Low birth weight is one of the most serious public health issues affecting newborns, with estimates ranging from 15% to 20% of all births worldwide. According to the Ethiopian demographic health survey report, the prevalence of Low Birth Weight rose from 11% in 2011 to 13% in 2016. The high proportion of birth weight in Ethiopia is hypothesized to be due to inadequate maternal diet which is associated with poor nutrition education during pregnancy. This study aimed to assess the effect of theory-based nutrition education during pregnancy through male partner involvement on birth weight in rural parts of the southwest Ethiopia.A community-based quasi-experimental study was conducted.A total of 403 pregnant women were selected from 22 rural kebeles of Illu Aba Bor Zone, Southwest Ethiopia from June to December 2019. Participants were assigned to one of the three study arms: Couple group:—husband and wife received nutrition education together, women alone:—pregnant women received the nutrition education alone and control group:—received the routine care during Antenatal care. The nutrition education was guided by theory of planned behavior. Monthly home visits were made to the pregnant women in the intervention groups and leaflets with key counseling messages were distributed to each woman in the intervention arms. A structured interviewer-administered questionnaire was used to collect the data. A qualitative 24‐h dietary recall was used to assess dietary data, and the Mid‐Upper Arm Circumference was used to assess nutritional status. Birth weight was measured within 24 hours of birth. Analysis of variance, linear mixed-effects model, and mediation analysis were used to assess effect of the intervention on birth weight.p = 0.037) respectively. The mean birth weight of babies born to women from the couple group was 0.42 kg greater than that of newborns born to women in the comparison group . The linear mixed effect model showed that the average birth weight of babies born from women in the couple group was 0.40 kg higher than that of the control group . The direct effect of the intervention on birth weight of babies born from women in the couple group was 0.23  whereas the indirect effect mediated by maternal dietary diversity practice was 0.18 , accounting for 43.9% of the total effect of the intervention.A higher proportion of the newborns in the control group had low birth weight as compared to the couple group and the women alone group (18.1% vs 7.0% vs 11.5%, The involvement of males and the application of the theory of planned behavior in nutrition education interventions during pregnancy resulted in improved birth weight. Maternal dietary diversity mediated the effect of nutrition education on birth weight. The findings highlight the implication of improving pregnant women’s nutrition education through male involvement and the application of theories to improve birth weight. The World Health Organization (WHO) defines low birth weight (LBW) as a birth weight of less than 2500 grams regardless of gestational age . It is tWorldwide, LBW is one of the major public health problems that put forth short-term health effects, like hypoglycemia , and hypLBW is a key indicator of the progress towards the achievement of the global nutrition targets , as a 30Nutrition education is an essential consideration for improving the health of women of reproductive age and pregnancy outcomes. Nutrition education programs are important as they target enhancing dietary intake by promoting behavioral changes such as food choice and cooking ability, goal-setting, motivation, and supporting efforts for change. Dean et al., for example, discussed how preconception nutrition-specific interventions, specifically increased folic acid, and multivitamin supplements, resulted in positive pregnancy outcomes in pregnant women . FurtherTheory and models can be used to identify individual characteristics and the surrounding environment, which can aid in behavior change as a result of educational interventions. Behavior modification theories and models can be extremely beneficial in the development and evaluation of comprehensive educational programs . The TheInvolving husbands in nutrition-related social behavior-change programs is particularly crucial in countries where women’s decision-making autonomy is limited and households are typically headed by men . Recent Male involvement interventions in maternal health  and reprA community-based quasi-experimental study was conducted among pregnant women in rural communities of Ilu Aba Bor zone, Southwest Ethiopia. The zone is one of the 21 zones of Oromia National Regional State, located at a distance of 600 km from the capital in the southwest direction. It is located in the western part of the region, between 340 52 12 "E and 410 34 55E longitude and 70 27 40N and 90 02N latitude. The zone is divided into 14 districts, each with 23 urban and 263 rural kebeles and a population of 934,783, with 467,553 males and 465,792 females. Agriculture is the dominant means of livelihood in the Zone. The study was conducted from July to December 2019.Pregnant women in their first and early second trimesters (up to 16 weeks of gestation) were the study participants. G*Power 3.0.10  was usedWe enrolled all consenting married pregnant women in their first 16 weeks of gestation because the intervention was to be implemented before the delivery period. Furthermore, pregnant women who had lived in the study area for at least 6 months were included to maintain homogeneity in access to nutrition-related information and health services. Pregnant women with the diagnosis of Hypertension, Diabetes Mellitus requiring a special diet and nutritional needs were excluded. Participants were also not included in the analysis for others reasons such as abortion, failure to comply, relocation, and not informed birth weight.In the first stage, four districts were selected. In the second stage, these districts were stratified into three according to the geographic direction and proximity to each other. The districts were allocated to a control group or one of the two intervention groups. Then, Kebeles (the lowest administrative unit) were selected at random from the districts that were selected. Pregnant women were enumerated using house-to-house visits in all of the selected Kebeles, and all that fulfilled the inclusion criteria were included in the study . Due to A theory-guided community-based nutrition education intervention on maternal diets was used. The current study was not intended to test a theoretical model; rather, it was useful in directing what types of variables and processes might be important in shaping maternal health behaviors and thus required attention in the intervention. Participants were assigned to one of the three study arms: Couple group:—husband and wife received health education together, women alone:—pregnant women received health education alone and control group:—received no education.After reviewing the World Health Organization’s (WHO) guidelines and the Training of Trainers Manual of the Federal Democratic Republic of Ethiopia, the nutrition education protocol was established , 35. TheTwo approaches were used to implement the intervention. These include group nutrition education for intervention groups as well as monthly home visits and counseling for pregnant women to assist them in adopting the recommended practices after the nutrition education. Group nutrition education was given monthly at health posts to husbands and pregnant women together in one group and women alone in the other. The nutrition education was given monthly for three sessions and each education session lasted for 45 to 60 minutes. In addition, one health extension worker (HEW) was assigned to each intervention village to provide counseling and support to mothers. Before going into the field, the HEWs were trained and given counseling resources.All pregnant women seeking antenatal care (ANC) received nutrition counseling following a national standard protocol. Pregnant women in both the control and intervention groups had access to this service.The intervention’s fidelity was assessed using best practice recommendations developed by the National Institutes of Health (NIH) Behavioral Change Consortium. The criteria were used to evaluate the intervention design, counselor training, counseling process, intervention receipt, and enactment of skills gained from the intervention . The intA pre-tested structured interviewer-administered questionnaire was used to collect data on dietary diversity practice and demographic characteristics, such as household wealth status, household food security status, obstetric-related factors, and the intervention. The tool was developed after a review of various literature and standard guidelines , 37–39 TThe primary and secondary outcomes of this intervention were the dietary diversity and nutritional status of the pregnant women, respectively. The final outcome, birth weight was assessed using a digital weighing