To compare the rates of adverse pregnancy outcomes between women with normal and abnormal inhibin-A levels.Based on a prospective database of Down syndrome screening program, the consecutive records were comprehensively reviewed. Pregnancies were classified into three groups: normal, high (> 2 MoM) and low (< 0.5 MoM) inhibin-A levels. The pregnancies with medical diseases, chromosome abnormalities and fetal anomalies were excluded. The primary outcomes were the rates of preterm birth, preeclampsia, and fetal growth restriction (FGR).Of 6679 recruited pregnancies, 5080 met the inclusion criteria, including 4600, 205 and 275 pregnancies in the group of normal, high, and low inhibin-A levels respectively. The rates of preterm birth, preeclampsia and FGR were significantly higher in the group of high levels; , whereas the rates of other adverse outcomes were comparable. However, the rate of spontaneous preterm birth among women with high inhibin-A was not significantly increased. Based on multivariate analysis, the preterm birth rate was not significantly associated with inhibin-A levels, but it was rather a consequence of preeclampsia and FGR. Low levels of serum inhibin-A were not significantly associated with any adverse outcomes.High levels of maternal serum inhibin-A in the second trimester are significantly associated with abnormal placentation, which increases the risk of preeclampsia and FGR with a consequence of indicated preterm birth but not a risk of spontaneous preterm birth. In contrast, low inhibin-A levels were not associated with any common adverse pregnancy outcomes. The quad test or quadruple test is the most commonly used serum screening test for fetal Down syndrome, consisting of alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and inhibin-A. According to a systematic review in 2012 [Also preterm birth and preeclampsia are serious obstetric problems experienced worldwide. Several attempts have been made to prevent preterm birth and preeclampsia. For example, progesterone administration is recommended for preterm birth prevention in women with higher risk of spontaneous preterm birth , and aspCurrently, we have implemented a screening program for fetal Down syndrome with serum markers in second-trimester pregnant women, as a pilot-study project in Thailand. All the participants underwent quad test free of charge, supported by the government. Under the project, baseline data, laboratory results and obstetric outcomes were followed-up and prospectively recorded. Accordingly, we could take advantage of such screening to study the association between various serum biomarkers and adverse pregnancy outcomes. Several studies have been published on the association between unexplained abnormal serum biomarker levels, including the first trimester serum markers (beta-hCG and PAPP-A) and second trimester triple serum markers , and adverse pregnancy outcomes, especially preeclampsia, fetal growth restriction and preterm births –8. NeverA cohort study, as a secondary analysis, was conducted with ethical approval by the Institute Review Board, based on a prospective database of Down syndrome screening program by quad test. On the database development, the women were recruited with written informed consent at Chiang Mai University hospital and its network of hospitals in the northern part of Thailand. The consecutive records between October 2016 and March 2018 were assessed and comprehensively reviewed. The inclusion criteria were as follows: 1) singleton pregnancy and 2) gestational age of 15–20 weeks, based on ultrasound biometry of crown-rump length in the first trimester or biparietal diameter in the first half of pregnancy. The exclusion criteria were as follows: 1) fetal structural or chromosomal abnormalities, 2) pregnancy with medical disorders such as heart disease, pre-gestational diabetes mellitus, chronic hypertension, etc., and 3) loss to follow-up, unknown pregnancy outcomes or unavailable data. Pregnancies were categorized into three groups, including the group of normal inhibin-A levels, high levels (> 2 MoM) and low levels (< 0.5 MoM). The primary outcomes were the rates of preterm birth, preeclampsia, and fetal growth restriction (FGR). Additionally, route of delivery, low APGAR scores as well as antepartum and postpartum hemorrhage were also assessed as secondary outcomes.The baseline data of the participants were prospectively evaluated and recorded in the research record form at the time of maternal blood sampling and stored in the computerized database at our research center, Maharaj Nakorn Chiang Mai Hospital and its network of hospitals. The baseline characteristics were as follows: maternal age, parity, ethnicity, height, body weight, body mass index (BMI), gestational age, medical diseases, familial diseases, education, occupations, and smoking habit. The maternal blood samples were then sent to the laboratory and were centrifuged for separation of blood components. The bio-assay procedures of inhibin-A were performed by the same experienced technicians at the research center. The bio-assays for inhibin-A were carried out in batches to get rid of inter-assay variations. The bio-assays were run using DELFIA® Xpress system . The laboratory quality control was regularly validated by third-party experts under the primary project of the National Research University and Thailand’s Office of the Higher Education Commission. The measured levels of maternal serum inhibin-A were then automatically converted to MoM (multiple of medians), using the built-in western reference ranges with ethnic correction; the MoMs were also corrected for maternal weight, smoking and diabetes.The enrolled participants who met the inclusion criteria were divided into three subgroups as follows:  normal i> 140 mmHg or diastolic BP > 90 mmHg together with proteinuria 1+ or more on urinary dipstick or urine protein creatinine ratio more than 0.3 or 24-h urinary protein greater than 300 mg after 20 gestational weeks, 4) LBW (low birth weight): birth weight less than 2500 g, 5) low APGAR scores: the scores of less than 7 at 5 min, 6) antepartum hemorrhage: uterine bleeding after 20 gestational weeks, and [Definitions of obstetric outcomes were as follows: 1) preterm delivery: giving birth before 37 complete weeks of gestation, including spontaneous and indicated preterm birth , 2) FGR: fetuses with birth weight lower than the 10th percentile, using the fetal growth rate graph of Thai reference ranges, 3) Preeclampsia: systolic BP P-value < 0.05 was considered statistically significant. The statistical analysis was done with SPSS .The baseline characteristics between the normal and abnormal groups were compared by Student’s T-test or Mann-Whitney-U for continuous variables and Chi-square test for categorical data. The percentages of preterm birth, preeclampsia, FGR, low birth weight, low APGAR scores, antepartum hemorrhage and postpartum hemorrhage were compared between the groups of abnormal (high and low) inhibin-A concentrations and the group of normal concentrations, using Chi square as well as relative risks with 95% CI. Binary logistic regression analysis was performed to adjust the confounders of the main outcomes. During the study period, 6679 pregnancies undergoing fetal Down syndrome screening with quad test were recruited. Of this number, 1599 were excluded because of medical conditions (804), such as chronic hypertension, diabetes mellitus, heart disease etc., unavailable pregnancy outcomes, fetal anomalies or chromosome abnormalities (804), and abortion before 20 weeks , as presp-value 0.049, 7.3% vs 2.0%, p-value < 0.001; 10.2% vs 3.3%, p-value < 0.001; and 15.1% vs 9.5%, p-value 0.008 respectively), while the percentage of other adverse obstetric outcomes, including low APGAR scores, antepartum hemorrhage, postpartum hemorrhage and route of delivery were not significantly different between the two groups, as presented in Table p-value 0.356). Likewise, after adjusting for the potential confounding factors by logistic regression analysis, preterm birth was not significantly associated with high inhibin-A  but significantly related to preeclampsia  and advanced maternal age , as presented in Table p-value < 0.001), as shown in Table The analysis revealed that the rates of preterm birth, preeclampsia, fetal growth restriction, and low birth weight were significantly higher in the group of high levels than those in the normal group; , as presented in Fig. p-value < 0.001; odd ratio 3.34; 95% CI: 2.77–4.04), as presented in Fig. Regarding the comparison of Kaplan Meier curve of gestational age at delivery between the women with high and normal inhibin-A levels, Cox regression analysis showed that after adjusting for potential confounding factors, gestational age at delivery was not significantly different  The sample size was relatively small for comparisons of some rare secondary outcomes such as fetal death. 2) There were a significant number of women with unavailable data or loss to follow-up. 3) Since all participants resided in the northern part of Thailand, the outcomes may not be generalized to other geographical areas. 4) Analysis of the effects of combination of inhibin-A with other serum biomarkers on pregnancy outcomes was not performed. The strengths of this study are as follows: 1) The obstetric outcomes were followed up by the research group and prospectively recorded to the database. 2) Most of the known possible confounding factors were excluded prior to analysis, such as fetal anomaly, chromosome abnormalities, maternal medical diseases, etc. 3) All lab tests were carried out by the same experts, using the same lab machine in the same settings. 4) The network of hospitals included both urban and rural people, more reflective of all our population than tertiary referral centers or hospitals in the private sector.Elevation of maternal serum inhibin-A in the second trimester is significantly associated with abnormal placentation, which increases the risk of preeclampsia and fetal growth restriction with a consequence of indicated preterm birth but not significantly associated with spontaneous preterm birth. In contrast, low inhibin-A levels are not associated with any common adverse pregnancy outcome.


