The outcome of singleton pregnancies after IVF/ICSI in women before and after hysteroscopic resection of a uterine septum compared to normal controls

Objective(s)

To evaluate the effect of hysteroscopic resection of a large uterine septum (Class V according to the American Fertility Society (AFS) classification) and of a small partial uterine septum (Class VI according to AFS classification or arcuate uterus) on the abortion rate in pregnancies after IVF and ICSI.

Study design

The retrospective matched control study included 31 women who conceived following IVF or ICSI before hysteroscopic resection of a large (12 women) or small partial (19 women) uterine septum and 106 women who conceived following IVF or ICSI after hysteroscopic resection of a large (49 women) or small partial (57 women) uterine septum. For each pregnancy in the study group, we found two consecutive pregnant control women from the IVF/ICSI registry who had a normal uterus and were matched for age, BMI, stimulation protocol and the use of IVF or ICSI and for various infertility causes. The abortion/pregnancy rate was the main outcome measure. Data on the septum length were obtained during hysteroscopic resection by comparing the length of the 1.4 cm long yellow tip of the electric knife to the length of the resected septum.

Results

The abortion rate before hysteroscopic metroplasty was significantly higher, both in women with a small partial septum (78.9% before resection vs. 23.7% in the normal controls, OR 12.08) and a large septum (83.3% before resection vs. 16.7% in normal controls, OR 25.00) compared to women with a normal uterus. After the surgery, the abortion rate was comparable to the abortion rate in women with normal uterus: in both women with a small partial and women with a larger septum.

Conclusion(s)

Similar to a large uterine septum, a small partial uterine septum is an important and hysteroscopically preventable risk factor for spontaneous abortion in pregnancies after IVF and ICSI.     

Reducing the preterm birth rate: a population health strategy

The rate of preterm birth has been increasing in Canada and the United States. Efforts to prevent preterm birth have been largely ineffective. A population health strategy that integrates disease prevention and health promotion is needed. In this article, the five categories of health determinants proposed by the Federal, Provincial and Territorial Advisory Committee on Population Health are used as a framework to discuss risk factors and propose policies and interventions to reduce the preterm birth rate.     

Oral micronized progesterone for prevention of preterm birth

Objective

To evaluate oral micronized progesterone (OMP) to prevent preterm birth (PTB).

Methods

A randomized, double-blind, placebo-controlled trial of 150 women with at least one PTB who received 100 mg of OMP or placebo twice a day from recruitment (18-24 weeks) until 36 weeks or delivery.

Results

PTB occurred in 29 (39.2%) women in the OMP group (n = 74) compared with 44 (59.5%) in the control group (n = 74, P = 0.002). Mean gestational age at delivery was higher in the OMP group (36.1 vs 34.0 weeks, P < 0.001). Fewer preterm births occurred between 28 and 31 weeks plus 6 days in the OMP group (RR 0.20; 95% CI, 0.05-0.73, P < 0.001). Neonatal age at delivery (34 vs 32 weeks, P < 0.001), birth weight (2400 vs 1890 g, P < 0.001), NICU stay (> 24 h, P < 0.001), and Apgar scores (P < 0.001) were more favorable in the OMP group, and fewer neonatal deaths occurred (3 vs 7, P = 0.190).

Conclusion

OMP reduced the risk of PTB between 28 and 31 weeks plus 6 days, NICU admissions, and neonatal morbidity and mortality in high risk patients.     

Rationale for current and future progestin-based therapies to prevent preterm birth

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. The only medicinal therapy currently recommended to prevent PTB is prophylactic progestin therapy in the form of micronized progesterone (P4) administered daily via vaginal suppository from the 24th to the 34th week of gestation or 17α-hydroxyprogesterone caproate in oil administered weekly from the 16th to the 36th week of gestation via an intramuscular injection. These therapies decrease the risk of PTB in women with an elevated risk of PTB indicated by a history of PTB or by a short cervix measured by sonography at mid-gestation. The mechanism by which progestin therapy prevents PTB in some women is not clear but may involve non-progestin mechanism and/or supplementation of localized progestin deficiency. Advances in understanding the molecular biology and physiology of P4 signaling via the P4 receptor isoforms in uterine cells reveal novel therapeutic targets; this may improve the effectiveness of progestin therapy to prevent PTB in the majority of pregnancies by targeting key steps in the pathway leading to inflammation-induced parturition.     