scale  and recorded by the midwives within 24 hours of the baby’s birth. Before each measurement, the scale was calibrated with a known-weight object. Furthermore, before weighing each newborn, the reading on the scale was reset to zero. The same professionals determined stillbirth (no indications of life at birth after 24 weeks of gestation) and pre-term birth (PTB) (before 37 weeks of gestation) at birth.The dietary diversity of individual women was determined using a 24-hour qualitative dietary recall. Women’s dietary diversity (WDD) is a nine-food-group score that is used to assess a diet’s micronutrient sufficient . The preThe Ethiopian Demographic and Health Survey’s wealth constructs were used to assess household wealth status, which included household assets, utilities, and housing features .The collected data were entered into Epi data version 3.5.1 and then exported to SPSS version 23 for analysis. Summary statistics such as mean and percentages were used to describe the study population based on the study outcomes, demographic features, and other pertinent risk factors. The analysis did not include multiple births, premature births, and stillbirths. A chi-squared test was used to compare the baseline characteristics of the two interventions and control groups. Analysis of Variance (ANOVA) was used to compare means between the control and intervention groups, and when ANOVA was statistically significant, a post hoc test (Tukey HSD test) was used to determine the level of significance of values between and within groups. A p-value of less than 0.05 was considered statistically significant.The food groups were categorized into nine food groups. Finally, the food groups were summed to generate a dietary diversity score (DDS), which was ranked into tertile. A detailed description of the dietary assessment is described elsewhere . PrincipThe linear mixed-effects model was used to examine the effect of the intervention on birth weight considering kebeles as clusters and birth weights nested within the clusters. Kebeles were analyzed as random effects due to the correlation of observations due the clustering of individuals within the selected Kebeles. The model was adjusted for potential confounders such as maternal age, maternal education, maternal occupation, family size, newborn sex, baseline MUAC, and baseline DDS. Before fitting the model, the normality assumption of the outcome variable, birth weight, was tested using Shapiro-Wilk’s test, and the test revealed that the assumption was satisfied (p > 0.05). We used the Akaike information criterion (AIC) to help us choose the best statistical model. We selected the model that had the smallest AIC. Variables in the bivariate linear mixed regression model with p-values less than 0.2 were selected as candidate variables for the multivariable linear mixed model analysis. The effectiveness of the intervention was determined by examining the interaction between time and the intervention.Furthermore, the nutrition education intervention provided to pregnant women on the importance of eating a diverse diet may have both direct and indirect effects on birth weight. Taking this into account, mediation analysis was also performed to assess the intervention’s direct and indirect effects on birth weight. Birth weight was the outcome variable and intervention was the predictor of the outcome. The dietary practice was the mediator of the intervention effect. The PROCESS macro version 3.4 for SPSS, developed by Andrew F Hayes , was useThe study followed the Helsinki Declaration on Human Subjects Medical Research . The InsA total of 341 newborns  birth weight was measured within 24 hours of birth and included in the final analysis. The socio-demographic characteristics of all three groups were comparable at baseline . The floP = 0.072). After nutrition education, there was a statistically significant difference in mean DDS among the three groups  (P = 0.615). However, there was a statistically significant difference in the end-line nutritional status among the three groups  (P = 0.0378).According to the findings of this study, the baseline mean dietary diversity scores among the three groups were comparable  . SimilarP<0.001) . More woA higher proportion of the newborns in the control group had low birth weight as compared to the couple group and the women alone group  respectively . The meap = 0.04) in the first model (empty model). The intra-cluster correlation coefficient was 0.068. The average birth weight in the couple group was 0.40 kgs higher and in the women alone group 0.14 kgs higher than the control group , according to the linear mixed-effects model . The estimate of indirect effect indicated that the effect of nutrition education through male involvement mediated through a change in maternal dietary diversity practice resulted in increased birth weight by 0.18 ). The total effect of the intervention, on average, increased birth weight by 0.40 . Maternal dietary diversity practice mediated 43.9% of the effect of the intervention on birth weight   and enhanced maternal wellbeing and delivery outcomes. The women alone group received the nutrition education alone, whereas the control group received routine education during antenatal care. A similar finding was reported in a study in Nepal, in which women who were educated alongside their husbands were more likely than women who received education alone to attend a postpartum visit . AnotherThe intervention had a direct effect of 0.23 on birth weight. One explanation for the intervention’s immediate positive effect is the fundamental information provided in the nutrition education, which may have helped women better understand what makes a healthy diet during pregnancy, which may have further improved healthy behaviors and led to an increase in birth weight. A similar finding was reported in a study in the West Gojam Zone of Ethiopia in which theory-based nutrition education had a direct effect on birth weight .The intervention effect on birth weight was mediated by women’s dietary diversity practices. This could be because women in the couple group received nutrition education about maternal diet using the TPB, which may have increased women’s knowledge of the consequences of poor diet, the benefits of eating a balanced diet, food preparation, and weight gain, which in turn improved birth weight. Further, the male partner involvement in the nutrition education during pregnancy may have promoted positive maternal behaviors such as healthier eating that may have reduced risk of fetal growth restriction and low birth weight. Furthermore, nutrition education may have changed the cultural beliefs that tended to limit the consumption of a diversified diet. This result is in line with a systematic review of studies on the effect of nutrition interventions on birth weight, which found that nutrition interventions had an indirect effect on birth weight .The findings have practical implications for preventing low birth weight. The fact that significantly lower numbers of newborns have LBW in the couple group implies the need for enacting community-level education through male partner involvement using theory-enhanced approaches.The use of theory-based nutrition education, the participation of husbands in the nutrition education intervention, the follow-up from early pregnancy through delivery, and the utilization of intervention methodologies are all strengths of this study. Further, the baseline characteristics across the three groups were comparable. However, the study was not without limitations. Participants were purposively assigned to the control or intervention groups. Due to the lack of randomization, there is a risk of bias. In addition, follow-up demographic characteristics were not collected during child delivery and many LBW risk factors such as the mother’s height and morbidity experience during pregnancy, which has previously been identified in studies, were not controlled for in this study. Further, all of the responses, with the exception of the MUAC and birth weight measurement, were relied on the women’s self-report, recall, and sincerity in responding to the questions.This study showed that a theory-based nutrition education intervention during pregnancy improved birth weight among pregnant women in Ethiopia. Pregnant women who received nutrition education with their husbands showed the greatest improvement. Dietary diversity was also found to be a mediator in the effect of the intervention on birth weight. This finding suggests that community-level education should be implemented through male engagement and theory-based techniques. The findings of this study can be used to draw key conclusions that will inform policies that seek to motivate males to support maternal and child nutrition. The result further provides a basis for further extensive research that will expand outcomes to include the long term sustenance of the behavior.S1 File(DOCX)Click here for additional data file.S2 File(SAV)Click here for additional data file.