Several biomarkers are used to measure iron deficiency (ID) during pregnancy, but the prevalence of ID and its association with adverse birth outcomes shows inconsistent results. The aim of this study was to examine the prevalence of ID in third trimester using multiple indicators of iron status and the relationship with birth outcomes in Chinese population.We conducted a retrospective observational cohort study of 11,581 pregnant women between 2016 and 2017 in Changzhou City, Jiangsu Province, China. We obtained the data  and the concentrations of ID biomarkers from our hospitalization information system and laboratory information system, respectively. Using serum ferritin (SF), serum transferrin (ST) and their ratio as criteria of ID, we investigated associations between birth outcomes and late pregnancy ID.The prevalence of ID in our study was 51.82% as defined by low SF (< 12 μg/L), 54.43% as defined by high ST (> 4 g/L) and 53.90% as defined by high ratio of ST/SF (Log 10 transform > 5.52). Maternal ST/SF ratio was associated with higher mean birth weight . Third trimester maternal ID, defined by ST/SF ratio, was associated with lower risks of preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) infants, higher risks of macrosomia and large for gestational age (LGA) babies .ID in the third-trimester of pregnancy are frequent in Chinese women. Our findings suggest that the ratio of ST/SF measured in late pregnancy could be useful as a significant predictor of unfavorable birth outcomes.The online version of this article (10.1186/s12986-019-0360-9) contains supplementary material, which is available to authorized users. Pregnant women are particularly vulnerable to iron deficiency (ID) because of increasing iron requirements of pregnancy. Globally, it is reported that the prevalence of ID varies greatly during pregnancy, ranging from 6.5 to 39.2% in United States and Canada, 28–85% in Europe, 31.4% in Korea and 19.6% in Australia, depending on the criteria used and iron supplementation .However, SF is an acute-phase protein, which is significantly increased in response to infection or inflammation. The confounding effects of inflammation may lead to misdiagnosis of ID in individuals and underestimation of the prevalence of ID in study population. To evaluate iron status in population by SF concentration, WHO currently recommends the simultaneous measurement of inflammatory markers or the exclusion of individuals with inflammation from analysis . TransfeThis retrospective cohort study included a consecutive sample of pregnant women delivered in Changzhou Maternity and Child Health Care Hospital between April 2016 and March 2017. The ethics committee of the hospital approved the protocol of this study (No.ZD201803). We obtained the written informed consent and anonymously analyzed the data from this cohort. Based on the inclusion and exclusion criteria, we established this cohort. Inclusion criteria included: 1) pregnant women aged > 18; 2) pregnancy at 28–41 weeks of gestation; 3) integrated and clear medical records; 4) singleton pregnancy and live birth born without birth defects. Exclusion criteria were as follows: 1) multiple pregnancy; 2) missing integrated and clear medical records; 3) preexisting illnesses before getting pregnant: diabetes mellitus (type 1 or 2), chronic hypertension, thyroid diseases, chronic heart, liver and kidney diseases, immune rheumatic disease or thyroid diseases and syphilis prior to pregnancy; 4) cigarette smokers and alcohol drinkers in pregnancy. We reviewed and collected the detailed hospitalization data including maternal characteristics, history of past illness and bad hobby, pregnancy complications, labour, delivery and neonatal outcomes from our hospitalization information system. Also, laboratory information system in our hospital provided data on pregnant woman’s SF, ST and serum hsCRP values. Maternal ferritin, transferrin and hsCRP concentrations were analyzed by means of chemiluminescent immunoassay, immune turbidimetry and particle enhanced immunonephelometry using specific automated analyzers, respectively . The hemoglobin was detected by hematology analyzer . Two established definitions of ID were applied: SF < 12 μg/L and ST > 4 g/L according to the previous studies . Based oWe considered gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP), preeclampsia (PE) and pregnancy-induced hypertension (PIH) as major pregnancy complications; and PTB, small for gestational age (SGA), large for gestational age (LGA), LBW, macrosomia as unfavorable birth outcomes. We discriminated these abnormal outcomes from hospital data according to diagnosis by the clinician. Depending on the International Diabetic Pregnancy Association (IADPSG) criteria, 75 g oral glucose tolerance test was used to diagnose GDM at 24–28 weeks of gestation . ICP alwhttp://www.R-project.org). A p-value < 0.05 was considered as statistical significance.Continuous variables with normal distribution and skewed distribution were presented as mean ± SD and median , respectively. Categorical variables were described as N (%). ID prevalence in our cohort was determined by these definitions of serum ferritin, transferrin and their ratio. The levels of these non-normally distributed iron biomarkers among women with or without high hsCRP (> 5 mg/L) were described by median and 25th and 75th percentiles. To compare differences between ID group and replete group, non-parametric and parametric methods were properly used to examine statistical significance. General linear analysis was applied to examine the association of serum biomarkers for ID with fetal growth . After adjusting for maternal age, BMI, gravidity, parity, hemoglobin level, Logistic regression analysis was used to explore the associations between maternal ID and pregnancy outcomes. OR and 95% CI for PTB were additionally corrected for GDM, ICP, PE, PIH, systolic and diastolic blood pressure and infant sex. These values for SGA, LGA, LBW and macrosomia were further adjusted for gestational age at delivery. Furthermore, ORs and 95% CIs for different pregnancy outcomes with quartiles of ST, SF and their ratio were evaluated by logistic regression analysis controlling for available confounders, hsCRP and hem oglobin levels. All statistical analyses were conducted using statistical software EmpowerStats  and R . In addition, ST showed positive association with gestational age  and negative association with birth length , for Q4 vs. Q1 . No statistically significant association of maternal SF with gestational age was observed.Table p = 0.06, p = 0.10, respectively). However, these relationships were of statistical significance when using the ratio of ST to SF as ID criterion .The ORs and 95% CIs for pregnancy outcomes with maternal ID were presented in Table p for trend < 0.01). Elevated ST had positive association with GDM, ICP, macrosomia and LGA . Interestingly, PTB, LBW and SGA were decreased in correlation with the Q4 of ST .As regards to pregnancy complications, pregnancy ID defined with SF remained significantly associated with decreased risk of GDM, ICP and PE . On the contrary, pregnancy ID defined with ST showed significantly associated with increased risk of GDM and ICP in all women  or women with hsCRP ≤5 mg/L . Furthermore, Table To our knowledge, this is the largest report to investigate the prevalence of ID and adverse outcomes in Chinese pregnant women. Our study shows that more than half of Chinese pregnant women are ID based on SF, ST and their ratio during late pregnancy. ID in the third trimester is associated with increased risk for macrosomia and LGA infants, and decreased risk of PTB, LBW and SGA babies. Up till to now, there have no published data on the association between maternal ST concentrations and subsequent birth outcomes. In this retrospective observational study, we also examined the association of the quartiles of ST and ST/SF ratio with birth outcomes. Maternal ST concentrations and ST/SF ratio are positively associated with the risk of macrosomia and LGA babies and negatively associated with the risk for PTB, LBW and SGA newborns.Compared with anemia diagnosed by hemoglobin, there is fewer reports on the associations of maternal iron status classified by SF with adverse birth outcomes. Furthermore, available findings show inconsistent results. In early pregnancy, low SF concentrations (< 15 μg/L) were associated with increased risk of SGA in one study, and a high level of SF (>75th percentile) was only correlated with an elevated risk of PTB in another report, however, no significant associations of ID (SF < 12 μg/L) with birth outcomes were observed in the third study , 16, 17.Furthermore, the present study suggested maternal ID defined by SF < 12 μg/L in late pregnancy was significantly associated with decreased risk for PTB, LBW and SGA neonates. As we know, it is the larger observational cohort study correlated reduced SF concentration (< 12 μg/L) in the third trimester with low risk of these adverse birth outcomes. Our findings were inconsistent with previous reports the relationship between ID and these pregnancy outcomes with some reporting no a relationship between ID and birth outcomes , 18, 22,ID is considered to be the most common nutritional deficit in the world. The prevalence of ID in developing countries is far greater than that in developed countries . InsuffiIn terms of birth outcomes, previous study by Khambalia et al. found that ID defined by total body iron (TBI), but not SF and STfR was associated with increased risk of LGA infants . Our finSeveral strengths of the present cohort study included as follows: 1) sufficient sample size of pregnant women with different levels of ferritin and transferrin or major birth outcomes, 2) some potential confounders were firstly excluded before analysis including subjects with most pre-existing diseases or fetal congenital malformation, and known confounding factors such as maternal age and BMI or hsCRP and hemoglobin level were also corrected by logistic regression analysis, 3) the levels of ID biomarkers as well as hsCRP, hemoglobin and the birth outcomes were prospectively documented in laboratory and hospitalization database, respectively, 4) all the tests were carried out in the same laboratory using same machines with same settings, 5) our hospital network included the rural and urban populations reflecting the general population rather than the referral center for high-risk women. However, the current study still has some limitations. Because of the use of a retrospective database, we were unable to investigate the association of maternal ID with risk of adverse pregnancy outcomes in the first and second trimester. The third trimester of pregnancy is the most important period for fetal growth, however, it is believed that the majority of late pregnancy disorders originate from earlier pregnancy . It is uMore than half of Chinese women have experienced late pregnancy ID, which gives the importance of routine screening for anemia in pregnant women and iron research for suspected ID women. The correlation between ID defined by ST/SF ratio and risks of adverse birth outcomes requires further investigation in other study populations. Our findings and those reported in other studies suggest that if increased SF levels are true reflection of iron excess in mothers, and are associated with adverse birth outcomes, the rationality of routine iron supplementation for all pregnant women should be reexamined.Additional file 1:Table S1. Percentiles of birth weight for a population with the mean birth weight at 40 weeks of gestation of 3513.8 g in China. (DOCX 27 kb)


