Several studies have reported that birth by caesarean section is associated with increased risk of lower respiratory tract infections in the child, but it is unclear whether this applies to any caesarean section or specifically to planned caesareans. Furthermore, although infections of the upper respiratory tract are very common during childhood, there is a scarcity of studies examining whether caesarean is also a risk factor for this site of infection.We obtained data from two UK cohorts: the Millennium Cohort Study (MCS) and linked administrative datasets of the population of Wales through the Secure Anonymised Information Linkage (SAIL) databank. The study focused on term-born singleton infants and included 15,580 infants born 2000–2002 (MCS) and 392,145 infants born 2002–2016 (SAIL). We used information about mode of birth  from maternal report in the MCS and from hospital birth records in SAIL. Unplanned hospital admission for lower respiratory tract infection (LRTI) was ascertained from maternal report in the MCS and from hospital record ICD codes in SAIL. Information about admissions for upper respiratory tract infection (URTI) was available from SAIL only. Cox regression was used to estimate hazard ratios for each outcome and cohort separately while accounting for a wide range of confounders. Gestational age at birth was further examined as a potential added, indirect risk of planned caesarean birth due to the early delivery.The rate of hospital admission for LRTI was 4.6 per 100 child years in the MCS and 5.9 per 100 child years in SAIL. Emergency caesarean was not associated with LRTI admission during infancy in either cohort. In the MCS, planned caesarean was associated with a hazard ratio of 1.39  which further increased to 1.65  when gestational age was not adjusted for. In SAIL, the adjusted hazard ratio was 1.10 , which increased to 1.17  when gestational age was not adjusted for. The rate of hospital admission for URTI was 5.9 per 100 child years in SAIL. Following adjustments, emergency caesarean was found to have a hazard ratio of 1.09  for hospital admission for URTI. Planned caesarean was associated with a hazard ratio of 1.11  which increased to 1.17  when gestational age was not adjusted for.The risk of severe LRTIs during infancy is moderately elevated in infants born by planned caesarean compared to those born vaginally. Infants born by any type of caesarean may also be at a small increased risk of severe URTIs. The estimated effect sizes are stronger if including the indirect effect arising from planning the caesarean birth for an earlier gestation than would have occurred spontaneously. Further studies are needed to confirm these results. Caesarean section rates have risen steeply in recent years, particularly in high and middle-income countries . In EnglAcute respiratory infections are common during childhood. These infections include those manifesting in the lower respiratory tract such as bronchiolitis or pneumonia, and those of the upper respiratory tract such as the common cold, tonsillitis and laryngitis. The majority of respiratory infections are treated in primary care, however, some require hospitalisation. In Wales, for example, approximately 11% of infants were reported to require hospital admission for a respiratory infection by age 1 year . These aCaesarean section is a risk factor for hospital admission for lower respiratory infections (LRTIs), both during infancy –9 and laIn addition to mode of birth, other perinatal factors are also associated with respiratory morbidity. Gestational age at birth is an independent risk factor for childhood infections and respiratory illness , 15–17. The aim of the current study was to further elucidate whether birth by planned or emergency caesarean section is associated with increased risk of hospital admission due to LRTI or URTI in infancy.The study used anonymised data from two birth cohorts analysed separately: the longitudinal UK Millennium Cohort Study and a birth cohort defined through linkage of routinely collected data for the population of Wales.The Millennium Cohort Study (MCS) is a nationally representative longitudinal study of babies born between September 2000 and January 2002 that were alive and living in the UK at age 9 months. The sample does not include babies who died prior to this age, but these constituted ~0.5% of all births . The MCSThe Secure Anonymized Information Linkage Databank (SAIL) is a data repository developed at Swansea University that stores anonymized data for the population of Wales. This databank hosts several health and administrative datasets of person-level data. Individuals can be linked between the various datasets using a unique Anonymous Linking Field (ALF) encrypted code, which is generated based on NHS number or personal identifiers , 26.We defined a cohort of infants born between January 2002 and July 2016 to mothers resident in Wales as ascertained from the National Child Community Health Database (NCCHD)   excluding those with a major health problem immediately following the birth . A majorMode of birth was categorised as vaginal delivery, assisted vaginal delivery, planned caesarean section or emergency caesarean section . In the The study outcomes were hospital admission in infancy for lower respiratory infection or for upper respiratory infection. In the MCS, this was collected through mother’s report of hospital admissions due to ‘chest infection or pneumonia’ selected from a pre-defined list, together with the child’s age in months at admission. Almost all MCS sample infants (97%) were followed-up for at least 9 months.st birthday for 98% of the SAIL cohort.In the SAIL cohort, information about outcomes was collected from hospital admissions recorded in PEDW. The outcomes were defined as an emergency (unplanned) admission during infancy with a diagnosis code indicating a lower respiratory tract infection  or an upper respiratory tract infection (J00-J06) . AdmissiPotential explanatory variables were ascertained through parental report in the MCS and through information derived from the NCCHD, WDS or PEDW delivery record in SAIL .Hazard ratios for each mode of birth compared with vaginal delivery (the reference group) were estimated using Cox regression analysis. In the MCS, follow-up began at time of discharge from hospital of birth (median 2 days) and in SAIL follow-up began at time of birth. Follow-up ended at the first hospital admission for LRTI or URTI or was censored in the MCS at age at interview  and in SAIL at time of emigration from Wales, death, or February 2017. Statistical analyses of the MCS accounted for the complex survey design as well as weighting for non-response using Stata version 13 ‘survey commands’. Statistical analyses of the SAIL cohort accounted for within-family clustering since most infants had a sibling in the cohort (60%). The Cox regression assumption of constant hazard ratios was verified in the MCS using log-log plots and interaction with time and in SAIL using log-log plots and assessing whether hazard ratios are substantially different when follow-up is split into two time periods.a priori and the association of other variables found to be associated (P<0.1) with the exposure and the outcome was examined in a two stage process. Initially, socio-demographic variables and maternal-perinatal variables , breastfeeding (15%) and ethnicity (11%) and therefore a category of ‘missing’ was included for these variables. Complete case analysis and multiple imputation were used in sensitivity analyses (S1 Text in In the case of planned caesarean section (but less commonly in emergency caesarean), gestational age at birth is the result of the planned mode of birth. We aimed to quantify the risk of respiratory infection due to caesarean section while taking account of the potential added risk from an earlier delivery at early term (37–38 weeks). Final models were therefore repeated without adjustment for gestational age.Wheezing is a common symptom of respiratory infection, therefore a sensitivity analysis was carried out in the MCS including ‘wheezing or asthma’ in the outcome definition. To address the possibility of reverse causality of a prenatal infection leading both to need for a caesarean birth and to later infant infection, we carried out an additional sensitivity analysis in the MCS excluding infants with a report of infection in the perinatal period. Further sensitivity analyses limiting to observations where mode of birth had been validated using an additional data source  of infants were admitted at least once for LRTI in the MCS sample (574 cases) and 5.6%  in the SAIL sample . To aid comparability, the proportion of infants born in 2002 and admitted up to age 9.2 months in SAIL was examined. This proportion was found to be 4.0% , similar to 3.4% in the MCS. The rate of admission peaked at the 2The rate of hospital admission for LRTI was 4.6 per 100 child-years in the MCS and 5.9 per 100 child-years in the SAIL cohort . In the Findings from further sensitivity analyses were consistent with the main results. These included using validated mode of birth data in both cohorts  . The rate of admission increased towards the infant’s 1The rate of URTI hospital admission was 5.9 per 100 child-years . InfantsTo obtain hazard ratios that also comprise the indirect effect of the planned caesarean through the earlier timing of the delivery (e.g. 37–38 weeks), final models were repeated without adjusting for gestational age. The size of effects found in assisted vaginal delivery and emergency caesarean were unchanged . HoweverOur study demonstrated that birth by planned caesarean section is an independent risk factor associated with 10–39% increase in risk for LRTI hospital admission during infancy. Our study further showed that birth by planned or emergency caesarean section is an independent risk factor associated with a 9–11% increase