Gravidity modifies the associations of age and spousal age difference with couple's fecundability: a large cohort study from China.

STUDY QUESTION: Do couple's age ranges for optimal fecundability, and the associations with fecundability of couple's age combinations and age differences differ with gravidity? SUMMARY ANSWER: The couple's age range of optimal fecundability and age combinations differed with gravidity, and gravidity might modify the associations of age and spousal age difference with couple's fecundability. WHAT IS KNOWN ALREADY: Age is one of the strongest determinants of fecundability, but the existing studies have certain limitations in study population, couple's extreme age combinations and age differences, and have not explored whether the association between age and fecundability differs with gravidity. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study. 5 407 499 general reproductive-aged couples (not diagnosed with infertility) participated in the National Free Pre-conception Check-up Projects during 2015-2017. They were followed up for pregnancy outcomes through telephone interviews every 3 months until they became pregnant or were followed up for 1 year. PARTICIPANTS/MATERIALS, SETTING, METHODS: The main outcome was time to pregnancy, and the fecundability odds ratios and 95% CIs were estimated using the Cox models for discrete survival time. The associations of age and spousal age difference with fecundability were evaluated by restricted cubic splines. MAIN RESULTS AND THE ROLE OF CHANCE: In this large cohort of general reproductive-aged population, the age of optimal fecundability of multigravida couples was older than that of nulligravida couples, but their subsequent fecundability declined more sharply with age. The decline in female fecundability was more pronounced with age, with fecundability dropping by ∼30% in both nulligravida and multigravida couples whose female partners aged ≥35 years. In the nulligravida group, the fecundability of couples who were both ≤24 years with the same age was the highest, which decreased steadily with the increase of spousal age difference, and younger male partners did not seem to contribute to improving couple's fecundability. In the multigravida group, couples with female partners aged 25-34 years and a spousal age difference of -5 to 5 years showed higher fecundability, and the effect of spousal age difference on couple's fecundability became suddenly apparent when female partners aged around 40 years. Young male partners were unable to change the decisive effect of female partner's age over 40 years on couple's reduced fecundability, regardless of gravidity. LIMITATIONS, REASONS FOR CAUTION: Lacking the time for couples to attempt pregnancy before enrollment, and some couples might suspend pregnancy plans during follow-up because of certain emergencies, which would misestimate the fecundability. Due to the lack of information on sperm quality and sexual frequency of couples, we could not adjust for these factors. Moreover, due to population characteristics, the extrapolation of our results required caution. WIDER IMPLICATIONS OF THE FINDINGS: The couple's age range of optimal fecundability, age combinations, and spousal age difference on fecundability varied with gravidity. Female age-related decline in fecundability was more dominant in couple's fecundability. Targeted fertility guidance should be provided to couples with different age combinations and gravidities. STUDY FUNDING/COMPETING INTEREST(S): This research received funding from the Project of National Research Institute for Family Planning (Grant No. 2018NRIFPJ03), the National Key Research and Development Program of China (Grant No. 2016YFC1000307), and the National Human Genetic Resources Sharing Service Platform (Grant No. 2005DKA21300), People's Republic of China. The funders had no role in study design, analysis, decision to publish, or preparation of the manuscript. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Assessment of male creatinine levels and fecundity in couples planning pregnancy: a national cohort study in China.

STUDY QUESTION: Is there an association between male creatinine levels and time to pregnancy (TTP) in couples planning pregnancy? SUMMARY ANSWER: Low and high male creatinine concentrations were associated with reduced couple fecundity. WHAT IS KNOWN ALREADY: Abundant evidence suggests male creatinine dysfunction is associated with infertility in males with kidney diseases. However, the association of preconception creatinine levels with reduced fecundity among general reproductive-aged couples lacks evidence from an in-depth population study. STUDY DESIGN, SIZE, DURATION: Based on the population-based cohort study from the National Free Preconception Check-up Projects, 4 023 204 couples were recruited and met the inclusion criteria from 1 January 2015 to 31 December 2017. They were planning pregnancy and were followed up every 3 months until achieving pregnancy as detected by gynaecological ultrasonography or were followed up for 1 year for the analysis of TTP. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cox regression models were used to estimate hazard ratios (HRs) and 95% CI for creatinine deciles. Restricted cubic spline regression was adopted for the dose-response relationship of creatinine with HRs. R statistical software was used for data analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Of the included participants, 2 756 538 (68.52%) couples successfully conceived. The median male serum creatinine was 81.50 µmol/l. Compared with the reference group (78.00-81.49 µmol/l) including the median creatinine, fecundity in the first (≤64.89 µmol/l), second (64.90-69.99 µmol/l), third (70.00-73.99 µmol/l), and tenth (≥101.00 µmol/l) deciles decreased by 8%, 5%, 2%, and 1%, respectively (Decile 1 Adjusted HR 0.92, 95% CI 0.91-0.92; Decile 2 Adjusted HR 0.95, 95% CI 0.95-0.96; Decile 3 Adjusted HR 0.98, 95% CI 0.97-0.99; Decile 10 Adjusted HR 0.99, 95% CI 0.98-0.99). An inverse-U-shaped association was consistently presented among males such that non-inferiority for fecundity was shown when creatinine was in the 81.66-104.90 µmol/l range (P for non-linearity < 0.001). For males over 40 years old, the risk of fecundity impairment was more obvious and the recommended range of creatinine levels for TTP was reduced and more narrow, compared with that for younger males. LIMITATIONS, REASONS FOR CAUTION: Not including the time couples spend preparing for pregnancy before enrolment would lead to an overestimation of fecundity; additionally some couples place pregnancy plans on hold due to special emergencies, which would not have been recognized. Due to the lack of information regarding semen quality, psychological factors, sexual intercourse frequencies, and hazardous environmental factors, we could not adjust for these factors. Some variates were self-reported and dichotomized, which were prone to bias. Direct variables reflecting muscle mass and impaired kidney function were lacking. Thus, extrapolation should be done with caution. WIDER IMPLICATIONS OF THE FINDINGS: Male creatinine is associated with couples' fecundity and the relationship varied by age. This study provides a better understanding of the potential implications and significance of different creatinine levels and their association with the clinical significance regarding couples' fecundity. STUDY FUNDING/COMPETING INTEREST(S): This research has received funding from the National Natural Science Foundation of China (Grant No. 81872634), the Basic Research Funds of Central Public Welfare Research Institutes of China (Grant No. 2023GJZ03), the National Key Research and Development Program of China (Grant No. 2016YFC1000307), and the Project of National Research Institute for Family Planning (Grant No. 2018NRIFPJ03), People's Republic of China. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