Exposure to life-threatening stressful situations and the risk of preterm birth and low birth weight

Objective

To evaluate the association between exposure to life-threatening rocket attacks and the risks of preterm birth (PTB) and low birth weight (LBW).

Methods

The present retrospective cohort study compared the outcomes of 1851 births by women exposed to rocket attacks and 2979 births by unexposed women. The timing, frequency, and intensity of exposure were calculated for each trimester and for the entire pregnancy period. Demographic and medical data were abstracted from the patients’ records.

Results

The rates of PTB and LBW were higher among exposed than unexposed women (PTB: 9.1% versus 6.8%, P = 0.004; LBW: 7.6% versus 5.8%, P = 0.02). The rate of infants who were small for gestational age did not differ between the groups. After controlling for potential confounders, the risks for PTB and LBW remained significantly higher in the exposed group (PTB: adjusted odds ratio 1.3 [95% confidence interval, 1.1–1.7]; LBW: adjusted odds ratio 1.3 [95% confidence interval, 1.03–1.7]). There was no linear association between the intensity of exposure and the risk of PTB or LBW.

Conclusion

Maternal exposure to intermittent but repeated life-threatening rocket attacks for a prolonged period might be associated with increased risks of PTB and LBW.     

Maternal risk factors for preterm birth: a country-based population analysis

Objective

The aim of this study was to identify maternal risk factors for spontaneous preterm birth (PTB) compared to delivery at term, in order to recognize high risk women and to provide a global overview of the Italian situation.

Study design

A multicenter, observational and retrospective, cross-sectional study was designed. The study population comprised 7634 women recruited in 9 different University Maternity Hospitals in Italy. The main criteria for inclusion were: women having had vaginal preterm or term spontaneous delivery in each participating centre during the study period. The records related to deliveries occurring between April and December 2008. A multivariable logistic regression was employed to identify independent predictors of spontaneous preterm birth. Odds ratios (ORs) and 95% confidence intervals (95% CI) were reported with two-tailed probability (p) values. Statistical calculations were carried out using SAS version 9.1. A two-tailed p-value of 0.05 was used to define statistical significant results.

Results

A significant increased risk of PTB was found in women with BMI > 25 (OR = 1.662; 95% CI = 1.033–2.676; p-value = 0.0365) and in women employed in heavy work (OR = 1.947; 95% CI = 1.182–3.207; p-value = 0.0089). Moreover there was a significant association between PTB and previous reproductive history. In fact a history of previous abortion (OR = 1.954; 95% CI = 1.162–3.285; p-value = 0.0116) or previous cesarean section (OR = 2.904; 95% CI = 1.066–7.910; p-value = 0.0371) was positively correlated to the increased risk of PTB and an important statistically significant association was calculated between PTB and previous pre-term delivery (OR = 3.412; 95% CI = 1.342–8.676; p-value = 0.0099). All the other covariates examined as potential risk factors for PTB were not found to be statistically significantly related (p-value > 0.05).

Conclusions

The present study, applied to a substantial sample of Italian population, demonstrates that there are peculiar risk factors for spontaneous PTB in the Italian population examined. It shows an association between preterm delivery and certain maternal factors as: BMI, employment, previous abortions, previous PTBs and previous cesarean section.     

What we have learned about the role of 17-alpha-hydroxyprogesterone caproate in the prevention of preterm birth

Despite major advances in neonatal care, the burden of preterm birth remains high. This is not unexpected since strategies to identify and treat risk factors in early pregnancy have not been very effective in reducing the preterm birth rate. Initial studies suggested a potential benefit for 17-alpha-hydroxyprogesterone caproate (17-OHPC) in decreasing the risk of recurrent preterm birth women with a singleton gestation. However, the use of 17-OHPC has not conferred benefit for other categories of women at high risk for preterm delivery (twins, triplets, and short cervical length). The increasing body of evidence suggests that preterm birth is a complex condition with variable mechanisms of disease and significant individual heterogeneity. This review will examine the plausibility of 17-OHPC in preventing preterm birth and the investigation of its clinical efficacy. We will also highlight factors to explain variations in clinical trial outcomes and outline the trajectory needed for future investigations.     

Risk factors for preterm birth in Vietnam.

