The Born in Guangzhou Cohort Study enables generational genetic discoveries.

Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health1. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study2 (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.

Genome-wide association and Mendelian randomisation analysis among 30,699 Chinese pregnant women identifies novel genetic and molecular risk factors for gestational diabetes and glycaemic traits.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is the most common disorder in pregnancy; however, its underlying causes remain obscure. This study aimed to investigate the genetic and molecular risk factors contributing to GDM and glycaemic traits. METHODS: We collected non-invasive prenatal test (NIPT) sequencing data along with four glycaemic and 55 biochemical measurements from 30,699 pregnant women during a 2 year period at Shenzhen Baoan Women's and Children's Hospital in China. Genome-wide association studies (GWAS) were conducted between genotypes derived from NIPTs and GDM diagnosis, baseline glycaemic levels and glycaemic levels after glucose challenges. In total, 3317 women were diagnosed with GDM, while 19,565 served as control participants. The results were replicated using two independent cohorts. Additionally, we performed one-sample Mendelian randomisation to explore potential causal associations between the 55 biochemical measurements and risk of GDM and glycaemic levels. RESULTS: We identified four genetic loci significantly associated with GDM susceptibility. Among these, MTNR1B exhibited the highest significance (rs10830963-G, OR [95% CI] 1.57 [1.45, 1.70], p=4.42×10-29), although its effect on type 2 diabetes was modest. Furthermore, we found 31 genetic loci, including 14 novel loci, that were significantly associated with the four glycaemic traits. The replication rates of these associations with GDM, fasting plasma glucose levels and 0 h, 1 h and 2 h OGTT glucose levels were 4 out of 4, 6 out of 9, 10 out of 11, 5 out of 7 and 4 out of 4, respectively. Mendelian randomisation analysis suggested that a genetically regulated higher lymphocytes percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with elevated glucose levels and an increased risk of GDM. CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic basis of GDM and glycaemic traits during pregnancy in an East Asian population and highlight the potential role of inflammatory pathways in the aetiology of GDM and variations in glycaemic levels. DATA AVAILABILITY: Summary statistics for GDM; fasting plasma glucose; 0 h, 1 h and 2h OGTT; and the 55 biomarkers are available in the GWAS Atlas (study accession no.: GVP000001, https://ngdc.cncb.ac.cn/gwas/browse/GVP000001) .

Association and mediation pathways of maternal hyperglycaemia and liability to gestational diabetes with neonatal outcomes: A two-sample Mendelian randomization study.

AIMS: Maternal hyperglycemia is linked to adverse neonatal outcomes. However, current evidence was insufficient for mechanistic pathways. We aim to use two-sample Mendelian randomization (MR) to obtain a comprehensive understanding of the causal association and mediation pathways. MATERIALS AND METHODS: Genetic variants of fasting glucose (FG), insulin sensitivity index (ISI), glycated haemoglobin (HbA1c), gestational diabetes mellitus (GDM) and type 2 diabetes (T2D) were used as instruments (N = 50 404-898 130). The associations with offspring birthweight, gestational duration, spontaneous preterm and post-term birth were assessed by the inverse-variance weighted method, using summary statistics of European genome-wide association studies (N = 131 279-210 248). Sensitivity analyses, including multivariable MR removing pleiotropic effect from maternal body mass index (BMI), assessed the robustness. Mediation via placental weight and maternal hypertension were assessed via a two-step MR design. RESULTS: FG (0.46 SD per mmol/L, 95% confidence interval [95% CI]: 0.32, 0.61) and GDM liability (0.18 SD per log odds, 95% CI: 0.08, 0.18) were positively associated with birthweight, with consistent findings for HbA1c, T2D liability and ISI. These associations were mediated by placental weight (proportion mediated: 32.8% to 77.7%). Higher HbA1c, GDM and T2D liability were associated with preterm birth (odds ratios for GDM: 1.07, 95% CI: 1.01, 1.14) and shorter gestational duration, whilst the association for T2D attenuated after adjusted for maternal BMI and gestational hypertension. CONCLUSION: Maternal hyperglycemia is associated with higher birthweight (possibly indicating macrosomia), mediated via increased placental growth. GDM and T2D liability are related to preterm birth, whilst the association for T2D liability is driven by maternal adiposity.