An immune window of opportunity to prevent spontaneous abortion: prepregnancy peripheral leukocytes and subsets were associated with a decreased risk of spontaneous abortion.

STUDY QUESTION: Do prepregnancy peripheral leukocytes (PPLs) and their subsets influence the risk of spontaneous abortion (SAB)? SUMMARY ANSWER: PPLs and their subsets are associated with the risk of SAB. WHAT IS KNOWN ALREADY: Compelling studies have revealed the crucial role of maternal peripheral leukocytes in embryo implantation and pregnancy maintenance. Adaptive changes are made by PPLs and their subsets after conception. STUDY DESIGN, SIZE, DURATION: This population-based retrospective cohort study was based on data from the National Free Pre-pregnancy Check-up Project (NFPCP) in mainland China. Couples preparing for pregnancy within the next six months were provided with free prepregnancy health examinations and counseling services for reproductive health. The current study was based on 1 310 494 female NFPCP participants aged 20-49 who became pregnant in 2016. After sequentially excluding 235 456 participants lost to follow-up, with multiple births, and who failed to complete blood tests, a total of 1 075 038 participants were included in the primary analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: PPLs and their subset counts and ratios were measured. The main outcome was SAB. A multivariable logistic regression model was used to estimate the odds ratio (OR) and 95% CI of SAB associated with PPLs and their subsets, and restricted cubic spline (RCS) was used to estimate the nonlinear exposure-response relationship. MAIN RESULTS AND ROLE OF CHANCE: Of the included pregnant participants, a total of 35 529 SAB events (3.30%) were recorded. Compared to participants with reference values of PPLs, the ORs (95% CIs) of leukopenia and leukocytosis for SAB were 1.14 (1.09-1.20) and 0.74 (0.69-0.79), respectively. The RCS result revealed a monotonous decreasing trend (Pnonlinear < 0.05). Similar relationships were observed for the neutrophil count and ratio, monocyte count, and middle-sized cell count and ratio. The lymphocyte ratio showed a positive and nonlinear relationship with the risk of SAB (Pnonlinear < 0.05). Both eosinophils and basophils showed positive relationships with the risk of SAB (eosinophil Pnonlinear > 0.05 and basophil Pnonlinear < 0.05). LIMITATIONS, REASONS FOR CAUTION: Chemical abortion events and the cause of SAB were not collected at follow-up. Whether women with abnormal PPLs had recovered during periconception was not determined. WIDER IMPLICATIONS OF THE FINDINGS: PPLs and their subsets are associated with the risk of SAB. Leukopenia and neutropenia screening in women preparing for pregnancy and developing a feasible PPL stimulation approach should be emphasized to utilize the immune window of opportunity to prevent SAB. STUDY FUNDING/COMPETING INTEREST(S): This study was approved by the Institutional Research Review Board of the National Health and Family Planning Commission. This study was supported by the National Key Research and Development Program of China (grants 2021YFC2700705 [Y.Y.] and 2016YFC100307 [X.M.]) and the National Natural Science Foundation of China (grant no. 82003472 [L.W.]). The funding source was not involved in the study design, data collection, analysis and interpretation of the data, writing the report, or the decision to submit this article for publication. No competing interests. TRIAL REGISTRATION NUMBER: N/A.

The association between the maternal pre-pregnancy platelet count and fecundability in mainland China: a population-based cohort study.

