The effect of endometriosis on live birth rate and other reproductive outcomes in ART cycles: a cohort study

Study question: What is the effect of endometriosis compared to unexplained subfertility on live birth rate in women undergoing IVF and embryo transfer (ET)? Summary answer: Endometriosis decreases live birth rate in women undergoing IVF-ET treatment, particularly with increasing severity of the disease. What is known already: Endometriosis affects up to 50% of women seeking fertility treatment and is known to reduce fecundity. There remains a debate as to effects of endometriosis on the outcomes of IVF treatment, with live birth being a secondary outcome or not reported in most studies. Study design, size, duration: A retrospective cohort study analyzing data of IVF treatment cycles from January 2000 to December 2014 was carried out. Participants/materials, setting, methods: Women with endometriosis (n = 531) and women with unexplained subfertility (n = 737) undergoing a first cycle of IVF-ET in a tertiary fertility treatment center were included in the study. The primary outcome was live birth. Other outcome measures were response to ovarian stimulation, embryo development and implantation rate. Bivariate and multivariate logistic regression analysis was performed and differences compared using Chi squared test of Student’s t-test as appropriate. Main results and the role of chance: Women with endometriosis had 24% less likelihood of a live birth when compared to those with unexplained subfertility [odds ratio (OR) 0.76 (95% CI, 0.59–0.98) P = 0.035]. This effect became more apparent with increasing severity of endometriosis. Using multivariable logistic regression analysis, the trend for lower live birth rate remained but did not reach statistical significance [adjusted OR 0.76 (95% CI 0.56–1.03), P = 0.078]. Women with endometriosis were as likely as those with unexplained subfertility to have a singleton live birth when two embryos were transferred as opposed to a single ET [OR 1.38 (95% CI 0.73–2.62), P = 0.32 and OR 3.22 (95% CI 1.7–6.05), P = 0.0003, respectively]. Compared to women with unexplained subfertility, those with endometriosis had fewer oocytes retrieved [(10.54 (95% CI 10.13–0.95) and 9.15 (95% CI 8.69–9.6), respectively], lower blastocyst transfer [OR 0.24 (95% CI 0.12–0.5), P = 0.0001] and a significantly reduced implantation rate [OR 0.73 (0.58–0.92), P = 0.007]. Limitations reasons for caution: The study is limited by a retrospective design. By limiting the study to a single ET cycle, it was not possible to assess the cumulative outcome including use of all frozen embryos. Wider implications of the findings: Endometriosis has similar phenotypes among women in different populations and would be expected to have a similar effect on fertility. These results are therefore generalizable to other populations of women. Study funding/competing interest(s): None. Trial registration number: Not applicable

A Competing-Risk Approach for Modeling Length of Stay in Severe Malaria Patients in South-East Asia and the Implications for Planning of Hospital Services.

Background: Management of severe malaria with limited resources requires comprehensive planning. Expected length of stay (LOS) and the factors influencing it are useful in the planning and optimisation of service delivery. Methods: A secondary, competing-risk approach to survival analysis was performed for 1217 adult severe malaria patients from the South-East Asia Quinine Artesunate Malaria Trial. Results: Twenty percent of patients died; 95.4% within 7 days compared to 70.3% of those who were discharged. Median time to discharge was 6 days. Compared to quinine, artesunate increased discharge incidence (subdistribution-Hazard ratio, 1.24; [95% confidence interval 1.09-1.40]; P = .001) and decreased incidence of death (0.60; [0.46-0.80]; P < .001). Low Glasgow coma scale (discharge, 1.08 [1.06-1.11], P < .001; death, 0.85 [0.82-0.89], P < .001), high blood urea-nitrogen (discharge, 0.99 [0.99-0.995], P < .001; death, 1.00 [1.00-1.01], P = .012), acidotic base-excess (discharge, 1.05 [1.03-1.06], P < .001; death, 0.90 [0.88-0.93], P < .001), and development of shock (discharge, 0.25 [0.13-0.47], P < .001; death, 2.14 [1.46-3.12], P < .001), or coma (discharge, 0.46 [0.32-0.65], P < .001; death, 2.30 [1.58-3.36], P < .001) decreased cumulative incidence of discharge and increased incidence of death. Conventional Kaplan-Meier survival analysis overestimated cumulative incidence compared to competing-risk model. Conclusions: Clinical factors on admission and during hospitalisation influence LOS in severe malaria, presenting targets to improve health and service efficiency. Artesunate has the potential to increase LOS, which should be accounted for when planning services. In-hospital death is a competing risk for discharge; an important consideration in LOS models to reduce overestimation of risk and misrepresentation of associations

Secondary sex ratio in assisted reproduction: an analysis of 1 376 454 treatment cycles performed in the UK.

