Arthralgia in midlife Singaporean women: the Integrated Women's Health Program (IWHP).

OBJECTIVE: Arthralgia is a common menopausal complaint in midlife women, and its causes remain unclear. We examined the prevalence of menopausal arthralgia with various factors including sleep quality, depression/anxiety, muscle strength and physical performance among midlife Singaporean women. METHODS: The Integrated Women's Health Program (IWHP) comprised 1120 healthy, community-dwelling women of Chinese, Malay or Indian ethnicities (aged 45-69 years) attending well-women clinics at the National University Hospital, Singapore. Sociodemographic, menopausal, reproductive and health data were obtained with validated questionnaires. Muscle strength, physical performance and dual-energy X-ray absorptiometry were measured. Women with moderate to very severe symptoms using the Menopause Rating Scale were classified as having arthralgia. Multivariable logistic regression analyses examined risk factors for arthralgia. RESULTS: One-third of the participants reported arthralgia, and 12.7%, 16.2% and 71.2% were in the premenopausal, perimenopausal and postmenopausal period, respectively. Menopausal symptoms, such as vaginal dryness (adjusted odds ratio [aOR]: 2.64, 95% confidence interval [CI]: 1.64, 4.24) and physical/mental exhaustion (aOR: 2.83, 95% CI: 1.79, 4.47), were independent risk factors for arthralgia. Poor muscle strength (aOR: 2.20, 95% CI: 1.29, 3.76), obesity (aOR: 1.94, 95% CI: 1.13, 3.32) and rheumatoid arthritis (aOR: 7.73, 95% CI: 4.47, 13.36) were also independently associated with arthralgia after adjustment for confounders. CONCLUSIONS: Arthralgia in midlife Singaporean women was associated with menopausal symptoms of vaginal dryness and physical and mental exhaustion. Women with poor muscle strength were more likely to experience menopausal arthralgia.

Gestational Serum Retinol Deficiency Is Associated with Enamel Hypoplasia.

Enamel hypoplasia (EH) is a prevalent developmental defect of teeth that can result from various insults, including prenatal nutrient deficiencies. This study aimed to evaluate the association between prenatal serum retinol deficiency and EH in the deciduous teeth of offspring at 2-y of age. A cohort of 1,450 pregnant women was enrolled, and their prenatal nutritional status was assessed between 12 and 14 wk of gestation. Maternal serum retinol, serum 25-hydroxyvitamin D (25OHD), hemoglobin, body mass index, and birth outcomes, infant feeding practices, family socioeconomic status, and demographic information were recorded. Oral health examinations were conducted for the children semiannually, and EH was diagnosed using the Modified DDE index on all the surfaces of erupted teeth. A modified Poisson regression analysis was used to assess the cumulative risk of EH over a period of 2-y. A total of 920 (63.4%) mother-child pairs completed the study, and the cumulative EH prevalence among offspring after 2-y of follow-up was 16.5% (N = 152; 87/1,114 children in the first year and 132/920 in the second year, with 20/920 having EH only in the first year). After adjusting for potential confounders, maternal serum retinol deficiency significantly increased the risk of deciduous EH (risk ratio [RR], 2.0; 95% confidence interval [CI], 1.1-3.7). In addition, deficient serum 25OHD (RR, 6.5; 95% CI, 4.0-10.7), caesarean delivery (RR, 1.6; 95% CI, 1.0-2.4), Muslim (RR, 2.9; 95% CI, 2.0-4.1) and Christian (RR, 2.4; 95% CI, 1.6-3.5) versus Hindu religions, and very preterm birth (RR, 1.7; 95% CI, 1.1-2.9) increased the risk of EH. Children presenting with EH had 2 or more teeth affected, and the maxillary incisors were the most frequently affected, followed by the first primary molars and canines. In conclusion, maternal serum retinol deficiency during the 12 to 14 wk of gestation may increase the risk of deciduous EH, besides the well-established 25OHD deficiency.

Excess mortality after hip fracture: fracture or pre-fall comorbidity?