Low birth weight is associated with a lower grip strength later in life. However, associations between birth weight among infants born at-term and factors driving associations between birth weight and grip strength are largely unknown. A cohort of 144,369 young men born at-term, including 10,791 individuals who had at least one male sibling/s, were followed until conscription where they performed a grip strength test. We used linear and non-linear regression analyses in the full cohort, and fixed-effects regression analyses in the sibling cohort, to address confounding by factors that are shared between siblings. After adjustment, each unit increase in birth weight z-score was associated with increases of 17.7  and 13.4 (10.1–16.6) newton grip strength, which converts to approximately 1.8 and 1.4 kilogram-force in the full and within-families cohorts, respectively. The associations did not vary with young adulthood BMI. Birth weight, within the at-term range, is robustly positively associated with grip strength in young adulthood among men across all BMI categories and associations appears to be mainly driven by factors that are not shared between siblings. These findings underline the importance of recognizing the influence of low birth weight, also within the at-term-range, on young adulthood muscle strength. Birth weight is not only determined by the prenatal environment, but also by genetic influences. Hence, associations between birth weight and later health outcomes may be a consequence of a compromised environment in utero or genetic factors that affect both birth weight and later health outcomes. Therefore, family studies are needed to provide further evidence of the extent to which the associations between birth weight and later health outcomes are explained by genetical factors and other family shared environmental factors. Gestational age is, in addition to birth weight, an important determinant of adult health4. It is becoming increasingly evident that infants born at-term (i.e. week 37–41) form a heterogeneous group5. Indeed, birth weight within the at-term range is associated with later health outcomes7. By using births within the at-term range, confounding by gestational age and/or prematurity can be ruled out. In all, these findings warrant further explorations of long‐term health markers associated to birth weight among infants born at-term.Low birth weight10. Furthermore, higher grip strength has been demonstrated to attenuate the increased mortality associated with an elevated BMI11, suggesting that grip strength has important health benefits across all BMI categories. There is a strong correlation (i.e. >0.8) between grip strength and total muscle strength in young males12, which makes grip strength an appropriate general indicator for overall muscle strength13. Muscle strength is the capacity to carry out work against a resistance, depending on several factors . Studies have suggested that the major factor influencing the observed inverse association between grip strength and mortality is not attributable to the muscle mass per se, but to muscle strength as a marker of muscle quality14. Overall, current evidence from epidemiological observational studies indicate that low birth weight, across all gestational ages, is associated with lower grip strength, even after adjusting for potential confounding factors15. However, most previous studies on the topic have been confined to small sample sizes, grip strength comparisons between preterm birth and term‐born controls being used as a homogenous comparator and/or unable to control whether such associations are explained by shared and/or non-shared familial factors15.One such important and modifiable health marker is grip strength which is associated with a wide range of health outcomes later in life, including all-cause mortality rates equivalent to that of well-established risk factors such as elevated blood pressure or body mass index (BMI)Therefore, the aim of this study was to investigate the association between birth weight, within the at-term range, and grip strength in young males. We further investigate whether any such association is explained by factors shared between siblings, and if associations differ with BMI in young adulthood.16, (ii) the Swedish Military Service Conscription Registry, (iii) the Population and Housing Censuses from 1970 and 1990 and (iv) the Multigenerational Register. The study was approved by the Regional Ethical Review Board, Stockholm (Dnr: 2016/1445-31/1).This prospective cohort study used unique personal identification numbers, assigned to each Swedish resident at birth, for record linkage of four different Swedish population-based registers: (i) the Medical Birth Register (MBR) containing validated data on >99% of all births in Sweden2) at conscription, as previously described17. Derivation of the analytical sample is presented in a flowchart in Fig. All men born at-term in Sweden 1973–1976  and who conscripted for military service in 1991–1994  were eligible for inclusion in the study. In that time period, conscription was mandatory by law, and young adults were relieved from conscription only due to confinement or if they suffered from severe medical condition. The study period was chosen to match the availability of perinatal exposure data from the MBR (available from 1973) and outcome grip strength data from the conscription registry. Exclusion criteria included incomplete data  including those who did not perform the grip test at conscription , or extreme values (n = 68) for weight (≤40 or ≥150 kg), height (≤150 or ≥210 cm) and BMI , using standard well-validated and daily calibrated isometric dynamometer test20. BMI (kg/m2) was classified according to World Health Organization (WHO) categories: underweight (BMI <18.5), normal weight (BMI 18.5–24.9), overweight (BMI 25–29.9) and obese (BMI ≥30)21. Parental education, where the highest education achieved by any of the parents was used as a measure of household socioeconomic position, was derived from the Population and Housing Censuses. Information regarding conscription center (six centers) and age at conscription were retrieved from the Conscription Registry. The MBR was used for information on further potential confounders, such as maternal diabetes, maternal hypertension, birth by caesarean section, maternal parity and maternal age at birth.Standardized scales and stadiometers were used to measure weight and height at conscription, respectivelyFirst, we descriptively present our cohort by dichotomizing the exposure and outcome by their respective median into four groups: (i) high grip strength/high birth weight z-score, (ii) high grip strength/low birth weight z-score, (iii) low grip strength/high birth weight z-score and (iv) low grip strength/low birth weight z-score Table . Second,Associations in our models are presented as crude estimates and adjusted for maternal diabetes (yes/no), maternal hypertension (yes/no), caesarean section (yes/no), parity , maternal age (continuous), highest parental education  and conscription office . We further employed restricted cubic splines with five knots at: 5, 27.5, 50, 72.5 and 95 percentiles, to assess departure from linearity  . The requirement to obtain informed consent was waived by the Regional Ethical Review Board, Stockholm (Dnr: 2016/1445-31/1). All research was performed in accordance with relevant guidelines/regulations.Table Table Figure Table Supplementary Table in utero.This total population-based study of 144,369 males showed that higher birth weight, within the at-term range (i.e. week 37 to 41), was prospectively and positively associated with grip strength in young adulthood (17–22 years) across all categories of BMI. Moreover, our within-sibling analysis, indicates that this association appears to be mainly driven by factors that are not shared between siblings. Consequently, the present study provides novel evidence to this emerging field. To the best of our knowledge, this is the first study that has examined associations of variations in the levels of grip strength, across all BMI categories, in young adulthood across different birth weights within the at-term range, using family-based analysis which provides a unique opportunity to explore whether this association is mainly driven by factors that are shared or non-shared between siblings. Although this study cannot disentangle causal pathways, grip strength may to some extent be determined already 22 and influenced by nutritional status during critical periods of early development23. This is supported by animal24 and human studies26 showing a reduced muscle fiber composition in those with low birth weight. Postnatal muscle growth (e.g. via strength exercise) occurs by growth of each muscle fiber, which to some extent can compensate a deficit in fiber number27. However, individuals born with fewer muscle fibers will be at considerable disadvantage in terms of muscle strength later in life. In addition, low birth weight is associated with abnormal development that triggers adaptations in tissues and organs, eventually resulting in permanent muscle related physiological alterations28, which my result in long-lasting impairments in muscle strength29.Explanations for the protective and lifelong effect that birth weight, within the at-term range, seems to have on grip strength could be that the number of mammalian muscle fibers is determined at or soon after birth30. Likewise, a common genetic cause of both low birth weight and low grip strength cannot be excluded. However, results from our within-sibling analysis, where shared influences between siblings such as genetic factors, parental socioeconomic influences etc. are held constant, only differed marginally from analyses based on the full cohort. This provides some support to the hypothesis that shared factors between siblings most likely only explain part of the observed associations between birth weight, within the at-term range, and grip strength These findings support the notion that a poor intrauterine nutrition leading to a low birth weight for gestational age is programming grip strength later in life. However, twin-pair analyses are needed to further detangle the genetic and in utero effects that may explain the association between birth weight, within the at-term range, and later grip strength.Meta-analysis data shows that grip strength has a strong genetic component with an estimated heritability of approximately 50%31. Consequently, varying levels of engagement in strength promoting physical activity among the study population may to some extent explain observed association between birth weight, within the at-term range, and grip strength in young adulthood. Our finding that birth weight, within the at-term-range, is associated with grip strength in young adulthood across all BMI categories suggests that this association is not simply explained by a skeletal size effect, since larger persons tend to have larger muscles. This is further supported by our sensitivity analysis showing a consistent positive association between birth weight z-score, within the at-term range, and grip strength regardless of the quartile of height.The observed associations between birth weight, within the at-term range, and grip strength may partly be explained by differences in upbringing between children born adequate and small for gestational age. For example, parents may choose to restrict low birth weight children’s participation in strength promoting physical activity because of perceptions of fragility8. Previous data has shown that higher grip strength essentially attenuates the negative effects from elevated BMI on mortality in men11. The weakest men (lowest fifth) in the most obese group has shown to have a 39% increased mortality risk  and this risk was negligible among the strongest men (highest fifth) in the same most obese group . Consequently, findings from this study showing that birth weight, even within at-term deliveries, is associated with grip strength in young adulthood across all categories of BMI, may be of public health interest.The study of early determinants of grip strength is of special interest since low grip strength in adolescence is strongly associated with a wide range of negative health outcomes later in life, including increased all-cause mortality rates equivalent to that for well-established risk factors such as elevated blood pressure or BMI32. Since approximately 15% of all live births are low birth weight births33, which are associated with lifelong health consequences35, preventing low birth weights, even within the at-term range, may have long-term effects on markers of health such as grip strength. It is of importance to state that not all low preterm or low birth weights can or should be prevented, for example spontaneously occurring births. However, recent trends towards shorter gestational lengths within the at‐term range can to some extent be attributed to the increases in the rates of planned cesarean deliveries36, which is a modifiable factor.The 17.7 unit increase in grip