in risk for URTI admission. When the effect of gestational age at delivery is not controlled, but rather included in the overall effect arising from the plan to deliver by caesarean, the effect size found is stronger.Prior studies have also identified planned caesarean as a risk factor for LRTI, as described here. However, the evidence regarding emergency caesarean is less conclusive, with some studies finding no increased risk, as in our study, and others identifying emergency caesarean as a risk factor as well.Large population-based studies from Australia concluded that both types of caesarean are risk factors for LRTI admission. A study from New South Wales  found anOther studies highlighted elective caesarean, but not emergency caesarean, as a risk factor for LRTI, similarly to our study. Studies conducted in Denmark , 11 and We are aware of only a single study that had examined the association of mode of birth with severe URTIs using population data. Similarly to our findings, the study found 12% elevated risk for admission in children born by emergency caesarean and a slightly larger 18% increased risk in children born by elective caesarean. A smaller study followed up 334 children in Copenhagen and did not find an association between caesarean section (any type) and URTIs, although an association with LRTI was found . Our resSome infants experiencing a hospital admission for respiratory infection will continue to have persistent episodes of infection or wheeze later in childhood. In certain cases, the admissions during infancy may be an early sign of subsequent asthma diagnosis . AnalogoBirth at every successive week earlier than 39 or 40 weeks is associated with increased risk of childhood infections , 15. DurThe main strength of our study is the use of two complementary cohorts to examine the association of mode of birth with LRTIs. The MCS includes rich data which enabled us to include variables such as breastfeeding that have not been previously well accounted for. The SAIL cohort was large enough to allow detection of modest effect sizes and provided a platform to investigate admission for URTIs. A further strength is our focus on term-born neonates, since prematurity is likely a strong confounder, as it influences the choice of mode of birth and is a risk factor for poor respiratory health . MoreoveLimitations of the study include the unavailability of information about URTI admissions in the MCS and examination of this outcome solely through the SAIL datasets. The SAIL cohort is limited in having only area-level information about socio-economic factors, crude data on breastfeeding and under measurement of variables such as maternal asthma, which was collected through diagnosis codes at delivery. For LRTI, the MCS is limited by measurement of this outcome through maternal report, although this might not be a serious limitation since it has been shown that mothers generally recall their child’s hospital admission well , particuSeveral biological mechanisms could potentially explain how a caesarean birth might affect subsequent risk of respiratory infection. First, the hormones of labour and the physical forces of contractions which squeeze amniotic fluid out of the lungs of the fetus, both have a role in establishing normal pulmonary function in the newborn . A birthPlanned caesarean section is a small but important risk factor for hospital admission for lower respiratory infections during infancy. Both planned and emergency caesarean section may be small risk factors for admissions due to upper respiratory infections. The risk of both types of respiratory infection is further elevated in infants born by planned caesarean due to the indirect increased risk from birth at an earlier gestational week. Although the effect sizes are modest, these excess risks are important in view of the large number of caesareans carried out globally.S1 File(DOCX)Click here for additional data file.


As mother-to-child transmission of HIV decreases, and the population of infants who are born HIV-exposed, but uninfected (HEU) continues to rise, there is a growing need to understand the development and health outcomes of infants who are HEU to ensure that they have the healthiest start to life.n = 20) and not on ART (n = 20) and new mothers without HIV (n = 20) through our clinics to study the effects of HEU on growth and immune- and neurodevelopment in infants in early life, and test the hypothesis that infants who were HEU would have poorer health outcomes compared to infants who were HIV-unexposed, uninfected (HUU). We also undertook exploratory analyses to investigate relationships between the early nutritional environment, food insecurity and infant development. Infant growth, neurodevelopment (Guide for Monitoring Child Development [GMCD]) and levels of monocyte subsets  were measured in infants at birth and 12 weeks (range 8–16 weeks).In a prospective cohort pilot study at Kalafong Hospital, Pretoria, South Africa, we aimed to determine if we could recruit new mothers living with HIV on antiretrovirals  on monocytes at birth among infants who were HEU compared to HUU. Maternal reports of food insecurity were associated with lower maternal nutrient intakes at 12 weeks postpartum and increased risk of stunting at birth for infants who were HEU, but not infants who were HUU.Our small feasibility pilot study suggests that HEU may adversely affect infant development, and further, infants who are HEU may be even more vulnerable to the programming effects of suboptimal nutrition in utero and postnatally. This pilot and preliminary analyses have been used to inform our research questions and protocol in our ongoing, full-scale study. We conducted a prospective cohort pilot feasibility study in Pretoria, South Africa, to determine if we could recruit women through our clinics to study the effects of exposure to maternal HIV infection in utero and during the breastfeeding period on growth and immune- and neurodevelopment in infants uninfected with HIV in early life.While our study was able to capture information on infant growth, immune function and neurodevelopment at two time points within the same infant population, the high mobility of individuals from communities in this area presented challenges to participant retention and follow-up.In an aim to improve participant retention, in our ongoing, full-scale prospective pregnancy and birth cohort study at Kalafong Hospital, Ward-based Primary Health Care Outreach teams have been employed to trace and contact women who miss a follow-up appointment.Maternal HIV infection profoundly affects maternal physiology and pregnancy outcomes. Annually, ~ 1.3 million women living with HIV become pregnant , and HIVuninfected (HEU) is rising )/(birth weight [g]). Weight gain from birth to 12 weeks postpartum (kg/day) was calculated using the weight of an infant at birth and follow-up and the days alive since birth at follow-up: (weight at 12 weeks postpartum [kg] − weight at birth [kg])/number of days alive.Infant weight, length and abdominal and head circumference were measured at birth and 12 weeks postpartum. Apgar score at 1 and 5 min was obtained. Infant anthropometry was age- and sex-standardised using the World Health Organization (WHO) growth standards  . A brainio (BBR) : BBR = 1++CD16−), intermediate (CD14++CD16+) and non-classical (CD14+CD16+) monocyte subsets were identified  of HEU attained vs. 85% standardised sample, Fig. A 3–5-month assessment was performed on the 8/31 (25.8%) infants at follow-up who were within this age range. Of these infants, 7/8 (87.5%) were HEU. Fewer infants at 3–5 months of age who were HEU had attained age-appropriate fine movement milestones in comparison to the GMCD international standardised sample (14.3% [p = 0.03). There were no other differences for anthropometric, Apgar scores or immune measures at birth within the HUU or HEU infant groups, when comparing infants who were versus were not at follow-up.Within the group of infants who were HUU, those who were not lost to follow-up had lower BMI at birth than those who were lost to follow-up  and Se  compared to mothers living without HIV  food runout, or an inability to afford balanced meals  compared to mothers who did not  or were unable to afford balanced meals  were less likely than mothers who never experienced food runout, or were always able to afford balanced meals, to be EBF at follow-up, irrespective of maternal HIV status  or formula fed from birth to 8 weeks of age Fig. . Feedingilk Fig. . There wilk Fig. . Mothersp = 0.01) or experiencing  food runout compared to those who reported not worrying about or experiencing food runout  and experiencing  food runout in comparison to those who did not  on intermediate monocytes at birth and 12 weeks in infants who were HEU. Increased CCR2 expression may result in increased recruitment of monocyte populations across the blood-brain barrier, which may have consequences for neurodevelopment, as the expression of CCR2 by CD14n adults , 49. Then adults . MCP-1 ln adults . ImportaWhen exploring relationships between food security and infant outcomes, we found that household food insecurity may associate with reduced infant length at 12 weeks postpartum, and infants who also experience HEU may be at an increased risk of stunting at birth compared to infants who are HUU and whose mothers also experience food-insecure conditions. Stunting is the most common manifestation of infant undernutrition globally . Our fin12, and a large proportion of mothers, irrespective of food insecurity circumstances, were at risk for inadequate intakes. Inadequate maternal vitamin B12 intakes have shown to cause secondary deficiencies in breastfed infants in the first 6 months of life, leading to delayed growth and neurodevelopment [Differences in maternal nutrient intakes between mothers living with and without HIV were minimal, and