Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis.
Topic: Hormone Therapy

The aim of this study is to assess the role of progesterone in preterm birth prevention.

PICO
Population: Pregnant women at risk of preterm birth
Intervention: Progesterone supplementation
Comparison: Placebo or standard care
Outcomes: Prevention of preterm birth

Included studies:
title: Comparative study of progesterone plasma levels after nasal spray and intramuscular administration of natural progesterone in menopausal women.
abstract: 11 mg natural progesterone (P) was administered to 20 healthy menopausal women by means of a nasal spray or intramuscular injection. Circulating P levels were calculated at various times after administration. The spray formulation yielded a CMax of 3.75 ng/ml at TMax = 60 min, the area under the curve (AUC)0-720 being 1,481.6 +/- 343. Intramuscular administration yielded a mean CMax of 4.137 ng/ml at TMax = 240 min, the AUC0-720 being 2,491.2 +/- 540. P absorption was faster through the nasal than through the intramuscular route, but intramuscular administration led to high serum levels for a much longer period.
title: Pharmacokinetics of progesterone in postmenopausal women: 1. Pharmacokinetics following intravaginal administration.
abstract: Progesterone was administered to postmenopausal women in a form of vaginal suppositories containing 100 and 200 mg active substance in Butyrum cacao (BC) and Massa estarinum (ME), a base with emulsifying properties. In the case of single doses, blood samples were taken at 2, 4, 6, 24, 48 and 72 h. Another group of patients received vaginal suppositories (100 mg progesterone) once a day for a 6 day period, with blood samples taken 12 h after each administration. The plasma levels of progesterone were evaluated by radioimmunoassay. The time of maximum concentration (tmax) was 4 h in most cases, and 6 h in the others. The plasma levels were not dose-proportional. Peak plasma concentrations were in the range of 10-15 ng/ml with a mean of 10.5 ng/ml for the 100 mg and 12 ng/ml for the 200 mg doses. The ratio of the mean area under the curve (AUC) for 200 mg and the mean AUC for the 100 mg dose was found to be 1.37. Replacing BC with ME resulted in the lowering of cmax and AUC, and an increase in tmax following a reducing in the rate and extent of adsorption. In the case of ME suppositories, the variability in AUC, cmax and tmax was greater compared to that observed with the BC suppositories. Elimination half-time was in the range of 9-10 h for BC and 14 h for ME suppositories. In vitro assessment of the release kinetics from a hydrophobic and an emulsion type base confirmed previous findings: the latter base assured better pharmaceutical availability. The repeated doses did not seem to produce an accumulation of progesterone in the plasma. On the contrary, a small decrease in plasma levels over time appeared during the 6 day period. Numerical analysis revealed an excellent goodness of fit for the in vivo experimental data via biexponential curves, i.e. a pseudomonocompartmental model.
title: Survival and cerebral palsy in low birthweight infants: implications for perinatal care.
abstract: Whilst only about a third of all cerebral palsy occurs in children who had been of low birthweight, recent increases in the survival of low and very low birthweight infants have coincided with significant increases in the numbers of cerebral palsy children amongst them. This paper analyses data from the Western Australian Cerebral Palsy Register and from the Maternal and Child Health Research Data Base for stillbirths, neonatal deaths and survivors to address the issues of increased survival, cerebral palsy and timing of brain damage. The analysis is inconclusive but suggestive that both antenatal and postnatal complications are important in the increases in cerebral palsy in low birthweight infants. The good news is that this means that a certain proportion of postnatally damaged low birthweight survivors could possibly be prevented by better neonatal care. The bad news is that the remaining proportion have probably received their damage well before delivery and the possibilities for prevention are still remote. Further studies of low birthweight infants with cerebral palsy are urgently required. They should include antenatal factors, investigating the various aetiological pathways to preterm birth, randomised controlled trials of neonatal interventions and searching for better neonatal predictors of brain damage.
title: Medroxyprogesterone acetate, but not progesterone, protects against inflammation-induced parturition and intrauterine fetal demise.
abstract: This study was undertaken to determine whether progestational agents can prevent inflammation-induced preterm parturition and fetal demise.
title: The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population.