strength (N) for each SD increase in birth weight z-score reported in this study, translates into approximately a two kilogram stronger grip strength. This may have clinically important implications. For example, data from the U.K. Biobank study in over 400,000 adults aged 40–69 years has shown that every three kilogram increment in grip strength was associated with approximately 8% lower mortality15. For example, a meta-analysis, including 17 studies and 21,344 individuals aged 5 to 86 years, showed that an extra kilogram of birth weight was associated with a 0.9 kilogram increase  in grip strength. However, none of the included studies did control for shared factors in within-sibling analyses and/or investigate the associations between birth weight, within the at-term range, and grip strength and/or whether associations varied with BMI. Thus far, only one small cohort study has demonstrated that within a twin-pair the heavier twin at birth has greater grip strength in adult life compared with the lighter sibling. In addition, the twin-pair analyses showed that associations between birth weight and adult grip strength were stronger in dizygotic than monozygotic twin-pairs, suggesting a potential influence of genetic factors, acting on both birth weight and adult grip strength37. Similarly, we found evidence for a stronger association between birth weight, within the at-term range, and grip strength in young adulthood in all included men compared with the within-sibling analysis including men who had one or more matchable male sibling/s.Studies investigating the associations between birth weight or gestational age and grip strength have been confined to grip strength comparisons between preterm births, not taking gestational age into account, and at-term born being used as homogenous comparator40. Finally, we rule out confounding by gestational age and/or prematurity by using births within the at-term range.The strengths of this study lies in the large sample size and accompanying statistical power. Furthermore, strengths include the population-based design and the long-term follow-up, where prospectively collected data at birth could be linked to grip strength at ages 17–22. We were also able to adjust for perinatal and other major determinants  of grip strength and the within-sibling analysis enabled us to disentangle whether associations were mainly driven by factors shared or non-shared between siblings. Furthermore, both exposure (birth weight within the at-term range) and outcome (grip strength) were measured using objective and standardized procedures. In fact, grip strength is the test of muscular strength that has shown the strongest evidence in relation to mortality41. Second, residual confounding could be present. For example, the lack of data on maternal nutrition and smoking habits (of mothers before/during pregnancy), could have had an impact on both the exposure (birth weight) and outcome (grip strength). However, smoking is more prevalent in families with low parental education. Thus, some of the effect of smoking on grip strength is accounted for in our models. Moreover, the within-families analysis accounts for habits  that are consistent over time. Fourth, the within-families analysis including siblings only allow us to partly control for shared genetic factors (50%) between siblings. It is unlikely that segregating genes, potentially influencing grip strength, are randomly distributed with regards to birth weight. Fifth, since the birth factors were recorded in the 70’s, gestational age was estimated by the last menstrual period, which has limited accuracy. This may affect our precision in determining the at-term range. Sixth, register-based studies have inherited limitations, e.g. unknown data quality and possible differences in data collection between institutions. Finally, it should be noted that we did not measure engagement in strength promoting physical activity, which can influence grip strength. Hence, it is possible that the associations between birth weight, within the at-term range, and grip strength in young adulthood may be mediated by engagement in strength promoting physical activity.This study is accompanied with several limitations. First, the cohort included only young adult men and the potential generalizability to women is largely unknown. Previous data has shown that the magnitude of association between birth weight and adult grip strength in women is approximately half of that seen in menIn summary, this large prospective cohort study has shown that higher birth weight, within the at-term range, is prospectively associated with higher grip strength in young male adults, across all categories of BMI and variations in height. Furthermore, our within-family analysis has shown that this association appears to be mainly driven by factors that are not shared between siblings, reducing the likelihood that this association is largely explained by genetics and other environmental factors shared within families. There are undeniably clinically relevant and strong prospective associations between grip strength in adolescence and later life health outcomes. Consequently, our novel findings both expand our understanding of determinants of grip strength and may have public health implications. For example, highlighting the importance of birth weight and heterogeneity among at-term deliveries, which have implications for how at-term deliveries are followed-up and monitored.SUPPLEMENTAL MATERIAL


Birth weight, which can be an indicator for risk of chronic diseases throughout the lifespan, is one of the most commonly used measures in the study of developmental origins of health and disease. There is limited information on the reliability of parent/guardian reported birth weight by race or by respondent type .Birth weight was reported by a respondent for 309 of the 333 (92.8%) study participants; of these, chart obtained birth weight was available for 236 (76.4%). There was good agreement between respondent report and chart obtained birth weight. Over half  of respondents reported a birth weight within ± 100 g of what was in the chart; 60.9% of black participants (n = 81) and 62.1% of white participants (n = 64) fell within 100 g. Overall, mothers were 3.31  times more likely than fathers to correctly recall the child’s birthweight within ± 100 g (p = 0.023). Respondent reported birth weight is a reliable alternative to chart obtained birth weight. Mothers were found to be most accurate in reporting birth weight of the child. Race/ethnicity was not significantly associated with reliability of birth weight reporting.The online version of this article (10.1186/s13104-018-3977-2) contains supplementary material, which is available to authorized users. Increasing evidence supports that the development of many chronic diseases in adulthood originates in utero . Black iBirth weight remains one of the most commonly used measures in the study of the developmental origins of health and disease. Birth weight is a measure easily obtained via questionnaire and has been shown to be highly accurate and reliable in a number of studies reporting maternal recall of child birth weight –8, makinThe purpose of the current study was to extend these previous findings by examining the accuracy of self-reported birth weight by parent/guardian respondent in a study of healthy adolescents (ages 14–17 years) and to determine if there were racial or parent/guardian status differences in the accuracy of self-report.Potential participants were identified by accessing the administrative data warehouse of Henry Ford Health System (HFHS), which provides medical care to 20% of the metropolitan Detroit population . The curDuring the interview, the parent/guardian was asked to self-report the child’s birth weight. Only children who were born at or who had their initial well-baby visit at HFHS-affiliated facilities had chart birth weight available. Using the child’s or mother’s unique medical record number, trained chart abstractors searched the EMR for each participant to obtain the weight at birth; paper charts were requested for those participants who did not have data in the EMR.2). Height, weight and BMI percentiles were calculated using the 2000 Centers for Disease Control and Prevention growth charts. BMI ≥ 85th percentile was considered overweight. Parent/guardian participants self-reported race/ethnicity, whether or not they were the biological parent of the adolescent, and the relationship type .At the research clinic visit, adolescent’s height was measured with a wall stadiometer and weight with an electronic balance; body mass index (BMI) was calculated . Differences in participant characteristics were compared using independent 2; 35.2%, respectively) compared to those without .Birth weight was reported for 309 of the 333 (92.8%) study participants  and white participants (− 19.2 ± 222.8 g) tended to underreport birth weight, but the numbers were not significantly different (p = 0.792). Only 65 (27.5%) respondents self-reported a birth weight identical to the chart obtained birthweight; 33.1% of black respondents (n = 44) and 20.4% of white respondents (n = 21) (p = 0.031). We compared participant demographics between those who did and did not self-report birth weight within ± 100 g of the child’s actual birth weight  while white mothers were more likely to slightly under-report birth weight (mean difference = − 8.3 ± 9.1 g) . We specIn a previous study by Lucia et al. on a cohort of adolescents in Michigan, reliability of maternal birth weight recall within ± 250 g was 87.1% . Our anaWe identified several characteristics that were significantly associated with the reporting of birth weight or the accuracy of birth weight in our sample. Overall, biological parents were more likely to have respondent reported birth weight than other caregivers. In addition, mothers were more likely than fathers to correctly recall the child’s birth weight within a 100 g margin, suggesting maternal recall of birth weight is more accurate than paternal recall. Median discrepancies of respondent reported and chart obtained birth weight were also significantly different when comparing mother’s, father’s and other caregivers’ birth weight recall, with mothers having the smallest median discrepancy. Evidence has shown that women are more likely to participate in research than men . TherefoOne of the main strengths of the study is the racial, educational and socioeconomic diversity of the study population as well as diversity in caregiver type . To our knowledge, the current study is one of very few conducted in the United States to include this type of diversity in caregivers. Another strength is the time interval between birth and collection of respondent reported birth weight during adolescence, confirming that reported birth weight continues to be a reliable measure well after birth.A limitation of this study includes the relatively small sample size and small number of caregivers who were not the child’s mothers, which did not allow for the examination of reliability of respondent reported birth weight among this group. While we did not find any differences among participants who had available chart obtained birth weights compared to those who did not except for higher BMI among those without chart obtained birth weight, it is possible that our findings are subject to selection bias.In conclusion, respondent reported birth weight is a reliable and efficient alternative to obtaining birth weight data from the medical record for use in research studies. In the current study sample, race was not associated with accuracy of respondent reported birthweight. Mothers were the most accurate in reporting birth weight of the child compared to fathers or other caregivers. Thus, caution should be exercised in using respondent reported birth weight when the person reporting the birth weight is not a biological parent, in particular, the mother. There were no other factors that were significantly associated with reliability of birth weight reporting.Additional file 1. Study recruitment schematic. BMI, body mass index; DOHad, Developmental Origins of Health and Disease; EMR, electronic medical record.Additional file 2. Univariable relationships of participant characteristics with whether or not the respondent was within 100 g of the child’s actual birth weight.