Fetal morbidity was not different. In vaginally completed deliveries duration of birth was significantly longer in vHR (557 min) as in vLR . Manual assistance to deliver the arms (‘Louwen maneuver’) positively correlated with birth weight  and the BW/CVO ratio . (4) Conclusions: A high fetal birth weight combined with a tiny CVO predicts higher cesarean section probability, longer birth duration and the necessity to perform arm delivery assistance. Birth weight and pelvic measurements should be topics of great importance in patients counselling.(1) Background: Guidelines on vaginal breech delivery require birth weight restrictions and neglect the impact of pelvic measurements despite contradicting evidence. There is a great need for more evidence on delivery outcome predicting factors for patients counselling. (2) Methods: We performed a prospective cohort study on 748 primiparous women intending vaginal breech birth and analyzed combined influence of fetal birth weight (BW) and the obstetric conjugate  on delivery outcome. (3) Results: We generated a BW/CVO ratio and devided our study cohort at median (257.8 g/cm) into a low ratio group  and a high ratio group . Cesarean section (CS) rate was significantly higher in HR (50.3%) as compared to LR (28.3%,  Vaginal delivery of fetuses in breech presentation has been established as a safe delivery option during the last decade. Numerous studies have shown that with careful patient selection, an experienced obstetrical team and an upright birth position maternal and fetal long-term outcome is not of disadvantage, compared to an elective cesarean section ,3,4,5,6.In counselling, patients have to decide on their attempted delivery mode based on the expertise and the information given by their obstetricians. Evidence based shared decision making should be the goal in each counseling session in order to succeed in finding the best individual approach for each patient. This includes explaining possible complications of an elective cesarean section, namely postpartum bleeding, wound infection and subsequent pregnancies complicated by previous cesarean section. In this context, avoiding a cesarean section should be discussed addressing fetal and maternal outcome as well as the probability to receive a cesarean section after the onset of labor. Of highest importance is safety in terms of fetal and maternal morbidity. Louwen et al. showed that fetal morbidity can be reduced when women deliver in an upright position . Also, in = 88) in this study because the birth position has been shown to influence birth outcome [The study was performed in accordance to the actual Helsinki Declaration. We performed a prospective cohort study on vaginally intended deliveries of term singletons in breech presentation (>37 weeks of pregnancy) of primiparous women at the Goethe University Hospital in Frankfurt from 01/2004–12/2019. Patients with complications with an impact on delivery mode, deliveries with a fetal birth weight of beneath 2500 g, multiple pregnancies and patients with not sufficiently treated diabetic illnesses were excluded from the study. As a standard in out center, all women with a breech presentation come for counseling prior to birth in which the benefits and risks of vaginally intended birth as well as planned cesarean section are explained. The university clinic’s ethics committee gave consent (420/11). Informed written consent was waived because data was mainly gathered after patient’s dismission. Standard clinical care applied. Vaginal breech deliveries are performed predominantly in an upright birth position. In rare cases, by choice of the patient or the obstetrician in charge, deliveries were continued/ended in dorsal position. Our analyses of vaginal deliveries exclude these births  is defined as the distance from the promontory to the back of the symphysis pubis.Counselling process, cohort selection and the hospitals regiments on vaginal breech delivery have been previously described within FRABAT study cohort publications ,14,15,21We generated two main study cohort subgroups. In order to do that we generated a birth weight/obstetric conjugate (CVO) ratio (BW/CVO). The study group was then divided by median split. The median of the whole cohort’s birth weight/CVO ratio was 257.8 g/cm. The division resulted in two study groups: One with a low birth weight and large obstetric conjugate  and one group with high birth weight and a small obstetric conjugate . The latter being the group with expected less favorable outcomes. Median split was performed in order to get two groups with equal sample size The modified PREMODA score used in this study previously has been described in other publications of the FRABAT collective ,14,15,212-test was used to detect group differences. Statistical analyses were performed using JMP software . A p-value of below 0.05 was considered as statistically significant.Variables were tested if normal distribution applied with the Kolmogorov-Smirnov test. Pearson’s χ2. 100 women had minor preconditions . Mean birth weight was 3339 g, mean obstetric conjugate  was 12.9 cm and overall cesarean section rate was 39.2%  and the CVO, we generated a Birth weight/CVO ratio. We performed a median split (Median of Birth weight/CVO Ratio = 257.8 g/cm) in order to generate two groups with equal sample sizes in a low ratio group (LR) and a high ratio group (HR).2, HR: 23.3 kg/m2; p = 0.001) and a longer duration of pregnancy . Significantly more patients received an epidural anesthesia in HR (69.3%) compared to LR  with the high ratio group (cHR). Most CS indications, e.g., birth arrest in first or second stage, mother’s wish or suspected amniotic infection were equally distributed . There wp = 0.040; p = 0.001; p = 0.152; p = 0.092; p = 0.482; In order to elucidate the impact of CVO and BW on the necessity to perform manual assistance in vaginal deliveries, we analyzed the sub cohorts of vaginal births in HR (vHR) and LR (vLR) after excluding births in dorsal position. There were significantly more births with an epidural anesthesia in vHR (67.6%) as compared to vLR , where favorable birth outcome was hypothesized mean birth weight was 3065 g and mean CVO was 13.1 cm. In the high ratio group (HR), mean birth weight was 3613 g and mean CVO was 12.7 cm. Fetal morbidity measured with a modified PREMODA score, adapted from the PREMODA study  was not p = 0.001, In vaginally completed breech deliveries, we were able to show that a high BW/CVO ratio is associated with significantly longer birth duration (414 min in vaginal low rate group, vLR versus 557 min in vaginal high rate group, vHR, A strength and novelty of this study is the analysis of the combined impact of fetal birth weight and pelvimetric measurements with clear results on how both parameters greatly influence birth course in primiparous women with a fetus in breech presentation. MRI assessment of the pelvis might not be feasible for most obstetric centers but the obstetric conjugate is also measurable by clinical examination. Values and the BW/CVO ratio might be used in women’s counselling, thus enabling an evidence based shared decision on the attempted birth mode when a breech presentation occurs at term. Since Klemt et al. published that a CVO of beneath 12 cm is correlated with a high cesarean section rate , many paIn this study we were able to show that a high fetal weight in combination with a low CVO is predictive for cesarean section, results in longer birth duration and correlates with the necessity to perform manual assistance of the arm delivery in primiparous women at term giving birth to a fetus in breech presentation. Fetal morbidity is not impacted by the BW/CVO ratio. This study gives valuable input and highly important evidence for patients counseling in breech cases at term. Fetal birth weight and pelvic measurements and their combined impact on birth outcome should be discussed with patients in order to enable their evidence-based decision on delivery mode attempt.