OBJECTIVE: To identify the risk of preterm birth and possible determinants among women in Hanoi, Vietnam. METHOD: Prospective cohort study of 1709 women with singleton live births at Hanoi Obstetrics and Gynecology Hospital, Hanoi, Vietnam, June-October 2002. Logistic regression analysis was used to examine predictors of preterm birth (<37 weeks' gestation). RESULT: The risk of preterm birth was 11.8%. Physically demanding work during pregnancy, two or more prior spontaneous abortions, history of preterm birth, vaginal bleeding, inadequate prenatal care during the first 20 weeks of gestation, and history of intrauterine device use with removal less than 12 months before the current pregnancy were associated with increased risk of preterm birth (adjusted odds ratios between 1.8 and 2.6). CONCLUSION: Preterm birth is relatively frequent in this population. Beyond established risk factors, these data implicated agricultural work and physical work demands with preterm birth, as well as history of recent IUD use.     

The global epidemiology of preterm birth

This article is a part of a series that focuses on the current state of evidence and practice related to preterm birth prevention. We provide an overview of current knowledge (and limitations) on the global epidemiology of preterm birth, particularly around how preterm birth is defined, measured, and classified, and what is known regarding its risk factors, causes, and outcomes. Despite the reported associations between preterm birth and a wide range of socio-demographic, medical, obstetric, fetal, and environmental factors, approximately two-thirds of preterm births occur without an evident risk factor. Efforts to standardize definitions and compare preterm birth rates internationally have yielded important insights into the epidemiology of preterm birth and how it could be prevented.     

Paternal involvement and support and risk of preterm birth: findings from the Boston birth cohort

Objective: To investigate to what extent paternal involvement and support during pregnancy were associated with preterm (PTB) and small-for-gestational age (SGA) births.

Methods: Using data from the Boston Birth Cohort (n?=?7047), multiple logistic regression models were performed to estimate the log odds of either PTB or SGA birth, with paternal involvement, paternal social support, and family and friend social support variables as the primary independent variables.

Results: About 10% of participating mothers reported their husbands not being involved or supportive during their pregnancies. Lack of paternal involvement was associated with 21% higher risk of PTB (OR?=?1.21, 95% CI: 1.01–1.45). Similarly, lack of paternal support was borderline associated with PTB (OR?=?1.13, 95% CI: 0.94–1.35). Also marginally significant, lack of paternal involvement (OR?=?1.18, 95% CI: 0.95–1.47) and father’s support (OR?=?1.19, 95% CI: 0.96–1.48) were associated with higher odds of SGA birth. No associations were found between familial and friend support during pregnancy and PTB or SGA.

Conclusions: Among predominantly low-income African Americans, lack of paternal involvement and lack of paternal support during pregnancy were associated with an increased risk of PTB, and suggestive of SGA birth. These findings, if confirmed in future research, underscore the important role a father can play in reducing PTB and/or SGA.     

Progesterone for the prevention of preterm birth: a critical evaluation of evidence

A systematic review of the literature identified nine randomised trials that evaluated the effects of progestational agents in the prevention of preterm delivery. These studies were of variable quality. Meta-analyses showed reductions in delivery rates before 37 weeks (OR 0.42, 95% CI 0.31-0.57) and 34 weeks (OR 0.51, 95% CI 0.34-0.77) as well as in respiratory distress syndrome (OR 0.55, 95% CI 0.31-0.96) with progestational agents. A cumulative meta-analysis showed that the treatment benefit for the outcome of delivery before 37 weeks exceeded the conventional level of statistical significance in 1975 (p<0.01); by 1985, the p-value was <0.001, and by 2003, it was <0.0001. Another cumulative meta-analysis in which the studies were added to the pooled analysis by decreasing quality score showed significant benefit even when the analysis was limited to just the highest quality trials (OR 0.47, 95% CI 0.33, 0.66, p<0.0001). An exploration of the applicability of the effects across various baseline risks using a L'abbe plot found that the benefit was consistent across a range of risks. A comprehensive review of both trial and observational data on harm did not show any demonstrable evidence of harm to mother and baby. Women at high risk of preterm birth should be recommended progestational agent therapy.     