mothers were at risk for inadequate macronutrient intakes irrespective of food insecurity reports. We also found maternal reports of experiencing food insecurity associated with lower vitamin Belopment . Food inelopment , and motelopment  or may helopment . In agreelopment .The translatability of the analyses presented are restricted by the pilot’s small sample size, limiting statistical power, and because model assumptions were affected due to non-normal data distribution and sample size. These exploratory analyses were intended to inform the development and refinement of our research questions and study protocol for a full-scale study investigating relationships between the early life nutritional environment, HEU and infant development. There was high attrition among both populations, particularly within the HUU group, which may have led to sample bias at follow-up. Individuals from communities in this area are highly mobile, and postpartum women, in particular, may be especially mobile . It is pStudy participant retention was challenging in this pilot; however, the study helped to identify barriers to recruitment and retention that were used to inform a revised full-scale study protocol. Exploratory data analyses revealed possible relationships between exposure to maternal HIV infection in the womb, household food insecurity and infant outcomes at birth and 12 weeks postpartum. We are now investigating these relationships in a full-scale, longitudinal observational study.Additional file 1: Supplementary Figure S1. Sequential gating approach for the measurement of CCR2 expression by CD14+ monocytes. The sequential gating approached used was as follows: First, the viable  cells were identified using a 7-AAD vs SS Log density plot. A “Viable” region was created around the 7-AAD negative cells. Gated on the “Viable”cells, a SSLog vs FS plot was used to capture intact cells in the “E” region. CD14+ monocytes were identified (“CD14+” region) using a CD14 vs SS Log density plot that were gated on viable, intact cells (“E” region). CD14+ monocytes that express CCR2 were quantified using a CD192 (CCR2) vs SS Log plot. The proportion of CD14+/CCR2+ cells were captured in the “CD14+ CCR2+” region. The gating strategy followed to quantify CCR2 expression by CD16+ neutrophils was similar to what was described for CD14+ monocytes, but instead of identifying CD14+ monocytes, CD16+ neutrophils were identified (“CD16+” region) using a CD16 vs SS Log density plot that were gated on viable, intact cells (“E” region). CD16+ neutrophils that express CCR2 were quantified using a CD192 (CCR2) vs SS Log plot. The proportion of CD14+/CCR2+ cells was captured in the “CD16+ CCR2+” region.Additional file 2: Supplementary Figure S2. Sequential gating approach for the measurement of CCR2 expression by monocyte subpopulations. Doublets and debris were removed (Region ‘K’) using a FS Area vs FS Height density plot. A 7-AAD vs SS Log density plot, gated on ‘K’ was used to exclude all non-viable cells. Viable cells were captured in region ‘Viable’. Viable CD14+ monocytes were identified (Region ‘CD14+ Monocytes’) using a CD14 APC vs SS Log density plot. Monocyte sub-populations were identified using a CD16 FITC vs CD14 PE density plot gated on viable, CD14+ monocytes. Four monocyte sub-populations were identified: CD14+/CD16-; CD14++/CD16-; CD14+/CD16+; and CD14++/CD16+. The percentage CCR2+ monocytes present in each of the respective monocyte sub-populations were identified using CD195 (CCR2) PE vs SS Log two-parameter plots gated on the respective sub-populations. The overlay plots within the black bordered square indicates the strategy used to determine CCR2 expression of the different monocyte subsets. The negative/positive staining boundaries were determined based on the negative expression of CCR2 by CD16++/CD14- neutrophils (indicated in red in the overlay plots). The CCR2+ populations are indicated in blue.Additional file 3: Supplementary Figure S3. Maternal intake of estimated average requirements for macronutrients, vitamins and minerals for mothers who report on household food security circumstances. Maternal reports of food insecurity did not associate with intake levels of macronutrients or minerals. Maternal reports of experiencing food runout or inability to afford balanced meals associated with lower intake of vitamin B12 . Many women, irrespective of food security reports, are at risk of inadequate macronutrient, vitamin and mineral intakes. Percent intake of EARs for 36 nutrients were calculated for lactating women 14-18, 19-30 or 31-50 years of age [s of age . CalculaAdditional file 4: Supplementary Figure S4. Cooccurrence of maternal HIV and food insecurity may increase risk of stunting at birth. Amongst infants whose mothers report worrying about food runout, risk of stunting at birth is greater for HEU compared to HUU infants . The red line represents the proportion of infants who had stunting at birth or 12 weeks PP. Mosaic plots are proportion (%) of HUU or HEU infants who have stunting (<-2 SD length-for-age standardised according to WHO child growth standards [tandards ) at birtAdditional file 5: Supplementary Figure S5. Food insecurity may associate with low attainment of GMCD milestones for HUU and HEU infants. Infants whose mothers reported household food insecurity did not attain 1-3 month GMCD milestones  for receptive language, large movement, relating and response behaviour or play activities, or 3-5 month GMCD milestones  for fine movement or relating and response behaviour in the same proportion as the international standardization sample. Maternal reports of food insecurity did not associate with risk of not attaining all 1-3 month or 3-5 month GMCD milestones . Data are proportion (%) of infants who attained all age-appropriate GMCD milestones. The horizontal dotted line represents the GMCD standardised international sample proportion (85%) of infants who attained all milestones in that age category, when they were in that age range. The numbers underneath the bars represent the number of infants attaining all milestones for each milestone. GMCD = Guide for monitoring child development; HUU = HIV-unexposed, uninfected infant; HEU = HIVexposed, uninfected infant.Additional file 6: Supplementary Table S1. Flow cytometry reagent list (including lasers and detectors used). Supplementary Table S2. Flow cytometry compensation matrix. Supplementary Table S3. Maternal nutrient intakes from one 24-hour dietary recall for mothers with and without HIV who attended follow up. Supplementary Table S4. Maternal nutrient intake from one 24-hour dietary recall for mothers who report experiencing food insecurity compared to those who do not experience food insecurity.


There was no association with quadriceps skinfold thickness (p = 0.2), suggesting that the increased adiposity was partially regionalized. In women who underwent oral glucose tolerance testing, nearly all of these associations were attenuated by adjusting for GDM. These results suggest that the increased offspring size at birth, including  adiposity associated with pregnancy, and MMS may be partially related to the development of GDM.Multiple micronutrient supplementation (MMS) in pregnancy has previously been associated with positive effects on fetal growth, but its value in high-income countries remains controversial. In this study, we investigated effects of pregnancy MMS on offspring size at birth and adiposity, along with risks of various maternal outcomes of pregnancy, using the prospective Cambridge Baby Growth Study. Maternal MMS was reported in 528 out of 970 women who completed pregnancy questionnaires. Gestational diabetes (GDM) was assessed using results from 75 g oral glucose tolerance tests at week 28 of pregnancy. Offspring size at birth was assessed using standard anthropometric measurements and adiposity using skinfold calipers. MMS was associated with increased risk of developing GDM (risk ratio = 1.86 (1.13–3.08),  Multiple micronutrient supplementation in pregnancy, as shown in a recent Cochrane review covering clinical trials that included a total of over 141,000 participants . This trIn this analysis, we investigated the potential effects of multiple micronutrient supplementation on adverse maternal outcomes and offspring growth in a relatively contemporary pregnancy and birth cohort recruited from a single center in Cambridge, UK . This coThe longitudinal Cambridge Baby Growth Study (CBGS) recruited women (and their partners and offspring) attending early pregnancy ultrasound clinics at the Rosie Maternity Hospital, Cambridge, UK between 2001–2009 . This obAlthough 2229 pregnant women were originally recruited to the cohort, all of whom were over 16 years of age and able to give consent, 571 of them withdrew prior to the birth of their baby and self-excluded from the study. From all of the women recruited to the CBGS during the years 2001–2009, the following were excluded from the present analysis: those who gave birth to twins , those that had already withdrawn from the study before the birth of their baby, and those that did not fill in and return their pregnancy questionnaire .The CBGS was granted ethical approval by the Cambridge Local Research Ethics Committee, Addenbrooke’s Hospital, Cambridge, UK (00/325). All procedures followed were in accordance with the institutional and international guidelines. Written informed consent was obtained from all women .Each of the pregnant women were given an extensive questionnaire at recruitment to fill in as pregnancy progressed (with assistance from trained research nurses if required) . These qFood frequency intakes were also collected from the pregnancy questionnaires . As partGDM was classified following overnight fasting and a standard 75 g oral glucose tolerance test (OGTT) around week 28 of pregnancy in 1074 of the women  using thBirth weight was recorded from