A complex metabolic network and its biomarkers regulate laccase production in white-rot fungus Cerrena unicolor 87613.

BACKGROUND: White-rot fungi are known to naturally produce high quantities of laccase, which exhibit commendable stability and catalytic efficiency. However, their laccase production does not meet the demands for industrial-scale applications. To address this limitation, it is crucial to optimize the conditions for laccase production. However, the regulatory mechanisms underlying different conditions remain unclear. This knowledge gap hinders the cost-effective application of laccases. RESULTS: In this study, we utilized transcriptomic and metabolomic data to investigate a promising laccase producer, Cerrena unicolor 87613, cultivated with fructose as the carbon source. Our comprehensive analysis of differentially expressed genes (DEGs) and differentially abundant metabolites (DAMs) aimed to identify changes in cellular processes that could affect laccase production. As a result, we discovered a complex metabolic network primarily involving carbon metabolism and amino acid metabolism, which exhibited contrasting changes between transcription and metabolic patterns. Within this network, we identified five biomarkers, including succinate, serine, methionine, glutamate and reduced glutathione, that played crucial roles in co-determining laccase production levels. CONCLUSIONS: Our study proposed a complex metabolic network and identified key biomarkers that determine the production level of laccase in the commercially promising Cerrena unicolor 87613. These findings not only shed light on the regulatory mechanisms of carbon sources in laccase production, but also provide a theoretical foundation for enhancing laccase production through strategic reprogramming of metabolic pathways, especially related to the citrate cycle and specific amino acid metabolism.

Association of common maternal infections with birth outcomes: a multinational cohort study.

PURPOSE: It is unclear whether common maternal infections during pregnancy are risk factors for adverse birth outcomes. We assessed the association between self-reported infections during pregnancy with preterm birth and small-for-gestational-age (SGA) in an international cohort consortium. METHODS: Data on 120,507 pregnant women were obtained from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA. Self-reported common infections during pregnancy included influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections, cystitis, urinary tract infection, and the symptoms fever and diarrhoea. Birth outcomes included preterm birth, low birth weight and SGA. Associations between maternal infections and birth outcomes were first assessed using Poisson regression in each cohort and then pooled using random-effect meta-analysis. Risk ratios (RR) and 95% confidence intervals (CI) were calculated, adjusted for potential confounders. RESULTS: Vaginal infections (pooled RR, 1.10; 95% CI, 1.02-1.20) and urinary tract infections (pooled RR, 1.17; 95% CI, 1.09-1.26) during pregnancy were associated with higher risk of preterm birth. Similar associations with low birth weight were also observed for these two infections. Fever during pregnancy was associated with higher risk of SGA (pooled RR, 1.07; 95% CI, 1.02-1.12). No other significant associations were observed between maternal infections/symptoms and birth outcomes. CONCLUSION: Vaginal infections and urinary infections during pregnancy were associated with a small increased risk of preterm birth and low birth weight, whereas fever was associated with SGA. These findings require confirmation in future studies with laboratory-confirmed infection diagnosis.

Impact of closed-off management due to COVID-19 rebound on maternal depression during pregnancy.

BACKGROUND: This study aimed to assess the impacts of closed-off measures with different strictness levels (lockdown, partial lockdown and non-lockdown) and geographic proximity to patients with coronavirus disease 2019 (COVID-19) on prenatal depression during an epidemic rebound of COVID-19. METHODS: This was a cross-sectional web-based survey including 880 pregnant women. Depressive symptoms were measured by Self-Rating Depression Scale (SDS) and geographic proximity was calculated using Geographic Information Systems. Linear and logistic regression were used to assess the associations of closed-off measures and geographic proximity with SDS scores and depressive symptoms. Restricted cubic splines were used to model non-linear associations between geographic proximity and depression symptoms. RESULTS: Compared with those living in non-lockdown areas, women in lockdown areas had higher SDS scores (adjusted ß: 3.51, 95% CI: 1.80, 5.21) and greater risk of depressive symptoms (adjusted OR: 4.00, 95% CI: 2.18, 7.35), but evidence for partial lockdown was not obvious. A progressive increase in the risk of depressive symptoms was found with decreasing distance to COVID-19 patients when geographic proximity was <8 kilometers. Compared to those in the 5th quintile of geographic proximity, women in the first, second and third quintiles had at least 6 times higher risk of depressive symptoms. CONCLUSIONS: Pregnant women under strict closed-off management during COVID-19 epidemic have high risk of depression. A specific range around the residences of reported COVID-19 patients should be underlined as potential clustering of high prenatal depression levels. Our findings highlight the importance of enhancing mental health management during the COVID-19 epidemic for pregnant women.