BACKGROUND: Currently, awareness about platelet count (PC) and its consequences for perinatal outcome have increased, but there is little reliable evidence on fecundability. METHODS: Based on the National Free Pre-conception Check-up Projects supported by the Chinese government, 5,524,886 couples met the inclusion criteria were included in this cohort study. Cox regression models were adopted to estimate fecundability ratios (FRs) and their 95% confidence intervals for pre-pregnancy PC quintiles. Restricted cubic splines were used to flexibly model and visualize the relationship of PC with FRs. Microsoft SQL server and R software were used for data management and analysis. RESULTS: The median of pre-pregnancy PC among women was 221.00×109/L. The first (<177.00 ×109/L) and second quintile (177.00-207.99 ×109/L) of PC showed slightly increased fecundability (Q1: adjusted FR 1.05, 95% CI 1.04-1.06; Q2: adjusted FR 1.04, 95% CI 1.03-1.05), while higher quintals (Q4: 236.00-271.99 ×109/L; Q5: ≥272.00 ×109/L) were related to reduction of fecundability, when compared with the third quintile of PC (208.00-235.99 ×109/L) (Q4: adjusted FR 0.96, 95% CI 0.95-0.97; Q5: adjusted FR 0.88, 95% CI 0.87-0.89). In the first quintiles (<177.00×109/L), only 20.93% women had PC below 129.94×109/L. An inverse-U shape association was consistently observed among women such that the lower PC of normal range (<118.03×109/L) and higher PC (>223.06×109/L) were associated with the risk of reduced female fecundability (P for non-linearity < 0.01). CONCLUSION: PC is associated with female fecundability. Further classification of PC levels may deepen our understanding of the early warnings and significance of female fecundability.

Structural transition of parenthood among Chinese nulliparous couples with planned pregnancies, 2013-2019.

BACKGROUND: The postponement of parenthood is a global public health issue that has received attention of many public health experts. However, few studies have investigated the postponement in marriage age, marriage and conception interval, and pregnancy age in terms of demographic and regional heterogenicities. METHODS: This is a cross-sectional, registry-based study, and a total of 13 894 601 nulliparous couples who participated in the National Free Pre-Pregnancy Check-ups Project and became pregnant during 2013-2019 were included. We calculated annual percentage change and forest plots for marriage age, marriage and conception interval, and pregnancy age. RESULTS: Late marriage (marriage age ≥ 35 years), long marriage and conception interval (marriage and conception interval ≥ 2 years), and advanced pregnancy (pregnancy age ≥ 35 years) increased from 1.20%, 22.01%, and 1.88% in 2013 to 1.69%, 32.75%, and 2.79% in 2019, respectively. The corresponding annual percentage changes were 6.55%, 8.44%, and 8.17%. Participants without higher education had a higher annual percentage change, but comparable prevalence for long marriage and conception interval with participants with higher education. Participants residing in second- or new first-tier cities, and the northeast of China who had a higher prevalence of parenthood postponement also had higher corresponding annual percentage changes. CONCLUSIONS: Structural postponement of parenthood with demographic and regional heterogenicities was observed among Chinese nulliparous couples with planned pregnancies during 2013-2019. Inclusive and comprehensive parenting support should be developed and implemented in mainland China to minimize the negative health effects arising from the postponement, especially for couples without higher education and living in new first/second-tier cities or the northeast China.

Preconception paternal/maternal BMI and risk of small/large for gestational age infant in over 4·7 million Chinese women aged 20-49 years: a population-based cohort study in China.

Evidence of couples' BMI and its influence on birth weight is limited and contradictory. Therefore, this study aims to assess the association between couple's preconception BMI and the risk of small for gestational age (SGA)/large for gestational age (LGA) infant, among over 4·7 million couples in a retrospective cohort study based on the National Free Pre-pregnancy Checkups Project between 1 December 2013 and 30 November 2016 in China. Among the live births, 256 718 (5·44 %) SGA events and 506 495 (10·73 %) LGA events were documented, respectively. After adjusting for confounders, underweight men had significantly higher risk (OR 1·17 (95 % CI 1·15, 1·19)) of SGA infants compared with men with normal BMI, while a significant and increased risk of LGA infants was obtained for overweight and obese men (OR 1·08 (95 % CI 1·06, 1·09); OR 1·19 (95 % CI 1·17, 1·20)), respectively. The restricted cubic spline result revealed a non-linear decreasing dose-response relationship of paternal BMI (less than 22·64) with SGA. Meanwhile, a non-linear increasing dose-response relationship of paternal BMI (more than 22·92) with LGA infants was observed. Moreover, similar results about the association between maternal preconception BMI and SGA/LGA infants were obtained. Abnormal preconception BMI in either women or men were associated with increased risk of SGA/LGA infants, respectively. Overall, couple's abnormal weight before pregnancy may be an important preventable risk factor for SGA/LGA infants.

The prevalence and influencing factors of anaemia among pre-pregnant women in mainland China: a large population-based, cross-sectional study.