Comorbidity and hip fracture independently increased mortality risk for 9 years in both sexes, with a significant additive interaction in the first year among women and through 6 years among men. INTRODUCTION: Hip fracture is associated with a persistently elevated mortality risk, but it is unknown whether the elevated risk is due to the fracture or to pre-fracture comorbidity. METHODS: In a population-based study in Singapore with 9 years of follow-up, patients age > 50 with first hip fracture from 2008 to 2017 were pair-matched to a cohort without hip fracture by age, sex, ethnicity, and pre-fracture Charlson Comorbidity Index (CCI). We investigated additive interaction using the relative excess risk due to interaction (RERI) and multiplicative interaction using the ratio of relative risks. RESULTS: Twenty-two thousand five hundred ninety of 22,826 patients with a first hip fracture in 2008-2017 were successfully matched. Hip fracture and comorbidity independently increased mortality risk for 9 years in both sexes. After adjustment for comorbidity, excess mortality risk continued to persist for 9 years post-fracture in both men and women. Women with a hip fracture and pre-fracture CCI > 4 had a higher relative risk (RR) of mortality at 9 years of 3.29 [95% confidence interval (CI) 3.01, 3.59] than those without comorbidity (RR 1.51, 95%CI 1.36, 1.68) compared to the referent without hip fracture or comorbidity. An additive interaction between hip fracture and pre-fracture CCI > 4 was observed in the first post-fracture year` [relative excess risk due to interaction (RERI) 1.99, 95%CI 0.97, 3.01]. For men with CCI ≥ 4, the positive additive interaction was observed through 6 years. CONCLUSIONS: Excess mortality risks post-fracture are attributable to both the fracture and pre-fracture comorbidity. Early interventions in hip fracture patients with high comorbidity could reduce their excess mortality.

Maternal risk factors and adverse birth outcomes associated with HELLP syndrome: a population-based study.

OBJECTIVES: We assessed the incidence, risk factors and adverse birth outcomes associated with elevated liver enzymes and low platelets (HELLP) syndrome. DESIGN: A retrospective population-based cohort study. SETTING: Canada (excluding Quebec), 2012/2013-2015/2016. POPULATION: Mothers with a singleton hospital live birth or stillbirth at ≥24 weeks' gestation (n = 1 078 323). METHODS: HELLP syndrome was identified using ICD-10-CA diagnostic code from delivery hospitalisation data. We used logistic regression to identify independent risk factors for HELLP syndrome by obtaining adjusted odds ratios (AOR) and 95% confidence intervals (CI), and to assess the associations with adverse outcomes. MAIN OUTCOME MEASURES: Adverse maternal (e.g. eclampsia) and fetal/neonatal outcomes (e.g. intraventricular haemorrhage, perinatal death). RESULTS: The incidence of HELLP syndrome was 2.5 per 1000 singleton deliveries (n = 2663). Risk factors included: age ≥35 years, rural residence, nulliparity, parity ≥4, pre-pregnancy and gestational hypertension and diabetes, assisted reproduction, chronic cardiac conditions, systemic lupus erythematosus, obesity, chronic hepatic conditions, placental disorders (e.g. fetomaternal transfusion) and congenital anomalies. PROM and age <25 years were inversely associated with HELLP syndrome (P-values <0.05). Women with the syndrome had a 10-fold higher maternal mortality (95% CI 1.6-84.3) and elevated severe maternal morbidity (9.6 versus 121.7 per 1000; AOR 12.5, 95% CI 11.1-14.1); and higher perinatal mortality (4.3 versus 21.0 per 1000; AOR 4.5, 95% CI 3.5-5.9) and perinatal mortality/severe neonatal morbidity (21.2 versus 202.4 per 1000; AOR 10.7, 95% CI 9.7-11.8). CONCLUSION: HELLP syndrome is associated with specific pre-pregnancy and pregnancy risk factors, higher rates of maternal death, and substantially higher severe maternal morbidity, perinatal mortality and severe neonatal morbidity. TWEETABLE ABSTRACT: HELLP syndrome is associated with higher maternal death rate, and substantially higher severe maternal and neonatal morbidity, and perinatal mortality.

Fecundity among women with polycystic ovary syndrome (PCOS)-a population-based study.