STUDY QUESTION: Does ART impact the secondary sex ratio (SSR) when compared to natural conception? SUMMARY ANSWER: IVF and ICSI as well as the stage of embryo transfer does impact the overall SSR. WHAT IS KNOWN ALREADY: The World Health Organization quotes SSR for natural conception to range between 103 and 110 males per 100 female births. STUDY DESIGN SIZE DURATION: A total of 1 376 454 ART cycles were identified, of which 1 002 698 (72.8%) cycles involved IVF or ICSI. Of these, 863 859 (85.2%) were fresh cycles and 124 654 (12.4%) were frozen cycles. Missing data were identified in 14 185 (1.4%) cycles. PARTICIPANTS/MATERIALS SETTING METHODS: All cycles recorded in the anonymized UK Human Fertilisation and Embryology Authority (HFEA) registry database between 1991 and 2016 were analysed. All singleton live births were included, and multiple births were excluded to avoid duplication. MAIN RESULTS AND THE ROLE OF CHANCE: The overall live birth rate per cycle for all IVF and ICSI treatments was 26.2% (n = 262 961), and the singleton live birth rate per cycle was 17.1% (n = 171 399). The overall SSR for this study was 104.0 males per 100 female births (binomial exact 95% CI: 103.1-105.0) for all IVF and ICSI cycles performed in the UK recorded through the HFEA. This was comparable to the overall SSR for England and Wales at 105.3 males per 100 female births (95% CI: 105.2-105.4) from 1991 to 2016 obtained from the Office of National Statistics database. Male predominance was seen with conventional insemination in fresh IVF treatment cycles (SSR 110.0 males per 100 female births; 95% CI: 108.6-111.5) when compared to micro-injection in fresh ICSI treatment cycles (SSR 97.8 males per 100 female births; 95% CI: 96.5-99.2; odds ratio (OR) 1.16, 95% CI 1.12-1.19, P < 0.0001), as well as with blastocyst stage embryo transfers (SSR 104.8 males per 100 female births; 95% CI: 103.5-106.2) when compared to a cleavage stage embryo transfer (SSR 101.2 males per 100 female births; 95% CI: 99.3-103.1; OR 1.03, 95% CI 1.01-1.06, P = 0.011) for all fertilization methods. LIMITATIONS REASONS FOR CAUTION: The quality of the data relies on the reporting system. Furthermore, success rates through ART have improved since 1991, with an increased number of blastocyst stage embryo transfers. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to date evaluating the impact of ART on SSR. The results demonstrate that, overall, ART does have an impact on the SSR when assessed according to the method of fertilization (ICSI increased female births while IVF increased males). However, given the ratio of IVF to ICSI cycles at present with 60% of cycles from IVF and 40% from ICSI, the overall SSR for ART closely reflects the population SSR for, largely, natural conceptions in England and Wales. STUDY FUNDING/COMPETING INTERESTS: The study received no funding. C.M.B. is a member of the independent data monitoring group for a clinical endometriosis trial by ObsEva. He is on the scientific advisory board for Myovant and medical advisory board for Flo Health. He has received research grants from Bayer AG, MDNA Life Sciences, Volition Rx and Roche Diagnostics as well as from Wellbeing of Women, Medical Research Council UK, the NIH, the UK National Institute for Health Research and the European Union. He is the current Chair of the Endometriosis Guideline Development Group for ESHRE and was a co-opted member of the Endometriosis Guideline Group by the UK National Institute for Health and Care Excellence (NICE). I.G. has received research grants from Wellbeing of Women, the European Union and Finox. TRIAL REGISTRATION NUMBER: Not applicable

Femur-Sparing Pattern of Abnormal Fetal Growth in Pregnant Women from New York City After Maternal Zika Virus Infection