Anaemia is a global public health problem affecting women worldwide, and reproductive-age women are at increased risk. We conducted a population-based cross-sectional study analysing the prevalence of overall anaemia and anaemia according to severity in Chinese pre-pregnant women to update current knowledge on anaemia epidemiology. Based on the National Free Preconception Check-up Projects supported by the Chinese government, 5 679 782 women participating in this project in 2017 were included in the present study. The cyanmethemoglobin method was applied to assess Hb concentrations. Univariate and multivariate logistic regressions were applied for associated factors. The prevalence of anaemia among Chinese pre-pregnant women was 21·64 % (mild: 14·10 %, moderate: 7·17 % and severe : 0·37 %). The prevalence of overall and severe anaemia was the highest in Tibet and the lowest in Beijing among thirty-one provinces. Women's age, region, ethnic origin, educational level, occupation and pregnancy history were all correlated with anaemia. Women with B blood type (adjusted OR (aOR) = 0·89), higher BMI (overweight: aOR = 0·84; obesity: aOR = 0·70) and alcohol consumption (aOR = 0·69) were less likely to have anaemia, while those with rhesus negative blood type (aOR = 1·10), history of anaemia (aOR = 2·60), older age at menarche (aOR = 1·19), heavy menstrual blood loss (aOR = 1·39), longer menstrual period (aOR = 1·09) and shorter menstrual cycle (aOR = 1·08) were more likely to suffer from anaemia. Meat or egg eaters were not significantly associated with severe anaemia. Anaemia is of moderate public health significance among Chinese pre-pregnant women. Interventions should be considered to prevent anaemia to the greatest extent possible to avoid potential harm in this population.

Paternal smoking and preterm birth: a population-based retrospective cohort study among non-smoking women aged 20-49 years in rural China.

BACKGROUND: To comprehensively evaluate the association of paternal smoking and preterm birth (PTB). METHODS: We performed a population-based retrospective cohort study in rural areas of China among 5,298,043 reproductive-aged couples who participated in the National Free Pre-Pregnancy Checkups Project (NFPCP), regarding outcome events that occurred in 2010-2016. Multivariate Cox proportional regression was used to estimate hazard ratio (HR) and 95% confident intervals (95%CI), and restricted cubic spline (RCS) were used to estimate the dose-response relationship. RESULTS: Compared to neither-smoker couples, the fully adjusted HR for PTB was 1.04 (95% CI, 1.03-1.04), 1.08 (0.96-1.22), and 1.11 (1.03-1.19) in the couples where only the female smoked, only the male smoked and both, respectively. HR of PTB for paternal smoking was 1.07 (1.06-1.07), compared with women without paternal smoking. Consistent with paternal smoking, preconception paternal smoking showed 1.07-fold higher risk of PTB (95%CI, 1.06-1.09). The multivariable-adjusted HRs of PTB were 1.05 (1.03-1.06), 1.04 (1.03-1.05), 1.05 (1.04-1.07), 1.07 (1.05-1.10) and 1.13 (1.12-1.14) for participants whose husband smoked 1-4, 5-9, 10-14, 15-19, and ≥ 20 cigarettes/day respectively, compared with participants without paternal smoking. The HRs of PTB also increased with the increment of paternal smoking and preconception paternal smoking categories (Plinear < 0.05). CONCLUSIONS: Paternal smoking and preconception paternal smoking was independently positively associated with PTB risk. The importance of tobacco control, should be emphasized during preconception and pregnancy counselling should be towards not only women but also their husband.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality, as well as other system immaturity problem. But as one of important environmental tobacco smoking sources of maternal secondhand smoking in the family, paternal smoking is worthy for deep exploring of its potential impacts on PTB. Moreover, evidence on the independent role of preconception paternal smoking is still lacking. Thus, we conducted a population-based retrospective cohort study to evaluate the association between paternal smoking and risk of PTB among among 5,298,043 reproductive-aged couples who participated in the National Free Pre-Pregnancy Checkups Project (NFPCP), regarding outcome events that occurred in 2010­2016.We found a significant association between paternal smoking and PTB. Smoking reduction should not only be advised to pregnant women but also to their partners to reduce PTB in their fetal. In addition, supporting patients to continue smoking reduction will be crucial when considering the adverse health outcome of smoking. Intervention of tobacco use before and during pregnancy, are critical for prevention of PTB. Avoiding both maternal and paternal smoking during pregnancy will benefit the developing fetus.

The association between serum alanine aminotransferase and hypertension: A national based cross-sectional analysis among over 21 million Chinese adults.