STUDY QUESTION: Does the long-term fecundity of women with polycystic ovary syndrome (PCOS) differ from those without PCOS? SUMMARY ANSWER: Cumulative probability of childbirth is similar between women with and without PCOS. WHAT IS KNOWN ALREADY: PCOS is the main cause of anovulatory infertility in women after menarche. Previous studies indirectly suggest that fecundity in women with PCOS over the longer term may not be lower than in women without PCOS. STUDY DESIGN, SIZE, DURATION: This is a population-based study using four linked Swedish national registries. A total of 45 395 women with PCOS and 217 049 non-PCOS women were included. Follow-up began at the age of 18 years and continued for a maximum of 26 years, from 1989 to the end of 2015. Childbirth was the main outcome, as identified from the Medical Birth Register. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women born between 1971 and 1997 who were identified with a PCOS diagnosis in the Swedish Patient Registry between 1 January 2001 and 31 December 2016 were included in the study population. Five controls per women with PCOS were randomly drawn from the Total Population Registry. The control women were born in the same year and living in the same municipality as the patient. The fecundity ratio (FR) was calculated by clustered Cox regression using a robust variance, adjusted for maternal birth period, country of birth and level of education. MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative probability of childbirth was 80.2% (95% CI, 79.5-80.9%) in women with PCOS and 78.2% (95% CI, 77.9-78.5%) in those without PCOS. Adjusted FR was 0.81 (95% CI, 0.80-0.82) for first childbirth and 0.58 (95% CI, 0.57-0.60) for first childbirth following a spontaneous pregnancy. The FR for second childbirth was 0.79 (95% CI, 0.77-0.80). Women with PCOS had more than one child less frequently than the comparison group. Within the PCOS group, early age at diagnosis, later birth year, Nordic country of origin and low educational level positively influenced the FR. LIMITATIONS, REASONS FOR CAUTION: Results are not adjusted for BMI, and time from intention to conceive to first childbirth could not be captured. Data on pregnancies, miscarriages or abortions and fertility treatment are unknown for women who did not give birth during the study period. Women with PCOS who did not seek medical assistance might have been incorrectly classified as not having the disease. Such misclassification would lead to an underestimation of the true association between PCOS and outcomes. WIDER IMPLICATIONS OF THE FINDINGS: While cumulative probability of childbirth is similar between groups, women with PCOS need longer time to achieve their first childbirth. Women with PCOS have a lower FR and give birth to fewer children per woman than women without PCOS. Early diagnosis of and information about PCOS may improve affected women's reproductive potential. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Swedish Society of Medicine. Inger Sundström Poromaa has, over the past 3 years, received compensation as a consultant and lecturer for Bayer Schering Pharma, MSD, Gedeon Richter, Peptonics and Lundbeck A/S. The other authors declare no competing interests.

Hip fractures in Singapore: ethnic differences and temporal trends in the new millennium.

Despite an increase in absolute numbers, the age-standardized incidence of hip fractures in Singapore declined in the period 2000 to 2017. Among the three major ethnic groups, Chinese women had the highest fracture rates but were the only group to show a temporal decline. INTRODUCTION: A study published in 2001 predicted a 30-50% increase in Singapore hip fracture incidence rates over the ensuing 30 years. To test that prediction, we examined the incidence of hip fracture in Singapore from 2000 to 2017. METHODS: We carried out a population-based study of hip fractures among Singapore residents aged ≥ 50 years. National medical insurance claims data were used to identify admissions with a primary discharge diagnosis of hip fracture. Age-adjusted rates, based on the age distribution of the Singapore population of 2000, were analyzed separately by sex and ethnicity (Chinese, Malay, or Indian). RESULTS: Over the 18-year study period, 36,082 first hip fractures were recorded. Total hip fracture admissions increased from 1487 to 2729 fractures/year in the years 2000 to 2017. Despite this absolute increase, age-adjusted fracture rates declined, with an average annual change of - 4.3 (95% CI - 5.0, - 3.5) and - 1.1 (95% CI - 1.7, - 0.5) fractures/100,000/year for women and men respectively. Chinese women had 1.4- and 1.9-fold higher age-adjusted rates than Malay and Indian women: 264 (95% CI 260, 267) versus 185 (95% CI 176, 193) and 141 (95% CI 132, 150) fractures/100,000/year, respectively. Despite their higher fracture rates, Chinese women were the only ethnic group exhibiting a decline, most evident in those ≥ 85 years, in age-adjusted fracture rate of - 5.3 (95% CI - 6.0, - 4.5) fractures/100,000/year. CONCLUSION: Although the absolute number of fractures increased, steep drops in elderly Chinese women drove a reduction in overall age-adjusted hip fracture rates. Increases in the older population will lead to a rise in total number of hip fractures, requiring budgetary planning and new preventive strategies.

Investigating fetal growth restriction and perinatal risks in appropriate for gestational age infants: using cohort and within-sibling analyses.