What are the reference intervals for creatinine and urea concentrations in healthy newborns, and is maternal comorbidity associated with the concentrations?In this cohort study including 13 354 newborns with umbilical cord blood samples and 444 children with newborn venous blood samples, more robust and gestational age–dependent reference intervals were generated for creatinine and urea in the first 16 months of life. Furthermore, maternal preeclampsia was associated with a significant 9-fold increase in the risk of high newborn creatinine concentrations.These novel findings have the potential to improve clinical decision-making and increase understanding of the consequences of maternal comorbidities for kidney function among newborns and infants. Kidney functional capacity is low at birth but doubles during the first 2 weeks of life and reaches near-adult levels at age 1 to 2 years. Existing reference intervals for markers of kidney function in newborns are mostly based on preterm newborns, newborns with illness, or small cohorts of term newborns, and the consequences of maternal comorbidities for newborn kidney function are sparsely described.To establish robust reference intervals for creatinine and urea in healthy children in early childhood and to assess whether maternal comorbidity is associated with newborn creatinine and urea concentrations.This multicenter, prospective, population-based cohort study assessed data and umbilical cord blood samples from participants in the Copenhagen Baby Heart Study (CBHS) who were born between April 1, 2016, and October 31, 2018, and venous blood samples from a subsample of CBHS participants who were enrolled in the COMPARE study between May 3, 2017, and November 4, 2018. Cord blood samples of 13 354 newborns from the CBHS and corresponding venous blood samples of 444 of those newborns from the COMPARE study were included. Blood samples were collected at birth, age 2 months, and age 14 to 16 months, with follow-up completed on February 12, 2020. Healthy nonadmitted term newborns from maternity wards at 3 hospitals in the Capital Region of Denmark were included.Maternal comorbidity.Creatinine and urea concentrations.Among 13 354 newborns in the CBHS cohort, characteristics of 12 938 children were stratified by sex and gestational age (GA). Of those, 6567 children (50.8%) were male; 5259 children (40.6%) were born at 37 to 39 weeks’ GA, and 7679 children (59.4%) were born at 40 to 42 weeks’ GA. Compared with children born at 40 to 42 weeks’ GA, those born at 37 to 39 weeks’ GA had lower birth weight, Apgar scores at 5 minutes, placental weight, and placental-fetal weight ratio. Children born at 37 to 39 weeks’ GA vs those born at 40 to 42 weeks’ GA were more frequently small for GA at birth and more likely to have placental insufficiency and exposure to maternal preeclampsia, maternal diabetes, maternal kidney disease, and maternal hypertension. Among children born at 37 to 39 weeks’ GA, reference intervals were 0.54 to 1.08 mg/dL for creatinine and 5.32 to 14.67 mg/dL for urea; among children born at 40 to 42 weeks’ GA, reference intervals were 0.57 to 1.19 mg/dL for creatinine and 5.60 to 14.85 mg/dL for urea. At birth, multifactorially adjusted odds ratios among children exposed to preeclampsia were 9.40  for a venous creatinine concentration higher than the upper reference limit, 4.29  for a venous creatinine concentration higher than the 90th percentile, and 3.10  for a venous creatinine concentration higher than the 80th percentile.In this study, improved reference intervals for creatinine and urea concentrations were generated. Preeclampsia was associated with an increased risk of high newborn creatinine concentrations, suggesting that newborns of mothers with preeclampsia need closer observation of their kidney function. This cohort study uses umbilical and venous blood samples from children in the Copenhagen Baby Heart Study and COMPARE study to create new reference intervals for creatinine and urea and assess the association of maternal comorbidity with newborn creatinine and urea concentrations. In addition, the burden of maternal comorbidities, such as preeclampsia, diabetes, hypertension, and overweight, has increased during the last several decades, and knowledge of the implications of these factors for neonatal kidney function is sparse.22Kidney functional capacity is low at birth but doubles during the first 2 weeks of life and reaches near-adult values at age 1 to 2 years.23 Kidney functional capacity is low during fetal life, and homeostasis is sustained by the placenta.25 During the first weeks of life, kidney function increases rapidly and reaches 90% of adult levels at age 1 year.3 Serum creatinine is used as a crude measure of kidney function, refined by different formulas for estimated glomerular filtration rates .14 During fetal life, creatinine and urea are transferred across the placental barrier, and fetal and newborn concentrations have been reported to correlate significantly with maternal concentrations.30 During the first few days of life, newborn creatinine concentration increases,17 leaving the reliability of creatinine as a marker of kidney function disputed in this early phase of life. An optimal marker is, however, still lacking.17 Cystatin C and β-trace protein have been suggested as alternative markers, but testing is costly and of limited availability, and the superiority of cystatin C has been questioned.9 The development of creatinine and urea concentrations over time during early life is not well described in healthy unselected nonhospitalized children. Furthermore, the consequences of maternal comorbidities during pregnancy for newborn kidney function are currently unknown.Assessment of kidney function is important for the detection of kidney disease and acute kidney injury (AKI) and for the ability to offer safe pharmacological treatment to neonates given that approximately 60% of all drugs are eliminated by the kidneys.Therefore, we evaluated creatinine and urea concentrations in the first 16 months of life in umbilical cord blood and venous blood samples from healthy, nonadmitted newborns to define robust reference intervals at birth stratified by gestational age (GA). Furthermore, we examined the association of maternal comorbidities with creatinine and urea concentrations in newborns. The study included 13 354 newborns with umbilical cord blood samples from the prospective population-based Copenhagen Baby Heart Study (CBHS). Among those, 444 newborns included in the COMPARE study had corresponding venous blood samples collected at birth, 363 infants had venous samples collected at age 2 months, and 156 children had venous samples collected at age 14 to 16 months.31 and were approved by the Regional Ethics Committee of the Capital Region of