Weight status changes from childhood to adulthood were associated with cardiometabolic outcomes in adulthood.

AIM: Few studies have assessed the association between weight changes from childhood to adulthood and cardiometabolic factors in adulthood. The aim of this study was to explore the relationships between weight changes from childhood to adulthood and cardiometabolic factors in adulthood using national Chinese data. METHODS: We included 649 participants from the China Health and Nutrition Survey from 1989 to 2009 and divided them into four groups by their body mass index from 6 to 37 years of age. They were selected using multistage random cluster sampling from 15 areas with large variations in economic and social development. Poisson regression models assessed associations between weight status changes and cardiometabolic outcomes in adulthood. RESULTS: The risk of multiple abnormal cardiometabolic outcomes in adulthood was increased in the 126 subjects with normal weight in childhood but overweight or obesity in adulthood and the 28 with obesity at both ages, compared to the 462 with normal weight at both ages. There was insufficient evidence to demonstrate that the 33 who had weight issues as children, but not as adults, had an increased risk. CONCLUSION: Being overweight or obese in both childhood and adulthood or during adulthood only increased the risk of abnormal cardiometabolic outcomes in adulthood. Larger studies need to investigate whether weight problems in childhood, but not adulthood, increase the risk.

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis.

AIMS: To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. METHODS AND RESULTS: Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. CONCLUSION: These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.

Is antenatal or early-life vitamin D associated with eczema or food allergy in childhood? A systematic review.

OBJECTIVE: To summarise the associations between antenatal or early-life blood vitamin D and the development of eczema/food allergy in childhood. DESIGN: A systematic review and meta-analyses were conducted to synthesize the published literature. Two reviewers independently performed the study selection and data extraction on Covidence. We assessed the risk of bias for observational studies by using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool for clinical trials. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). DATA SOURCES: We systematically searched PubMed and Embase from inception and April 2022. ELIGIBILITY CRITERIA: Human studies that investigated prospective associations between antenatal or early-life blood vitamin D levels, dietary intake or supplementation and childhood eczema/food allergy. RESULTS: Forty-three articles including six randomised controlled trials (RCTs) were included. Four RCTs of vitamin D supplementation during pregnancy showed no evidence of an effect on the incidence of eczema (pooled odds ratio [OR] = 0.85; 0.67-1.08, I2  = 6.7%, n = 2074). Three RCTs reported null associations between supplementation in pregnancy/infancy and food allergy. From six cohort studies, increasing cord blood vitamin D levels were associated with reduced prevalence of eczema at/close to age one (OR per 10 nmol/L increase = 0.89; 0.84-0.94, I2  = 0%, 2025 participants). We found no evidence of an association between maternal antenatal or infant vitamin D level or dietary intake and the development of food allergy or eczema in offspring. CONCLUSIONS: We found an association between higher vitamin D levels in cord blood and reduced risk of eczema in cohort studies. Further trials with maternal and infant supplementation are needed to confirm if vitamin D supplementation can effectively prevent eczema or food allergy in childhood. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, No. CRD42013005559.

Timing of infant formula introduction in relation to BMI and overweight at ages 1 and 3 years: the Born in Guangzhou Cohort Study (BIGCS).