OBJECTIVE: Fetal growth restriction refers to fetuses that fail to reach their growth potential. Studies within siblings may be useful to disclose fetal growth restriction in appropriate for gestational age (AGA) infants. We analysed associations between birthweight percentiles and perinatal risks in AGA infants, using both population-based and within-sibling analyses. DESIGN: Population-based cohort study. SETTING AND SAMPLE: Using nation-wide Swedish registries (1987-2012), we identified 2 134 924 singleton AGA births (10th-90th birthweight percentile for gestational age), of whom 1 377 326 were full siblings. METHODS: Unconditional Poisson regression was used for population analyses, and conditional (matched) Poisson regression for within-sibling analyses. We estimated associations between birthweight percentiles and stillbirth, neonatal mortality, and morbidity, using incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: Stillbirth and neonatal mortality risks declined with increasing birthweight percentiles, but the declines were larger in within-sibling analyses. Compared with the reference group (40th to <60th percentile), IRRs (95% CIs) of stillbirth for the lowest and highest percentile groups (10th to <25th and 75th-90th percentiles, respectively) were 1.87 (1.72-2.03) to 0.76 (0.68-0.85) in population analysis and 2.60 (2.27-2.98) and 0.43 (0.36-0.50) in within-sibling analysis. Neonatal morbidity risks in term non-malformed infants with low birthweight percentiles were generally only increased in within-sibling analyses. CONCLUSION: Using birthweight information from siblings may help to define fetal growth restriction in AGA infants. TWEETABLE ABSTRACT: Size of siblings helps to detect growth-restricted infants with seemingly normal birthweights.

Breastfeeding and long-term maternal metabolic health in the HUNT Study: a longitudinal population-based cohort study.

OBJECTIVE: Breastfeeding (BF) has been reported to improve long-term maternal metabolic health in observational studies, but not in the randomised controlled PROBIT study. Research also suggests that maternal pre-pregnant metabolic health may affect BF. We aimed to disentangle effects of BF on long-term maternal metabolic health from effects of pre-pregnant metabolic health on BF duration and long-term metabolic health. DESIGN: Longitudinal population-based cohort study. SETTING: Nord-Trøndelag county, Norway. POPULATION: Women with a first live-born baby (1987-2008) participating in the Nord-Trøndelag Health Study (HUNT). METHODS: Odds ratios (ORs) for short BF duration (<3 months) by pre-pregnant body mass index (BMI), waist circumference (WCF), blood pressures (BPs), and heart rate (HR) were adjusted for age and smoking using logistic regression. Mixed linear models were used to estimate effects of BF duration (<3, 3-6, >6 months) on mean values of metabolic health parameters from baseline to follow-up. MAIN OUTCOME MEASURES: Mean change in BMI, WCF, BPs, HR, serum-glucose, and serum-lipids from baseline to follow-up by BF duration categories. RESULTS: We analysed 1403 women with a median follow-up of 12 years (interquartile range 11-22). Pre-pregnant WCF and HR correlated inversely with BF duration. Pre-pregnant BMI had a u-shaped correlation-pattern with BF duration. We observed similar between-group differences in metabolic health parameters at baseline and at follow-up, which implies that mean change in metabolic health parameters was similar across BF groups. Those women who started out with the best health had the longest BF duration and ended up with the best health, and those women who started out with the poorest health had shortest BF duration and ended up with the poorest health. CONCLUSIONS: Our results do not support a causal relationship between long BF duration and improved metabolic health. It is more likely that pre-pregnant metabolic health affects both BF duration and long-term metabolic health. Reverse causality can explain previously observed improved long-term metabolic health after BF. TWEETABLE ABSTRACT: Breastfeeding seems not to affect long-term maternal metabolic health, but good pre-pregnant metabolic health does.

Modifiable risk factors in the first 1000 days for subsequent risk of childhood overweight in an Asian cohort: significance of parental overweight status.

BACKGROUND/OBJECTIVE: Many studies have identified early-life risk factors for subsequent childhood overweight/obesity, but few have evaluated how they combine to influence risk of childhood overweight/obesity. We examined associations, individually and in combination, of potentially modifiable risk factors in the first 1000 days after conception with childhood adiposity and risk of overweight/obesity in an Asian cohort. METHODS: Six risk factors were examined: maternal pre-pregnancy overweight/obesity (body mass index (BMI) ⩾25 kg m-2), paternal overweight/obesity at 24 months post delivery, maternal excessive gestational weight gain, raised maternal fasting glucose during pregnancy (⩾5.1 mmol l-1), breastfeeding duration <4 months and early introduction of solid foods (<4 months). Associations between number of risk factors and adiposity measures (BMI, waist-to-height ratio (WHtR), sum of skinfolds (SSFs), fat mass index (FMI) and overweight/obesity) at 48 months were assessed using multivariable regression models. RESULTS: Of 858 children followed up at 48 months, 172 (19%) had none, 274 (32%) had 1, 244 (29%) had 2, 126 (15%) had 3 and 42 (5%) had ⩾4 risk factors. Adjusting for confounders, significant graded positive associations were observed between number of risk factors and adiposity outcomes at 48 months. Compared with children with no risk factors, those with four or more risk factors had s.d. unit increases of 0.78 (95% confidence interval 0.41-1.15) for BMI, 0.79 (0.41-1.16) for WHtR, 0.46 (0.06-0.83) for SSF and 0.67 (0.07-1.27) for FMI. The adjusted relative risk of overweight/obesity in children with four or more risk factors was 11.1(2.5-49.1) compared with children with no risk factors. Children exposed to maternal pre-pregnancy (11.8(9.8-13.8)%) or paternal overweight status (10.6(9.6-11.6)%) had the largest individual predicted probability of child overweight/obesity. CONCLUSIONS: Early-life risk factors added cumulatively to increase childhood adiposity and risk of overweight/obesity. Early-life and preconception intervention programmes may be more effective in preventing overweight/obesity if they concurrently address these multiple modifiable risk factors.

