Progestogens for the prevention of preterm birth and risk of developing gestational diabetes mellitus: a meta-analysis.

BACKGROUND: Several articles have implied that progestogen supplementation during pregnancy to reduce the risk of preterm birth may increase the risk for developing gestational diabetes mellitus. OBJECTIVE: The purpose of the present meta-analysis was to accumulate existing evidence concerning this correlation. DATA SOURCES: We searched Medline (1966-2019), Scopus (2004-2019), Clinicaltrials.gov (2008-2019), EMBASE (1980-2019), Cochrane Central Register of Controlled Trials CENTRAL (1999-2019), and Google Scholar (2004-2019) databases. STUDY ELIGIBILITY CRITERIA: Randomized trials and observational studies were considered eligible for inclusion in the present meta-analysis. To minimize the possibility of article losses, we avoided language, country, and date restrictions. STUDY APPRAISAL AND SYNTHESIS METHODS: The methodological quality of included studies was evaluated with the Cochrane risk of bias and the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool. Meta-analysis was performed with the RevMan 5.3 and secondary analysis with the Open Meta-Analyst software. Trial sequential analysis was conducted with the trial sequential analysis program. RESULTS: Overall, 11 studies were included in the present meta-analysis that recruited 8085 women. The meta-analysis revealed that women who received 17-alpha hydroxyprogesterone caproate had increased the risk of developing gestational diabetes mellitus (risk ratio, 1.73, 95% confidence interval, 1.32-2.28), whereas women who received vaginal progesterone had a decreased risk, although the effect did not reach statistical significance because of the unstable estimate of confidence intervals (risk ratio, 0.82, 95% confidence interval, 0.50-1.12). Meta-regression analysis indicated that neither the methodological rationale for investigating the prevalence of gestational diabetes mellitus (incidence investigated as primary or secondary outcome) (coefficient of covariance, -0.36, 95% confidence interval, -0.85 to 0.13, P = .154) nor the type of investigated study (randomized controlled trial/observational) (coefficient of covariance -0.361, 95% confidence interval, -1.049 to 0.327, P = .304) significantly altered the results of the primary analysis. Trial sequential analysis suggested that the meta-analysis concerning the correlation of 17-alpha hydroxyprogesterone caproate was of adequate power to reach firm conclusions, whereas this was not confirmed in the case of vaginal progesterone. CONCLUSION: The results of the present meta-analysis clearly indicate that women who receive supplemental 17-alpha hydroxyprogesterone caproate for the prevention of preterm birth have an increased risk of developing gestational diabetes mellitus. On the other hand, evidence concerning women treated with vaginal progesterone remains inconclusive.

Exposure to the Synthetic Progestin, 17α-Hydroxyprogesterone Caproate During Development Impairs Cognitive Flexibility in Adulthood.

The synthetic progestin, 17α-hydroxyprogesterone caproate, is increasingly used for the prevention of premature birth in at-risk women, despite little understanding of the potential effects on the developing brain. Rodent models suggest that many regions of the developing brain are sensitive to progestins, including the mesocortical dopamine pathway, a neural circuit important for complex cognitive behaviors later in life. Nuclear progesterone receptor is expressed during perinatal development in dopaminergic cells of the ventral tegmental area that project to the medial prefrontal cortex. Progesterone receptor is also expressed in the subplate and in pyramidal cell layers II/III of medial prefrontal cortex during periods of dopaminergic synaptogenesis. In the present study, exposure to 17α-hydroxyprogesterone caproate during development of the mesocortical dopamine pathway in rats altered dopaminergic innervation of the prelimbic prefrontal cortex and impaired cognitive flexibility with increased perseveration later in life, perhaps to a greater extent in males. These studies provide evidence for developmental neurobehavioral effects of a drug in widespread clinical use and highlight the need for a reevaluation of the benefits and potential outcomes of prophylactic progestin administration for the prevention of premature delivery.

[Progesterone and preterm delivery: back to the future?]. / Progestérone et prévention de l'accouchement prématuré: retour vers le future?