Antenatal corticosteroid therapy (ACT) is used clinically to prepare the fetal lung for impending preterm birth, but animal and human studies link corticosteroids to smaller birth size. Whether ACT is associated with birth size is debated; therefore, we assessed differences in birth size in treated versus untreated pregnancies.n = 2,173) were born at term. First, results of unadjusted regression analyses using the entire sample showed the greatest reductions in BWT as compared to the other analytic methods: very preterm −61.26 g , preterm −232.90 g , near term −171.50 g , and at term −101.95 g . Second, using the entire sample, regression analyses adjusted for baseline and medical conditions showed significant differences in BWT between exposed and unexposed infants: very preterm −61.54 g , preterm −222.78 g , near term −159.25 g , and at term −91.62 g . Third, using the stringent PSM analyses based on matched subsamples, infants exposed to ACT weighed less at birth: −220.18 g , −140.68 g , and −89.38 g , born preterm, near term, and at term, respectively. Similarly, significant reductions in BL and HC were also observed using the three analytic methods. There were no differences among postterm infants regardless of analytic method. Likewise, we observed no differences with respect to PI. Additional analyses showed that exposed and unexposed infants had generally similar Apgar scores at birth, yet the ACT-treated infants received greater medical care during the first 7 days of life and beyond. Our study is mainly limited by lack of data in FMBR specifying the interval between treatment and birth as well as other potential confounders that could not be tested.This observational register-based study used data from the Finnish Medical Birth Register (FMBR) covering all births in Finland . We used unadjusted and adjusted regression analyses as well as propensity score matching (PSM) to analyze whether birth size differed by ACT exposure. PSM provides a stringent comparison, as subsamples were created matched on baseline and medical characteristics between treated and untreated women. All analyses were stratified by timing of birth. The primary study outcome was birth size: birth weight (BWT), birth length (BL), ponderal index (PI), and head circumference (HC) measured immediately after birth and recorded in the FMBR. Additional analyses explored indicators of neonatal health in relation to ACT exposure and birth size. A total of 278,508 live-born singleton births with ≥24 gestational completed weeks were registered in the FMBR during the 5-year study period. Over 4% of infants were born preterm, and 4,887 women were treated with ACT (1.75%). More than 44% of the exposed infants  is used clinically to prepare the fetal lung for impending preterm birth but may cause smaller birth size. In this national registry study, Alina Rodriguez and colleagues measure this association according to timing of birth. Presently, guidelines recommend one dose, repeated over 24 hours, of antenatal corticosteroid therapy (ACT) to accelerate fetal lung maturation in cases of threatened preterm birth in an effort to reduce infant mortality related to respiratory distress.Many exposed infants are born at term and thus exposed unnecessarily to potential harms of ACT.There is persistent concern about the potential risk of ACT to decrease birth size, but previous results in humans are uncertain.Most studies do not use birth size as the primary outcome and do not examine all measurements, i.e., birth weight (BWT), birth length (BL), head circumference (HC), and ponderal index (PI).The entire population of singleton and live-born infants in Finland was studied during a 5-year period —in total, 278,508 infants.Propensity score was used to generate matched subgroups of ACT-exposed and ACT-unexposed infants to compare size at birth.Exposure to ACT is consistently associated with smaller size at birth including BWT, BL, and HC among infants born preterm, near term, and at term, but not with PI in propensity score–matched analyses.Deficits in birth size in relation to ACT were greatest for infants born preterm regardless of analytic strategy.There was a clinically significant reduction in birth size among infants exposed to ACT and born at term—i.e., unnecessarily exposed—as compared to unexposed counterparts.ACT-exposed infants received more medical care than matched unexposed counterparts, counter to expectation, suggesting that treated infants’ health was more compromised at birth and required more medical intervention and that the expected prophylactic effect of ACT was not fully realized.Early care decisions need to identify high-risk patients and weigh benefits of ACT against potential harm of unnecessary exposure.These findings provide strong evidence indicating ACT is associated with reduced fetal growth in humans and provide an agenda for further studies and on par with reexamination of guidelines. Complications arising from preterm birth are the primary cause of mortality in children under 5 years old  and a leACT may disturb fetal growth  and consOur objective was to address previous shortcomings and investigate the association between ACT exposure and birth size—birth weight (BWT), birth length (BL), ponderal index (PI), and head circumference (HC)—using data from the nationwide Finnish Medical Birth Register (FMBR). Because we had complete country data available, we were able to specifically examine carefully matched pregnancies to address issues of confounding and examine whether ACT was related to birth size of infants born at term, i.e., who received the prophylactic treatment unnecessarily. Given the very large sample size, we set out to create balanced subgroups (treated versus untreated) for direct comparison, using propensity score matching (PSM). The subgroup matching took into account factors influencing ACT treatment. Additional analyses were conducted to explore whether indices of poor fetal health, potentially precipitating ACT treatment, were related to growth deficits. We hypothesized that ACT-exposed infants would be smaller at birth than unexposed infants in one or more of the birth size values.https://thl.fi/en/web/thlfi-en/about-us) in Finland, in accordance with national data protection legislation, authorized the release of the anonymized data for this register-based study and provided ethical approval. Individual informed consent was not required, as only deidentified data were used without any additional patient contact. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline , and stillbirths. ACT administration during the current pregnancy was recorded in FMBR as either received treatment or not. The recommended treatment consisted of betamethasone 12 mg administered twice, 24 hours apart. According to national guidelines, delivery can be postponed through tocolytic therapy to enable corticosteroid prophylaxis and referral to tertiary hospital, if necessary.3]).Using a uniform method across Finland, medical staff measure BWT accurate to ±1 g, BL, and HC in centimeters immediately after birth. We calculated PI using the standard formula , preterm (30–34), near term (35–37), at term (38–41), and postterm (≥42). Gestational age at birth is recorded in FMBR as the best estimate including last menstrual period and ultrasound examination. Women routinely undergo an early-pregnancy ultrasound scan by a specially trained midwife at maternity outpatient clinics across the country between 11 + 0 and 13 + 6 weeks of pregnancy. This scan is used to date pregnancies and is offered free of charge to all women registered at the antenatal clinics. Uptake is voluntary, and the majority use the service .The FMBR includes information of clinical relevance on sociodemographics, pregnancy medical history, and gestational complications, which we used as potential confounders, depicted in We examined the factors available in FMBR that could be used as indicators of neonatal health to shed light on whether any growth restriction was due to ACT or to poor fetal health, which would both limit growth and precipitate treatment.The Apgar score was implemented in 1952 as a quick way to evaluate the physical condition of the newborn by assessing heart rate, respiratory effort, muscle tone, reflex irritability, and color. The Apgar score conducted at 5 minutes after birth has been found to be an excellent predictor of infant survival in the first 28 days of life and thus considered a meaningful measure of neonatal health .Neonatal care is recorded in FMBR for the first 7 days of life. We used these data to compare ACT-exposed and ACT-unexposed infants. Data were also available indicating whether infants were still hospitalized beyond 7 days.Lastly, we present in the supporting information results by mode of delivery. Medically indicated preterm labor reflects a complication with the mother or fetus and occurs mostly because of preeclampsia, placental abruption or dysfunction, fetal distress, and fetal growth restriction . In contAll statistical analyses were planned a priori and carried out using SAS software, version 9.4 (SAS Institute). Our a priori thinking is depicted in Because all of the background and medical variables recorded in FMBR bear clinical relevance, all were included as confounders, including, e.g., those as identified in previous work such as cohabitation with expectant father –25. ThusLastly, we performed additional analyses to assess whether potential differences in birth size could be attributed to poorer health, as indexed by available data, among the exposed versus unexposed infants. We examined Apgar scores at 5 minutes , neonatal care, and mode of delivery.n = 2,173) were born at term, as shown in There were 278,508 live-born singleton births recorded in Finland during the study period. Of these, 11,896 (4.27%) infants were born preterm, 4,887 women were treated with ACT (1.75%), and 44% of the exposed infants  or longest (≥42 weeks) gestation in the stringent PSM analyses. Consistent differences were observed in BWT in matched analyses among preterm, near-term, and term infants, with the greatest reduction in BWT seen in preterm infants. Similarly, BL and HC were most compromised in the preterm group, and clinically significant reductions were also observed for the near-term and term groups. Observed reductions in size in relation to ACT were generally symmetrical, i.e., no difference in PI.To our knowledge, this is the largest study conducted to analyze the impact of ACT on birth size—4,887 individuals in total—and far exceeds the number used in the latest Cochrane review database of RCTs and BWT  using evOur primary outcome was birth size, so to accurately examine differences, we stratified all analyses by timing of birth and controlled for all available significant background variables. ACT is indicated to prepare lung maturation in preterm infants; thus, infants born at term represent the group who unnecessarily received treatment. This group provides an indication of whether growth deficits are due to ACT exposure or potentially to poor fetal health precipitating ACT.Term infants who were exposed to ACT showed significant and symmetrical reductions in all birth size measurements , indicating that even earlier treatment (at the time of threatened preterm birth) had a lasting impact on growth trajectory. The overall 89.38 g difference in BWT among the term group corresponds to a loss of about 5 days of optimum growth (at term) according to recent international standards . In compThe 5-minute Apgar scores indicated that infants born preterm, regardless of ACT treatment, were generally equally vigorous. At term, Apgar scores were slightly higher for unexposed male infants, whereas female infants had lower scores when born very preterm, near term, at term, or post term. These results are worthy of further investigation to determine whether ACT would have a differential