Denmark and the Danish Data Protection Agency. For all participants, written informed consent from legal guardians was obtained. Both studies followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.The CBHS and the COMPARE study adhered to the Declaration of Helsinki33; follow-up of some participants is ongoing. Children born between April 1, 2016, and October 31, 2018, at Copenhagen University Hospital–Rigshospitalet , Herlev Hospital, or Hvidovre Hospital were prenatally included in the study.33 Umbilical cord blood samples were collected immediately after birth in accordance with the CBHS study protocol.32 The CBHS had a high participation rate, with 55% of infants born in participating hospitals enrolled.33 Data on participant race and ethnicity were not included in the current study because analyses were primarily stratified by sex and GA; however, Vøgg et al33 reported that 78.9% of children in the CBHS had at least 1 parent with Danish citizenship, and 21.2% of mothers were of origins other than Denmark.The CBHS was a prospective multicenter population-based cohort study focusing on cardiac structure and function in 27 595 newborns and has been previously described in detail34 Follow-up was completed on February 12, 2020.Mothers enrolled in the CBHS who delivered at Rigshospitalet were also offered enrollment in the COMPARE study between May 3, 2017, and November 4, 2018. Exclusion criteria for the COMPARE study were birth at less than 37 weeks’ GA or birth at 42 weeks’ GA or greater and birth weight lower than 2500 g. In this subcohort of the CBHS, the sampling of umbilical cord blood was followed by parallel sampling of venous blood from the newborn, mother, and father from the antecubital vein approximately 2 hours after birth. The collection of venous blood samples was repeated at 2 months after birth in infants and their parents and again at age 14 to 16 months in children and their mothers.32 Creatinine and urea concentrations are reported in milligrams per deciliter . Additional information about biochemical measurements is provided in the eMethods in the Umbilical blood and venous blood samples were analyzed for biochemical markers, including creatinine and urea, using standard hospital clinical biochemistry equipment.35 with SGA defined as birth weight lower than the 2.3 percentile and equivalent to a birth weight less than 22% of the mean birth weight for a given GA. The placental-fetal weight ratio was calculated as placental weight divided by birth weight and reported as grams of placental weight per 1 gram of fetal weight.Demographic and clinical characteristics of mothers and newborns were extracted from the local obstetric and fetal medicine databases. Maternal age was recorded at delivery. Maternal body mass index  was self-reported and calculated using weight before pregnancy. Gestational age was determined from obstetric ultrasonography. Neonatal Apgar  scores were assessed at 1 minute and 5 minutes after birth using a scale of 1 to 10, with scores of 7 to 10 considered good to excellent health. Birth weight and length were measured at birth; neonates who were small for GA (SGA) at birth were identified using the formula of Marsál et al,International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. Relevant comorbidities included placental insufficiency, congenital malformation of the urinary system, and maternal preeclampsia, diabetes, hypertension, and kidney disease. Information on smoking was self-reported during a prepregnancy interview with a midwife during the first trimester. , and R Studio software, version 3.6 . Categorical variables are reported as numbers and percentages, and continuous variables are reported as medians and IQRs. Two-sided Tietz Textbook of Clinical Chemistry and Molecular Diagnostics36 for laboratories of clinical biochemistry. Thus, outliers  were removed. The 2.5 and 97.5 percentiles were defined using 4 different models: (1) no exclusions, (2) outliers removed according to the Tietz method,36 (3) individuals with exclusion criteria removed, and (4) both outliers and individuals with exclusion criteria removed. The exclusion criteria used in models 3 and 4 were defined as any record of preeclampsia, maternal diabetes, maternal kidney disease, congenital kidney deformity  in the CBHS had at least 1 parent with Danish citizenship.33 Values for some variables were missing among 1711 of 13 354 participants in the CBHS cohort. An assessment of missing values is shown in eTable 2 in the Characteristics of 12 938 children in the CBHS and 444 children in the COMPARE study, stratified by sex and GA, are shown in Among 444 children in the COMPARE subcohort, 217 (48.9%) were female, and 227 (51.1%) were male; 211 children (47.5%) were born at 37 to 39 weeks’ GA, and 233 (52.5%) were born at 40 to 42 weeks’ GA. The median maternal age in the COMPARE subcohort was 32 years , and the median maternal BMI was 23 . In both cohorts, the incidence of maternal comorbidities was low .P < .001), birth length , Apgar scores at 5 minutes , placental weight , and placental-fetal weight ratio . Children born at 37 to 39 weeks’ GA (n = 5259) vs those born at 40 to 42 weeks’ GA (n = 7679) were more frequently SGA at birth  and more likely to have placental insufficiency  and exposure to maternal preeclampsia , maternal diabetes , maternal kidney disease , and maternal hypertension .In the CBHS cohort, compared with children born at 40 to 42 weeks’ GA, those born at 37 to 39 weeks’ GA had lower birth weight  but were higher for urea . Median newborn venous concentrations at 2 hours were higher than maternal venous concentrations  and umbilical concentrations .The distributions of creatinine and urea concentrations in umbilical cord blood, maternal venous blood, and newborn venous blood at birth are shown in Pearson correlation coefficients between newborn venous blood and umbilical cord blood concentrations were 0.72  for creatinine and 0.97  for urea. Therefore, we created models describing the association between concentrations of creatinine and urea in newborn venous and umbilical cord blood.For creatinine, the equations were as follows: For urea, the equations were as follows: Changes in creatinine and urea concentrations from birth to age 2 months and birth to age 14 to 16 months are shown in P < .001) and urea . However, sex was not associated with concentrations of creatinine  or urea   are shown in Reference intervals for creatinine and urea concentrations for all 4 models are provided in eTable 7 and eTable 8 in the To examine the association of maternal comorbidity with creatinine and urea concentrations in umbilical cord blood, odds ratios (ORs) were calculated using a logistic regression analysis with cutoffs corresponding to the upper reference interval limit (0.98 mg/dL for creatinine and 14.29 mg/dL for urea) (eTable 10 and eTable 11 in the P = .005). Similar patterns were observed at age 2 months  ; however, the results were not statistically significant. Preeclampsia was found to be associated with a 3-fold increase in the risk of children’s urea concentrations higher than the 50th percentile at birth  . No associations between preeclampsia and urea concentrations were found at 2 months after birth  .Because maternal preeclampsia was the most significant exposure for high creatinine  and urea  concentrations in umbilical cord blood at birth , we alsoThe principal