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Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data

OBJECTIVE To determine whether the use of vaginal progesterone in asymptomatic women with a sonographic short cervix (≤ 25 mm) in the midtrimester reduces the risk of preterm birth and improves neonatal morbidity and mortality. STUDY DESIGN Individual patient data metaanalysis of randomized controlled trials. RESULTS Five trials of high quality were included with a total of 775 women and 827 infants. Treatment with vaginal progesterone was associated with a significant reduction in the rate of preterm birth <33 weeks (relative risk [RR], 0.58; 95% confidence interval [CI], 0.42-0.80), <35 weeks (RR, 0.69; 95% CI, 0.55-0.88), and <28 weeks (RR, 0.50; 95% CI, 0.30-0.81); respiratory distress syndrome (RR, 0.48; 95% CI, 0.30-0.76); composite neonatal morbidity and mortality (RR, 0.57; 95% CI, 0.40-0.81); birthweight <1500 g (RR, 0.55; 95% CI, 0.38-0.80); admission to neonatal intensive care unit (RR, 0.75; 95% CI, 0.59-0.94); and requirement for mechanical ventilation (RR, 0.66; 95% CI, 0.44-0.98). There were no significant differences between the vaginal progesterone and placebo groups in the rate of adverse maternal events or congenital anomalies. CONCLUSION Vaginal progesterone administration to asymptomatic women with a sonographic short cervix reduces the risk of preterm birth and neonatal morbidity and mortality.

Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo‐controlled trial on the effect of vaginal micronized progesterone

Studies on high‐risk singleton gestations have shown a preventive effect of progesterone treatment on preterm delivery. This study was conducted to investigate the preventive effect of vaginal micronized progesterone in a large population of twin gestations.

Obesity-related complications in Danish single cephalic term pregnancies.

OBJECTIVE: Our objective was to investigate the relationship between prepregnancy and obstetric body mass index (BMI) as well as fetal complications in a large, unselected cohort of Danish women with single cephalic pregnancies. METHODS: A cohort of 8,092 women from the Copenhagen First Trimester Study with a registered prepregnancy BMI and a single cephalic term delivery were stratified into 3 BMI groups: normal weight (BMI < 25 kg/m2), overweight (BMI 25–29.9 kg/m2), and obese (BMI ≥ 30 kg/m2). The effects of BMI and parity on the outcome were analyzed using multivariate logistic regression analyses. RESULTS: Overweight women had an odds ratio (OR) of 3.4 for diabetes, 1.9 for hypertension, 1.7 for preeclampsia, and 1.5 for cesarean delivery. The corresponding figures for obese women were 15.3, 4.8, 2.7, and 1.7, respectively. No relationship was found between BMI and vacuum extraction. Obese women had an increased risk of delivering macrosomic but also low birth weight children. No differences existed among the 3 weight groups with regard to neonatal morbidity estimated by Apgar score, umbilical cord pH, or admittance to a neonatal intensive care unit. Nulliparous women had an increased incidence of preeclampsia (OR 2.8), hypertension (OR 1.9), emergency cesarean delivery (OR 3.4), vacuum extraction (OR 5.6), and perineal rupture (OR 1.7) but a lower frequency of elective cesarean delivery (OR 0.25). CONCLUSION: The rate of complications during pregnancy and delivery increases with an increasing prepregnancy BMI in women with single cephalic term pregnancies, particularly in nulliparous women. LEVEL OF EVIDENCE: III

Association between maternal weight gain and birth weight

OBJECTIVE: To investigate the association between maternal weight gain and birth weight less than 3,000 g and greater than or equal to 4,000 g in underweight (body mass index [BMI] less than 19.8 kg/m2), normal weight (BMI 19.8–26.0 kg/m2), overweight (BMI 26.1–29.0 kg/m2), and obese (BMI greater than 29.0 kg/m2) women, with emphasis on the use of the American Institute of Medicine (IOM) recommendations in Denmark. METHODS: We analyzed data from 2,248 women with singleton, term pregnancies. The relationship between weight gain and risk of birth weight less than 3,000 g and greater than or equal to 4,000 g was examined in the four BMI groups, and use of IOM recommendations was tested by logistic regression analyses. RESULTS: We found an inverse relationship between maternal weight gain and the proportion of infants with a birth weight less than 3,000 g. Birth weight greater than or equal to 4,000 g increased with an increasing weight gain in underweight and normal-weight women, but the association was less apparent in overweight and obese women. Underweight women seemed to benefit from gaining more weight than recommended by the IOM, because the odds ratio (OR) of birth weight less than 3,000 g was 0.3 (95% confidence interval [CI] 0.1–0.9) and the OR was 1.7 for birthweight greater than or equal to 4,000 g (95% CI 0.8–3.6). The normal-weight women had an increased risk of birth weight less than 3,000 g (OR 2.4, 95% CI 1.5–3.7) if weight gain was below the recommended range, and the OR of birth weight greater than or equal to 4,000 g was 1.9 (95% CI 1.5–2.5) when the women gained more than recommended. CONCLUSION: The IOM recommendations may provide a basis for Danish recommendations to pregnant women, although the upper recommended limit for underweight women may have to be increased. LEVEL OF EVIDENCE: II