Mounting evidence suggests that the first few months of life are critical for the development of obesity. The relationships between the timing of solid food introduction and the risk of childhood obesity have been examined previously; however, evidence for the association of timing of infant formula introduction remains scarce. This study aimed to examine whether the timing of infant formula introduction is associated with growth z-scores and overweight at ages 1 and 3 years. This study included 5733 full-term (≥ 37 gestational weeks) and normal birth weight (≥ 2500 and < 4000 g) children in the Born in Guangzhou Cohort Study, a prospective cohort study with data collected at 6 weeks, 6, 12 and 36 months. Compared with infant formula introduction at 0-3 months, introduction at 4-6 months was associated with the lower BMI, weight-for-age and weight-for-length z-scores at 1 and 3 years old. Also, introduction at 4-6 months was associated with the lower odds of at-risk of overweight at age 1 (adjusted OR 0·72, 95 % CI 0·55, 0·94) and 3 years (adjusted OR 0·50, 95 % CI 0·30, 0·85). Introduction at 4-6 months also decreased the odds of overweight at age 1 year (adjusted OR 0·42, 95 % CI 0·21, 0·84) but not at age 3 years. Based on our findings, compared with introduction within the first 3 months, introduction at 4-6 months has a reduction on later high BMI risk and at-risk of overweight. However, these results need to be replicated in other well-designed studies before more firm recommendations can be made.

Factors influencing treatment status of syphilis among pregnant women: a retrospective cohort study in Guangzhou, China.

BACKGROUND: Many syphilis infected pregnant women do not receive treatment, representing a major missed opportunity to reduce the risk of syphilis-related adverse pregnancy outcomes. This study explored correlates of treatment among pregnant women with syphilis in Guangzhou, China. METHODS: Pregnant women with a diagnosis of syphilis in Guangzhou between January 2014 and December 2016 were included. Information of syphilis treatment and correlates were extracted from a comprehensive national case-reporting system. Multivariate logistic regression was used to identify the correlations between information on the demographic characteristics, previous history, clinical characteristics about current syphilis, information of diagnosing hospital, and receiving no treatment or inadequate treatment among syphilis-seropositive pregnant women. A causal mediation analysis was used to explore the potential mediating role of the timing of syphilis diagnosis in the correlates. RESULTS: Among 1248 syphilis-seropositive pregnant women, 379 (30.4%) women received no treatment or inadequate treatment. Migrant pregnant women (adjusted OR = 1.83, 95% CI: 1.25-2.73), multiparous participants (adjusted OR = 3.68, 95% CI: 2.51-5.50), unmarried participants (adjusted OR = 3.21, 95% CI: 1.97-5.28) and unemployed participants (adjusted OR = 2.43, 95% CI: 1.41-4.39) were more likely to receive no treatment or inadequate treatment. Participants who with history of syphilis infection (adjusted OR = 0.59, 95% CI: 0.42-0.82) and with high school and higher education participants (adjusted OR = 0.69, 95% CI: 0.49-0.97) were less likely to receive untreated or inadequately treatment. And that the impact of all these factors (except for the migrants) on treatment status are fully mediated through the syphilis diagnosis time, with the direct effect of migrants that would have resulted in a higher rate of no or inadequate treatment (OR = 2.34, 95% CI: 1.08-5.32) was partially cancelled out by the syphilis diagnosis time. CONCLUSIONS: Pregnant women who were migrant without local residence and women with syphilis diagnosed at a later gestational age were more likely to slip through the cracks of the existing antenatal care system. More programs should focus on eliminating these gaps of residence-related health inequalities. This research highlights actionable elements for health services interventions that could increase syphilis treatment rates among pregnant women.

Incremental predictive value of platelet parameters for preeclampsia: results from a large prospective cohort study.