the hospital notes. Other newborn measurements  were made by trained pediatric nurses as soon as possible after birth (at a median (inter-quartile range) age of two 1–16) days). Each measurement was made three times and the mean value was used. Body length was measured (to the nearest 0.1 cm) using a SECA 416 Infantometer. Head circumference was measured using a tape measure. Triceps , quadriceps , flank , and subscapular (the oblique angle below the left scapula) skinfold thicknesses were measured in triplicate on the left side of the body using Holtain calipers  [ days). EBody mass indexes (BMIs) were calculated as the height (or length for the newborn babies) divided by the (pre-pregnancy for the mothers) weight squared. Ponderal indexes at birth were calculated as the body length divided by the weight cubed.https://doi.org/10.17863/CAM.54014).The dataset generated and/or analyzed during the current study is available in the Apollo repository , or logistic regression. RRs were calculated using the Stata binreg function. Missing data were dealt with using case or listwise deletions, and p < 0.05 was considered statistically significant throughout. The statistical analyses were performed using either Stata  or R .Risk ratios/relative risks (RRs) of adverse pregnancy outcomes by multiple micronutrient supplementation were analyzed using logistic regression. Potential confounding of significant associations by dietary intakes were investigated by adjusting these models for food frequency intakes. Continuous variables were analyzed in statistical models using linear regression, adjusted for confounders where appropriate. Where the dependent variable residuals were skewed, the models were analyzed with prior transformation of the data so that the residuals were normally distributed. Other categorical variables were analyzed using a χWomen who were diagnosed with anemia supplemented their diets with (presumably prescribed) iron or folic acid. The various statistical analyses were also performed with women with anemia excluded to test whether the evident trends were also present in those women whose multiple micronutrient supplementation was unprescribed. Further sensitivity analyses were performed by excluding women over 30 years of age to assess whether evident trends had an age-related basis, and by excluding those women whose multiple micronutrient supplementation only began after they had undergone OGTTs, assess whether it was associated with the development of GDM rather than partially relating to a response to a diagnosis of GDM.This analysis included 970 study participants (442 of whom did not supplement their diets with multiple micronutrients and 528 that did). Of those that did supplement, 293 participants took Vitabiotics Pregnacare, 206 took Sanatogen Pronatal, and 67 took Tesco Multiplus Pregnancy . Supplementing with multiple micronutrients was also associated with an increased risk of developing GDM . None of the food frequency intakes confounded this relationship to any great extent (p = 0.4), gestational hypertension (p = 0.7), low birth weight (p = 0.8), SGA (p = 0.8), or premature birth (p = 0.2)  .Maternal multiple micronutrient supplementation in pregnancy was associated with a number of factors relating to increased size at birth and adiposity in the offspring . This inIn women for whom OGTT data were available, except for the association with head circumference, all of the associations appeared attenuated by adjusting for GDM . Even prSignificant associations with maternal GDM and increased offspring size at birth and adiposity were still evident even when women with anemia were excluded from the analyses .The increased risk of developing GDM associated with multiple micronutrient supplementation in pregnancy was still evident in mothers less than 30 years of age . The numIn this analysis, maternal multiple micronutrient supplementation in pregnancy in a population from a high-income country was associated with increased risk of GDM in the mother. It was also associated with results that are suggestive of increased offspring size at birth and adiposity. The consensus from previous studies in this area is that such supplementation is associated with reduced risk of offspring low birth weight and possibly reduced risk of the offspring being born SGA . ConsistDeficiencies in specific micronutrients, such as selenium, chromium, and zinc, have previously been shown to be associated with an increased risk of developing GDM . MultiplPrevious studies have shown associations between multiple micronutrient supplementation in pregnancy and increased size at birth, particularly birth weight and head circumference ,26,27,28This analysis was not able to, nor was it designed to, distinguish which of the constituents of multiple micronutrient preparations caused the increased size at birth and GDM risk, or whether there was an interactive effect of two or more of the micronutrients that did this. It also grouped together different multiple micronutrient brands, all of which contained at least three micronutrients and most of which contained at least 15 of them. The various preparations contained different micronutrients, different salts of the same micronutrients, or these micronutrients at different amounts. However, most pregnancy multiple micronutrient preparations are somewhat similar, and by grouping them together in this analysis, we had enough statistical power in the present analysis to detect differences in various indices of offspring size at birth and risk of maternal GDM. This analysis did not have access to whether the micronutrient supplementation was prescribed or unprescribed. However, sensitivity analyses that excluded women reporting anemia in pregnancy (who would have been prescribed with iron or folic acid) showed similar trends to those observed in the full analysis, suggesting that this may not have biased the results.Another potential limitation of the analysis could be possible biases introduced by its recruitment and analytical strategies. However, while the participants of the current analysis were not individually matched, the clinical characteristics of the group that supplemented with multiple micronutrients were very similar to those that did not supplement. The clinical characteristics of the whole group of participants in the present analysis were also very similar to those of women recruited to the CBGS who were excluded from it. In turn, the clinical characteristics of women recruited to the CBGS were representative of the whole population of women attending the Rosie Maternity Hospital, Cambridge, with the exception that they tended to be a little bit older and were more likely to be primiparous . The relOther limitations of the current analysis include the facts that the micronutrient supplementation was self-reported, and that limited account was taken as to when in pregnancy and for how long supplementation took place. However, at least as far as supplementation specifically with folic acid in pregnancy, self-reporting has been validated as accurate ,33. In wIn conclusion, in this analysis, we found evidence that maternal micronutrient supplementation in pregnancy is associated with increased size at birth and adiposity in the offspring in a population from a high-income country. It was also associated with increased risk of developing GDM in the mother, and the mechanisms that link GDM with increased size at birth may be partially responsible for the increased size at birth and adiposity resulting from maternal micronutrient supplementation in pregnancy.


Birth cohort studies are the most appropriate type of design to determine the causal relationship between potential risk factors during the prenatal or postnatal period and the health status of the newborn up to childhood and potentially adulthood. To date, there has been a growth in interest regarding observational population-based studies which are performed to provide answers to specific research questions for defined populations, for instance, assessing the exposure to environmental pollutants or drugs on the risk of developing a disease. Birth cohorts based on the recruitment and active follow-up of mothers and children allow the collection of biological material, and specific clinical and genetic information. However, they require a considerable amount of time and resources and, besides being usually of limited size, they are exposed to the risk of the loss of subjects to follow-up, with decreased statistical power and possible selection bias. For these reasons, linking the medical birth register with administrative health records for mothers and babies is increasingly being used in countries with a universal healthcare system, allowing researchers to identify large and unselected populations from birth, and to reconstruct relevant traits and care pathways of mothers and newborns. This Special Issue of the International Journal of Environmental Research and Public Health focuses on the current state of knowledge on perinatal and postnatal exposures and adverse pregnancy, maternal, fetal and neonatal outcomes through population-based birth cohort studies, with a specific focus on real-word data. The 12 accepted articles covered a wide range of themes that can be addressed specifically through birth cohort study design; however, only three were based on real word data with record-linkage to health administrative databases. In particular, two papers have addressed the topic of socioeconomic status considering several indicators both at the individual and contextual level. Two papers focused on inflammatory bowel diseases, both as an outcome of perinatal and antibiotic exposure in early life and as a condition associated with asthma, among children identified in a birth cohort based on a Regional Medical Birth Register. Three articles focused on medication use during pregnancy and its