Progesterone was widely used in France during the 1980s and 1990s to prevent preterm birth until some published cases of cholestasis suddenly stopped its prescription. Since then, multiple randomized controlled trials have emerged and demonstrated the efficiency of the treatment but also its safety at low doses. In order to clarify its indications, we performed a current literature review. We analyzed literature data according to different categories of risk and different routes of administration. Results confirm that progesterone is an efficient treatment to prevent preterm birth in singleton gestation with short cervical length, and in singleton gestation with prior preterm birth with or without short cervical length. Apart from these indications, progesterone, especially 17-alpha-hydroxyprogesterone (17OHP), should not be used outside research protocols.

Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth.

BACKGROUND: Preterm birth is a major complication of pregnancy associated with perinatal mortality and morbidity. Progesterone for the prevention of preterm labour has been advocated. OBJECTIVES: To assess the benefits and harms of progesterone for the prevention of preterm birth for women considered to be at increased risk of preterm birth and their infants. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (14 January 2013) and reviewed the reference list of all articles. SELECTION CRITERIA: Randomised controlled trials, in which progesterone was given for preventing preterm birth. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated trials for methodological quality and extracted data. MAIN RESULTS: Thirty-six randomised controlled trials (8523 women and 12,515 infants) were included. Progesterone versus placebo for women with a past history of spontaneous preterm birth Progesterone was associated with a statistically significant reduction in the risk of perinatal mortality (six studies; 1453 women; risk ratio (RR) 0.50, 95% confidence interval (CI) 0.33 to 0.75), preterm birth less than 34 weeks (five studies; 602 women; average RR 0.31, 95% CI 0.14 to 0.69), infant birthweight less than 2500 g (four studies; 692 infants; RR 0.58, 95% CI 0.42 to 0.79), use of assisted ventilation (three studies; 633 women; RR 0.40, 95% CI 0.18 to 0.90), necrotising enterocolitis (three studies; 1170 women; RR 0.30, 95% CI 0.10 to 0.89), neonatal death (six studies; 1453 women; RR 0.45, 95% CI 0.27 to 0.76), admission to neonatal intensive care unit (three studies; 389 women; RR 0.24, 95% CI 0.14 to 0.40), preterm birth less than 37 weeks (10 studies; 1750 women; average RR 0.55, 95% CI 0.42 to 0.74) and a statistically significant increase in pregnancy prolongation in weeks (one study; 148 women; mean difference (MD) 4.47, 95% CI 2.15 to 6.79). No differential effects in terms of route of administration, time of commencing therapy and dose of progesterone were observed for the majority of outcomes examined. Progesterone versus placebo for women with a short cervix identified on ultrasound Progesterone was associated with a statistically significant reduction in the risk of preterm birth less than 34 weeks (two studies; 438 women; RR 0.64, 95% CI 0.45 to 0.90), preterm birth at less than 28 weeks' gestation (two studies; 1115 women; RR 0.59, 95% CI 0.37 to 0.93) and increased risk of urticaria in women when compared with placebo (one study; 654 women; RR 5.03, 95% CI 1.11 to 22.78). It was not possible to assess the effect of route of progesterone administration, gestational age at commencing therapy, or total cumulative dose of medication. Progesterone versus placebo for women with a multiple pregnancy Progesterone was associated with no statistically significant differences for the reported outcomes. Progesterone versus no treatment/placebo for women following presentation with threatened preterm labour Progesterone, was associated with a statistically significant reduction in the risk of infant birthweight less than 2500 g (one study; 70 infants; RR 0.52, 95% CI 0.28 to 0.98). Progesterone versus placebo for women with 'other' risk factors for preterm birth Progesterone, was associated with a statistically significant reduction in the risk of infant birthweight less than 2500 g (three studies; 482 infants; RR 0.48, 95% CI 0.25 to 0.91). AUTHORS' CONCLUSIONS: The use of progesterone is associated with benefits in infant health following administration in women considered to be at increased risk of preterm birth due either to a prior preterm birth or where a short cervix has been identified on ultrasound examination. However, there is limited information available relating to longer-term infant and childhood outcomes, the assessment of which remains a priority.Further trials are required to assess the optimal timing, mode of administration and dose of administration of progesterone therapy when given to women considered to be at increased risk of early birth.