BACKGROUND: Inconsistent results were found in the association between serum alanine aminotransferase (ALT) and hypertension among population-based studies. This study evaluated the association between ALT and hypertension among Chinese reproductive-age population by utilizing registration data from National Free Pre-pregnancy Checkups Project in 2016-2017. METHODS: The 21,103,790 registered participants were eligible for analysis, including women who were 20-49 years old and men who were 20-59 years old with available data for ALT and blood pressure (BP). Logistic regression was conducted to estimate odds ratio (OR) for the association between ALT and hypertension as a binary outcome. Linear regression was used to examine the association between ALT and BP as a continuous outcome. RESULTS: In total, 4.21% of the participants were hypertensive, and 11.67% had elevated ALT (> 40 U/L). Hypertension prevalence was 3.63% and 8.56% among participants with normal and elevated ALT levels. A strong linear relationship was found between serum ALT levels and the odds of hypertension after adjustment for potential confounders. The multivariable-adjusted ORs for hypertension were 1, 1.22 (1.21, 1.22), 1.67 (1.65 1.68), 1.78 (1.76, 1.80), and 1.92 (1.90, 1.94) in participants with ALT levels of ≤ 20, 20.01-40, 40.01-60, 60.01-80, and > 80 U/L, respectively. Systolic and diastolic BPs rose by 1.83 and 1.20 mmHg on average, for each 20 U/L increase in ALT (P for trend < 0.001). The association was consistent among subgroups and tended to be stronger among populations who are overweight (body mass index ≥ 24 kg/m2) (χ2 = 52,228, P < 0.001), alcohol drinking (χ2 = 100,730, P < 0.001) and cigarette smoking (χ2 = 105,347, P < 0.001). CONCLUSIONS: Our cross-sectional analysis suggested a linear association between serum ALT and hypertension or BP, which indicated that abnormal liver metabolism marked by elevated serum ALT could play a role in hypertension or elevated BP condition.

Association between air particulate matter pollution and blood cell counts of women preparing for pregnancy: Baseline analysis of a national birth cohort in China.

BACKGROUND: Limited evidence is known about whether long-term exposures to air borne particulate matters of 2.5 µm or less (PM2.5) impact human hematologic index for women preparing for pregnancy. No study assessed the effect of PM1, which is small enough to reach the blood circulation. OBJECTIVE: To evaluate whether exposure to PM1 and PM2.5 is associated with blood cell count of woman preparing for pregnancy. METHOD: Based on the baseline data of a national birth cohort in China, we analysed the white blood cell (WBC), red blood cells (RBC) and thrombocyte counts of 1,203,565 women who are aged 18-45 years, being Han ethnicity, had no chronic disease and preparing for pregnancy. We matched their home addresses and examination date with daily concentrations of PM1 and PM2.5 which were estimated by a machine learning method with remote sensing, meteorological and land use information. Generalized additive mixed model to examine the associations between exposure to one-year average exposure to PMs prior to the health examination and the blood cells counts, after adjustment for potential individual variables. RESULTS: A 10 µg/m3 PM1 increment was associated with -1.49% (95%CI: 1.56%, -1.42%) difference in WBC count; with 0.33% (95%CI: 0.30%, 0.36%) difference of RBC count; and with 1.08% (95%CI: 1.01%, 1.15%) difference of thrombocyte count. For PM2.5, the corresponding difference was -0.47% (95%CI: 0.54%, -0.39%) for WBC; was 0.06% (95%CI: 0.03%, 0.09%) for RBC; and was 1.10% (95%CI: 1.02%, 1.18%) for thrombocyte. Women working as workers, being overweight and with tobacco smoking exposure had higher associations between PMs and hematologic index than their counterparts (p < 0.05 for interaction test). CONCLUSION: Long-term exposure to PMs were associated with decrement in WBC, as well as increment in RBC and thrombocytes among Han Chinese women preparing for pregnancy. Measures such as using air purifiers and wearing a mask in polluted areas should be improved to prevent women from the impact of PMs.

The trend of caesarean birth rate changes in China after 'universal two-child policy' era: a population-based study in 2013-2018.

BACKGROUND: The universal two-child policy in China which was announced in October 2015 might affect the caesarean birth rate. Few studies reported the caesarean birth rate affected by the policy especially after the universal two-child policy period. This study aimed to demonstrate the caesarean birth rate changes before and after the universal two-child policy and further elaborate the underlying influencing factors. METHODS: This nationwide, retrospective, population-based study was based on National Free Pre-Pregnancy Check-ups Project (NFPCP). Couples planning to conceive in next 6 months were encouraged to participate in NFPCP. Baseline information was collected using a standardized questionnaire with a face-to-face interview, and medical examinations were conducted. Two rounds of follow-up interviews were then conducted by trained nurses to update pregnancy status and outcomes. NFPCP participants who completed deliveries before December 31, 2018, were included in the current study. We used marginal effect of year to examine the trend of caesarean birth rate over time and interrupted time series (ITS) analysis to determine impacts of the universal two-child policy on the trend of caesarean birth rate. RESULTS: A total of 9,398,045 participants were included in the final analysis. High-risk factors to increase caesarean birth rate were identified. In the current study, the standardized caesarean birth rate declined from 34.1% in 2013 to 31.8% in 2015 and increased to 35.6% in 2018. ITS analysis showed the caesarean birth rate decreased by 0.1% (95% CI 0.1-0.1) per month before the release of universal two-child policy, 1.3% (95% CI 0.6-2.1%) absolute drop during the policy release month, and increased by 0.2% (95% CI 0.1-0.2%) per month after the policy implementation. For the period after the policy release, the increasing trends were observed in rural participants and urban primiparas. The prevalence of caesarean birth rates within China varied regionally. CONCLUSIONS: The decreasing trend of caesarean birth rate was reported after immediate release of the universal two-child policy. An increasing trend of caesarean birth rate was observed 2-3 years after the policy. It reminds us that the caesarean birth rate control is a long-lasting process and all the strategies need to be continually reinforced.

