received vaginal progesterone, the risk of preterm birth, mainly birth occurring before 34 weeks of gestation, was reduced by 20 percent. It has also been found that neonatal mortality and neonatal morbidity risks decreased. These risks included neonatal intensive care unit admission, respiratory distress syndrome, respiratory support, necrotizing enterocolitis, severe intraventricular hemorrhage, and retinopathy of prematurity. However, the exact relationship between vaginal progesterone supplementation and its effect on neonatal health has not been established.
What Are the Cases Where the Role of Progesterone Supplementation Is Unclear?
- Twin Pregnancy With No Prior Preterm Labor and Normal Cervix- In unselected multiple gestations, vaginal progesterone supplementation or even progesterone therapy is ineffective in reducing spontaneous preterm birth. One explanation could be that twin pregnancies may be less affected by changes in progesterone levels because the pathogenesis of preterm labor and delivery in multiple gestations may be different from that in singleton gestations (for example, increased uterine distention is more common in twins than in singletons and their endogenous progesterone levels are even higher than in singletons).
- Twin Pregnancy With Short Cervix- The data regarding it is insufficient however, as per the existing trials, it is concluded that compared to no treatment or a placebo, vaginal progesterone decreased preterm birth with less than 33 weeks of gestation.
- Twin Pregnancy With Prior Singleton Preterm Birth- An independent and additional risk factor for twin preterm birth is a previous spontaneous preterm birth of a singleton. Providing progesterone in such situations has not shown any significant changes or improvement and hence its use is disregarded in such cases.
- Singleton Pregnancy With Previous Preterm Birth of the Twins- Patients who previously experienced a spontaneous twin preterm birth are more likely to experience a singleton preterm birth in the future. No trial has specifically assessed the effectiveness of progesterone supplementation in patients with a singleton pregnancy and a prior spontaneous twin preterm birth. Hence, the role of vaginal progesterone in such cases is debatable.
- Positive Fetal Fibronectin Test- A positive cervicovaginal fetal fibronectin test indicates a major risk element for spontaneous preterm birth. However, little information is available on the use of progesterone supplementation in spontaneous preterm birth in such cases.
- Anomaly of the Uterus or Assisted Reproduction Techniques- Preterm birth appears to be more likely in some uterine anomaly patients and those who conceive using assisted reproductive technology. It is unknown whether vaginal progesterone therapy for these patients will prevent spontaneous preterm birth.
What Are the Adverse Effects of Vaginal Progesterone Supplementation?
- Possibility of Getting Gestational Diabetes- Progesterone has been linked to both diabetogenic and antidiabetogenic effects, but it is unclear how they collectively affect a pregnancy's risk of developing gestational diabetes.
- Potential for Venous Thrombosis- Since estrogen-progestin contraceptives are linked to an increased risk of venous thrombosis, the US Food and Drug Administration believes there is insufficient data to determine whether specific progesterone preparations or progestins used alone are also linked to an increased risk.
- Potential Long-Term Harm to Child’s Development- Children between the ages of six months and eight years who were exposed to progesterone during the second or third trimester of pregnancy did not have an increased risk of impaired neurodevelopment, according to studies. Sexual orientation, pubertal development, and mental health were not assessed.
Conclusion
It is also crucial to consider the specific pathogenic pathway that causes spontaneous preterm birth. A single intervention, such as progesterone supplementation, is unlikely to help all patients at risk or have the same level of risk reduction in all patient populations because spontaneous preterm birth is the final common pathway of several pathogenic processes, many of which involve a reduction in the expression or activity of the progesterone receptor. According to in vitro and animal studies, the formulation, dosage, route of administration, and plasma concentration (which differs among progestin-taking patients) all affect the effectiveness of vaginal progesterone supplementation. As per studies, vaginal progesterone therapy is most effective in patients with a singleton pregnancy, a small cervix, and a history of spontaneous preterm birth. In singleton pregnancies with a mid-trimester sonographic short cervix, vaginal progesterone reduces the risk of preterm birth and improves perinatal outcomes without any discernible negative effects on childhood neurodevelopment.