Peripheral Blood Leukocyte Telomere Length and Mortality Among 64 637 Individuals From the General Population

BACKGROUND Short telomeres in peripheral blood leukocytes are associated with older age and age-related diseases. We tested the hypotheses that short telomeres are associated with both increased cancer mortality and all-cause mortality. METHODS Individuals (n = 64637) were recruited from 1991 onwards from two Danish prospective cohort studies: the Copenhagen City Heart Study and the Copenhagen General Population Study. All had telomere length measured by quantitative polymerase chain reaction and the genotypes rs1317082 (TERC), rs7726159 (TERT), and rs2487999 (OBFC1) determined. The sum of telomere-shortening alleles from these three genotypes was calculated. We conducted Cox regression analyses and instrumental variable analyses using the allele sum as an instrument. All statistical tests were two-sided. RESULTS Among 7607 individuals who died during follow-up (0-22 years, median = 7 years), 2420 had cancer and 2633 had cardiovascular disease as causes of death. Decreasing telomere length deciles were associated with increasing all-cause mortality (P(trend) = 2*10(-15)). The multivariable-adjusted hazard ratio of all-cause mortality was 1.40 (95% confidence interval [CI] = 1.25 to 1.57) for individuals in the shortest vs the longest decile. Results were similar for cancer mortality and cardiovascular mortality. Telomere length decreased 69 base pairs (95% CI = 61 to 76) per allele for the allele sum, and the per-allele hazard ratio for cancer mortality was 0.95 (95% CI = 0.91 to 0.99). Allele sum was not associated with cardiovascular, other, or all-cause mortality. CONCLUSION Short telomeres in peripheral blood leukocytes were associated with high mortality in association analyses. In contrast, genetically determined short telomeres were associated with low cancer mortality but not with all-cause mortality.

Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis

In twin pregnancies, the rates of adverse perinatal outcome and subsequent long‐term morbidity are substantial, and mainly result from preterm birth (PTB).

Short telomere length, lung function and chronic obstructive pulmonary disease in 46 396 individuals

Background A previous case–control study of 100 individuals found that short telomere length was associated with a 28-fold increased risk of chronic obstructive pulmonary disease (COPD). Objectives To test the hypothesis that short telomere length is associated with reduced lung function and an increased risk of COPD. Methods Observational study of 46 396 individuals from the Danish general population. Measurements Leucocyte telomere length and spirometry were measured. COPD was defined using either fixed forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.70 as suggested by the Global initiative for chronic Obstructive Lung Disease (GOLD) or FEV1/FVC below the lower limit of normal (LLN). Results Telomere length decreased significantly with increasing age (p<10−300). FEV1, FVC and FEV1/FVC decreased with decreasing telomere length quartiles (p trend: 5×10−51, 5×10−35 and 6×10−137, respectively), but the associations attenuated after age and multivariable adjustment. The risk of COPD increased with decreasing telomere length quartile (p trend: p=7×10−92 for GOLD; p=8×10−44 for FEV1/FVC below LLN), but associations also attenuated after adjustment. Unadjusted and multivariable adjusted OR for shortest versus longest telomere length quartiles were 2.06 (95% CI 1.91 to 2.22) and 1.15 (95% CI 1.06 to 1.25) for GOLD and 1.73 (95% CI 1.60 to 1.88) and 1.19 (95% CI 1.09 to 1.30) for FEV1/FVC below LLN, respectively. Per 1000 base pairs decrease in telomere length, the multivariable adjusted OR was 1.07 (95% CI 1.03 to 1.10) for GOLD and 1.07 (95% CI 1.03 to 1.11) for FEV1/FVC below LLN. Conclusions Short telomere length is associated with decreased lung function and with increased risk of COPD, but the associations are markedly attenuated after adjustment. Our data support a modest correlation between telomere length and the lung function indices examined.