impact on maternal and fetal health. The effect of exposure to prenatal environmental risk factors on perinatal and childhood outcomes has been considered in two papers. Two papers analyzed ad hoc nationwide prospective birth cohorts set in Japan and UK. Finally, we included a systematic review with meta-analysis to evaluate the relation between growth restriction at birth and congenital heart defects. We think that this Special Issue may contribute to enriching the discussion of future challenges, opportunities, strengths and limitations for all research topics that can be investigated using a population-based birth cohort study design. Birth cohort studies are the most appropriate type of design to determine the causal relation between potential risk factors during the prenatal or postnatal period and the health status of the newborn up to childhood and potentially adulthood. Since individuals are followed longitudinally across their life span from birth, or even from the intrauterine period, birth cohorts allow us to delineate associations between early exposures and subsequent outcomes . DespitePopulation-based studies are defined as a group of individuals taken from the general population who share common characteristics, such as age, sex, or health conditions. These types of studies are performed to provide answers to specific research questions for defined populations, for instance assessing the response to a drug or the risk of developing a disease. The most delicate aspect is the selection of individuals included in the study: they should be representative of all individuals in the specific, a priori-defined population. Data collection in population-based studies relies both on linkage with available databases  and on procedures designed to ascertain study variables . ComputeBirth cohorts based on the prospective recruitment and active follow-up of mothers and children allow the collection of accurate information about exposures, outcomes and several covariates as well as biological material which is not usually included in retrospective studies. However, they require a considerable amount of time and resources and, besides being usually of limited size, they are exposed to the risk of a loss of subjects to follow-up, with decreased statistical power and possible selection bias. Furthermore, self-reporting is a common approach to acquire data in these studies with a risk of self-reporting bias .Progressive technological and organizational improvements in recording, storing, and integrating healthcare data have raised interest in the use of real-world data to enhance the efficiency of research and to bridge evidentiary gaps between clinical research and practice. Real-world data derive from a variety of sources, including health administrative databases (HADs) and electronic health records. HADs are designed to collect information for administrative purposes, relating to all healthcare services provided by the National Health Service, such as dispensations of drug prescriptions, hospital discharge records, medical birth records and mortality records, exemptions from health-care copayments and so on. However, they are increasingly being used to examine features of healthcare delivery such as practice patterns, quality of care, safety and effectiveness of drugs, and other parameters that can be evaluated by means of epidemiological studies, as well as to support healthcare and policy decision-making . LinkingInternational Journal of Environmental Research and Public Health (IJERPH) focuses on the current state of knowledge on perinatal and postnatal exposures and adverse pregnancy, maternal, fetal and neonatal outcomes through population-based birth cohort studies, with a specific focus on real-word data. The 12 accepted articles covered a wide range of themes that can be addressed specifically through birth cohort study design; however, only three were based on real word data with record-linkage to HADs [This Special Issue of the  to HADs ,11,12.Two papers addressed the topic of indicators of socioeconomic disadvantage ,13. EvidTwo papers focused on inflammatory bowel diseases, both as an outcome of perinatal and antibiotic exposure in early life and as a condition associated with asthma, among children identified in a birth cohort ,12. BothThree articles focused on medication use during pregnancy ,17,18, aSince pregnant women are always excluded from randomize controlled trials (RCT) due to ethical reason, it is very difficult to evaluate the safety of these drugs used during pregnancy. In this context, observational population-based cohort study designs offer an alternative to RCTs. The potential benefits of observational studies include the opportunity to evaluate a treatment’s effectiveness  rather than efficacy. Lower costs and difficulties that characterize observational studies allow researchers to enroll large numbers of patients, resulting in a greater statistical power. Therefore, it is possible to make inferences about differential effectiveness in subgroups of the population and generalize results to the overall population. However, beyond the limitations inherent in the observational nature of the approach, the lack of basilar information, and the consequent need of using proxies of the variables of interest, makes this approach particularly vulnerable to systematic uncertainty .To conclude, medication use during pregnancy is very common. In the paper published in this issue, Lupatelli and colleagues mapped the patterns of medication use in pregnancy, as well as the extent and type of prescribed medications that are purposely avoided by pregnant women in Italy through a cross-sectional, web-based study . AccordiExposure to prenatal environmental risk factors on perinatal and childhood outcomes has been considered in two papers ,21. MandThe other two papers analyzed ad hoc nationwide prospective birth cohorts set in Japan (Japan Environment and Children’s Study ) and theFinally, Ghanchi and colleagues conducted a systematic review with meta-analysis to evaluate the relation between growth restriction at birth and congenital heart defects. The majority of studies included in the meta-analysis were population-based studies .We, as Guest Editors, hope that this Special Issue may contribute to enriching the discussion of future challenges, opportunities, strengths and limitations for all research topics that can be investigated using a population-based birth cohort study design.


These defects continue to occur; however, they are yet to be recognized as public health problems in Kenya. The objective of this study was to estimate the prevalence of major external structural birth defects in Kiambu County in Kenya, 2014-2018.a cross-sectional study design was adopted; a retrospective review of medical records was conducted between 2014 and 2018 abstracting 873 birth defects. Following a predetermined inclusion criterion, a five-year prevalence numerator of 362 cases was determined, whereas, a five-year prevalence denominator of 299,854 cases of registered live-births was obtained from the birth registrar. Annual prevalence estimates of 29 sub-groups and 6 groups of these defects were calculated as the number of cases (numerator) divided by the number of live-births (denominator). Associated 95% binomial exact confidence intervals were also computed and expressed per 100,000 live-births.defects of the musculoskeletal system, the central nervous system, orofacial, genital organs, eye and anus were observed. Defects of the musculoskeletal system were the most prevalent, ranging from 22.98 (95% CI: 11.87-40.13) to 116.9 (95% CI: 92.98-145.08) per 100,000 live-births. Defects of the central nervous system followed ranging between 13.40 (95% CI: 5.39-27.61) and 32.79 (95% CI: 20.79-49.19) per 100,000 live-births.despite musculoskeletal system defects being the most common group, hypospadias; a defect of the male genital organ was the most prevalent among the sub-group of these defects. Worldwide, an estimated 134 million births are reported to occur each year of which 7.9 million 6%) are born with at least a major birth defect, mostly affecting the musculoskeletal system and the central system  ,4-6. Bir% are borGlobally, the prevalence of major external birth defects has been noted to vary by types, severity and geographical regions attributed to data paucity and case under-reporting ,7,11-14.Intrauterine fetal development (embryogenesis) occurs in the first 8 weeks of gestation (first trimester of gestation); a period of great public health importance because of its vulnerability to teratogenicity and the effectiveness of preventive strategies ,17. SimiStudy settings and design: this study was conducted in 13 public hospitals within Kiambu in Kenya. The county´s health department comprised of community health services, 70 dispensaries, 24 health centers, 10 sub-county hospitals and 3 county referral hospitals. The 13 study hospitals consisted of the ten sub-county hospitals; Kihara, Karuri, Wangige, Nyathuna, Lari-Rukuma, Ruiru, Tigoni, Lussigetti, Kigumo and Igegania and the three county referral hospitals; Kiambu, Thika and Gatundu, purposively selected. These hospitals offer reproductive, medical, pediatrics and surgical health services in the 13 sub-counties of Kiambu County; one of the 47 counties in Kenya. Community health services, dispensaries and health centers collaboratively link children born with major external structural birth defects to these hospitals for health care services. Kiambu County is largely urbanized and is the wealthiest among the 47 counties in Kenya. It borders Nairobi County to the south, Muranga and Nyandarua counties to the north, Nakuru and Kajiado counties to the west. It is the second-most densely inhabited county with a population estimate of 2.4 million after Nairobi County (4.3 million) out of 47.5 million nationally [tionally . Nakuru