Which anthropometric measures best reflect neonatal adiposity?

BACKGROUND: Studying the determinants and the long-term consequences of fetal adipose accretion requires accurate assessment of neonatal body composition. In large epidemiological studies, in-depth body composition measurement methods are usually not feasible for cost and logistical reasons, and there is a need to identify anthropometric measures that adequately reflect neonatal adiposity. METHODS: In a multiethnic Asian mother-offspring cohort in Singapore, anthropometric measures (weight, length, abdominal circumference, skinfold thicknesses) were measured using standardized protocols in newborn infants, and anthropometric indices (weight/length, weight/length2 (body mass index, BMI), weight/length3 (ponderal index, PI)) derived. Neonatal total adiposity was measured using air displacement plethysmography (ADP) and abdominal adiposity using magnetic resonance imaging (MRI). Correlations of the anthropometric measures with ADP- and MRI-based adiposity were assessed using Pearson's correlation coefficients (rp), including in subsamples stratified by sex and ethnicity. RESULTS: Study neonates (n=251) had a mean (s.d.) age of 10.2 (2.5) days. Correlations between ADP-based fat mass (ADPFM) and anthropometric measures were moderate (rp range: 0.44-0.67), with the strongest being with weight/length, weight, BMI and sum of skinfolds (rp=0.67, 0.66, 0.62, 0.62, respectively, all P<0.01). All anthropometric measures except skinfold thicknesses correlated more strongly with ADP-based fat-free mass than ADPFM, indicating that skinfold measures may have more discriminative power in terms of neonatal total body adiposity. For MRI-based measures, weight and weight/length consistently showed strong positive correlations (rp⩾0.7) with abdominal adipose tissue compartments. These correlations were consistent in boys and girls, across different ethnic groups, and when conventional determinants of neonatal adiposity were adjusted for potential confounding. Abdominal circumference was not strongly associated with ADPFM or abdominal fat mass. CONCLUSIONS: Simple anthropometric measures (weight and weight/length) correlated strongly with neonatal adiposity, with some evidence for greater discriminative power for skinfold measures. These simple measures could be of value in large epidemiological studies.

Body composition measurement in young children using quantitative magnetic resonance: a comparison with air displacement plethysmography.

BACKGROUND: Quantitative magnetic resonance (QMR) has been increasingly used to measure human body composition, but its use and validation in children is limited. OBJECTIVE: We compared body composition measurement by QMR and air displacement plethysmography (ADP) in preschool children from Singapore's multi-ethnic Asian population (n = 152; mean ± SD age: 5.0 ± 0.1 years). METHODS: Agreements between QMR-based and ADP-based fat mass and fat mass index (FMI) were assessed using intraclass correlation coefficient (ICC), reduced major axis regression and Bland-Altman plot analyses. Analyses were stratified for the child's sex. RESULTS: Substantial agreement was observed between QMR-based and ADP-based fat mass (ICC: 0.85) and FMI (ICC: 0.82). Reduced major axis regression analysis suggested that QMR measurements were generally lower than ADP measurements. Bland-Altman analysis similarly revealed that QMR-based fat mass were (mean difference [95% limits of agreement]) -0.5 (-2.1 to +1.1) kg lower than ADP-based fat mass and QMR-based FMI were -0.4 (-1.8 to +0.9) kg/m2 lower than ADP-based FMI. Stratification by offspring sex revealed better agreement of QMR and ADP measurements in girls than in boys. CONCLUSIONS: QMR-based fat mass and FMI showed substantial agreement with, but was generally lower than, ADP-based measures in young Asian children.