impact on Apgar scores dependent on fetal sex. Recent evidence shows distinct biological pathways linking fetal sex with various complications associated with restricted growth .It is noteworthy that both male and female infants exposed to ACT were more likely to receive medical interventions and to remain hospitalized beyond 7 days, though the overall number of hospitalized infants was small. Our matched and stratified analyses show that there were no differences in care regarding RDS—e.g., neonatal intensive care unit (NICU), respirator care, or intubation—for the very preterm or postterm infants whether or not they had received ACT. In fact, these medical interventions related to RDS were more likely among ACT-treated infants than controls born preterm, near term, or at term. These findings suggest that ACT was confounded by medical indication. Moreover, it is also possible that reduced growth associated with ACT contributes to compromised neonatal health, thus leading to more medical interventions. These results are similar to those recently reported  showing Reductions in size of infants also consistently differed by mode of delivery and ACT. For preterm, near-term, and term-born infants, we observed a graded difference in BWT reductions, with the highest growth deficits for the unplanned cesarean deliveries, followed by planned cesarean, and the least reductions in the vaginally delivered group. These findings merit further investigation to disentangle the effects.HC in relation to ACT is seldom reported. The few studies that do report HC report similar deficits ,34–35; HBL is strongly associated with adult height, more so than other birth measurements , and aduThis study has several unique strengths afforded by the use of objective population-based register data. As far as we know, no other study is based on such a large sample or has focused on birth size as the primary outcome. Though observational in nature, the size of this study provided the opportunity to carefully match infants on baseline characteristics that could have influenced clinical decisions to treat, including risk factors/complications  that can lead to both spontaneous and elective preterm birth as well as intrauterine growth retardation. The PSM technique enabled us to limit possible bias and include five matched controls per patient for most analyses, which has been found to be the optimum number for bias reduction . In thisWe stratified our analysis by gestational age. Stratification is the method of choice for controlling potential confounding and for identifying effect modification related to timing of birth , which wAn advantage of carrying out our study in Finland is the high-quality and uniform antenatal care that is offered free of charge to women residing in Finland. Most women have on average 15 antenatal care visits . There aWe concentrated on live-born infants because our emphasis is on growth restriction among survivors. Stillbirths in high-income countries are also associated with avoidable maternal lifestyle factors such as obesity and smoking , factorsLack of detail in FMBR concerning ACT is the main limitation of this study. For example, we lacked information on the time lag between ACT and birth , drug name, dose, or number of doses (which would enable drug-specific conclusions). Betamethasone remains biologically active for a period ranging between 36 and 54 hours after administration. Thus, the infants who were born shortly after ACT administration would be unlikely to receive the full effect of the drug. Any growth deficit would be due to compromised fetal health. In contrast, those born at least 3 days after treatment are likely to have had a full effect of the drug. Growth deficits in these infants would be due to both compromised health that led to treatment in the first place and the ACT itself. However, we expect that national guidelines were implemented that recommend a single dose of betamethasone and use tocolytic therapy to delay birth when needed. Data on serial ultrasound scans are not recorded in FMBR. Studies with serial ultrasound scanning would elucidate this issue by monitoring growth trajectory before and after ACT to determine the independent effects attributable to restricted growth due to poor health versus due to treatment. As seen in our DAG representation, unmeasured factors including genetic liability and lifestyle characteristics, such as health-related behaviors and mental health, are important factors to include. Thus, the information gained herein is useful for designing future cohort studies, which would not be restricted by population-based register data but would likely be of a smaller sample size.Our data underline the need to establish clinical practices to predict parturition with greater accuracy to avoid inessential treatment, as nearly 45% of exposed infants were born at term. Our report should serve as an impetus for identifying techniques to more accurately predict preterm labor. Such advances have been preliminarily reported for a blood test that could cheaply and accurately predict parturition [S1 TableACT, antenatal corticosteroid therapy.(DOCX)Click here for additional data file.S2 TableACT, antenatal corticosteroid therapy; PSM, propensity score matching.(DOCX)Click here for additional data file.S3 TableACT, antenatal corticosteroid therapy; PSM, propensity score matching.(DOCX)Click here for additional data file.S4 TableACT, antenatal corticosteroid therapy; PSM, propensity score matching.(DOCX)Click here for additional data file.S1 ChecklistSTROBE, Strengthening the Reporting of Observational Studies in Epidemiology.(DOCX)Click here for additional data file.


Preterm birth can interrupt lung development in utero and is associated with early life factors, which adversely affects the developing respiratory system. Studies on preterm birth and asthma risk are comparatively sparse and the results are not consistent.Multivariate analyses were performed on a cross-sectional data from the National Survey of Children’s Health (NSCH) collected in 2011 to 2012. The NSCH was a nationally representative telephone survey sponsored by the Maternal and Child Health Bureau and conducted by the National Center for Health Statistics. A cross-sectional analysis using data from the US on 90,721 children was conducted to examine the relationship between preterm birth and asthma risk.A total of 90,721 children under 17 years were included and 12% of the children were reported as preterm birth. The prevalence of diagnosed asthma was 15%, with a male to female ratio of 1.26:1. Children who were born preterm were 1.64 times  more likely to develop asthma compared with those who were born term after controlling for confounders. Similarly, children who were low birth weight were 1.43 times  more likely for asthma, and the odds ratio increased to 1.77 for those both preborn and low birth weight. Child’s gender, race/ethnicity, age, family structure, family income levels, and household smoking were significantly associated with the odds of reported asthma.Preterm birth was associated with increased risk of asthma among US children, supporting the notion that preterm birth may play a critical role in asthma development.The online version of this article (10.1186/s13052-018-0583-9) contains supplementary material, which is available to authorized users. Asthma is a heterogeneous disease, characterized by chronic airway inflammation , which iPreterm births are one of the leading health burdens of children, which are reported to be related to increased risks of many health problems . The freSome researchers found no correlation between preterm birth and a doctor’s diagnosis of asthma , and argThis was a secondary analysis using the third survey data from the NSCH, which was conducted between 2011 and 2012. The NSCH was a cross-sectional, nationally representative telephone survey sponsored by the Maternal and Child Health Bureau and conducted by the National Center for Health Statistics . The stuThe outcome of interest was asthma. According to World Health Organization (WHO) guideline, asthma is a chronic disease characterized by recurrent attacks of breathlessness and wheezing . In thisThe primary predictor variable was preterm birth, which means the birth of an infant before 37 weeks of pregnancy . In thisCovariates to control for potential confounding were chosen on the basis of asthma risk factors in previous studies. The confounders included children age, gender, race, family member education level, family structure and income level, household smoking, and neighborhood garbage exposure. Although other factors such as breastfed might have been useful to evaluate, there was a skip pattern in the survey and the data was not reliable for analyzing this factor.Demographic variables including children age and gender were provided by respondents in the NSCH survey. Race or ethnicity was categorized as Hispanic, non-Hispanic-white, non-Hispanic-black or other; Family member education level was defined as highest level of education obtained by anyone in household . Family structure was categorized as currently married, cohabiting, living apart, never married, or no parents in household. Family income levels were derived from the question Since [S.C.] was born, how often has it been hard to get by on your family’s income, for example, it was hard to cover the basics like food or housing?], the responses were coded as never, not very often, somewhat often, and very often. It was recently reported that children asthma was associated with indoor and outdoor pollution , 23, thup-value of < 0.05 was considered statistically significant. All analyses were performed using Stata 13.0 .First, correlations between variables were checked. The multicollinearity between variables was explored, and the results indicated that multicollinearity was not a big problem . Respondents were informed that the study was voluntary and confidential at the beginning of the survey. Verbal consent for participation in the study was obtained from NSCH respondents as the survey was conducted via telephone.Based on the parent-report, the overall prevalence of preterm birth was 12% and that of asthma was 15%, with a male to female ratio of 1.26:1. The gender distribution of the study population was relatively equal. 51% of the children in the study were non-Hispanic white, followed by Hispanic (21%), non-Hispanic black (17%), and other non-Hispanic (11%) among children born preterm. There was a similar distribution among those who were born at term. The majority of children (47%) were in households where at least one resident had more than a high school education. Children who were preborn tend to live with parents not currently married (62% versus 62%), who lived apart (15% versus13%), never married (11% versus 8.8%) or no parents in household (2.7% versus 2.4%) compared to those who were term born. What’s more, they come from family who were more likely to report very often difficult to pay for bills (8.7% compared to 6.7%). 