tionally . All mostionally . Additiotionally . AgriculStudy population and participation eligibility: the study population  comprised all children born to resident women of Kiambu County between January 1st, 2014 and December 31st, 2018. Cases  were defined as live-births with at least one clinically-obvious major external structural birth defect referenced and/or described by a primary healthcare provider, either in the delivery rooms or neonatal units. These defects were considered for this study because they were easily recognizable visually or through physical examination at birth or shortly after birth by a healthcare provider. Additionally, case ascertainment was less likely to be affected by regional differences in referral and medical treatment compared to other anomalies. Primary health care providers consisted of midwives, medical officers and obstetricians in delivery-rooms, whereas, in neonatal units, the primary providers comprised nurses, midwives, medical officers, clinicians and pediatricians. The choice of the study population helped to provide a glimpse of the public health magnitude of these defects in Kiambu County. The results acted as a pointer to the “silent epidemic” and were intended to inform public health planning, policy decisions and actions on public health surveillance and birth defect-specific interventions.Exclusion criteria: the study excluded stillbirths, new-born to non-resident women of Kiambu County and new-born with a clinically undetectable or unobvious birth defect at birth or soon after birth. Additionally, externally occurring structural birth defects with no significant medical and financial implications were excluded from the study.Sources and collation of numerator data: the study extracted numerator data from maternity files, maternity registers, neonatal inpatient files and neonatal daily-bed returns. Maternity files contain records about women admitted in delivery rooms for childbirth. Information captured in these files is demographic, social, medical, surgical and reproductive history, admission findings, intra-partum and postpartum care. These files have summary sections for recording birth defects visually identified at birth or soon after birth by the primary health care providers. Summaries of the maternity files are then entered in maternity registers for the compilation of hospital reports and used as complementary sources of data. Similarly, neonatal inpatient files contain maternal information described in the maternity files above and information of the neonates. Information about neonates is further summarized in daily-bed returns and used as supplementary sources of data. Before data collection, six research assistants (RAs) were recruited and trained in data extraction techniques to ensure that the abstraction process was carried out in a standardized manner. To obtain the numerator data, medical-related records described above were reviewed over the five-year study period. All MESBDs referenced and/or described by primary health care providers were extracted and entered in a predefined data abstraction tool. Information captured during data extraction included names of the study hospitals, sources of data, sub-county of residence, dates of admission, dates of birth, sex of the newborn children, definitions or descriptions of the birth defects, referrals from homes, peripheral health facilities and to other health facilities.On the other hand, annual prevalence denominators (the number of registered live-births) was drawn from the Kenya Vital Statistics Report, 2017 (KVSR 2017); a publication of Civil Registration Services . The regEthical considerations: ethical approval was obtained from Kenyatta National Hospital (KNH)-University of Nairobi (UoN) Ethics Review Committee (Ref. No: KNH-ERC/A/44). Data collected were also de-identified using anonymous codes.Statistical analysis: data obtained from secondary data abstraction tools were double-entered into an excel-spreadsheet by two independent data clerks to minimize errors. The principal investigator exported the validated dataset to Stata software, version 14  for cleaning and analyses. The prevalence estimates of major external structural birth defects were calculated as the number of cases (numerator) divided by the total number of live-births (denominator) using the formula below:Associated 95% binomial exact confidence intervals were also computed and expressed per 100,000 live-births. Summary results were presented in proportions using frequency tables and graphs to show the distribution of these defects in the county.The study observed 362 cases categorized into six groups and 29 sub-groups of major external structural birth defects . DefectsThe study further showed anencephaly (30.65%), hydrocephalus (25.81%) and spina bifida (16.13%) were common among the defects of the central nervous system . ConspicTo our knowledge, this is the first cross-sectional study conducted to estimate the prevalence of major external structural birth defects in Kiambu County. Despite the rarity of these defects, their effects are adverse, thus underscore the assembly and analysis of locally available data to understand the public health magnitude of the problem . This coDefects of the musculoskeletal system and those of the central nervous system were shown by the study as the most prevalent in Kiambu County. These findings are indeed consistent with the results of other studies carried out in the region, such as Ethiopia ,15,16,23Even though this study reported 29 sub-groups of the six groups of MESBDs with musculoskeletal and central nervous defects as the most common among the groups in general, hypospadias (82.50%); a male genital organ defect, was the most frequently occurring sub-group of MESBDs. Although many studies have not been reporting findings on defects of genital organs, this study further showed epispadias; another defect of the male genital organ was similarly common in the county. This could be suggestive of a constant prevalence of the most common risk factors for hypospadias and other genital defects such as advanced maternal age (35 years) and BMI (>26) . NotablyCertain limitations were however noted during the study period; first and foremost, there were inadequate stores and shelves for the medical records leading to heaped pools of records not necessarily arranged in an ordered manner and sometimes leading to defaced records. Secondly, medical records used in this study were not designed for epidemiological studies, therefore, researchers perused over many pages of maternity files to identify summary sections of the files where major external structural birth defects were defined, referenced, or described. Additionally, although the files were accessible in one of county referral hospitals, summary sections of maternity files for recording MESBDs were missing, therefore no records were abstracted for the five-year study period in this facility. In 2017, maternity files in another county referral hospital were not accessed because they were relocated to an unknown place within the hospital, explaining a decline in prevalence estimates observed . FurtherThis was the first study to estimate a region-specific prevalence of major structural birth defects in Kenya. Despite the limitations of the study and the fact that defects of the musculoskeletal, central nervous system were the most frequent groups of major external structural birth defects, hypospadias; a defect of the male genital organ was the most prevalent among the 29 sub-groups of the defects in the county. Additionally, anencephaly, was the most commonly occurring neural tube defect despite being associated mostly with stillbirths. This observation pointed at the possibility of constant exposure to women of reproductive age to potential risk factors for a myriad of major external structural birth defects. In the absence of effective prevention and control measures, accessible corrective and rehabilitative services for major external structural birth defects; adverse health effects, psychosocial impacts, developmental challenges and reduced economic productivity arising from lifelong disabilities are inevitable. Establishing county-specific and national surveillance systems for major external structural birth defects will be of great public health importance in understanding the public health magnitude of these defects, regionally and nationally. Lastly, we recommend that future studies should investigate risk factors for major external structural birth defects in Kiambu County with a view of cascading similar studies across the country for purposes of informing designs and formulations of defect-specific surveillance, prevention and control strategies.There is a wide-spread limitation of local data for major birth defects leading to underestimation of their prevalence;The prevalence of major external structural birth defects is known to vary from region to region and from one period to the other;The burden associated with major external structural birth defects includes childhood morbidity, childhood mortality, lifelong disabilities, reduced quality of life, reduced life expectancy and reduced economic productivity.Overall, the study showed defects of the musculoskeletal and central nervous systems were the most frequent among the six groups of MESBDs in the county. However, hypospadias (82.50%), cleft lip with the palate (77.08%) and congenital talipes equinovarus (73.08%) were the most commonly occurring among the 29 sub-groups of MESBDs in the county;Although anencephaly is the leading cause of stillbirths associated with severe birth defects, it was among the most prevalent (30.65%) among the sub-groups of MESBDs among live-births and the highest among defects of the central nervous system;The study showed a spiraling trajectory of major external structural birth defects during the five-year study period.