Long-term exposure to airborne particulate matter of 1 µm or less and blood pressure in healthy young adults: A national study with 1.2 million pregnancy planners.

No evidence exists concerning the effect of airborne particulate matter of 1 µm or less (PM1) on blood pressure of young adults planning for pregnancy. We collected health examination information of about 1.2 million couples (aged 18-45 years) from a national birth cohort in China from Jan 1, 2013 to Oct 1, 2014 and matched their home address to daily PM1 and PM2.5 concentrations, which were predicted by remote sensing information. Generalized additive mixed models were used to analyze associations between long-term exposure to PM and blood pressure, after controlling for individual factors. A 10 µg/m3 increase in PM1 was associated with increased systolic blood pressure (SBP) for 0.26 (95%CI: 0.24, 0.29) mmHg in females and 0.29 (95%CI: 0.26, 0.31) mmHg in males, respectively. PM1 was also associated with increased DBP for 0.22 (95%CI: 0.20, 0.23) mmHg in females and 0.17 (95%CI: 0.15, 0.19) mmHg in males, respectively. Similar effects on blood pressure were found for PM2.5, meanwhile, the effect of PM2.5 on SBP increased with the scale of PM1 included in PM2.5 (p for interaction term <0.01). In summary, long-term exposure to PM1 as well as PM2.5 was associated with increased SBP and DBP of Chinese young adults planning for pregnancy.

Preconception Hb concentration with risk of spontaneous abortion: a population-based cohort study in over 3·9 million women across rural China.

OBJECTIVE: Evidence on the relationship between maternal Hb concentration and spontaneous abortion (SA) risk is limited and conflicting. The purpose of the study was to evaluate whether maternal preconception anaemia or high Hb concentration is associated with risk of SA. DESIGN: A population-based cohort study established between 2013 and 2017. SETTINGS: Local maternal and child care service centres in each county. PARTICIPANTS: In total, 3 971 428 women aged 20-49 years, who participated in National Free Pre-Pregnancy Checkups Project from 2013 to 2016 and successfully got pregnant before 2017 in rural China. RESULTS: A total of 101 700 (2·56 %) women were recorded having SA, with highest SA rate in women with severe anaemia (4·58 %). Compared with women with Hb of 110-149 g/l, the multivariable-adjusted OR for SA was 1·52 (95 % CI: 1·25, 1·86) for women with Hb < 70 g/l, 0·92 (0·84, 1·01) for 70-99 g/l, 0·80 (0·77, 0·83) for 100-109 g/l, 1·11 (1·08, 1·15) for 150-159 g/l, 1·12 (1·04, 1·20) for 160-169 g/l and 1·02 (0·93, 1·12) for ≥ 170 g/l, respectively. An approximate U-shaped curve for the risk of SA with Hb concentrations was observed when Hb concentrations less than 145 g/l, above which the association plateaued (Pnon-linear < 0·001). CONCLUSIONS: Severe anaemia and high Hb concentration before pregnancy were associated with an increased risk of SA. Women with mild anaemia prior to pregnancy had lower risk of SA. Underlying mechanisms need to be further studied.

Preconception diabetes mellitus and adverse pregnancy outcomes in over 6.4 million women: A population-based cohort study in China.