Maternal hyperglycemia in singleton pregnancies conceived by IVF may be modified by first-trimester BMI.

STUDY QUESTION: Does IVF independently increase the risk of gestational diabetes mellitus (GDM) and is this increase in risk modified by maternal body mass index? SUMMARY ANSWER: IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women (BMI > 25 kg/m2). WHAT IS KNOWN ALREADY: IVF has been associated with increased risk of GDM, but most previous studies did not adequately assess confounding or effect modification by other risk factors. STUDY DESIGN, SIZE, DURATION: Cross-sectional study using data from 1089 women with singleton pregnancies who participated in a Singaporean birth cohort study (GUSTO) and received a 75 g oral glucose tolerance test (OGTT) at 26-28 weeks gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1089 women (n = 1013 conceived spontaneously, n = 76 conceived through IVF) with singleton pregnancies received a 75 g OGTT at 26-28 weeks gestation. Fasting and 2 h postprandial blood glucose levels were assayed. World Health Organization criteria (1999) standard criteria were used to classify GDM: ≥7.0 mmol/L for fasting and/or ≥7.8 mmol/L for 2-h postprandial plasma glucose levels, which was the clinical guideline in use during the study. MAIN RESULTS AND THE ROLE OF CHANCE: IVF pregnancies had nearly double the odds of GDM (OR = 1.83, 95% CI: 1.03-3.26) and elevated fasting (mean difference = 0.12 mmol/L, 95% CI: 0.00-0.24) and OGTT 2-h blood glucose levels (mean difference = 0.64 mmol/L, 95% CI: 0.27-1.01), after adjusting for commonly recognized risk factors for GDM. After stratification by first-trimester BMI, these increased risks of GDM (OR = 3.54, 95% CI: 1.44-8.72) and elevated fasting (mean difference = 0.39 mmol/L, 95% CI: 0.13-0.65) and 2-h blood (mean difference = 1.24 mmol/L, 95% CI: 0.56-1.91) glucose levels were significant only in the IVF group who is also overweight or obese (BMI > 25 kg/m2). LIMITATIONS REASONS FOR CAUTION: One limitation of our study is the absence of a 1 h post-OGTT plasma glucose sample, as we were using the 1999 WHO diagnostic criteria (the clinical guideline in Singapore) at the time of our study, instead of the revised 2013 WHO diagnostic criteria. Our cohort may not be representative of the general Singapore obstetric population, although participants were recruited from the two largest maternity hospitals in the country and include both private and subsidized patients. WIDER IMPLICATIONS OF THE FINDINGS: IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women. Our findings reinforce the need to advise overweight or obese women contemplating IVF to lose weight before the procedure to reduce their risk of GDM and hyperglycemia-related adverse outcomes arising therefrom. In settings where universal GDM screening is not routine, overweight or obese women who conceive by IVF should be screened. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Program and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore (NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014). Additional funding was provided by the Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR). K.M.G. and Y.S.C. have received lecture fees from Nestle Nutrition Institute and Danone, respectively. K.M.G., Y.S.C. and S.Y.C. are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. The other authors have nothing to disclose. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Impact of stillbirths on international comparisons of preterm birth rates: a secondary analysis of the WHO multi-country survey of Maternal and Newborn Health.

OBJECTIVE: To evaluate the extent to which stillbirths affect international comparisons of preterm birth rates in low- and middle-income countries. DESIGN: Secondary analysis of a multi-country cross-sectional study. SETTING: 29 countries participating in the World Health Organization Multicountry Survey on Maternal and Newborn Health. POPULATION: 258 215 singleton deliveries in 286 hospitals. METHODS: We describe how inclusion or exclusion of stillbirth affect rates of preterm births in 29 countries. MAIN OUTCOME MEASURES: Preterm delivery. RESULTS: In all countries, preterm birth rates were substantially lower when based on live births only, than when based on total births. However, the increase in preterm birth rates with inclusion of stillbirths was substantially higher in low Human Development Index (HDI) countries [median 18.2%, interquartile range (17.2-34.6%)] compared with medium (4.3%, 3.0-6.7%), and high-HDI countries (4.8%, 4.4-5.5%). CONCLUSION: Inclusion of stillbirths leads to higher estimates of preterm birth rate in all countries, with a disproportionately large effect in low-HDI countries. Preterm birth rates based on live births alone do not accurately reflect international disparities in perinatal health; thus improved registration and reporting of stillbirths are necessary. TWEETABLE ABSTRACT: Inclusion of stillbirths increases preterm birth rates estimates, especially in low-HDI countries.

