Is micronized vaginal progesterone effective for the prevention of preeclampsia in twin pregnancies?

OBJECTIVE: There is increasing evidence that hypertensive disorders of pregnancy (HDPs), such as preeclampsia, share common etiologic pathways with preterm labor that center on the dysregulation of inflammatory fl ammatory processes, aberrant placentation, and endothelial dysfunction.1,2 1,2 A substantial imbalance in maternal plasma concentrations of angiogenic placental growth factor and antiangiogenic factors, such as soluble vascular endothelial growth factor receptor-1, in various obstetrical syndromes, including preeclampsia, spontaneous preterm labor with intact membranes, fetal death, perivillous fi brin deposition, and small-for-gestational-age newborns has been identified.3 fi ed. 3 These shared mechanisms suggest a potential therapeutic overlap, providing a rationale for investigating progesterone as a prophylactic intervention in HDPs. Endogenous progesterone is known for its role in maintaining pregnancy by promoting uterine quiescence and has anti-inflammatory fl ammatory properties, which may modulate the inflammatory fl ammatory response implicated in the pathogenesis of HDPs. This is primarily via up-regulating human leukocyte antigen-G expression, which inhibits the host decidual natural killer cells. However, preeclampsia may affect this physiological process of decidualization and limit trophoblastic invasion ability. In an in vitro model, progesterone reduced the activation of inflammatory fl ammatory genes and pathways, including toll-like receptor 4 or nuclear transcription factor K B and NOD-like receptor family pyrin domain containing 1 or NOD-like receptor family pyrin domain containing 3 inflammasomes, fl ammasomes, in monocytes from pregnant women with preeclampsia, highlighting its potential as an immunomo- - dulatory agent.4 4 A recent meta-analysis by Melo et al5 5 has suggested that micronized vaginal progesterone initiated in the fi rst trimester of pregnancy reduced the risk of any HDP by 29% and lowered the risk of preeclampsia by 39% compared with placebo, whereas progesterone commenced in the second or third trimester of pregnancy was not associated with statistically significant fi cant reductions. Although the quantitative meta- analysis included populations of twin pregnancies, a separate subgroup analysis was not provided. The current recommendation for the prevention of preeclampsia is the use of low-dose aspirin.6,7 6,7 It is still debatable whether exogenous progesterone can perform a similar role to endogenous progesterone in promoting the invasion of trophoblast cells by increasing endometrium receptivity.8 8 If it does, it could help reduce the risk of HDPs as poor placentation has been linked with these conditions via spiral artery remodeling. In summary, the relationship between progesterone and its association or causation in preeclampsia remains underexplored, and therefore, our study aimed to explore the hypothesis that micronized vaginal progesterone use in the fi rst trimester of pregnancy is associated with reduced risk of HDPs, including preeclampsia, in twin pregnancies. STUDY DESIGN: This retrospective cohort study included 2056 twin pregnancies managed at St George's ' s University Hospital, a tertiary referral center in the United Kingdom, from January 2000 to November 2023. Pregnancies with fetal structural anomalies, miscarriage or termination, higher-order multifetal pregnancies, or chronic hypertension were excluded (n=256). = 256). The study outcomes were preeclampsia and HDPs, diagnosed according to the International Society for the Study of Hypertension in Pregnancy guideline.9 9 Pregnancy outcomes were compared between the pregnancies receiving progesterone and those that did not. As per National Institute for Health and Care Excellence guidelines, twin pregnancies that have any of the following risk factors-hypertension - hypertension in a previous pregnancy, chronic hypertension, renal disease, autoimmune disorder, diabetes mellitus, nulliparity, maternal age above 40 years, pregnancy interval more than 10 years, body mass index (BMI) of > 35 kg/m2, 2 , or family history of preeclampsia-were - were started on low-dose aspirin.7 7 Hence, further subcategorization of our twin cohort was performed on the basis of the antenatal use of low-dose aspirin. We investigated the association of progesterone use with preeclampsia and HDPs using the Cox proportional hazards model while adjusting for maternal age, BMI, ethnicity, and smoking status. RESULTS: The analysis included 1800 twin pregnancies. The incidence of HDPs and preeclampsia was 10.2% (n=183) = 183) and 5.4% (n=98), = 98), respectively. In the study cohort, 69 patients (3.8%) had progesterone in the fi rst trimester of pregnancy without aspirin, 105 patients (5.8%) had progesterone in the fi rst trimester of pregnancy and aspirin, 1156 patients (64.2%) received aspirin only, and 470 patients (26.1%) did not receive any medication. Nulliparous women (adjusted hazard ratio [aHR], 2.05; 95% confidencefidence interval [CI], 1.31-3.21;- 3.21; P=.002) = .002) and women of African Caribbean ethnicity (aHR, 1.83; 95% CI, 1.02-3.28;- 3.28; P=.043) = .043) had a significantlyficantly higher risk of developing preeclampsia. The incidence rate of preeclampsia was 7% (33/470) for women who were neither on aspirin or progesterone, whereas the incidence rates of preeclampsia in progesterone-only groups and combined aspirin and progesterone use groups were 5.8% (4/69) and 7.6% (8/105), respectively (Figure 1). After adjusting for maternal age, BMI, nulliparity, ethnicity, and smoking status, women with twin pregnancies who received aspirin without progesterone showed a significant fi cant reduction in preeclampsia risk compared with women with twin pregnancies who did not use any medication (4.6% [53/1156] vs 7% [33/470]; aHR, 0.62; 95% CI, 0.40-0.97;- 0.97; P = .036). Progesterone use without aspirin (aHR, 0.83; 95% CI, 0.37-1.83;- 1.83; P = .637) and combined use (aHR, 0.71; 95% CI, 0.25-2.03;- 2.03; P = .527) were both associated with reduced risk of preeclampsia, but the effects did not reach statistical significance fi cance (Figure 2, top figure). No treatment modality showed a significantly fi cantly lower risk of HDPs compared to women not using progesterone or aspirin in the adjusted analyses (hazard ratio: 0.94 for aspirin without progesterone [P=.709], P = .709], 0.85 for aspirin with progesterone [P=.646], P = .646], and 1.04 for progesterone only [P=.907]) P = .907]) (Figure 2, bottom figure). CONCLUSION: Our findings do not support the hypothesis that the use of stand-alone micronized vaginal progesterone or its combination with aspirin is superior to the use of aspirin alone for reducing the risk of HDPs or preeclampsia in twin pregnancies. Our results are limited by their retrospective nature and the possibility of unmeasured and unaccounted confounding in treatment groups.-