27% of children who were born preterm lived in households with someone who used of cigarettes, cigars, or pipe tobacco, while 24% of those were born at term; 16% of children lived in a neighborhood with litter or garbage on the street or sidewalk, there was no difference between preterm- and term-born children  after adjusting for child gender, age, race, parents’ education level, family structure, family income levels, household smoking and neighborhood garbage status  and asthma among children aged 0–17 years in the 2011–2012 NSCH survey. The results demonstrated that children who were born preterm were more likely to develop asthma compared with those who were born at term. We also found low birth weight as an independent risk factor for asthma. It is noteworthy that those who were both preterm born and low birth weight had higher odds ratios for asthma. Covariates, including male sex, black race, age, parent’s not currently married, low income levels, and household smoking remained significant in the model, indicating that they were stronger predictors for developing asthma. The implication that children that preborn or low birth weight have a propensity for respiratory disease, is consistent with the results of previous studies , 24–26.This study was based on the NSCH database, which is the largest, most comprehensive survey on the health of children in the United States to date. The 2011–2012 NSCH study covered 95,677 sampled children aged 0–17 years, with geographic distribution and cultural diversity. Thus findings deriving from the dataset could reflect the situation of United States generation. The analytic sample size was 90,721, which accounted for 90% of the eligible population. Sensitivity analysis showed that there was no difference in excluded observations due to missing or invalid information. The large sample size in this analysis allows a more precise estimate of the relationship between preterm birth or low birth weight and the development of asthma.14 used the Third National Health and Nutrition national Survey (1988–1994), found that asthma was associated with late preterm birth, but the result was not statistically significant. However, a recent cohort study conducted in US reported that late-preterm and term birth was not independently associated with a risk of asthma  born prematurely, that is, more than 3 weeks before [his/her] due date?” An analysis comparing clinical estimates and LMP estimates of gestational age showed that infants born at 28–36 weeks gestation were prone to show misclassification error , deliverDespite limitations listed above, this study provides insights into the research on the relationship between preterm birth and asthma. Compared with infants born at term, infants born prematurely are more susceptible to respiratory morbidities during their birth hospitalization and neonatal period . PretermIn conclusion, our study demonstrated that preterm birth was a risk factor for asthma with sufficient statistic power in a nationally representative sample. Additional longitudinal researches are needed to confirm the observation and establish the causal inference relationship.Additional file 1:Table S1. Variables, Original Survey Questions, and Recoded factors Used in analyses of 2011-2012 data from NSCH. Table S2. Correlations among preterm birth and other covariates. (DOCX 23 kb)


Atherosclerosis is an inflammatory process involving activation of monocytes recruited by various chemoattractant factors, among which lipoprotein(a) and its specific apolipoprotein apo(a). Lp(a) contains a specific apolipoprotein apo(a) which size is determined by a variable number of repeats of a specific structural domain, the kringle IV type 2 (IV-2). Lp(a) plasma concentration and apo(a) size is inversely correlated, and smaller apo(a) are major risk factors for coronary heart disease.The aim of this study was to evaluate the effect of recombinant apo(a) isoforms  on monocytes interacting with type I collagen.Apo(a) isoforms stimulated reactive oxygen species (ROS) and matrix metalloproteinase-9 (MMP-9) production by monocytes, and not modified monocytes adhesion on type I collagen. This effect was specific of apo(a) since no effect was observed in the presence of plasminogen and was inversely related to apo(a) size. The lysine analogue 6-aminohexanoic acid which blocks the lysine binding sites (LBS), and carboxypeptidase B (CpB) which cleaves carboxy-terminal lysine residues, abolished apo(a)-induced ROS and MMP-9 production, highlighting an effect mediated by apo(a) lysing-binding sites.These results indicate that activation of collagen-primed monocytes stimulated with apo(a) is a Kringle number-dependent effect and reinforce the hypothesis of a role for small size apo(a) isoforms in atherothrombosis. A characteristic feature in the development of atherosclerotic lesions is the accumulation of foam cells, i.e. monocyte-derived macrophages that store cholesteryl esters, resulting from low-density lipoprotein (LDL) uptake . An LDL-. However, the molecular mechanisms supporting its involvement in the promotion of atherogenic events have not yet been fully identified. Apo(a) could bind oxidized phospholipids and has greater propensity to localize in blood vessel walls to interact with Lysine Binding Sites (LBS) and fibrin, responsible for a thrombogenic effect by inhibition of plasmin activity [The ability of high Lp(a) value to predict ischemic myocardial infarction risk in the general population is not modified by inflammation or food intake . Howeveractivity , 17.Most of acute cardiovascular events result from disruption of atherosclerotic plaques that release thrombogenic components. Since ruptured fibrous caps are often heavily infiltrated by foam cells, it has been suggested that monocytes/macrophages played a pivotal role in plaque rupture because of their involvement in extracellular matrix (ECM) remodelling . Accordixβ2 integrin [Our group has previously shown that type I collagen, the major ECM component, modulated monocyte functions through interaction with αintegrin . Since aType I collagen was extracted from Sprague Dawley rat tail tendons  as previously described , 19. Col3) were purified as described elsewhere [The plasmids pCMV-A10, −A18, −A34 were transfected by electroporation into the adenovirus-transformed human embryonic kidney cell line 293 and recombinant apo(a) isoforms present in culture medium supplemented with proteinase inhibitors  NaN2, 1 mM MgCl2, pH 7.4) before use.Whole blood was obtained from healthy volunteers after informed consent, Laboratory of Hematology, University Hospital, Reims . All the donors were aware that their blood could be used for transfusion and for potential analyses and research (they had the right to refuse as provided by French Law) and peripheral monocytes were isolated by counterflow centrifugal elutriation . Each exThe effect of apo(a) on monocytes was evaluated by incubating cells with apo(a) isoforms of different sizes at variable concentrations (20 to 200 nM). To study the mechanism of interaction between apo(a) and collagen-primed monocytes, experiments were performed either by adding (simultaneously) 100 mM 6-aminohexanoic acid (AHA) or by replacing apo(a) with 100 nM plasminogen  and 10 μM amiloride . In another set of experiments, monocytes were pretreated with 200 μg/ml carboxypeptidase B  in Dulbecco’s solution for 1 hour at 37 °C under gentle shaking.5 monocytes in Dulbecco’s solution containing 16.7 μM nitroblue tetrazolium (NBT) for 2 h at 37 °C in 96-well coated plates. NBT reduction was assessed by absorbance measurement at 560 nm [ROS production was evaluated by incubating 1.5 × 10t 560 nm .6 cells for 48 h at 37 °C was measured by ELISA  MMP-9, R&D Systems Europe, Lille, France).Total MMP-9 (pro and active forms) secreted in culture medium by 10p ≤ 0.05 using Student’s t-test.All results have been expressed as ratios to the control series, in order to minimize the inter-donor variability of monocyte preparations. They were obtained from four independent experiments performed each in triplicate, using different preparations of monocytes. Differences of means were considered significant at p = 0.12, non-significant) to + 39% for 200 nM (p < 0.01) . However, only type I collagen induced ROS production by monocytes Fig. . Apo(a) p < 0.01 and + 35%, p < 0.05, respectively), the highest stimulating effect being triggered by the 10 K isoform. In contrast, no significant effect was observed in the presence of the 34 K apo(a) isoform  isoforms of different sizes  on monocytes seeded on type I collagen were compared. None of the apo(a) isoforms altered monocyte adhesion to type I collagen (data not shown). ROS release by monocytes after a 2 h-incubation on collagen was significantly increased by both the 10 K and the 18 K isoforms  in the presence of 10 K and 18 K apo(a) isoforms than in control conditions (i.e. without apo(a)), whereas it was only 1.3 fold enhanced (non-significant) in the presence of the 34 K apo(a) isoform .In order to identify the molecular mechanisms involved in the interaction of apo(a) with monocytes stimulated by type I collagen, experiments were performed using the kringle IV type 2-free apo(a), i.e. 10 K apo(a). First, monocytes seeded on type I collagen were incubated with 100 nM 10 K apo(a) and 100 mM AHA a lysine structural analog used as a competitor for apo(a) lysine binding sites (LBS). The stimulating effect of 10 K apo(a) isoform on ROS and MMP-9 production was completely abolished by AHA, suggesting an LBS-mediated mechanism Fig. a and b. Second, monocytes were incubated with plasminogen instead of apo(a), in order to evaluate the specificity of apo(a) effects. Plasminogen was considered the most relevant control protein because of the structural homologies between the two molecules. In order to test the LBS-binding effect in functional isolation, the formation of plasmin was prevented with the use of amiloride, an uPA inhibitor. In these conditions, plasminogen had no significant effect on monocyte activation, as evaluated by ROS and MMP-9 production Fig. a and b.Third, the potential involvement of monocyte membrane proteins susceptible to interact with apo(a) via carboxy-terminal lysine residues was checked by preincubating cells with CpB. Pretreatment of cells with CpB completely abolished the stimulating effect of apo(a) on collagen-primed monocytes Fig. c. Mβ2 integrin [xβ2 integrin [Apo(a) is a potential good candidate to interact with inflammatory cells (e.g. monocytes) and ECM molecules (e.g. fibronectin and collagens) in the arterial wall, because it is a potent chemoattractant for monocytes, which specifically interacts with αintegrin . This stOur results show that ROS and MMP-9 production by monocytes stimulated by type I collagen is significantly enhanced by apo(a). This effect is specific of apo(a) since no effect was observed in the presence of plasminogen, a structural analogue of apo(a). Interestingly, the extent of stimulation was inversely proportional to the number of kringle IV-2 repeats, which is consistent with the deleterious role of small size isoforms in atherosclerosis progression described in the literature –12. FurtMβ2 integrin [According to these results, we could expect that small and high size apo(a) isoforms supported different molecular mechanisms of interaction. Based on apo(a) sequence homology with plasminogen, which interacts with cell receptors via the LBS substructures of its kringle domains , we inveintegrin . Howeverintegrin .Kringle IV type 2-dependent high size apo(a) isoforms proved unable to further activate monocytes stimulated by collagen, which suggests a molecular size component effect. Becker and al. found in 2003 that the efficiency of Lp(a) assembly in vivo can be modulated by an accessory protein(s) that alters the conformational status of apo(a) . We propMoreover, these results also suggest that the collagen-dependent enhancement of monocyte proteolytic and inflammatory functions by apo(a) is probably related to a specific effect of type I collagen enabling signalling events that mediate differentiation of peripheral monocytes into resident macrophages . Apo(a) In this study we use r-apo(a), it should be interesting to compare the Lp(a) effect from donors (with different isoform sizes), to see if the same trends hold.Our results point to a protective role of kringle IV type 2 copies on the deleterious effect of apo(a) and reinforce the hypothesis of a role for small size apo(a) isoforms in atherothrombosis, through destabilization of atheroma plaque due to ROS and MMP-9 release by monocytes according to a lysine-dependent mechanism. These findings provide a novel insight into a better understanding of apoliproprotein (a) isoforms role in thrombo embolic diseases.