BACKGROUND: Zika virus (ZIKV) is a mosquito-transmitted flavivirus, which can induce fetal brain injury and growth restriction following maternal infection during pregnancy. Prenatal diagnosis of ZIKV-associated fetal injury in the absence of microcephaly is challenging due to an incomplete understanding of how maternal ZIKV infection affects fetal growth and the use of different sonographic reference standards around the world. We hypothesized that skeletal growth is unaffected by ZIKV infection and that the femur length can represent an internal standard to detect growth deceleration of the fetal head and/or abdomen by ultrasound. OBJECTIVE: To determine if maternal ZIKV infection is associated with a femur-sparing pattern of intrauterine growth restriction (IUGR) through analysis of fetal biometric measures and/or body ratios using the INTERGROWTH-21st Project (IG-21) and World Health Organization Fetal Growth Chart (WHO-FGC) sonographic references. STUDY DESIGN: Pregnant women diagnosed with a possible recent ZIKV infection at Columbia University Medical Center after traveling to an endemic area were retrospectively identified and included if a fetal ultrasound was performed. Data was collected regarding ZIKV testing, fetal biometry, pregnancy and neonatal outcomes. The IG-21 and WHO-FGC sonographic standards were applied to obtain Z-scores and/or percentiles for fetal head, abdominal circumference (HC, AC) and femur length (FL) specific for each gestational week. A novel IG-21 standard was also developed to generate Z-scores for fetal body ratios with respect to femur length (HC:FL, AC:FL). Data was then grouped within clinically relevant gestational age strata (34 weeks) to analyze time-dependent effects of ZIKV infection on fetal size. Statistical analysis was performed using Wilcoxon signed-rank test on paired data, comparing either AC or HC to FL. RESULTS: A total of 56 pregnant women were included in the study with laboratory evidence of a confirmed or possible recent ZIKV infection. Based on the CDC definition for microcephaly after congenital ZIKV exposure, microcephaly was diagnosed in 5% (3/56) by both the IG-21 and WHO-FGC standards (HC Z-score ≤ -2 or ≤ 2.3%). Using IG-21, IUGR was diagnosed in 18% of pregnancies (10/56; AC Z-score ≤-1.3, <10%). Analysis of fetal size using the last ultrasound scan for all subjects revealed a significantly abnormal skewing of fetal biometrics with a smaller AC versus FL by either IG-21 or WHO-FGC (p<0.001 for both). A difference in distribution of fetal AC compared to FL was first apparent in the 24-27 6/7 week strata (IG-21, p=0.002; WHO-FGC, p=0.001). A significantly smaller HC compared to FL was also observed by IG-21 as early as the 28-33 6/7 week strata (IG-21, p=0.007). Overall, a femur-sparing pattern of growth restriction was detected in 52% of pregnancies with either an HC:FL or AC:FL fetal body ratio less than the 10th percentile (IG-21 Z-score ≤-1.3). CONCLUSIONS: An unusual femur-sparing pattern of fetal growth restriction was detected in the majority of fetuses with congenital ZIKV exposure. Fetal body ratios may represent a more sensitive ultrasound biomarker to detect viral injury in nonmicrocephalic fetuses that could impart long-term risk for complications of congenital ZIKV infection

International standards for fetal brain structures based on serial ultrasound measurements from the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project.

OBJECTIVE: To create prescriptive growth standards for five fetal brain structures, measured by ultrasound, from healthy, well-nourished women, at low risk of impaired fetal growth and poor perinatal outcomes, taking part in the Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21st Project. METHODS: This was a complementary analysis of a large, population-based, multicentre, longitudinal study. We measured, in planes reconstructed from 3-dimensional (3D) ultrasound volumes of the fetal head at different time points in pregnancy, the size of the parieto-occipital fissure (POF), Sylvian fissure (SF), anterior horn of the lateral ventricle (AV), atrium of the posterior ventricle (PV) and cisterna magna (CM). The sample analysed was randomly selected from the overall FGLS population, ensuring an equal distribution amongst the eight diverse participating sites and of 3D ultrasound volumes across pregnancy (range: 15 - 36 weeks' gestation). Fractional polynomials were used to the construct standards. Growth and development of the infants were assessed at 1 and 2 years of age to confirm their adequacy for constructing international standards. RESULTS: From the entire FGLS cohort of 4321 women, 451 (10.4%) were randomly selected. After exclusions, 3D ultrasound volumes from 442 fetuses born without congenital malformations were used to create the charts. The fetal brain structures of interest were identified in 90% of cases. All structures showed increasing size with gestation and increasing variability for the POF, SF, PV and CM. The 3rd , 5th , 50th , 95th and 97th smoothed centile are presented. The 5th centile of POF and SF were 2.8 and 4.3 at 22 weeks and 4.2 and 9.4mm at 32 weeks respectively. The 95th centile of PV and CM were 8.5 and 7.4 at 22 weeks and 8.5 and 9.4mm at 32 weeks respectively. CONCLUSIONS: We have produced prescriptive size standards for fetal brain structures based on prospectively enrolled pregnancies at low risk of abnormal outcomes. We recommend these as international standards for the assessment of measurements obtained by ultrasound from fetal brain structures

International standards for early fetal size and pregnancy dating based on ultrasound measurement of crown-rump length in the first trimester of pregnancy.