Postnatal height and adiposity gain, childhood blood pressure and prehypertension risk in an Asian birth cohort.

OBJECTIVE: There have been hypotheses that early life adiposity gain may influence blood pressure (BP) later in life. We examined associations between timing of height, body mass index (BMI) and adiposity gains in early life with BP at 48 months in an Asian pregnancy-birth cohort. METHODS: In 719 children, velocities for height, BMI and abdominal circumference (AC) were calculated at five intervals [0-3, 3-12, 12-24, 24-36 and 36-48 months]. Triceps (TS) and subscapular skinfold (SS) velocities were calculated between 0-18, 18-36 and 36-48 months. Systolic (SBP) and diastolic blood pressure (DBP) was measured at 48 months. Growth velocities at later periods were adjusted for growth velocities in preceding intervals, as well as measurements at birth. RESULTS: After adjusting for confounders and child height at BP measurement, each unit z-score gain in BMI, AC, TS and SS velocities at 36-48 months were associated with 2.3 (95% CI:1.6, 3.1), 2.1 (1.3, 2.8), 1.4 (0.6, 2.2) and 1.8 (1, 2.6) mmHg higher SBP respectively, and 0.9 (0.4, 1.4), 0.9 (0.4, 1.3), 0.6 (0.1, 1.1) and 0.8 (0.3, 1.3) mmHg higher DBP respectively. BMI and adiposity velocities (AC, TS or SS) at various intervals in the first 36 months however, were not associated with BP. Faster BMI, AC, TS and SS velocities, but not height, at 36-48 months were associated with 0.22 (0.15, 0.29), 0.17 (0.10, 0.24), 0.11 (0.04, 0.19) and 0.15 (0.08, 0.23) units higher SBP z-score respectively, and OR=1.46 (95% CI: 1.13-1.90), 1.49 (1.17-1.92), 1.45 (1.09-1.92) and 1.43 (1.09, 1.88) times higher risk of prehypertension/hypertension respectively at 48 months. CONCLUSIONS: Our results indicated that faster BMI and adiposity (AC, TS or SS) velocities only at the preceding interval before 48 months (36-48 months), but not at earlier intervals in the first 36 months, are predictive of BP and prehypertension/hypertension at 48 months.

Maternal influenza and birth outcomes: systematic review of comparative studies.

BACKGROUND: Although pregnant women are considered at high risk for severe influenza disease, comparative studies of maternal influenza and birth outcomes have not been comprehensively summarised. OBJECTIVE: To review comparative studies evaluating maternal influenza disease and birth outcomes. SEARCH STRATEGY: We searched bibliographic databases from inception to December 2014. SELECTION CRITERIA: Studies of preterm birth, small-for-gestational-age (SGA) birth or fetal death, comparing women with and without clinical influenza illness or laboratory-confirmed influenza infection during pregnancy. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data and assessed study quality. MAIN RESULTS: Heterogeneity across 16 studies reporting preterm birth precluded meta-analysis. In a subgroup of the highest-quality studies, two reported significantly increased preterm birth (risk ratios (RR) from 2.4 to 4.0) following severe 2009 pandemic H1N1 (pH1N1) influenza illness, whereas those assessing mild-to-moderate pH1N1 or seasonal influenza found no association. Five studies of SGA birth showed no discernible patterns with respect to influenza disease severity (pooled odds ratio 1.24; 95% CI 0.96-1.59). Two fetal death studies were of sufficient quality and size to permit meaningful interpretation. Both reported an increased risk of fetal death following maternal pH1N1 disease (RR 1.9 for mild-to-moderate disease and 4.2 for severe disease). CONCLUSIONS: Comparative studies of preterm birth, SGA birth and fetal death following maternal influenza disease are limited in number and quality. An association between severe pH1N1 disease and preterm birth and fetal death was reported by several studies; however, these limited data do not permit firm conclusions on the magnitude of any association. TWEETABLE ABSTRACT: Comparative studies are limited in quality but suggest severe pandemic H1N1 influenza increases preterm birth.

Variations in very preterm birth rates in 30 high-income countries: are valid international comparisons possible using routine data?