BACKGROUND: Platelet parameters during pregnancy were associated with the risk of preeclampsia (PE), but the predictive value of these parameters for PE remained unclear. Our aim was to clarify the individual and incremental predictive value of platelet parameters, including platelet count (PC), mean platelet volume (MPV), plateletcrit (PCT), and platelet distribution width (PDW) for PE. METHODS: This study was based on the Born in Guangzhou Cohort Study in China. Data on platelet parameters were extracted from medical records of routine prenatal examinations. Receiver operating characteristic (ROC) curve was performed to analyze the predictive ability of platelet parameters for PE. Maternal characteristic factors proposed by NICE and ACOG were used to develop the base model. Detection rate (DR), integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI) were calculated compared with the base model to assess the incremental predictive value of platelet parameters. RESULTS: A total of 30,401 pregnancies were included in this study, of which 376 (1.24%) were diagnosed with PE. Higher levels of PC and PCT were observed at 12-19 gestational weeks in women who developed PE later. However, no platelet parameters before 20 weeks of gestation reliably distinguished between PE complicated pregnancy and non-PE complicated pregnancy, with all values of the areas under the ROC curves (AUC) below 0.70. The addition of platelet parameters at 16-19 gestational weeks to the base model increased the DR for preterm PE from 22.9 to 31.4% at a fixed false positive rate of 5%, improved the AUC from 0.775 to 0.849 (p = 0.015), and yielded a NRI of 0.793 (p < 0.001), and an IDI of 0.0069 (p = 0.035). Less but significant improvement in prediction performance was also observed for term PE and total PE when all the four platelet parameters were added to the base model. CONCLUSIONS: Although no single platelet parameter at the early stage of pregnancy identified PE with high accuracy, the addition of platelet parameters to known independent risk factors could improve the prediction of PE.

Associations of maternal weight status with the risk of offspring atopic dermatitis and wheezing by 1 year of age.

BACKGROUND: Maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) have been linked to offspring allergic disorders. However, associations observed in previous studies were inconsistent and might be confounded by unmeasured familial factors. We aimed to examine the associations of maternal weight with offspring allergic disorders by using paternal BMI as a negative control exposure. METHODS: We included the data of 10,522 children from the Born in Guangzhou Cohort Study, 2012-2017. Data on maternal weight were obtained from questionnaires and obstetric records, and paternal weight was collected from questionnaires. Atopic dermatitis (AD) and wheezing at the age of 1 year were defined according to parent-reported physician diagnosis. Risk ratios (RRs) were estimated by log-binominal regression with mutual adjustment for maternal and paternal weight status. RESULTS: By the age of 1 year, 16.2% and 7.9% of children were diagnosed with AD and wheezing, respectively. While maternal pre-pregnancy BMI as a continuous variable was not associated with offspring AD, infants of pre-pregnancy overweight/obese women had a higher risk of AD than those born to normal weight women; no such associations were observed for paternal BMI. Both maternal pre-pregnancy BMI and paternal BMI were positively associated with the risk of offspring wheezing. Maternal GWG was not associated with AD or wheezing. CONCLUSIONS: Our findings suggest that maternal pre-pregnancy overweight/obesity might increase the risk of infant AD via intrauterine mechanisms, whereas the association with wheezing might be confounded by uncontrolled familial factors. These findings may be valuable in early-life prevention for offspring allergic diseases.

Combined effects of air pollutants on gestational diabetes mellitus: A prospective cohort study.

Exposures to multiple air pollutants during pregnancy have been associated with the risk of gestational diabetes mellitus (GDM). However, their combined effects are unclear. We aimed to evaluate the combined associations of five air pollutants from pre-pregnancy to the 2nd trimester with GDM. This study included 20,113 participants from the Born in Guangzhou Cohort Study (BIGCS). The inverse distance-weighted models were used to estimate individual air pollutant exposure, namely ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter less than 10 µm in diameter (PM10), and less than 2.5 µm in diameter (PM2.5). We estimated stage-specific associations of air pollutants with GDM using generalized estimating equation, and departures from additive joint effects were assessed using the relative excess risk (RERI) and the joint relative risk (JRR). Of the 20,113 participants, 3440 women (17.1%) were diagnosed with GDM. In the adjusted model, increased concentrations of O3 and SO2 3-6 months before pregnancy were associated with GDM occurrence, as well as O3 and PM10 in the 1st trimester, the adjusted relative risk (95% confident intervals) [RRs (95%CI)] ranged from 1.05 (1.00, 1.09) to 1.21 (1.04, 1.40). The largest JRR for GDM was the combination of SO2, NO2, and PM10 in the 1st trimester (JRR = 1.32, 95% CI: 1.10, 1.59). The JRR for O3 and SO2 was less than their additive joint effects [RERI = -0.25 (-0.47, -0.04), P for interaction = 0.048]. Associations of air pollutants with GDM differed somewhat by pre-pregnancy BMI and season. This study added new evidence to the current understanding of the combined effects of multiple air pollutants on GDM. Public health strategies were needed to reduce the adverse effects of air pollution exposure on pregnant women.