BACKGROUND: Diabetes mellitus (DM) increases the risk of adverse maternal and neonatal outcomes, and optimization of glycemic control during pregnancy can help mitigate risks associated with diabetes. However, studies seldom focus precisely on maternal blood glucose level prior to pregnancy. We aimed to evaluate the associations between preconception blood fasting plasma glucose (FPG) level and subsequent pregnancy outcomes. METHODS AND FINDINGS: We conducted a population-based retrospective cohort study among 6,447,339 women aged 20-49 years old who participated in National Free Pre-Pregnancy Checkups Project and completed pregnancy outcomes follow-up between 2010 and 2016 in China. During the preconception health examination, serum FPG concentration was measured, and self-reported history of DM was collected. Women were classified into three groups (normal FPG group: FPG < 5.6 mmol/L and no self-reported history of DM; impaired fasting glucose [IFG]: FPG 5.6-6.9 mmol/L and no self-reported history of DM; and DM: FPG ≥ 7.0 mmol/L or self-reported history of DM). The primary outcomes were adverse pregnancy outcomes, including spontaneous abortion, preterm birth (PTB), macrosomia, small for gestational age infant (SGA), birth defect, and perinatal infant death. Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI) after adjusting for confounding variables. The mean age of women was 25.24 years, 91.47% were of Han nationality, and 92.85% were from rural areas. The incidence of DM and IFG was 1.18% (76,297) and 13.15% (847,737), respectively. Only 917 (1.20%) women reported a history of DM (awareness of their DM status), of whom 37.28% (337) had an elevated preconception FPG level (≥ 5.6 mmol/L), regarded as noncontrolled DM. A total of 1,005,568 (15.60%) women had adverse pregnancy outcomes. Compared with women with normal FPG, women with IFG had higher risks of spontaneous abortion (OR 1.08; 95% CI 1.06-1.09; P < 0.001), PTB (1.02; 1.01-1.03; P < 0.001), macrosomia (1.07; 1.06-1.08; P < 0.001), SGA (1.06; 1.02-1.10; P = 0.007), and perinatal infant death (1.08; 1.03-1.12; P < 0.001); the corresponding ORs for women with DM were 1.11 (95% CI 1.07-1.15; P < 0.001), 1.17 (1.14-1.20; P < 0.001), 1.13 (1.09-1.16; P < 0.001), 1.17 (1.04-1.32; P = 0.008), and 1.59 (1.44-1.76; P < 0.001). Women with DM also had a higher risk of birth defect (OR 1.42; 95% CI 1.15-1.91; P = 0.002). Among women without self-reported history of DM, there was a positive linear association between FPG levels and spontaneous abortion, PTB, macrosomia, SGA, and perinatal infant death (P for trend <0.001, <0.001, <0.001, 0.001, <0.001). Information about hypoglycemic medication before or during pregnancy was not collected, and we cannot adjust it in the analysis, which could result in underestimation of risks. Data on 2-hour plasma glucose level and HbA1c concentration were not available, and the glycemic control status was evaluated according to FPG value in women with DM. CONCLUSIONS: Women with preconception IFG or DM had higher risk of adverse pregnancy outcomes, including spontaneous abortion, PTB, macrosomia, SGA, and perinatal infant death. Preconception glycemic control through appropriate methods is one of the most important aspects of preconception care and should not be ignored by policy makers.

Preconception Hb concentration and risk of preterm birth in over 2·7 million Chinese women aged 20-49 years: a population-based cohort study.

Evidence on the association between maternal Hb concentration and preterm birth (PTB) risk is inconclusive. This paper aimed to explore whether women with anaemia or high Hb level before pregnancy would be at higher risk of PTB. We conducted a population-based cohort study with 2 722 274 women aged 20-49 years, who participated in National Free Pre-Pregnancy Checkups Project between 2013 and 2015 and delivered a singleton before 2016 in rural China. Logistic models were used to estimate OR and 95 % CI after adjusting for confounding variables. Restricted cubic spline models were applied to evaluate the dose-response relationships. A total of 192 819 (7·08 %) women had preterm deliveries. Compared with women with Hb of 110-149 g/l, the multivariable-adjusted OR for PTB was 1·19 (95 % CI 0·98, 1·44) for women with Hb<70 g/l, 1·01 (95 % CI 0·97, 1·03) for 70-99 g/l, 0·96 (95 % CI 0·95, 0·98) for 100-109 g/l, 1·04 (95 % CI 1·01, 1·06) for 150-159 g/l, 1·11 (95 % CI 1·05, 1·17) for 160-169 g/l and 1·19 (95 % CI 1·11, 1·27) for ≥170 g/l, respectively. The multivariable-adjusted OR for very PTB (VPTB) was 1·07 (95 % CI 1·03, 1·12) and 1·06 (95 % CI 1·01, 1·12) for women with Hb <110 and ≥150 g/l, compared with those with Hb of 110-149 g/l, respectively. Our study identified a U-shaped relationship between maternal preconception Hb concentration and PTB risk. Both preconception anaemia and high Hb level can significantly increase VPTB risk. Appropriate intervention for women with abnormal Hb levels before pregnancy is very necessary.

High-Throughput Sequencing Reveals Immunological Characteristics of the TRB-/IgH-CDR3 Region of Umbilical Cord Blood.

OBJECTIVE: To compare the differences of immunological characteristics between newborn and adults, we performed high-throughput sequencing to reveal the diversity of umbilical cord blood and adult peripheral blood at both T-cell receptor beta chain (TRB) and immunoglobulin heavy chain (IGH) levels. STUDY DESIGN: High-throughput sequencing was performed to analyze the expression of TRB-CDR3 and IGH-CDR3 in circulating T and B cells isolated from 20 healthy adults, 56 pregnant women, and 40 newborns. RESULTS: Our results revealed different immunological characteristics between newborn and adults, such as distinctive complementarity determining region 3 (CDR3) lengths, usage bias of variable and joining segments, random nucleotide addition, a large number of unique CDR3 peptides, and a greater repertoire diversity. Moreover, each newborn had a distinctive TRB-/IGH-CDR3 repertoire that was independent of the maternal immune status. CONCLUSIONS: This study presents comprehensive, unrestricted profiles of the TRB/IGH-CDR3 repertoire of newborns, pregnant women, and healthy adults at a sequence-level resolution. Our data may contribute to a better understanding of the immune system of newborns and benefit the efficient application of umbilical cord blood transplantation in future.

Prevalence of Underweight, Overweight, and Obesity Among Reproductive-Age Women and Adolescent Girls in Rural China.