abstract: A prior report suggested that active-duty pregnant women are at increased risk for low-birth weight infants and a higher perinatal mortality rate. The present double-blind investigation was designed to prospectively evaluate that risk and to test the efficacy of 17 alpha-hydroxyprogesterone caproate to prevent reported complications. Three groups of active-duty women were studied, beginning between 16 and 20 weeks' gestation. They were similar for parity, previous abortion, race, cigarette smoking, and marital status. Of these, 80 were given 17 alpha-hydroxyprogesterone caproate, 88 received placebo, and 78 declined to participate in the protocol. There was no significant differences in the three groups when comparisons were made for low-birth weight infants and for perinatal mortality. However, when comparison was made to a military dependent population, they had a significantly worse outcome with regard to both perinatal mortality (p = 0.001) and infants with a birth weight less than 2,500 gm (p = 0.01). We concluded that pregnant military personnel were at increased risk for adverse pregnancy outcome, but that this risk was not altered by therapy with 17 alpha-hydroxyprogesterone caproate.
title: 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.
abstract: The purpose of this study was to evaluate the effect of prophylactic vaginal progesterone in decreasing preterm birth rate in a high-risk population.
title: Progesterone supplementation during early gestations after IVF or ICSI has no effect on the delivery rates: a randomized controlled trial.
abstract: The aim was to study whether prolongation of luteal support during early pregnancy influences the delivery rate after IVF.
title: Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate.
abstract: Eighty pregnant women at high risk of giving birth prematurely were divided randomly into two groups. Treatment with either 17 alpha-hydroxyprogesterone caproate, 250 mg by intramuscular injection once a week, or a placebo was given in a double-blind fashion. Imminent premature labor occurred in 29.0% of the treated group and in 59.4% of the control group (p less than 0.025). The rate of premature deliveries was also significantly lower in the treated group (16.1%) than in the control group (37.82%) (p less than 0.05). There were no cases of perinatal death or fetal malformations in either group. The mean birth weight of all infants of the treated group was significantly higher than in those of the control group (3111.9 +/- 905 gm versus 2680 +/- 813.4 gm, p less than 0.05). The results support treatment with progesterone caproate for the prevention of premature labor.
title: Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor.
abstract: We conducted a double-blind study to determine the efficacy of 17alpha-hydroxyprogesterone caproate in preventing premature delivery in 43 high-risk patients. Premature delivery did not occur in 18 patients receiving the progestational agent, whereas 41 per cent of the 22 receiving the palcebo had premature delivery (P less than 0.01). The mean duration of pregnancy and the mean birth weight in the former group (38.6 weeks +/- 1.6 S.D., and 2836 g +/- 412 S.D.) were both significantly greater (P less than 0.025) than that in the latter (35.2 weeks +/- 6.7 S.D.; 2361 g +/- 1085 S.D.). The perinatal mortality rate in the group given the progestational agent (O per cent) was significantly less than that observed in the placebo group (27 per cent) (P less than 0.05). Although there were no complications attributable to the progestational drug, the study population was too small for assessment of immediate or long term safety. However, the results indicate a possible obstetric use for this drug.
title: 17-alpha-Hydroxyprogesterone caproate and natural progesterone in assisted reproduction: a comparative study.
abstract: The use of luteal phase support has been demonstrated in patients undergoing an IVF/ET procedure. This study was designed to compare the absorption and the efficacy of two different luteal supports: 17-alpha-hydroxyprogesterone caproate (Lentogest, AMSA, Italy) and natural Progesterone (Prontogest, AMSA, Italy). A total of 80 patients received luteal supplementation with 50 mg of natural P/day intramuscularly, until beta-hCG evaluation. Then, in case of positive beta-hCG, patients were randomly divided into two groups (A and B) in order to compare two different protocols: Group A, 17-OHPc (341 mg once a week) and Group B, natural P (50 mg/day) both intramuscularly and extended for 10-12 weeks. Our study showed that the treatment with 17-OHPc results in a higher percentage of pregnancy rate compared to natural P, but the differences are not statistically significant. Thus, we emphasize that 17-OHPc preparation for better acceptance appears to be the most suitable and comfortable method for luteal phase support.
title: Hospital admissions in the first year of life in very preterm infants.
abstract: To analyse hospital readmissions to 1 year in infants < 33 weeks' gestation.