OBJECTIVES: There are no international standards for relating fetal crown-rump length (CRL) to gestational age (GA), and most existing charts have considerable methodological limitations. The INTERGROWTH-21(st) Project aimed to produce the first international standards for early fetal size and ultrasound dating of pregnancy based on CRL measurement. METHODS: Urban areas in eight geographically diverse countries that met strict eligibility criteria were selected for the prospective, population-based recruitment, between 9 + 0 and 13 + 6 weeks' gestation, of healthy well-nourished women with singleton pregnancies at low risk of fetal growth impairment. GA was calculated on the basis of a certain last menstrual period, regular menstrual cycle and lack of hormonal medication or breastfeeding in the preceding 2 months. CRL was measured using strict protocols and quality-control measures. All women were followed up throughout pregnancy until delivery and hospital discharge. Cases of neonatal and fetal death, severe pregnancy complications and congenital abnormalities were excluded from the study. RESULTS: A total of 4607 women were enrolled in the Fetal Growth Longitudinal Study, one of the three main components of the INTERGROWTH-21(st) Project, of whom 4321 had a live singleton birth in the absence of severe maternal conditions or congenital abnormalities detected by ultrasound or at birth. The CRL was measured in 56 women at < 9 + 0 weeks' gestation; these were excluded, resulting in 4265 women who contributed data to the final analysis. The mean CRL and SD increased with GA almost linearly, and their relationship to GA is given by the following two equations (in which GA is in days and CRL in mm): mean CRL = -50.6562 + (0.815118 × GA) + (0.00535302 × GA(2) ); and SD of CRL = -2.21626 + (0.0984894 × GA). GA estimation is carried out according to the two equations: GA = 40.9041 + (3.21585 × CRL(0.5) ) + (0.348956 × CRL); and SD of GA = 2.39102 + (0.0193474 × CRL). CONCLUSIONS: We have produced international prescriptive standards for early fetal linear size and ultrasound dating of pregnancy in the first trimester that can be used throughout the world

Effect of High Fiber Cereal Intake on Satiety and Gastrointestinal Symptoms during Ramadan.

(1) Background: Fasting during Ramadan involves large changes in daily eating patterns which strongly impacts the daily biorhythm and challenges the regular function of the digestive tract. The aim of this study was to assess satiety, bowel habits, body composition, blood glycaemia, and blood lipidemia after the consumption of high fiber cereal at dawn (Sohor) during the month of Ramadan; (2) Methods: A two-arm randomized, controlled, single-blinded, parallel-design study was conducted in Ramadan month. Participants were randomized to consume either 90 g of high fiber cereal (11 g fiber/90 g) at Sohor for 20 consecutive days (intervention group, n = 45) or to maintain their habitual diet intake (control group; n = 36); (3) Results: The intervention group reported higher satiety rating scores, improved bowel habits and reduced bloating frequency after the 20-day intervention. Significantly higher intake of carbohydrates and dietary fiber were observed in the intervention group. Total cholesterol and low density lipoprotein (LDL) cholesterol were significantly lower among the intervention group compared to the control group (p-value = 0.043, and p-value = 0.033, respectively) at the end of the intervention. No significant differences in body weight, body fat percentage, waist circumference, body mass index, blood glucose, high density lipoprotein (HDL) cholesterol, and triglycerides were observed between the two groups; (4) Conclusions: Consuming high fiber cereal had a positive effect on health and well-being during the month of Ramadan with better satiety, improved bowel functions, and improved blood lipids

Two-Dimensional Echocardiography Estimates of Fetal Ventricular Mass throughout Gestation.

BACKGROUND: Two-dimensional (2D) ultrasound quality has improved in recent years. Quantification of cardiac dimensions is important to screen and monitor certain fetal conditions. We assessed the feasibility and reproducibility of fetal ventricular measures using 2D echocardiography, reported normal ranges in our cohort, and compared estimates to other modalities. METHODS: Mass and end-diastolic volume were estimated by manual contouring in the four-chamber view using TomTec Image Arena 4.6 in end diastole. Nomograms were created from smoothed centiles of measures, constructed using fractional polynomials after log transformation. The results were compared to those of previous studies using other modalities. RESULTS: A total of 294 scans from 146 fetuses from 15+0 to 41+6 weeks of gestation were included. Seven percent of scans were unanalysable and intraobserver variability was good (intraclass correlation coefficients for left and right ventricular mass 0.97 [0.87-0.99] and 0.99 [0.95-1.0], respectively). Mass and volume increased exponentially, showing good agreement with 3D mass estimates up to 28 weeks of gestation, after which our measurements were in better agreement with neonatal cardiac magnetic resonance imaging. There was good agreement with 4D volume estimates for the left ventricle. CONCLUSION: Current state-of-the-art 2D echocardiography platforms provide accurate, feasible, and reproducible fetal ventricular measures across gestation, and in certain circumstances may be the modality of choice

Randomized Interventional Study on Prediction of Preeclampsia/Eclampsia in Women With Suspected Preeclampsia: INSPIRE.