Increased incidence of gestational diabetes in women receiving prophylactic 17alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery.

OBJECTIVE: Progesterone has a known diabetogenic effect. We sought to determine whether the incidence of gestational diabetes mellitus (GDM) is altered in women receiving weekly 17alpha-hydroxyprogesterone caproate (17P) prophylaxis for the prevention of recurrent preterm birth. RESEARCH DESIGN AND METHODS: Singleton gestations in women having a history of preterm delivery were identified from a database containing prospectively collected information from women receiving outpatient nursing services related to a high-risk pregnancy. Included were patients enrolled for outpatient management at <27 weeks' gestation with documented pregnancy outcome and delivery at >28 weeks. Patients with preexisting diabetes were excluded. The incidence of GDM was compared between patients who received prophylactic intramuscular 17P (250-mg weekly injection initiated between 16.0 and 20.9 weeks' gestation) and those who did not. RESULTS: Maternal BMI and age were similar. The incidence of GDM was 12.9% in the 17P group (n = 557) compared with 4.9% in control subjects (n = 1,524, P < 0.001; odds ratio 2.9 [95% CI 2.1-4.1]). CONCLUSIONS: The use of 17P for the prevention of recurrent preterm delivery is associated with an increased risk of developing GDM. Early GDM screening is appropriate for women receiving 17P prophylaxis.

[Genomic and extragenomic mechanisms of antiglucocorticoid action of gestagens on thymocytes].

Effects of a new synthetic progesterone derivative 17a-acetoxy-3b-butanoyloxy-6-methyl-pregna-4,6-dien-20-one (ABMP) and the reference gestagen preparations on the rat thymus were evaluated by the degree of variation of the intracellular levels of calcium and cAMP, 3H-uridine inclusion into RNA, thymocyte viability, and thymus mass. It is shown that gestagens can produce antiglucocorticoid action on thymocytes, this activity being most pronounced in the case of ABMP.

Prenatal administration of progesterone for preventing preterm birth.

BACKGROUND: Preterm birth is the major complication of pregnancy associated with perinatal mortality and morbidity and occurs in up to 6% to 10% of all births. Administration of progesterone for the prevention of preterm labour has been advocated. OBJECTIVES: To assess the benefits and harms of progesterone administration during pregnancy in the prevention of preterm birth. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Specialised Register of Controlled Trials (March 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2004), MEDLINE (1965 to January 2005), EMBASE (1988 to August 2004), and Current Contents (1997 to August 2004). SELECTION CRITERIA: All published and unpublished randomised controlled trials, in which progesterone was given by any route for preventing preterm birth. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group were used. Evaluation of methodological quality and trial data extraction were undertaken independently by two authors. Results are presented using relative risk with 95% confidence intervals. MAIN RESULTS: For all women administered progesterone, there was a reduction in the risk of preterm birth less than 37 weeks (six studies, 988 participants, relative risk (RR) 0.65, 95% confidence interval (CI) 0.54 to 0.79) and preterm birth less than 34 weeks (one study, 142 participants, RR 0.15, 95% CI 0.04 to 0.64). Infants born to mothers administered progesterone were less likely to have birthweight less than 2500 grams (four studies, 763 infants, RR 0.63, 95% CI 0.49 to 0.81) or intraventricular haemorrhage (one study, 458 infants, RR 0.25, 95% CI 0.08 to 0.82). There was no difference in perinatal death between women administered progesterone and those administered placebo (five studies, 921 participants, RR 0.66, 95% CI 0.37 to 1.19). There were no other differences reported for maternal or neonatal outcomes. AUTHORS' CONCLUSIONS: Intramuscular progesterone is associated with a reduction in the risk of preterm birth less than 37 weeks' gestation, and infant birthweight less than 2500 grams. However, other important maternal and infant outcomes have been poorly reported to date, with most outcomes reported from a single trial only (Meis 2003). It is unclear if the prolongation of gestation translates into improved maternal and longer-term infant health outcomes. Similarly, information regarding the potential harms of progesterone therapy to prevent preterm birth is limited. Further information is required about the use of vaginal progesterone in the prevention of preterm birth.