Two rabbit lines are divergently selected for increasing or decreasing the variability of litter size at birth. Decreasing the litter size variability produces more resilient females with less sensitivity to diseases, being an indirect selection way to improve environmental sensitivity. The kits’ survival rate at weaning was higher in the homogeneous line. Moreover, this line led to a greater uniformity of the kits’ weight at weaning, although the weight variability at birth was higher, which could be due to a higher lactation capacity of the homogeneous line.A divergent selection experiment on environmental sensitivity was performed in rabbits. The aim was to estimate the correlated response in kit weight and survival, litter weight, and weight distance from birth to weaning. The weight distance was calculated as the absolute value of the differences between the individual value and the mean value of its litter. The relationship between the probability of survival at 4 d of age, and the weight at birth, was studied. Environmental sensitivity was measured as litter size variability. A total of 2484 kits from 127 does from the low line, and 1916 kits of 114 does from the high line of the 12th generation were weighed. Both of the lines showed similar individual and litter weights at birth and weaning, and a similar survival rate at birth, and at 4 d of age. The survival rate at weaning was higher in the low line . The weight distance was higher at birth, but lower at weaning in the low line . When the weight at birth was high, the kits had a higher survival rate. In conclusion, selection for environmental sensitivity showed a correlated response in the kits’ survival, and in the homogeneity of litter weight at weaning. The aim of genetic selection in maternal rabbit lines has traditionally been to improve the mean of productive traits: Litter size , or the Selection for environmental sensitivity, measured as litter size variability, is an indirect selection methodology for improving resilience and robustness ,7. A divAll experimental procedures involving animals were approved by the Miguel Hernández University of Elche Research Ethics Committee (Reference number 2019/VSC/PEA/0017), in accordance with Council Directives 98/58/EC and 2010/63/EU.A divergent selection experiment for litter size variability was carried out over twelve generations. The selection was based on the phenotypic variance of the litter size of each doe, after correcting the litter size for both year–season and parity–lactation status .®, De Heus Nutrición Animal, La Coruña, Spain). Food and water were provided ad libitum. The same feeding conditions were provided for both lactating and non-lactating does. Does were housed in individual cages (37.5 × 33 × 90 cm) under a constant photoperiod of 16 h continuous light: 8 h continuous darkness, and with controlled ventilation throughout the experiment. The experiment took place from December to September. The temperature and relative humidity were recorded every 15 min with a Tinytag data logger . The rabbits were fed a standard commercial diet , the number born alive (NBA), the number born dead (NBD), the number of rabbits at 4 days of age (N4), and the number of rabbits at weaning (NW) were recorded. The rabbits were individually weighed and sexed within 24 h after birth. Some of the kits had suckled before being weighed. The milk intake was verified by recording a white mark in the abdominal area. The kits were also weighed at weaning. A total of 2484 kits from 127 does from the low line, and 1916 kits of 114 does from the high line were weighed.The following traits were analyzed: LS; survival at birth (NBA/LS); survival at 4 days of age (N4/NBA); survival at weaning (NW/N4); the individual weight at birth of live and dead kits; the individual weight at weaning; the litter weight at birth of total kits and kits alive; the litter weight at weaning; and the weight distance of live, dead, and weaned rabbits. The weight distance was calculated as the absolute value of the differences between the individual value and the mean value of its litter.i is the line effect with two levels (the high and the low lines); Sj is the season effect with three levels ; LPk is the lactation–parity effect with five levels ; pijkl is the dam permanent effect with 241 levels; and eijkl is the residual term.The model used for analyzing the LS and the litter survival rates was:i is the line-survival effect ; IMl is the intake of milk effect (whether the kit suckled or not before being weighed); SEm is the sex effect ; pijklmn is the dam permanent effect with 241 levels; cijklmno is the common litter effect with 541 levels; b is the regression coefficient of the covariate; LSijklmno is the covariate litter size; and eijklmnop is the residual term. The individual weight at birth for the live and dead kits, and their corresponding distance were analyzed using the following model:Litter weights, individual weights at weaning, and the distance were analyzed with the same model, but the line effect with two levels (high and low lines) was used instead of the line-survival effect.p), where Gp was the (co)variance matrix between these effects. Residuals priori distribution was N . Residuals, permanent environmental effects, and common litter effects are uncorrelated. The priors for the variances were also bounded uniform. Features of the marginal posterior distributions for all of the unknowns were estimated using Gibbs sampling. The Threshold Model program was used [All of the analyses were performed using Bayesian methodology . Boundedwas used . We usedwas used , and Monwas used .The relationship between the probability of survival from birth to 4 d of age, and the individual weight at birth was analyzed by logistic regression. The model included line, season, parity–lactation , milk intake, and sex effects. Descriptive results of the traits by line are presented in The probability of survival at 4 d of age, and weight at birth were not affected by sex (P = 0.47). Both of the lines showed similar probabilities of survival at 4 d of age, with the same weight at birth (P = 0.12; Kits born in winter had less of a probability of survival than those that were born in summer or spring (P < 0.0001; Kits that suckled always had a higher probability of survival than the kits that did not suckle (P < 0.0001; Our divergent selection experiment for environmental sensitivity has shown that this trait is genetically determined . This haWeight distance has been used as the dispersion measure, instead of the standard deviation of the weight of the litter, because it provides one record per individual instead of one per litter. It seems that there is a correlated response on both of the weight distances at birth and at weaning, but with opposite sign; the kits’ weight is more variable at birth in the low line, but then less variable at weaning. To date, there is no information available on the weight distance at birth in rabbits, but Peiró et al. have shown similar values of weight distance at weaning .Maternal care in the first days after parturition is clearly related to the ingestion of energy by the kits, which is directly related to their survival . So, theThe probability of individual survival at 4 d of age is related to birth weight, as the kits with lower birth weight have a lower probability of survival. Neonates require a protective environment, adequate nutrition, and special maternal care in order to survive . So, theThe kits’ fat tissue is high at birth, and decreases thereafter . The ingWhen lactation and gestation were overlapping, the probability of survival was lower than in nulliparous and non-lactating does. It is well known that does undergo a nutritional deficit when lactation and pregnancy overlap ,27, and The low line leads to a greater uniformity of kit weight at weaning than the high line, although the variability of weight at birth is higher, which could be due to a higher lactation capacity of the doe. In conclusion, selection for litter size variability shows a negative correlated response in the uniformity of weights at birth, and a positive correlated response in survival and the uniformity of weights at weaning, without affecting individual and litter weight.