contribution of the present large cohort study was the generation of more robust and GA-dependent reference intervals for creatinine and urea in newborns. Furthermore, maternal preeclampsia was found to be associated with an increased risk of high newborn creatinine and urea concentrations.29 Overall, creatinine and urea concentrations in umbilical and maternal blood were similar, whereas concentrations in newborn venous blood collected approximately 2 hours after birth differed significantly from those in umbilical and maternal blood, suggesting an accumulation after umbilical cord clamping. The equations provided in this study, however, enabled estimation of newborn creatinine and urea concentrations from umbilical cord blood and may thus prevent some venipuncture procedures in newborns.In this study of umbilical and venous creatinine and urea concentrations in a large cohort of healthy term newborns with follow-up and parallel maternal venous samples, findings were consistent with previous studies reporting correlations of creatinine and urea in maternal venous blood with either fetal, umbilical cord, or newborn venous blood.37 In the present study, we were able to generate reference intervals based on healthy term infants, and we included a sufficient number of individuals to justify stratification by GA given that creatinine and urea concentrations differed significantly by GA. Stratification by GA was also supported by a recent review.25 In addition, newborns were excluded if their mothers had diagnoses that may have had implications for kidney function markers, which avoided confounding of the reference intervals by extreme values. Compared with previous studies,13 the presently generated reference intervals for creatinine concentrations at birth were based on a larger number of individuals and a more homogeneous population. A previous study,10 which included a similar number of children aged approximately 14 to 16 months and was comparable in size with our study, supported the present findings. In addition, the presently generated reference intervals categorized substantially fewer children with low or high creatinine and urea concentrations compared with existing Danish intervals and may thus provide a better basis for clinical decision-making when assessing term neonates. Furthermore, the reference intervals may help to identify children at risk of AKI. The reference intervals for urea found in the present study were narrower and applied to more well-defined age groups compared with current Danish reference intervals.Robust reference intervals are important for clinical decision-making; however, current Danish reference intervals of creatinine concentrations through the first year of life have been determined based on small groups of children (ranging from 5-95 children).40 Preeclampsia was associated with an up to 4-fold increased risk of high newborn creatinine  or urea  concentration in umbilical cord blood. This increased risk was sustained in newborn venous blood samples at birth, and a pattern was present at age 2 months, suggesting that attention should be given to kidney function in these children. This finding was supported by previous studies41 reporting pregnancy-induced hypertension to be associated with high creatinine concentrations and AKI in premature or hospitalized neonates. Because preeclampsia has been reported to be associated with high maternal creatinine concentrations,42 it is uncertain whether the risk of high newborn creatinine and urea concentrations associated with preeclampsia reflected higher maternal concentrations. Notably, we were able to adjust for maternal creatinine serum levels. The association between preeclampsia and high newborn creatinine concentrations persisted after this adjustment, suggesting that our findings could not solely be explained by maternal concentrations. More in-depth discussion is provided in the eDiscussion in the Notably, we found maternal comorbidity to be associated with the risk of high creatinine and urea concentrations in the newborn. Preeclampsia, maternal diabetes, maternal hypertension, and maternal overweight were associated with an increased risk of high creatinine and urea concentrations in the newborn, supporting previous observations on the risk of kidney disease associated with these comorbidities.33This study has several strengths, including the large prospective population-based cohort of healthy term newborns, with 13 354 umbilical cord blood samples and parallel venous blood samples collected from 444 individuals at birth and follow-up conducted among 363 children at age 2 months and 156 children at age 14 to 16 months. This large sample combined with follow-up allowed us to generate reference intervals of kidney function markers in 3 age groups during the first 16 months of life in healthy children. Other major strengths are the paired samples from both maternal venous blood and umbilical cord and newborn venous blood at birth; the extensive information on diagnoses; and the high participation rate in the CBHS, with enrollment of 55% of infants born in the participating hospitals.33 These limitations are, however, well-known issues in voluntary epidemiological studies and are, to some extent, compensated for by the high participation rate of the study. The maternal population had low BMI and a low incidence of comorbidities; however, these characteristics are representative of the entire population giving birth during the same period in the same hospitals.33 The number of newborn venous samples (n = 444) is small compared with the number of umbilical cord samples (n = 13 354); the venous samples were, however, collected from healthy newborns who did not otherwise require blood sampling. The equations for estimating newborn concentrations from umbilical blood provided in this study warrant validation in other cohorts of healthy term children. Moreover, the study mainly includes healthy term newborns; thus, it is not certain whether the results are generalizable to preterm newborns or newborns with illness. As suggested by the Tietz method,36 at least 120 individuals are recommended for creating reference intervals. This sample size was only just violated in the age 14- to 16-month group after exclusion of outliers and exclusion criteria due to less willingness to continue study participation as the children grew older. However, considerably more individuals are included in the presently generated reference intervals compared with existing intervals.The study also has limitations, including the overrepresentation of participants with higher socioeconomic status and educational level and mothers with Danish ethnicity.This cohort study generated robust reference intervals for creatinine and urea concentrations stratified by GA at birth, age 2 months, and age 14 to 16 months and described the development of creatinine and urea concentrations in the first period of life. Furthermore, the study found an association between maternal comorbidities, especially preeclampsia, and an increased risk of high newborn creatinine and urea concentrations. This association suggests that more attention should be given to kidney function in children of mothers with preeclampsia. These novel findings may improve clinical decision-making and increase understanding of the consequences of maternal comorbidities for kidney function in newborns and infants.