Preinduction cervical ripening with the Foley catheter and the risk of subsequent preterm birth

OBJECTIVE: The Foley catheter is a safe and effective form of preinduction cervical ripening and is quickly growing in popularity. Its major effect appears to be through mechanical dilation, which has raised the concern that the use of the Foley catheter for cervical ripening may damage the cervix and result in a higher rate of subsequent preterm birth. STUDY DESIGN: We conducted a review of all induction of labor at our institution from July 1998 to July 2001 that required preinduction cervical ripening and had a subsequent birth. The primary outcome variable was preterm birth at <35 weeks of gestation. Demographic and potential confounding variables were analyzed. A probability value of <.05 was considered significant. RESULTS: The cases of 126 women (63 women in the Foley group and 63 women in the prostaglandin group) were studied. Women in the prostaglandin group had a prostaglandin agent used. There was no difference in maternal age, gravidity, parity, Bishop score, total time of induction, gestational age, oxytocin use, maximum oxytocin level, tobacco or drug use, or type of delivery in the index pregnancy between the groups. In the subsequent pregnancies, there were no differences in maternal age, gravidity, parity, spontaneous abortions, terminations, cone or Loop Electrosurgical Excision Procedure (LEEP) procedures, history of cervical manipulation, tobacco or drug use, stillbirth, need for induction, mode of delivery, episiotomy, gestational age at delivery, Apgar scores, labor duration, use of oxytocin, or birth weight. There were no differences in preterm birth at 37, 35, or 32 weeks of gestation between the groups. CONCLUSION: The use of the Foley catheter for preinduction cervical ripening does not appear to increase the risk of preterm birth in a subsequent pregnancy.     

Biomarkers for predicting spontaneous preterm birth: an umbrella systematic review

Objective: To identify all systematic reviews investigating the role of maternal and fetal biomarkers for predicting spontaneous preterm birth (SPTB).

Methods: Medline and Web of Sciences databases were searched electronically. Studies exploring the association between maternal biomarkers and spontaneous delivery were considered suitable for inclusion. A synthesis of the systematic reviews was performed with the umbrella methodology. Statistical measures of association (Odd ratio, OR, relative risk, RR) and predictive accuracy (sensitivity, specificity, positive and negative likelihood ratios were used to synthesize results of the included studies.

Results: 21,614 articles were identified, 542 were assessed with respect to their eligibility for inclusion and 14 systematic reviews included. Cervical fibronectin was the biomarkers which showed the highest strength of association with the occurrence of SPTB (delivery within 24?h OR 7, 95%CI 3–17; delivery <7?days (OR 12, 95%CI 8–16). Maternal serum alpha fetoprotein, was associated with an OR of 4 and 3 for early and late SPTB. C-reactive protein had an OR of 2 (95%CI 1–2) and 8 (95%CI 4–16) when detected in maternal plasma and amniotic fluid, respectively. Among cytokines, interleukin-6 had an OR and an LR?+?for SPTB of 2 and 12 when detected in maternal serum.

Conclusions: Cervical fetal fibronectin, alpha fetoprotein, C- reactive protein and interleukin 6 can have an overall good diagnostic accuracy in identifying pregnancies at risk of SPTB. Large prospective studies in different sub-set of women are needed to ascertain whether the combination of different serological and imaging marker can improve antenatal prediction of this condition.     

Resectoscope or Versapoint for hysteroscopic metroplasty.

OBJECTIVE: To assess the feasibility, safety, and reproductive outcome of hysteroscopic metroplasty using the Versapoint device compared with the resectoscope using the Collins loop. METHODS: Sixty-three women diagnosed with partial septate uterus were included in the study. Forty-two women underwent hysteroscopic metroplasty using Versapoint and 21 women had the procedure using the resectoscope. Operating time, complications, pregnancy rate, and mode of delivery were recorded. Data were analyzed with the Mann-Whitney test. RESULTS: Operating time was 20.5 min for the resectoscope group and 15.4 min for the Versapoint group (P<0.05). Pregnancy rate, delivery rate, and spontaneous abortions were similar in both groups. CONCLUSION: Operative hysteroscopy with Versapoint does not require cervical dilation, thus avoiding cervical incompetence, cervical lacerations, and uterine perforation. The Versapoint technique is a safe and effective alternative to the resectoscope. It could be used predominantly in nulligravida women, especially in those with cervical canal stenosis.     