Sub-optimal maternal lipid levels during pregnancy may be implicated in the pathophysiological mechanisms leading to low birth weight (LBW) and small-for-gestational-age (SGA). We aimed to determine whether maternal lipid levels across pregnancy were associated with birth weight and the risks of LBW and SGA in rural Gambia.This secondary analysis of the ENID trial involved 573 pregnant women with term deliveries. Plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglycerides (TG) were analyzed at enrolment (mean (SD) = 13.9 (3.3) weeks gestation), 20 and 30 weeks gestation as continuous variables and percentile groups. Regression models with adjustment for confounders were used to examine associations between gestational lipid levels and birth weight and the risks of LBW (birth weight < 2500 g) and SGA (<10th percentile INTERGROWTH-21ST for birth weight).P = 0.011) reduction in relative risk of LBW. At 20 weeks gestation, every unit increase in TC levels was associated with a 1.3% reduction in relative risk of LBW (P = 0.002). Low (<10th percentile) HDL-c at enrolment or at 20 weeks gestation was associated with a 2.6 (P = 0.007) and 3.0 (P = 0.003) times greater risk of LBW, respectively, compared with referent (10th─90th) HDL-c. High (>90th percentile) LDL-c at 30 weeks gestation was associated with a 55% lower risk of SGA compared with referent LDL-c (P = 0.017). Increased levels of TC  at 20 weeks gestation and of TC  and LDL-c  at 30 weeks gestation were all associated with higher birth weight.There were 7.9% LBW and 32.5% SGA infants. At enrolment, every unit increase in HDL-c was associated with a 2.7% (In rural Gambia, lipid levels during pregnancy were associated with infant birth weight and the risks of LBW and SGA. Associations varied by lipid class and changed across pregnancy, indicating an adaptive process by which maternal lipids may influence fetal growth and birth outcomes.ISRCTN49285450 on: 12/11/2009.This trial was registered as  The published ENID trial protocol provides complete details of the trial  while anThe randomization procedure allocated eligible pregnant women to one of four prenatal nutritional supplements; (i) iron folic-acid (FeFol) tablets, the standard of care as per Gambian Government guidelines; (ii) multiple micronutrients (MMN) tablets, a combination of 22 micronutrients designed for use during pregnancy by UNICEF/WHO/UNU ; (iii) pAt enrolment  = 13.9 (3.3) weeks gestation), gestational age was assessed using a Siemens ACUSON Antares Ultrasound Imaging System  with a CH6–2 (5.71 MHz) transducer). Further clinic visits were conducted at 20 and 30 weeks gestation. At all visits, data were collected on maternal anthropometry, Hb, blood pressure, and a urinary analysis was performed. A sample of venous blood (10 mL) was also collected following an overnight fast and plasma samples were stored on ice until processing within 1 h of collection. Standardized and validated equipment and standard operating protocols were used and applied for all measurements. A study midwife visited women and their newborns within 72 h of delivery for a standard maternal and newborn health check. Infant weight and length were measured using digital infant scales  with 10 g precision and a portable infant roll meter  to the nearest 0.1 cm, respectively.All maternal plasma samples were collected after an overnight fast and analyzed in the MRC Keneba laboratory for TC, HDL-c, low-density lipoprotein cholesterol (LDL-c), and TG levels using enzymatic colorimetric assays with Roche/Hitachi reagents and COBAS INTEGRA® 400 plus analyzer . The few samples that were physiologically aberrant, such as samples with detectable HDL-c and LDL-c levels but with a TC level near zero, were excluded from the analysis.2 at each measurement time point in gestation. Maternal gestational weight gain was calculated by subtracting maternal weight between; enrolment and 20 weeks gestation, 20 and 30 weeks’ gestation, and enrolment and 30 weeks gestation, and by dividing each subtraction by the number of weeks between weight measurements and expressed in kg/week. Maternal morbidity was determined based on the number of self-reports of morbidity episodes  assessed by questionnaire and divided by the number of weeks enrolled in the trial (n/week). Compliance to supplementation from enrolment to delivery (%) was computed by dividing the number of jars of LNS products (PE and PE + MMN)  or count of tablets (MMN and FeFol) the women consumed by the number received and multiplying by 100. Birth season of the infant was defined as dry (November to May) or rainy (June to October).Low birth weight (LBW) was characterized as a birth weight below 2500 g and compared to normal birth weight (NBW) (≥2500 g) . Small-fMaternal and infant variables were compared between LBW and NBW infants, and between SGA and AGA infants by Student’s t-test with Welch correction for unequal sample sizes. Unadjusted mean TC, HDL-c, LDL-c, and TG levels at enrolment and 20 and 30 weeks’ gestation were calculated with 95% confidence intervals (95% CI) and compared by Student’s t-test. Changes in maternal lipid levels across gestation were examined using a Wilcoxon rank-sum test for ordered groups and a paired sample t-test. Maternal lipid levels were analyzed as continuous variables and grouped into low (<10th), referent (10th–90th), and high (>90th) percentiles. Binary regression models were used to measure the relative risks (RR) of LBW and SGA associated with maternal lipid levels included as continuous or categorical variables (by percentile groups). Reduction in relative risk (RRR) expressed as a percentage was calculated as RRR% = (1-RR) × 100. The RR values for the analyses of the risks of LBW and SGA are presented in Additional Tables A2), 68.2% were normal weight (BMI 18.5─24.9), 9.1% were overweight (BMI 25─29.9) and 2.1% were obese (BMI ≥ 30 kg/m2). Underweight women were significantly more likely to have a LBW  or SGA  infant compared to women with a BMI > 18.5 kg/m2. Table P < 0.05). LBW infants were all born SGA and were more likely to be female (P = 0.012). Women with SGA infants also had a lower BMI at all gestational time points , a lower gestational weight gain between enrolment and 30 weeks gestation (P = 0.028) and higher gestational age at delivery (P = 0.012) compared with women with AGA infants. SGA infants were more likely to be born with a normal birth weight than with a LBW . There were no significant differences in risk of LBW or SGA by maternal nutritional supplement group.A total of 573 pregnant women with singleton term infants were included in this study. There were 45 (7.9%) cases of LBW and 186 (32.5%) cases of SGA. At enrolment, 20.6% of women were underweight (BMI < 18.5 kg/mP < 0.001) while mean HDL-c levels increased slightly from enrolment to 20 weeks gestation  before decreasing back, by 30 weeks gestation, to similar levels observed at enrolment . Longitudinal changes in maternal lipid levels were compared by LBW vs NBW and SGA vs AGA  , and TG  levels at 30 weeks gestation compared to women with AGA infants  reduction in the relative risk of LBW and every unit increase in TC levels at 20 weeks gestation were associated with a 1.3% reduction in the relative risk of LBW (P = 0.002) (Table P = 0.007) and 3.0 (P = 0.003) higher risk of delivering a LBW infant compared to women with referent (10th─90th percentile) HDL-c level, respectively  (Table P = 0.017) lower risk of delivering an SGA infant compared to women with referent (10th─90th percentile) LDL-c levels (Table P = 0.035) lower risk of delivering an SGA infant compared to women with referent (10th─90th percentile) TG, however, this association was lost following adjustment for confounding factors (Table Tables ls Table . In the P < 0.05) (Table P = 0.027) and of TC  and LDLc  at 30 weeks gestation remained associated with a higher birth weight (Table P < 0.05)  Table . After aP = 0.028) and 30  weeks gestation, and supplementation with PE was associated with higher LDL-c levels  at 30 weeks gestation (Table AP = 0.021) whereas a higher BMI was associated with increased LDL-c levels . At 20 and 30 weeks gestation, higher BMIs were linked to increased TG levels   Table A. However) Table A. Additio) Table A or birthIn this cohort of pregnant women from rural Gambia, plasma lipid levels were lower compared to those reported in studies from high-income countries –29 or urn = 631) reported a decrease in maternal HDL-c levels between 18 and 28 weeks gestation [Consistent with previous studies, we observed an increase in plasma TC, LDL-c and TG levels across pregnancy , 26, 27,estation . These on = 261), women with low TC in early pregnancy had a 2-fold increased risk of delivering an LBW infant compared to women with TC levels within the mid-range [In line with previous research from a range of settings, relationships between maternal TC, HDL-c, LDL-c, and TG levels during pregnancy and size at birth were observed in our study. An association between increased TC levels at 20 weeks gestation and a reduced risk of LBW was detected and increased TC levels at both 20 and 30 weeks’ gestation were associated with higher birth weight. In a study conducted in Nigeria (id-range . Likewisid-range . These fid-range . Althougid-range –31.n = 1207) reported that low HDL-c measured at 16–27 weeks gestation was associated with a lower birth weight [Similar to our findings of an association between low HDL-c in the second trimester and greater risk of LBW, a study conducted in the US n = 07 reporth weight –34. Durih weight , includih weight , a shorth weight , 37. Oneh weight , 39.n = 66) which reported an association between low LDL-c in the first trimester and IUGR [Additionally, at 30 weeks gestation, we detected associations between high LDL-c and reduced risk of SGA and between increased LDL-c levels and higher infant birth weight. This corroborates the findings of a study conducted in Scotland  [n = 144) from Tanzania [n = 1463) [Although all LBW infants were also born SGA in our study, the results show differences in the relationships between maternal lipids during pregnancy and the risks of LBW and SGA. While increased HDL-c or TC levels in the first half of pregnancy were linked to a reduced risk of LBW, high LDL-c or TG at 30 weeks gestation were related to a reduced risk of SGA. This suggests that the pathophysiological mechanisms linking gestational lipid levels to the risk of LBW may arise early in gestation, during the anabolic phase of pregnancy characterized by an accumulation of fat in maternal adipose tissue . Inadequn = 653)  and withTanzania . In cont = 1463) . Altered = 1463) , 53.Maternal undernutrition during pregnancy causes metabolic stresses which may adversely impact on fetal growth and birth outcomes. In this study and others, underweight women were found more likely to have an LBW or SGA infant compared to women with a normal weight –51. FurtThe major strengths