American Journal of Obstetrics and Gynecology, 188(2), 419-424, 2003
Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study
Roberto E Bittar, Mário Henrique Burlacchini de Carvalho, Marcelo Zugaib
The purpose of this study was to evaluate the effect of prophylactic vaginal progesterone in decreasing preterm birth rate in a high-risk population.
Study Design
A randomized, double-blind, placebo-controlled study included 142 high-risk singleton pregnancies. Progesterone (100 mg) or placebo was administered daily by vaginal suppository and all patients underwent uterine contraction monitoring with an external tocodynamometer once a week for 60 minutes, between 24 and 34 weeks of gestation. Progesterone (n = 72) and placebo (n = 70) groups were compared for epidemiologic characteristics, uterine contraction frequency, and incidence of preterm birth. Data were compared by chi(2) analysis and Fisher exact test.
Results
The preterm birth rate was 21.1% (30/142). Differences in uterine activity were found between the progesterone and placebo groups (23.6% vs 54.3%, respectively; P <.05) and in preterm birth between progesterone and placebo (13.8% vs 28.5%, respectively; P <.05). More women were delivered before 34 weeks in the placebo group (18.5%) than in the progesterone group (2.7%) (P <.05).
Conclusion
Prophylactic vaginal progesterone reduced the frequency of uterine contractions and the rate of preterm delivery in women at high risk for prematurity.
PMID 12592250 12592250 DOI 10.1067/mob.2003.41 10.1067/mob.2003.41
Cite this article
da Fonseca, E. B., Bittar, R. E., Carvalho, M. H. B., & Zugaib, M. (2003). Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. American journal of obstetrics and gynecology, 188(2), 419-424. https://doi.org/10.1067/mob.2003.41
da Fonseca EB, Bittar RE, Carvalho MHB, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol. 2003;188(2):419-424. doi:10.1067/mob.2003.41
da Fonseca, Eduardo B., et al. "Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study." American journal of obstetrics and gynecology, vol. 188, no. 2, 2003, pp. 419-424.
To evaluate whether myo-inositol supplementation, an insulin sensitizer, reduces the rate of gestational diabetes mellitus (GDM) and lowers insulin resistance in obese pregnant women. In an open-label, randomized trial, myo-inositol (2 g plus 200 micrograms folic acid twice a day) or placebo (200 micrograms folic acid twice a day) was administered from the first trimester to delivery in pregnant obese women (prepregnancy body mass index 30 or greater. We calculated that 101 women in each arm would be required to demonstrate a 65% GDM reduction in the myo-inositol group with a statistical power of 80% (α=0.05). The primary outcomes were the incidence of GDM and the change in insulin resistance from enrollment until the diagnostic oral glucose tolerance test. From January 2011 to April 2014, 220 pregnant women at 12-13 weeks of gestation were randomized at two Italian university hospitals, 110 to myo-inositol and 110 to placebo. Most characteristics were similar between groups. The GDM rate was significantly reduced in the myo-inositol group compared with the control group, 14.0% compared with 33.6%, respectively (P=.001; odds ratio 0.34, 95% confidence interval 0.17-0.68). Furthermore, women treated with myo-inositol showed a significantly greater reduction in the homeostasis model assessment of insulin resistance compared with the control group, -1.0±3.1 compared with 0.1±1.8 (P=.048). Myo-inositol supplementation, started in the first trimester, in obese pregnant women seems to reduce the incidence in GDM through a reduction of insulin resistance. ClinicalTrials.gov, www.clinicaltrials.gov, NCT01047982.