Predicting preterm birth: a cost-effectiveness analysis

OBJECTIVE: The objective of this study was to compare the cost-effectiveness of 9 strategies for the management of threatened preterm labor. STUDY DESIGN: We derived 6 management options from the literature. These were (1) to treat all women with tocolytics and corticosteroids ("treat all"); (2) to treat all women while awaiting results of the "traditional" fetal fibronectin test results, then discontinue treatment on those with negative results; (3) to treat only those with abnormal cervical length measurements as detected by ultrasonography; (4) to treat only those with abnormal "rapid" fetal fibronectin test results; (5) to perform rapid fetal fibronectin testing and cervical length measurements and treat those with a positive result on either or both; (6) not to treat any women ("treat none"). To assess the contributions of tocolytics and corticosteroids to our outcomes, we analyzed 3 additional treatment options: (7) to treat all women with outpatient corticosteroids but not give tocolytics, (8) to administer corticosteroids to all but give tocolytics only to those with abnormal rapid fetal fibronectin test results, and (9) to administer corticosteroids to all but give tocolytics only to those with abnormal cervical length. We used decision analytic techniques to perform a cost-effectiveness analysis. RESULTS: A decision tree was constructed on the basis of these strategies. We reviewed the literature to derive all probability information. We derived sensitivity and specificity for delivery <37 weeks for fetal fibronectin and for abnormal cervical length. Outcomes of interest were respiratory distress syndrome and neonatal death. We derived cost variables from institutional statistics and from values quoted in the literature. Total costs, cases of respiratory distress syndrome, neonatal deaths, and cost-effectiveness ratios were calculated for each of the strategies. We conducted sensitivity analyses on all variables. Universal administration of outpatient corticosteroids was the least expensive option, but it resulted in more cases of respiratory distress syndrome and deaths than "treat all." Rapid fetal fibronectin plus corticosteroids, traditional fetal fibronectin, and cervical length plus corticosteroids were the next least expensive options and resulted in numbers of cases of respiratory distress syndrome and deaths that were similar to those in the "treat all" strategy. The "rapid" fetal fibronectin test, cervical length measurement, rapid fetal fibronectin test plus cervical length measurement, and "treat none" strategies resulted in more respiratory distress syndrome, more deaths, and higher costs. Treating all patients resulted in the fewest number of cases of respiratory distress syndrome and deaths but the greatest costs. CONCLUSION: Risk prediction strategies with the fetal fibronectin assay or corticosteroids plus rapid fetal fibronectin testing or cervical length assessment may offer cost savings compared with treatment of all women with threatened preterm labor and may prevent similar numbers of cases of respiratory distress syndrome and neonatal deaths.     

N-acetylcysteine attenuates the maternal and fetal proinflammatory response to intrauterine LPS injection in an animal model for preterm birth and brain injury

Objective.?Maternal immune activation (MIA) is associated with preterm birth (PTB) and abnormal neurologic outcome. We hypothesized that N-acetylcysteine (NAC) would decrease PTB and neonatal brain injury acting as an anti-inflammatory.

Methods.?Pregnant CD-1 mice received intrauterine LPS or saline on day 15/20. They received NAC or saline and were monitored until delivery. Pups were followed and sacrificed on postnatal days 1/30 and brains were collected. Immunostaining for heavy-chain neurofilament protein (NF-H), myelin basic protein (MBP), and proteolipid protein (PLP) was performed. In another group, animals were sacrificed 6?h after treatment, and fetal brain, placenta, and myometrium were collected. Il-6, Il-1β, Il-10, and tumor necrosis factor (TNF)-α mRNA expression was determined. Nonparametric analysis was used for analysis, and pairwise comparisons were performed when appropriate.

Results.?Lipopolysaccharide (LPS) caused PTB (79 vs. 0%, p?<?0.005), and this was reduced by NAC [0.45 (95% CI: 0.26–0.83), p?<?0.008]. LPS increased IL-6 expression in myometrium and placenta. This was attenuated by NAC in myometrium. IL-1β, IL-6, and TNF-α expression increased in the fetal brain with LPS. LPS produced altered NF-H, MBP, and PLP staining, and these effects were attenuated by NAC.

Conclusion.?NAC attenuates inflammation in this MIA model and reduces PTB and white matter injury. It is an interesting candidate for study for prevention of PTB and neurologic injury.