Association of gestational weight gain with maternal and infant outcomes: A systematic review and meta-analysis

Importance Body mass index (BMI) and gestational weight gain are increasing globally. In 2009, the Institute of Medicine (IOM) provided specific recommendations regarding the ideal gestational weight gain. However, the association between gestational weight gain consistent with theIOM guidelines and pregnancy outcomes is unclear. Objective To perform a systematic review, meta-analysis, and metaregression to evaluate associations between gestational weight gain above or below the IOM guidelines (gain of 12.5-18 kg for underweight women [BMI <18.5]; 11.5-16 kg for normal-weight women [BMI 18.5-24.9]; 7-11 kg for overweight women [BMI 25-29.9]; and 5-9 kg for obese women [BMI ≥30]) and maternal and infant outcomes. Data Sources and Study Selection Search of EMBASE, Evidence-Based Medicine Reviews, MEDLINE, and MEDLINE In-Process between January 1, 1999, and February 7, 2017, for observational studies stratified by prepregnancy BMI category and total gestational weight gain. Data Extraction and Synthesis Data were extracted by 2 independent reviewers. Odds ratios (ORs) and absolute risk differences (ARDs) per live birth were calculated using a random-effects model based on a subset of studies with available data. Main Outcomes and Measures Primary outcomes were small for gestational age (SGA), preterm birth, and large for gestational age (LGA). Secondary outcomes were macrosomia, cesarean delivery, and gestational diabetes mellitus. Results Of 5354 identified studies, 23 (n = 1 309 136 women) met inclusion criteria. Gestational weight gain was below or above guidelines in 23% and 47% of pregnancies, respectively. Gestational weight gain below the recommendations was associated with higher risk of SGA (OR, 1.53 [95% CI, 1.44-1.64]; ARD, 5% [95% CI, 4%-6%]) and preterm birth (OR, 1.70 [1.32-2.20]; ARD, 5% [3%-8%]) and lower risk of LGA (OR, 0.59 [0.55-0.64]; ARD, −2% [−10% to −6%]) and macrosomia (OR, 0.60 [0.52-0.68]; ARD, −2% [−3% to −1%]); cesarean delivery showed no significant difference (OR, 0.98 [0.96-1.02]; ARD, 0% [−2% to 1%]). Gestational weight gain above the recommendations was associated with lower risk of SGA (OR, 0.66 [0.63-0.69]; ARD, −3%; [−4% to −2%]) and preterm birth (OR, 0.77 [0.69-0.86]; ARD, −2% [−2% to −1%]) and higher risk of LGA (OR, 1.85 [1.76-1.95]; ARD, 4% [2%-5%]), macrosomia (OR, 1.95 [1.79-2.11]; ARD, 6% [4%-9%]), and cesarean delivery (OR, 1.30 [1.25-1.35]; ARD, 4% [3%-6%]). Gestational diabetes mellitus could not be evaluated because of the nature of available data. Conclusions and Relevance In this systematic review and meta-analysis of more than 1 million pregnant women, 47% had gestational weight gain greater than IOM recommendations and 23% had gestational weight gain less than IOM recommendations. Gestational weight gain greater than or less than guideline recommendations, compared with weight gain within recommended levels, was associated with higher risk of adverse maternal and infant outcomes.

Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies

Background. A Cochrane review in 2006 concluded that further knowledge is required before recommendation can be made with regard to progesterone in the prevention of preterm birth. Objective. To provide an update on the preventive effect of progesterone on preterm birth in singleton pregnancies. Search strategy. A search in the PubMed, Embase, and Cochrane database was performed using the keywords: pregnancy, progesterone, preterm birth/preterm delivery, preterm labor, controlled trial, and randomized controlled trial. Selection criteria. Studies on singleton pregnancies. Data collection and analysis. A meta‐analysis was performed on randomized trials including singleton pregnancies with previous preterm birth. Main results. Two new randomized controlled trials of women with previous preterm birth were added to the four analyzed in the Cochrane review, and the meta‐analysis of all six studies now showed that progesterone supplementation was associated with a significant reduction of delivery before 32 weeks and of perinatal mortality. Furthermore, a third trial showed a positive effect on women with a short cervix at 23 weeks, and a fourth study showed that progesterone reduces the risk of preterm delivery in women with preterm labor. Conclusions. In women with a singleton pregnancy and previous preterm delivery, progesterone reduces the rates of preterm delivery before 32 weeks, perinatal death, as well as respiratory distress syndrome and necrotizing enterocolitis in the newborn. Women with a short cervix or preterm labor may also benefit from progesterone, but further evidence is needed to support such a recommendation. Follow‐up studies should focus on possible metabolic complications in the mother or the offspring.

Vaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis

Progesterone treatment reduces the risk of preterm delivery in high‐risk singleton pregnancies. Our aim was to evaluate the preventive effect of vaginal progesterone in high‐risk twins.