The ratio of maternal serum sFlt-1 (soluble fms-like tyrosine kinase 1) to PlGF (placental growth factor) has been used retrospectively to rule out the occurrence of preeclampsia, a pregnancy hypertensive disorder, within 7 days in women presenting with clinical suspicion of preeclampsia. A prospective, interventional, parallel-group, randomized clinical trial evaluated the use of sFlt-1/PlGF ratio in women presenting with suspected preeclampsia. Women were assigned to reveal (sFlt-1/PlGF result known to clinicians) or nonreveal (result unknown) arms. A ratio cutoff of 38 was used to define low (≤38) and elevated risk (>38) of developing the condition in the subsequent week. The primary end point was hospitalization within 24 hours of the test. Secondary end points were development of preeclampsia and other adverse maternal-fetal outcomes. We recruited 370 women (186 reveal versus 184 nonreveal). Preeclampsia occurred in 85 women (23%). The number of admissions was not significantly different between groups (n=48 nonreveal versus n=60 reveal; P=0.192). The reveal trial arm admitted 100% of the cases that developed preeclampsia within 7 days, whereas the nonreveal admitted 83% (P=0.038). Use of the test yielded a sensitivity of 100% (95% CI, 85.8-100) and a negative predictive value of 100% (95% CI, 97.1-100) compared with a sensitivity of 83.3 (95% CI, 58.6-96.4) and negative predictive value of 97.8 (95% CI, 93.7-99.5) with clinical practice alone. Use of the sFlt-1/PlGF ratio significantly improved clinical precision without changing the admission rate. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN87470468

International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project

Background: In 2006, WHO produced international growth standards for infants and children up to age 5 years on the basis of recommendations from a WHO expert committee. Using the same methods and conceptual approach, the Fetal Growth Longitudinal Study (FGLS), part of the INTERGROWTH-21st Project, aimed to develop international growth and size standards for fetuses. Methods: The multicentre, population-based FGLS assessed fetal growth in geographically defined urban populations in eight countries, in which most of the health and nutritional needs of mothers were met and adequate antenatal care was provided. We used ultrasound to take fetal anthropometric measurements prospectively from 14 weeks and 0 days of gestation until birth in a cohort of women with adequate health and nutritional status who were at low risk of intrauterine growth restriction. All women had a reliable estimate of gestational age confirmed by ultrasound measurement of fetal crown–rump length in the first trimester. The five primary ultrasound measures of fetal growth—head circumference, biparietal diameter, occipitofrontal diameter, abdominal circumference, and femur length—were obtained every 5 weeks (within 1 week either side) from 14 weeks to 42 weeks of gestation. The best fitting curves for the five measures were selected using second-degree fractional polynomials and further modelled in a multilevel framework to account for the longitudinal design of the study. Findings: We screened 13 108 women commencing antenatal care at less than 14 weeks and 0 days of gestation, of whom 4607 (35%) were eligible. 4321 (94%) eligible women had pregnancies without major complications and delivered live singletons without congenital malformations (the analysis population). We documented very low maternal and perinatal mortality and morbidity, confirming that the participants were at low risk of adverse outcomes. For each of the five fetal growth measures, the mean differences between the observed and smoothed centiles for the 3rd, 50th, and 97th centiles, respectively, were small: 2·25 mm (SD 3·0), 0·02 mm (3·0), and −2·69 mm (3·2) for head circumference; 0·83 mm (0·9), −0·05 mm (0·8), and −0·84 mm (1·0) for biparietal diameter; 0·63 mm (1·2), 0·04 mm (1·1), and −1·05 mm (1·3) for occipitofrontal diameter; 2·99 mm (3·1), 0·25 mm (3·2), and −4·22 mm (3·7) for abdominal circumference; and 0·62 mm (0·8), 0·03 mm (0·8), and −0·65 mm (0·8) for femur length. We calculated the 3rd, 5th 10th, 50th, 90th, 95th and 97th centile curves according to gestational age for these ultrasound measures, representing the international standards for fetal growth. Interpretation: We recommend these international fetal growth standards for the clinical interpretation of routinely taken ultrasound measurements and for comparisons across populations. Funding: Bill & Melinda Gates Foundation