Gestational weight gain rates in the first and second trimesters are associated with small for gestational age among underweight women: a prospective birth cohort study.

BACKGROUND: Despite the well-studied effects of gestational weight gain (GWG) on offspring health, little is known about the association of trimester-specific GWG with offspring birth weight among underweight pregnant women. This study aimed to explore the association of trimester-specific GWG rate with small for gestational age (SGA) in underweight women. METHODS: The GWG rate of underweight pregnant women (pre-pregnancy body mass index [BMI] lower than 18.5 kg/m2) of the Born in Guangzhou Cohort Study was calculated as the weight gain during a specific trimester divided by the corresponding duration of week. Total GWG was calculated as the weight difference between pre-pregnancy and delivery, and was categorized into inadequate, adequate, and excessive weight gain based on the 2009 Institute of Medicine (IOM) weight gain recommendation. The INTERGROWTH-21st standards were used to define SGA. Logistic regression models were used to examine the associations of total GWG and trimester-specific GWG rates with SGA. Associations between trimester-specific GWG rates and SGA were also analyzed separately based on different total GWG categories (i.e. inadequate and adequate/excessive GWG). RESULTS: Of the 3839 participants, SGA births occurred in 397 (10.3%), and mean GWG was 14.9 kg (SD 3.9). A lower risk of SGA was observed among women with higher GWG rate (per 0.5 kg/week increase) during the first (adjusted OR [aOR] 0.74, 95%CI 0.57, 0.96) and second (adjusted OR [aOR] 0.40, 95%CI 0.30, 0.55) but not third trimester. Similar association between higher GWG rate during the second trimester and a decreased risk of SGA were observed among women with inadequate (< 12.5 kg) and adequate/excessive (≥12.5 kg) total GWG, respectively. Compared to women with adequate GWG rate, women with inadequate GWG rate during the second trimester had a significantly increased risk of SGA (aOR 1.58, 95% CI 1.14, 2.20). CONCLUSIONS: Second-trimester GWG might be the key driver for the association between inadequate GWG and increased risk of SGA births in underweight women.

METTL3 regulates skeletal muscle specific miRNAs at both transcriptional and post-transcriptional levels.

METTL3 increasing the mature miRNA levels via N6-Methyladenosine (m6A) modification of primary miRNA (pri-miRNA) transcripts has emerged as an important post-transcriptional regulation of miRNA biogenesis. Our previous studies and others have showed that muscle specific miRNAs are essential for skeletal muscle differentiation. Whether these miRNAs are also regulated by METTL3 is still unclear. Here, we found that m6A motifs were present around most of these miRNAs, which were indeed m6A modified as confirmed by m6A-modified RNA immunoprecipitation (m6A RIP). However, we surprisingly found that these muscle specific miRNAs were repressed instead of increased by METTL3 in C2C12 in vitro differentiation and mouse skeletal muscle regeneration after injury in vivo model. To elucidate the underlined mechanism, we performed reporter assays in 293T cells and validated METTL3 increasing these miRNAs at post-transcriptional level as expected. Furthermore, in myogenic C2C12 cells, we found that METTL3 not only repressed the expression of myogenic transcription factors (TFs) which can enhance the muscle specific miRNAs, but also increased the expression of epigenetic regulators which can repress these miRNAs. Thus, METTL3 could repress the muscle specific miRNAs at transcriptional level indirectly. Taken together, our results demonstrated that skeletal muscle specific miRNAs were repressed by METTL3 and such repression is likely synthesized transcriptional and post-transcriptional regulations.

Prevalence of congenital microcephaly and its risk factors in an area at risk of Zika outbreaks.

