Previous studies have suggested that maternal intake of progestins during early pregnancy may be associated with an increased risk of hypospadias. Progesterone and its derivatives are commonly prescribed during early pregnancy, for example, in cases of luteal phase dysfunction and in conjunction with ovulation stimulation drugs.
To examine whether risk of hypospadias was associated with periconceptional progestin intake.
The National Birth Defects Prevention Study, a population-based, multistate, case-control study including deliveries that had estimated due dates from October, 1997 to December, 2000.
Participation in the study was 71% among case mothers and 68% among control mothers. This analysis included 502 subjects diagnosed with second- or third-degree hypospadias (ie, the urethra opened at the penile shaft, scrotum, or perineum) and 1286 male, live-born, nonmalformed control subjects.
Forty-two case mothers (8.4%) and 31 control mothers (2.4%) reported any pregnancy-related progestin intake from 4 weeks before through 14 weeks after conception, resulting in an odds ratio of 3.7 (95% confidence interval [CI], 2.3-6.0). Analyses stratified by several potential covariates also suggested elevated risks. For example, among the 10 cases and 13 controls who did not report any fertility-related procedures or treatments other than progestins, the odds ratio was 2.2 (95% CI, 1.0-5.0). Progestin intake for the purpose of contraception was not associated with increased risk.
This study found that pregnancy-related intake of progestins was associated with increased hypospadias risk.
"In utero exposure to progestins has not been associated with an increased risk of congenital anomalies, with the possible exception of hypospadias.64 This possible association has been reported for progestins in general, but not for 17OH-PC specifically. "
[Show abstract][Hide abstract] ABSTRACT: Prevention of preterm delivery is a major desiderate in contemporary obstetrics and a societal necessity. The means to achieve this goal remain elusive. Progesterone has been used in an attempt to prevent preterm delivery since the 1970s, but the evidence initially accumulated was fraught by mixed results and was based on mostly underpowered studies with variable eligibility criteria, including history of spontaneous abortion as an indication for treatment. More recent randomized controlled clinical trials restimulated the interest in progesterone supplementation, suggesting that progesterone may favorably influence the rate of preterm delivery. Preterm delivery is a complex disorder and consequently it is unlikely that one generalized prevention strategy will be effective in all patients. Further, an additional impediment in accepting progesterone as the "magic bullet" in the prevention of preterm delivery is that its mechanism of action is not fully understood and the optimal formulations, route of administration, and dose have yet to be established. We have concerned ourselves in this review with the most recent status of 17 alpha-hydroxyprogesterone caproate (17OH-PC) supplementation for prevention of preterm delivery. Our intention is to emphasize the efficacy, safety, and patient acceptability of this intervention, based on a comprehensive and unbiased review of the available literature. Currently there are insufficient data to suggest that 17OH-PC is superior or inferior to natural progesterone. Based on available evidence, we suggest a differential approach giving preferential consideration to either 17OH-PC or other progestins based on obstetric history and cervical surveillance. Progestin therapy for risk factors other than a history of preterm birth and/or a short cervix in the current pregnancy is not currently supported by the published evidence. The experience to date with 17OH-PC indicates that there are population subgroups that may be harmed by administration of 17OH-PC. Therefore, extending the use of 17OH-PC to unstudied populations or for indications that are not evidence-based is inadvisable outside of a research protocol.
"Orally administered P has a first-pass effect in which a high concentration is sent to the portal circulation, which, in turn, results in the production of many liver metabolites of P, some of which may be teratogenic. Despite the available literature on the teratogenic effects of prenatal oral P use [29,30], this agent is still used routinely by many practitioners. Therefore, taking into consideration the burden of LPS treatment, the adverse reactions to P and updated results suggesting that P supplementation during early pregnancy after IVF/ICSI might be unnecessary, we questioned whether the practice of early pregnancy P supplementation in IVF/ICSI patients should be discontinued. "
[Show abstract][Hide abstract] ABSTRACT: Background
Progesterone supplementation after in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) can improve the rates of clinical pregnancy and live birth, but the optimal duration of treatment remains controversial. The objective of this meta-analysis was to investigate the effects of early progesterone cessation on pregnancy outcomes in women undergoing IVF/ICSI.
We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Chinese biomedicine (CBM) literature database, and the Wanfang database. The final search was performed in July 2012. All available randomised trials that compared the effects of early progesterone cessation with progesterone continuation during early pregnancy after IVF/ICSI were included. The main outcome measures were live birth rate, miscarriage rate and ongoing pregnancy rate. Fixed or random-effects models were chosen to calculate the risk ratio (RR).
Six eligible studies with a total of 1,201 randomised participants were included in the final analysis. No statistically significant differences were detected between patients who underwent early progesterone cessation and those who received progesterone continuation for luteal phase support in terms of live birth rate (RR: 0.95, 95% CI: 0.86–1.05), miscarriage rate (RR: 1.01, 95% CI: 0.74–1.38) or ongoing pregnancy rate (RR: 0.97, 95% CI: 0.90–1.05). These results did not change after a sensitivity analysis.
The currently available evidence suggests that progesterone supplementation beyond the first positive hCG test after IVF/ICSI might generally be unnecessary, although large-scale randomised controlled trials are needed to strengthen this conclusion.
"(i.e., natural progesterone and synthetic progesterone and testosterone derivatives that produce biologic effects similar to those of progesterone) for the purpose of preventing pregnancy loss or other complications (Kallen et al., 1992; Carmichael et al., 2005). Progestin intake for the purpose of contraception does not appear to be associated with increased risk of hypospadias (Carmichael et al., 2005; Wogelius et al., 2006). This inconsistency is not surprising, given that the dose and types of progestins used in oral contraceptives and for pregnancy-related issues are very different, as are their mechanisms of action (Williams and Stancel, 1996). "
[Show abstract][Hide abstract] ABSTRACT: This review evaluates current knowledge related to trends in the prevalence of hypospadias, the association of hypospadias with endocrine-disrupting exposures, and the potential contribution of genetic susceptibility to its etiology. The review focuses on epidemiologic evidence. Increasing prevalence of hypospadias has been observed, but such increases tend to be localized to specific regions or time periods. Thus, generalized statements that hypospadias is increasing are unsupported. Owing to the limitations of study designs and inconsistent results, firm conclusions cannot be made regarding the association of endocrine-disrupting exposures with hypospadias. Studies with more rigorous study designs (e.g., larger and more detailed phenotypes) and exposure assessment that encompasses more breadth and depth (e.g., specific endocrine-related chemicals) will be critical to make better inferences about these important environmental exposures. Many candidate genes for hypospadias have been identified, but few of them have been examined to an extent that enables solid conclusions. Further study is needed that includes larger sample sizes, comparison groups that are more representative of the populations from which the cases were derived, phenotype-specific analyses, and more extensive exploration of variants. In conclusion, examining the associations of environmental and genetic factors with hypospadias remain important areas of inquiry, although our actual understanding of their contribution to hypospadias risk in humans is currently limited.
Birth Defects Research Part A Clinical and Molecular Teratology 07/2012; 94(7):499-510. DOI:10.1002/bdra.23021 · 2.09 Impact Factor
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