Although low-dose aspirin has been reported to reduce the incidence of preeclampsia among women at high risk for this complication, its efficacy and safety in healthy, nulliparous pregnant women are not known. We studied 3135 normotensive nulliparous women who were 13 to 26 weeks pregnant to determine whether treatment with aspirin reduced the incidence of preeclampsia. Of this group, 1570 women received 60 mg of aspirin per day and 1565 received placebo for the remainder of their pregnancies. We also evaluated the effect of aspirin on maternal and neonatal morbidity. Of the original group of 3135 women, 2985 (95 percent) were followed throughout pregnancy and the immediate puerperium. The incidence of preeclampsia was lower in the aspirin group (69 of 1485 women [4.6 percent]) than in the placebo group (94 of 1500 women [6.3 percent]) (relative risk, 0.7; 95 percent confidence interval, 0.6 to 1.0; P = 0.05), whereas the incidence of gestational hypertension was 6.7 and 5.9 percent, respectively. There were no significant differences in the infants' birth weight or in the incidence of fetal growth retardation, postpartum hemorrhage, or neonatal bleeding problems between the two groups. Subgroup analysis showed that preeclampsia occurred primarily in women whose initial systolic blood pressure was 120 to 134 mm Hg (incidence among such women, 5.6 percent in the aspirin group vs. 11.9 percent in the placebo group; P = 0.01). The incidence of abruptio placentae was greater among the women who received aspirin (11 women, vs. 2 in the placebo group; P = 0.01). Low-dose aspirin decreases the incidence of preeclampsia among nulliparous women, primarily through its effect in those who have elevated systolic blood pressure initially. This treatment does not decrease perinatal morbidity but increases the risk of abruptio placentae.
EndometriosisAMH and Ovarian ReserveSurgical Staging and TypologyAnti-Müllerian Hormone
Endometriosis is a chronic, gynecologic condition in which tissue similar to the lining of the uterus implants throughout the body. Women with endometriosis have a higher prevalence of infertility and a greater risk of early natural menopause compared to those without endometriosis. This study aimed to evaluate preoperative serum AMH levels among women with and without incident endometriosis and to assess whether levels differ by surgical staging and typology. The ENDO (Endometriosis: Natural History, Diagnosis, and Outcomes) study was conducted between 2007 and 2009. The ENDO study consisted of an operative and population cohort (n=600). Only those in the ENDO operative cohort from the Utah site were used for this analysis, and included women aged 18 to 44 years who were scheduled for gynecologic surgery, irrespective of clinical indication (n=476). AMH levels were measured from stored serum collected before surgery using a quantitative enzyme-linked immunosorbent assay. After excluding participants with missing outcome data (n=51), unilateral oophorectomy (n=8), or those within the population cohort (n=69), 348 participants remained for the analysis. Surgically confirmed endometriosis diagnosis, staging (American Society for Reproductive Medicine I-IV), and typology (superficial, deep, ovarian) were ascertained by the operative report. Outliers for AMH (>14.0 ng/mL) were excluded from the analyses and AMH values were log-transformed. Multivariable linear regression models adjusted for age (squared and continuous), body mass index, serum cotinine levels, and exogenous hormonal contraceptive use were conducted. Percentage differences in AMH were calculated as (exp[β]-1)×100, and 95% confidence intervals were reported. Compared with no endometriosis, incident endometriosis diagnosis was associated with lower AMH levels (-19.8%; 95% confidence interval, -37.0 to 1.0); however, this association was not statistically significant. Stage III to IV disease was associated with 40.1% lower AMH levels (95% confidence interval, -58.9 to -12.7). Ovarian endometriomas were most strongly associated with lower AMH levels (-54.3%; 95% confidence interval, -69.4 to -31.8), with a more pronounced association among those with infertility (-72.6%; 95% confidence interval, -85.4 to -48.5). Deep (-24.1%; 95% confidence interval, -48.2 to 11.0) and superficial (-15.5%; 95% confidence interval, -34.6 to 9.3) endometriosis also showed a trend toward lower AMH levels, but these findings were not statistically significant. Compared with a postoperative diagnosis of a normal pelvis, incident endometriosis was associated with 26.8% lower AMH levels (95% confidence interval, -44.6 to -3.4). Stage III to IV disease was associated with 47.8% lower AMH levels (95% confidence interval, -65.8 to -23.2), and all subtypes of endometriosis were statistically significantly associated with lower levels of AMH compared with a postoperative diagnosis of a normal pelvis (ovarian: -60.8%; 95% confidence interval, -74.4 to -39.9; -34.3%; 95% confidence interval, -56.2 to -1.4; -24.8%; 95% confidence interval, -43.9 to -0.8). Ovarian and moderate to severe (stage III-IV) endometriosis were associated with markedly lower AMH levels compared with no endometriosis. Compared with a postoperative diagnosis of a normal pelvis, incident endometriosis and moderate to severe stages (stage III-IV) were associated with statistically significantly lower AMH levels. Additionally, typology (deep, ovarian, or superficial) was associated with statistically significantly lower AMH levels. However, this association was likely driven by the presence of ovarian endometriomas across all subtypes. These findings are consistent with previous studies and demonstrate that endometriosis lesions themselves, independent of surgical intervention, influence AMH levels.