BACKGROUND: Prevalence of neonatal microcephaly in populations without Zika-epidemics is sparse. The study aimed to report baseline prevalence of congenital microcephaly and its relationship with prenatal factors in an area at risk of Zika outbreak. METHODS: This study included singletons born after 24 gestational weeks in 2017-2018 at four hospitals in Guangzhou, China. Microcephaly was defined as a head circumference at birth >3SD below the mean for sex and gestational age. Prevalence of microcephaly was estimated by binomial exact method. Multivariable logistic regression was used to examine the associations of microcephaly with prenatal factors. The population attributable fraction (PAF) for associated risk factors was calculated. RESULTS: Of 46,610 live births included, 154 (3.3, 95% CI 2.8-3.9 per 1000 live births) microcephalies were identified. Maternal hepatitis B virus carriers (HBV, OR 1.80, 95% CI 1.05-3.10) and primipara (OR 2.68, 95% CI 1.89-3.81) had higher risk of having a microcephalic baby. Higher prevalence of microcephaly was observed in women who had premature labor (OR 1.98, 95% CI 1.17-3.34) and had a baby with fetal growth restriction (OR 16.38, 95% CI 11.81-22.71). Four identified factors (HBV, primiparity, preterm labor, and fetal growth restriction) contributed to 66.4% of the risk of microcephaly. CONCLUSIONS: The prevalence of microcephaly in Guangzhou was higher than expected. This study identified four prenatal risk factors that, together, contributed to two-thirds of the increased risk of microcephaly. This is the first reported association between maternal HBV carrier status and microcephaly.

[Burden of nutritional deficiencies of children under 5 years old in China, 1990-2015].

OBJECTIVE: To quantify and describe the distribution and trends of burden of nutritional deficiencies among children under 5 years old in China from 1990 to 2015. METHODS: Subnational data of China on children under 5 years old in 33 provinces and autonomous regions, which including 31 mainland regions, Hong Kong and Macao Special Administrative Regions, were extracted from the result of Global Burden of Disease Study 2015(GBD 2015). Based on the method of descriptive epidemiology, we analyzed the prevalence, mortality as well as disability adjusted life year(DALY) rate of nutritional deficiencies among children under 5 years old by sex, time and locations in China, as well as its temporal trend since 1990. RESULTS: In 2015, the prevalence of nutritional deficiencies among children under 5 years old was 17. 26%, and the DALY rate was 776. 26 person-years per 100000. Compared to 1990, the DALY rate of nutritional deficiencies declined by 71. 42%. The DALY rate of nutritional deficiencies decreased in the past 25 years in Eastern, Central and Western China. Meanwhile, the gap in disease burden between boys and girls declined. Among diseases caused by nutritional deficiencies, burden of protein-energy malnutrition and iron deficiency anemia among children under 5 years old were relatively higher. Compared to 1990, the DALY rate of iron deficiency anemia among children under 5 years old declined by 15. 68%, which was lower than other nutritional deficiencies among children in 2015. CONCLUSION: From 1990 to 2015, the disease burden caused by nutritional deficiencies among Chinese children under 5 years old showed downtrend. There were still differences of disease burden distributions between regions and common nutritional deficiencies.

Maternal cigarette smoking before and during pregnancy and the risk of preterm birth: A dose-response analysis of 25 million mother-infant pairs.