OBJECTIVE: Concerns about differences in registration practices across countries have limited the use of routine data for international very preterm birth (VPT) rate comparisons. DESIGN: Population-based study. SETTING: Twenty-seven European countries, the United States, Canada and Japan in 2010. POPULATION: A total of 9 376 252 singleton births. METHOD: We requested aggregated gestational age data on live births, stillbirths and terminations of pregnancy (TOP) before 32 weeks of gestation, and information on registration practices for these births. We compared VPT rates and assessed the impact of births at 22-23 weeks of gestation, and different criteria for inclusion of stillbirths and TOP on country rates and rankings. MAIN OUTCOME MEASURES: Singleton very preterm birth rate, defined as singleton stillbirths and live births before 32 completed weeks of gestation per 1000 total births, excluding TOP if identifiable in the data source. RESULTS: Rates varied from 5.7 to 15.7 per 1000 total births and 4.0 to 11.9 per 1000 live births. Country registration practices were related to percentage of births at 22-23 weeks of gestation (between 1% and 23% of very preterm births) and stillbirths (between 6% and 40% of very preterm births). After excluding births at 22-23 weeks, rate variations remained high and with a few exceptions, country rankings were unchanged. CONCLUSIONS: International comparisons of very preterm birth rates using routine data should exclude births at 22-23 weeks of gestation and terminations of pregnancy. The persistent large rate variations after these exclusions warrant continued surveillance of VPT rates at 24 weeks and over in high-income countries. TWEETABLE ABSTRACT: International comparisons of VPT rates should exclude births at 22-23 weeks of gestation and terminations of pregnancy.

Small-for-gestational-age birth and maternal plasma antioxidant levels in mid-gestation: a nested case-control study.

OBJECTIVE: To assess whether maternal plasma antioxidant levels in mid-pregnancy are associated with small-for-gestational-age (SGA) birth. DESIGN: Case-control study nested within a population-based cohort study. SETTING: Four hospitals in Montreal, Canada. POPULATION: Pregnant women recruited before 24 weeks of gestation, whose pregnancies were not complicated by pre-eclampsia or preterm delivery. METHODS: Blood samples were obtained at 24-26 weeks and assayed for nutritionally derived antioxidant levels in SGA cases (n = 324) and randomly selected controls with birthweights between the 25th and 75th centiles (n = 672). We performed logistic regression analyses using the standardised z-score of each antioxidant as the main independent variable, after summing highly correlated antioxidants or combining via principle component analysis. We adjusted for risk factors for SGA that were associated with antioxidant levels. MAIN OUTCOME MEASURES: SGA, birthweight <10th centile for gestational age and sex. RESULTS: Retinol was positively associated with risk of SGA (adjusted odds ratio [OR] 1.41; 95% confidence interval [95% CI] 1.22-1.63, per SD increase). Carotenoids (log of the sum of ß-carotene, lutein/zeaxanthin, α- and ß-cryptoxanthin) were negatively associated with SGA (adjusted OR 0.64; 95% CI 0.54-0.78, per SD increase). We found no significant associations between SGA and lycopene or any of the forms of vitamin E assessed, including α-tocopherol, corrected α-tocopherol (per nmol/l of low-density lipoprotein articles), or γ-tocopherol. CONCLUSIONS: Elevated retinol may be associated with an increased risk of SGA, whereas elevated carotenoid levels may reduce the risk. A better understanding of the nature of these associations is required, however, before recommending specific nutritional interventions in an attempt to prevent SGA birth.

Breast-feeding and health consequences in early childhood: is there an impact of time-dependent confounding?

BACKGROUND: Estimated effects of breast-feeding on childhood health vary between studies, possibly due to confounding by baseline maternal and child characteristics. Possible time-dependent confounding has received little consideration. Our aim was to evaluate the impact of such confounding. METHODS: We estimated the relationship between cumulative exclusive breast-feeding up to 6 months and wheezing, rash and body mass index (BMI) at 12 months [in the Whistler cohort (n = 494) and PROBIT (n = 11,463)], and wheezing, rash, asthma, hay fever, eczema, allergy and BMI at age 6.5 years (PROBIT). We adjusted for time-dependent confounding by weight, length, rash, respiratory illness and day care attendance using marginal structural models (MSMs). RESULTS: Weight and day care attendance appeared potential time-dependent confounders, since these predicted breast-feeding status and were influenced by previous breast-feeding. However, adjustment for time-dependent confounders did not markedly change the estimated associations. For example, in PROBIT the adjusted increase in BMI at 12 months per 1-month increase in exclusive breast-feeding was 0.04 (95% CI -0.09 to 0.01) using logistic regression and -0.06 (95% CI -0.11 to -0.01) using MSM. In Whistler, these estimates were each -0.05 (95% CI -0.10 to 0.00). CONCLUSIONS: In two cohort studies, there was little evidence of time-dependent confounding by weight, length, rash, respiratory illness or day care attendance of the effects of breast-feeding on early childhood health.