General OB/GYNUterine Closure TechniqueHysterotomy RepairCesarean Scar Complications
Bujold E et al., 2026·American Journal of Obstetrics and Gynecology
Normal uterine function depends on cyclical regeneration and the capacity to sustain pregnancy. A cesarean incision represents an injury to this remarkable organ. Although the uterus possesses exceptional healing potential, cesarean delivery increases the risk of secondary infertility, pelvic pain, uterine rupture, and abnormal placentation in subsequent pregnancies. The two most important determinants of successful hysterotomy healing after cesarean delivery are the location of the incision and the surgical technique used for closure. The anatomic site of entry-whether the corpus, lower uterine segment, or cervix-defines the tissue composition, vascularity, and contractility at the wound margins, which in turn influence how the scar remodels and withstands subsequent pregnancies. Surgical technique is also important. A robust body of experimental and clinical evidence demonstrates that restoring anatomic integrity by reapproximating uterine layers while excluding the endometrium produces stronger scars and reduces late complications. The rationale for excluding the endometrium is to prevent displacement of endometrial tissue into the myometrium and to avoid mucosal tearing against a foreign body (i.e. suture material), both of which predispose to defective healing. When the endometrium is incorporated, healing is often impaired, leading to niches or isthmoceles, adenomyosis, and endometriosis at the scar site. Over time, these defects have been recognized as contributors to abnormal bleeding, pelvic pain, infertility, uterine rupture, and placenta accreta spectrum disorders. Despite this evidence, single-layer closures that incorporate endometrium became widely adopted because of their speed and simplicity, while their long-term sequels were initially underappreciated. This has prompted renewed scrutiny of closure techniques, including comparisons of single-layer vs double-layer closure, locking vs nonlocking sutures, type of sutures, and the direction of suture. Collectively, the data show that optimal closure respects uterine anatomy, restores the natural alignment of tissues, and achieves hemostasis without compromising perfusion or strangulating tissues. Building on these principles, we herein describe a refined 3-layer closure. The first layer approximates decidua and junctional myometrium while excluding surface endometrium to prevent tissue entrapment and bacterial contamination. The second layer restores anatomic wall integrity by reapproximating the bulk of the myometrium, thereby reinforcing strength and distributing tension across the scar. The third layer reapproximates superficial myometrium and serosa, smoothing the uterine surface and reducing adhesions. This technique is not simply a return to traditional double-layer methods or an extension of single-layer practice, but rather a refinement that integrates lessons from visceral surgery and contemporary obstetric data. Its rationale is to restore anatomy, secure hemostasis without ischemia, and preserve long-term uterine function. While short-term safety appears comparable across closure methods, evidence increasingly indicates that long-term reproductive outcomes depend on how closure respects tissue biology. We argue that appropriate repair is more meticulous restoration of uterine anatomy should take precedence over operative speed. The enduring success of a hysterotomy repair depends on the surgical technique employed, as it directly affects women's future reproductive health.