OBJECTIVES: To provide prevalence and trends of underweight, overweight, and obesity among reproductive-age women and adolescent girls in rural China. METHODS: We measured weight and height in 16 742 344 women aged 20 to 49 years and 178 556 girls aged 15 to 19 years from the National Free Preconception Health Examination Project between 2010 and 2014. RESULTS: Among women, the prevalence of underweight was 7.8% (95% confidence interval [CI] = 7.7%, 7.9%), and overweight or obesity was 16.5% (95% CI = 16.4%, 16.6%; World Health Organization criteria). Among adolescents, prevalence of underweight was 6.0% (95% CI = 5.7%, 6.2%; Centers for Disease Control and Prevention criteria) and overweight or obesity was 8.3% (95% CI = 7.9% to 8.8%; International Obesity Task Force criteria). According to Chinese criteria, overweight and obesity prevalence was 24.8% (95% CI = 24.7%, 24.9%) for women and 17.2% (95% CI = 16.6%, 17.8%) for adolescents, and underweight prevalence was 2.9% (95% CI = 2.8%, 3.1%) for adolescents. Considerable disparities existed in prevalence and trends within subpopulations (age groups, parity, region, education levels, and socioeconomic status). CONCLUSIONS: Our results reveal coexisting underweight and overweight or obesity among rural women and adolescents of reproductive age, which requires public health attention.

Folic acid supplementation, preconception body mass index, and preterm delivery: findings from the preconception cohort data in a Chinese rural population.

BACKGROUND: Folic acid (FA) supplementation before and during the first trimester can reduce the risk of occurrence of preterm delivery (PTD). Preconception body mass index (BMI) is also associated with PTD. This study aimed to investigate the combined effect of FA supplements and preconception BMI on the risk of PTD. METHODS: The data of a cohort from 2010-2011 that was obtained through a preconception care service in China was used (including 172,206 women). A multivariable regression model was used to investigate the association between maternal preconception conditions and the risk of PTD. The interaction of preconception BMI and FA supplementation was measured by a logistic regression model. RESULTS: Taking FA supplements in the preconception period or in the first trimester reduced the risk of PTD (odds ratio [OR] = 0.58 and OR = 0.61, respectively). Women with an abnormal BMI had an increased risk of PTD (OR = 1.09, OR = 1.10, and OR = 1.17 for underweight, overweight, and obese, respectively). Preconception BMI showed an interaction with the protective effect of FA supplementation for PTD. With regard to the interaction of FA supplementation, the adjusted odds ratio (aOR) was 0.57 (95% CI: 0.51, 0.64) in underweight women, 0.85 (95% CI: 0.73, 0.98) in overweight women, and 0.77 (95% CI, 0.65, 0.91) in obese women. Preconception BMI also showed an interaction with the time of FA supplementation. Women with a normal BMI who began to take FA supplements in the preconception period had the lowest risk of PTD (aORs: 0.58 vs. 0.65 beginning in the first trimester). The aORs at preconception and the first trimester in the underweight group were 0.56 vs. 0.60. The aORs at preconception and the first trimester were 0.94 vs. 0.65 and 1.15 vs. 0.60 in the overweight and obesity groups, respectively. CONCLUSIONS: In our study, FA supplements reduced the risk of PTD, while abnormal BMI raised the risk of PTD, although higher BMI categories did not have this higher risk once adjusted analysis was conducted. The protective effect of FA supplementation for PTD was reduced in women with overweight or obesity. To get better protection of FA supplementation, women with normal BMI or underweight should begin to use in preconception, while women with overweight or obesity should begin to use after conception.

Spatial patterns of the congenital heart disease prevalence among 0- to 14-year-old children in Sichuan Basin, P. R China, from 2004 to 2009.

BACKGROUND: Congenital heart disease (CHD) is the most common type of major birth defects in Sichuan, the most populous province in China. The detailed etiology of CHD is unknown but some environmental factors are suspected as the cause of this disease. However, the geographical variations in CHD prevalence would be highly valuable in providing a clue on the role of the environment in CHD etiology. Here, we investigate the spatial patterns and geographic differences in CHD prevalence among 0- to 14-year-old children, discuss the possible environmental risk factors that might be associated with CHD prevalence in Sichuan Basin from 2004 to 2009. METHODS: The hierarchical Bayesian model was used to estimate CHD prevalence at the township level. Spatial autocorrelation statistics were performed, and a hot-spot analysis with different distance thresholds was used to identify the spatial pattern of CHD prevalence. Distribution and clustering maps were drawn using geographic information system tools. RESULTS: CHD prevalence was significantly clustered in Sichuan Basin in different spatial scale. Typical hot/cold clusters were identified, and possible CHD causes were discussed. The association between selected hypothetical environmental factors of maternal exposure and CHD prevalence was evaluated. CONCLUSIONS: The largest hot-spot clustering phenomena and the CHD prevalence clustering trend among 0- to 14-year-old children in the study area showed a plausibly close similarity with those observed in the Tuojiang River Basin. The high ecological risk of heavy metal(Cd, As, and Pb)sediments in the middle and lower streams of the Tuojiang River watershed and ammonia-nitrogen pollution may have contribution to the high prevalence of CHD in this area.