BACKGROUND: Most of the women who smoke before pregnancy continue smoking during pregnancy, and some start to quit smoking after being pregnant, although existing guidelines for pregnancy recommend that women who smoke should quit smoking before pregnancy. Findings about the timing and intensity of maternal smoking, especially low-intensity smoking (1-9 cigarettes per day), and preterm birth are still inconsistent and ambiguous. This study aimed to examine the association of the timing of smoking and doses of smoking before pregnancy and during the first or second trimester of pregnancy with preterm birth in a large-scale population-based retrospective cohort study. METHODS AND FINDINGS: We used nationwide birth certificate data from singleton mother-infant pairs in the United States National Vital Statistics System, 2011-2018. All adult women with live singleton births, without preexisting hypertension or diabetes, and with complete data on smoking and gestational age at delivery were included. Participants reported their smoking status (yes or no) and daily number of cigarettes consumed before and during each trimester of pregnancy. The outcome of interest was preterm birth, defined as a birth before 37 weeks of gestation. Logistic regression models were used to estimate the odds ratio (OR) with 95% confidence intervals (CIs) of preterm birth associated with smoking status and the number of cigarettes consumed, adjusting for maternal age, race/ethnicity, parity, education levels, prepregnancy BMI, previous history of preterm birth, marital status, infant sex, and initiation of prenatal care. This study included 25,623,479 women, with a mean age of 29 years (range 20-50 years); 13,742,486 (53.6%) participants were of non-Hispanic white ancestry, 5,971,598 (23.3%) of Hispanic ancestry, and 3,417,456 (13.34%) of non-Hispanic black ancestry. The prevalence of preterm birth was 9.3% (n = 2,378,398). We found that maternal smoking during pregnancy, even at a very low level of intensity, was associated with an increased risk of preterm delivery. The adjusted ORs (95% CI) of preterm birth for mothers who smoked 1-2, 3-5, 6-9, 10-19, and ≥20 cigarettes per day during the first trimester compared with mothers who did not smoke were 1.31 (1.29-1.33), 1.31 (1.30-1.32), 1.33 (1.31-1.35), 1.44 (1.43-1.45), and 1.53 (1.52-1.55), respectively (all P values < 0.001), whereas for those who smoked during the second trimester, the corresponding ORs were 1.37 (1.35-1.39), 1.36 (1.35-1.38), 1.36 (1.34-1.38), 1.48 (1.47-1.49), and 1.59 (1.58-1.61), respectively (all P values < 0.001). Furthermore, smokers who quit before pregnancy, regardless of smoking intensity, had a comparable risk of preterm birth with nonsmokers, although this was not the case when cessation occurred in the first or second trimester of pregnancy. The major limitation of this study is the self-reported information about smoking, which may be subject to information bias. In addition, we cannot rule out the possibility of residual confounding caused by unmeasured factors in an observational research design. CONCLUSIONS: In this study, we observed that low-intensity cigarette consumption during either the first or second trimester of pregnancy, even as low as 1-2 cigarettes per day, was associated with an increased risk of preterm birth. These findings suggest that there is no safe level or safe trimester for maternal smoking during pregnancy. Women of reproductive age who smoke should be strongly encouraged and supported to quit smoking before pregnancy.

Glucose, Insulin, and Lipids in Cord Blood of Neonates and Their Association with Birthweight: Differential Metabolic Risk of Large for Gestational Age and Small for Gestational Age Babies.

OBJECTIVES: To investigate the association of birthweight percentile with cord blood glucose, lipids, and insulin levels. STUDY DESIGN: Data obtained from 1522 newborns were included in the Born in Guangzhou Cohort study. The generalized additive model and multivariable linear regression model were used to explore the nonlinear and linear relationships between birthweight and cord blood metabolic measures, and to evaluate the differences of metabolic measures Z-scores among small for gestational age, appropriate for gestational age, and large for gestational age babies. RESULTS: Birthweight Z-score was linearly associated with increased cord blood insulin Z-score (adjusted ß = 0.30; 95% CI, 0.22-0.37). Compared with appropriate for gestational age babies, neonates born small for gestational age had significantly higher cord blood triglycerides Z-score (adjusted mean difference [MDadj], 0.60; 95% CI, 0.40-0.79) and lower cord blood insulin (MDadj, -0.37; 95% CI, -0.57 to -0.16), high-density lipoprotein cholesterol (MDadj, -0.34; 95% CI, -0.55 to -0.13), total cholesterol (MDadj, -0.26; 95% CI, -0.47 to -0.05), and low-density lipoprotein (MDadj, -0.23; 95% CI, -0.43 to -0.02) Z-scores, and neonates born large for gestational age had higher cord blood insulin Z-score (MDadj, 0.31; 95% CI, 0.09 to 0.52). CONCLUSIONS: Our findings support the hypothesis that babies born small for gestational age and large for gestational age are exposed to different intrauterine environments, which may contribute to altered fat accumulation patterns with implications for the risk of metabolic dysfunction later in life. There is a need to consider the development of tailored intervention strategies to prevent metabolic dysfunction in adult life for these babies.