To determine the effect of integrated and concurrent delivery of health, nutrition, water, sanitation and hygiene (WaSH), and psychosocial care interventions during the preconception period alone, during pregnancy and early childhood, and throughout preconception, pregnancy, and early childhood on birth outcomes and linear growth at 24 months of age compared with routine care.Individually randomised factorial trial.Low and middle income neighbourhoods of Delhi, India.13 500 women were randomised to receive preconception interventions (n=6722) or routine care (n=6778). 2652 and 2269 pregnant women were randomised again to receive pregnancy and early childhood interventions or routine care. The analysis of birth outcomes included 1290 live births for the preconception, pregnancy, and early childhood interventions (group A), 1276 for the preconception intervention (group B), 1093 for the pregnancy and early childhood interventions (group C), and 1093 for the control (group D). Children aged 24 months by 30 June 2021 were included in the 24 month outcome analysis .Health, nutrition, psychosocial care and support, and WaSH interventions were delivered during preconception, pregnancy, and early childhood periods.The primary outcomes were low birth weight, small for gestational age, preterm, and mean birth weight. At 24 months, the outcomes were mean length-for-age z scores and proportion stunted. Three prespecified comparisons were made: preconception intervention groups (A+B) versus no preconception intervention groups (C+D); pregnancy and early childhood intervention groups (A+C) versus routine care during pregnancy and early childhood (B+D) and preconception, pregnancy, and early childhood interventions groups (A) versus control group (D).The proportion with low birth weight was lower in the preconception intervention groups (506/2235) than in the no preconception intervention groups . The proportion with low birth weight was lower in the pregnancy intervention groups (502/2096) than in the no pregnancy intervention groups (506/2028) but the upper limit of the confidence interval crossed null effect . There was a larger effect on proportion with low birth weight in the group that received interventions in the preconception and pregnancy periods (267/1141) compared with the control group . The proportion stunted at 24 months of age was substantially lower in the pregnancy and early childhood intervention groups (79/746) compared with the groups that did not receive these interventions , and in the group that received preconception, pregnancy, and early childhood interventions (47/453) compared with the control group . No effect on stunting at 24 months was observed in the preconception intervention groups (132/892) compared with the no preconception intervention groups (83/564).An intervention package delivered during preconception, pregnancy, and early childhood substantially reduced low birth weight and stunting at 24 months. Pregnancy and early childhood interventions alone had lower but important effects on birth outcomes and 24 month outcomes. Preconception interventions alone had an important effect on birth outcomes but not on 24 month outcomes.Clinical Trial Registry—India CTRI/2017/06/008908. Low birth weight (LBW) and stunting (length-for-age z score<−2 standard deviations) continue to be important impediments for children to survive and thrive, and for achievement of sustainable development goals.Globally, 20.5 million 14.6%) infants are born with LBW annually, with 48% in south Asia..6% infanResearch addressing LBW and stunting reduction has primarily focused on nutrition interventions. These studies found modest effects. The largest impact on birth weight of 0.1 standard deviation was seen with iron folic acid supplementation, and on stunting (15% reduction) through education and provision of complementary foods.There is growing recognition of the importance of interventions starting before pregnancy. Studies indicate that health, nutritional, and psychosocial status before conception could be linked to LBW and stunting.This study aimed to evaluate the effect of an integrated package of health, nutrition, psychosocial support, and water, sanitation and hygiene (WaSH) interventions delivered during pregnancy and early childhood periods on birth outcomes related to LBW and on linear growth at 24 months of age. We used a factorial design to examine the impact of the package when delivered only in the preconception period, and the combined effect of implementation of the package in preconception, pregnancy, and early childhood periods. The design also enabled us to examine the effect of maternal height reflecting intergenerational adversities and genetics on the efficacy of interventions to improve birth and child outcomes.The Women and Infants Integrated Interventions for Growth Study (WINGS) is an individually randomised trial with factorial design conducted in low income to lower middle income neighbourhoods of Delhi, India. The study methods have been previously published.Married women aged 18-30 years with no or one child were identified through a survey. Women living in temporary housing and those moving away were excluded. Written informed consent was obtained for participation. Enrolled women were randomised to receive preconception interventions or routine care (first randomisation). Women were followed up until pregnant or up to 18 months after enrolment. Women received ultrasonographic confirmation of pregnancy and were then randomised (second randomisation) to pregnancy and early childhood interventions or to routine care. Outcomes were measured at birth and 24 months of age.Women were randomised using permuted blocks and stratified by maternal height (<150 cm and ≥150 cm). Group allocation (1:1) was through a web based system. The two step randomisation resulted in four groups: preconception, pregnancy and early childhood interventions (A), preconception interventions only (B), pregnancy and early childhood interventions only (C), no preconception interventions, and routine pregnancy and early childhood care (D). The randomisation list was prepared by an independent statistician.We could not mask participants and teams because of the nature of the interventions. Outcomes were assessed by an independent team not involved in delivering interventions or aware of the group allocation before measurements.The interventions were in four domains: health, nutrition, psychosocial care and support, and WaSH during the preconception, pregnancy, and early childhood (0-24 months) periods . These iWomen in the control group were advised to seek care from government sources (free of cost) to access family planning services and weekly iron folic acid supplementation . The study team screened women in the intervention group for reproductive tract infections, tuberculosis, thyroid disorders, hypertension, prediabetes, diabetes, undernutrition, anaemia, and