of this study include the use of a large cohort from a population in rural sub-Saharan Africa, bringing new perspectives into the relationships between maternal lipids and infant birth outcomes in populations where the burden of LBW and SGA is the highest and where research findings are limited. The measurements of maternal plasma TC, HDL-c, LDL-c, and TG levels at three-time points across pregnancy allow a greater understanding of the adaptive process through which maternal lipids impact on fetal growth. The assessment of potential associations using maternal lipid levels as continuous variables and percentile groups with or without adjustment with confounding factors allowed a robust and thorough analysis of the links between gestational lipids and birth weight-related outcomes.Limitations of this study should be noted, and caution should be taken in the interpretation of the results. This study is a secondary analysis of a clinical trial of nutritional supplementation which by its observational design precludes any conclusion on causal links between maternal lipid levels and infant’s size at birth. Pregnant women in our study were healthy, had a singleton infant and received supplementation and comprehensive antenatal care throughout pregnancy, and therefore may not be representative of all eligible Gambian women. A further limitation of the trial design was the lack of data or samples from late pregnancy to allow lipid measurements after 30 weeks gestation. Such data may have contributed to the understanding of the relationships between gestational lipids and birth outcomes.In conclusion, our data from rural sub-Saharan Africa indicate that maternal plasma lipid levels during pregnancy may influence fetal growth, thereby impacting on birth weight and the risks of LBW and SGA. Importantly, our findings suggest that distinct pathophysiological pathways may be involved in the relationships between maternal lipid levels during pregnancy and LBW and SGA outcomes, with differential effects according to the lipid component and the stage of gestation. Additionally, in this cohort of primarily subsistence farming women, underweight women were found at greater risk of having an LBW or SGA infant, highlighting the critical role of maternal nutritional status on birth weight outcomes. Thus, our study supports interventions that monitor and optimize maternal lipid levels across pregnancy while promoting an adequate gestational weight gain.Additional file 1 Table A1. Nutritional composition of the allocated daily intake of pregnancy supplements. Table A2. Relative risk of LBW (95%CI) associated with maternal total, HDL and LDL cholesterol and triglycerides levels at enrolment, 20 and 30 weeks gestation. Table A3. Relative risk of SGA (95%CI) associated with maternal total, HDL and LDL cholesterol and triglycerides levels at enrolment, 20 and 30 weeks’ gestation. Table A4. Associations between maternal nutritional supplement groups and maternal total, HDL and LDL cholesterol and triglycerides levels at enrolment, 20 and 30 weeks gestation. Table A5. Beta coefficients  of associations between maternal total, HDL, LDL cholesterol and triglycerides levels and BMI at enrolment, 20 and 30 weeks gestation. Table A6. Associations between maternal nutritional supplement groups and maternal BMI at enrolment, 20 and 30 weeks gestation. Table A7. Relative risk of LBW and SGA by maternal nutritional supplementation groups. Table A8. Beta coefficient of the associations between maternal nutritional supplement groups during pregnancy and birth weight.


Preterm birth is a worldwide epidemic and a leading cause of neonatal mortality. In this study, we aimed to evaluate the incidence, risk factors and consequences of preterm birth in Nepal.This was an observational study conducted in 12 public hospitals of Nepal. All the babies born during the study period were included in the study. Babies born < 37 weeks of gestation were classified as preterm births. For the association and outcomes for preterm birth, univariate followed by multiple regression analysis was conducted.The incidence of preterm was found to be 93 per 1000 live births. Mothers aged less than 20 years  had a high risk for preterm birth. Similarly, education of the mother was a significant predictor for preterm birth: illiterate mothers , literate mothers  and mothers having basic level of education . Socio-demographic factors such as smoking , use of polluted fuel  and sex of baby ; obstetric factors such as nulliparity , multiple delivery , severe anemia during pregnancy , antenatal visit during second trimester  and third trimester , < 4 antenatal visits during pregnancy  were found to be significant risk factors of preterm birth. Preterm has a risk for pre-discharge mortality .In this study, we found high incidence of preterm birth. Various socio-demographic, obstetric and neonatal risk factors were associated with preterm birth. Risk factor modifications and timely interventions will help in the reduction of preterm births and associated mortalities.ISRCTN30829654. Preterm birth (< 37 weeks of gestation) is one of the leading causes of neonatal morbidity and mortality and a significant public health burden , 2. EverBabies born preterm have a higher risk of dying as reported from a multi-country study conducted in low- and middle-income countries (LMICs) . The greSeveral factors have been identified as risks for preterm birth. Socio-demographic factors such as ethnicity, older age of mothers and smoking have been reported as risk factors for preterm birth , 12. LowStudies have also been conducted showing provider-initiated interventions like induction of labor and caesarean section are attributable to preterm births , 18, 19.The study aimed to evaluate the incidence, risk factors and consequences of preterm birth in Nepal.This observational study is nested within the Helping Babies Breathe Quality Improvement Project in 12 hospitals of Nepal . These hAll babies who were delivered in the selected hospitals were included for this study.The mothers of the newborn babies who did not provide consent were excluded.A data surveillance system was established in all the hospitals to collect data on babies and their mothers. It included data collectors based in each of the hospitals with data coordinators, who collected data on all pregnant women from admission until discharge through extraction and exit interviews. All pregnant women who were admitted to the hospital for delivery and who consented to data collection were given unique identification (ID) numbers. Data was collected during labor, delivery and post-partum period. Study IDs were allocated for each hospital, which were assigned by the data collectors for each individual pregnant woman. For obstetric information, data were extracted from patient file and Maternity Register using a data retrieval form . The cleaned data were exported into Statistical Package for the Social Sciences (SPSS) for further data analysis.Preterm births – Babies born before 37 weeks of gestation.Pre-discharge mortality – The death of newborn before discharge.Maternal age, ethnicity, education, smoking history and sex of the baby were included.Antenatal care (ANC) visit, time of ANC visit and severe anemia during pregnancy were included.Parity, induction of labor, mode of delivery, multiple deliveries, major malformation and were included.P-value of < 0.05 was considered to be significant. Missing values were excluded from the analysis. Multivariable regression analysis was done for variables that were significant in univariate analysis.The incidence of preterm births was calculated. For socio-demographic and obstetric characteristics, binary logistics regression was performed to analyze the level of association with preterm births. A total of 63,099 women were admitted and 60,742 deliveries were conducted during the study period. Among the deliveries, 54,778 were term babies while 5964 babies were born preterm Fig. . The incp < 0.001) with preterm births. Similarly, obstetric characteristics such as multiple delivery, primiparity, time of first ANC visit, frequency of ANC visits, major malformation and severe anemia during pregnancy were found to be significantly associated with preterm births. Female babies were significantly associated with preterm births  were due to preterm births and its complications. Similarly, preterm births had 11-times more risk of pre-discharge mortality   when compared to mothers less than 20 years of age. For mothers above 35 years, the risk was 1.2 times higher , however the association was found not significant. In comparison to mothers with secondary and higher education level, the risk of preterm births for illiterate mothers was 40% higher , for literate mothers was 20% higher  and mothers having basic level of education was 20%higher . Similarly, the risk of preterm births among nulliparous mothers was 33% higher  compared to multiparous mothers. Time for ANC visits was significantly associated with preterm births with those mothers going for ANC visits in the second trimester was 13% higher  than those who went in the first trimester. The risk of preterm birth was 13% higher  for mothers who had a history of smoking. Further, polluted fuel , multiple deliveries  and severe anemia during pregnancy  were also significantly associated with preterm births. Female babies were at 1.18 times higher risk of being born preterm compared to males   that have been discussed in the research articles as these data were either not collected in our study or they were underreported. Another limitation was that not all mothers took part in the interviews and for those who took part, the information might subject to recall bias. Further, we only analyzed pre-discharge mortality and therefore this study does not consider long term consequences. We did not collect data on other outcomes like birth-related injuries and other associated factors hence they are not reported in our study. One strength of this study is its’ large representative sample from 12 different hospitals. Hence, the results are a likely representation of the incidence of preterm births in Nepal.This study found that factors such as age of mother, literacy levels, smoking habits, delay in seeking ANC services, use of polluted fuel, multiple deliveries and severe anemia can provide as a risk factor for preterm birth.The incidence of preterm in Nepal remains high. Based on the risk factors linked to preterm identified by this study, implementation of interventions focusing on improving women’s literacy, providing better access to clean fuel options, and improving lifestyle, may serve as a protective factor for preterm birth.Further, improving access to ANC services allowing for better identification of complications, informed choices and safe delivery services can help in reducing risks and consequences associated with preterm births.Additional file 1.Additional file 2.