depressive symptoms and treated them according to standard protocols.Trial community workers or Sanginis (friends) visited homes weekly to reinforce interventions, replenish supplies, and help to manage health conditions. Women with moderate to severe anaemia, thyroid disorders, reproductive tract infections, or undernutrition were contacted more frequently.Women randomised to the preconception intervention and the no preconception intervention groups were contacted monthly to enquire about missed periods. Women had a transabdominal ultrasound to confirm pregnancy when two consecutive missed periods were reported.Women in the control group were advised to register for antenatal care at a government or private facility, have at least four antenatal care check-ups, consume iron folic acid, calcium, vitamin D daily throughout pregnancy, access supplementary foods through the Integrated Child Development Services (ICDS) scheme and plan to deliver in health facilities . In the intervention group, pregnant women were screened for anaemia, gestational diabetes mellitus, thyroid disorders, gestational hypertension, gestational weight gain, asymptomatic bacteriuria, reproductive tract infections, and depressive symptoms during monthly antenatal care visits. Hospital registration for childbirth was encouraged. Women were given micronutrient supplements, iron folic acid, calcium and vitamin D daily, and albendazole once during pregnancy. Weekly supplies of locally prepared snacks  were provided for daily consumption in women with body mass index <25. Milk was provided six days a week to all women and its consumption was observed. Weight of pregnant women was monitored every month and inadequate weight gain was identified according to Institute of Medicine guidelines.Women in the control group were advised to go for a postnatal health check-up, and to consume iron folic acid, calcium, vitamin D, and supplementary foods daily through the ICDS scheme . In the intervention group, trial community workers, Prernas (inspiration), enabled postnatal visits to facilities. Snacks, milk , micronutrient supplements, iron folic acid, calcium, and vitamin D were given for six months to meet additional requirements during lactation. Counselling on positive thinking and problem solving skills, screening and management of depressive symptoms, and WaSH interventions were continued. Hand washing, use of diapers, appropriate disposal of faeces, and a clean play area for the child were promoted .In the control group, mothers were advised to breastfeed their babies exclusively for the first six months, and continue breastfeeding for at least two years. They were also encouraged to arrange home visits by the community health workers in the first 42 days of life, and to collect supplementary food from ICDS and iron folic acid from 6 to 24 months .In the intervention group, newborns were home visited within 24 hours of birth or hospital discharge, five times in the first month, monthly until 12 months, and three monthly thereafter up to 24 months of age.Weights were measured during home visits and children with inadequate weight gain (<15th centile from birth to 6 months and <25th centile weight velocity/month from 6 to 24 months) were referred to lactation counsellors and paediatricians.Mothers were taught age specific child play, responsive care, and stimulation activities. Development milestones were assessed three monthly by Prernas.age z score <–2 standard deviations of the WHO child growth standards), wasted (weight-for-height z score <−2 standard deviations of the WHO child growth standards), underweight (weight-for-age z score <−2 standard deviations of the WHO child growth standards) during 6-24 months, weight and length trajectories from birth to 24 months, anaemia status at 24 months, morbidity, and hospital admission from birth to 24 months .The primary outcomes at birth were proportion LBW (birth weight <2500 g), preterm birth , SGA (birth weight centile <10th using INTERGROWTH-21st standards), and mean birth weight and length. At 24 months of age, these were mean length-for-age z scores and proportion stunted. The key secondary outcomes for women were infection, hypothyroid status, weight, anaemia status, and depressive symptoms at the end of preconception, during pregnancy, and postpartum. The key secondary outcomes for children were proportion stunted  and the ethics committee.v C+D); effect of pregnancy and early childhood interventions (groups A+C v B+D); and the combined effect of interventions from preconception until two years after birth (group A v D). We also displayed comparisons of individual groups and assessed interaction between preconception interventions and pregnancy and early childhood interventions for all primary outcomes. We used 98.3% confidence intervals of effect sizes for all primary and secondary outcomes to adjust for the three comparisons (significance level 0.05/3 or 0.017).We developed an a priori analysis approach for this factorial design, randomised controlled trial to evaluate the three study hypotheses by making three comparisons for all primary and secondary outcomes: effect of preconception interventions  and stunting (proportion stunted and mean length-for-age z score at 24 months of age). Our a priori decision was not to adjust for multiple comparisons because the primary outcomes were likely to be correlated, we were not addressing a universal null hypothesis, and formal adjustments for multiplicity are unlikely to enhance interpretation.v C+D) or pregnancy and early childhood interventions (groups A+C v B+D). We used 0.20 standard deviation mean difference for birth weight or length, length-for-age z score at 24 months, 30% relative reduction for LBW, preterm birth, SGA, and stunting at 24 months for the combined effect of preconception and pregnancy and early childhood interventions compared with the control group (group A v D). We aimed for 1100 live births (based on the outcome with the largest sample size) and 600 children at 24 months in each of the four groups. To achieve 4400 live births, we enrolled 13 500 women in the preconception period.Sample sizes were calculated for 90% power (80% for preterm birth) and 95% confidence interval for comparison between groups. We assumed at least 0.15 standard deviation mean difference for birth weight or length and length-for-age z score at 24 months, 25% relative reduction for LBW, preterm birth and SGA, and stunting at 24 months for the impact of preconception . After the interim analysis for 24 month outcomes, the DSMC recommended stopping the study based on indisputable evidence of beneficial effects using the prespecified stopping rule at P<0.001 for outcomes at 24 months.We used generalised linear models of the Poisson family with a log link function and Gaussian family with an identity link function to calculate incidence rate ratio and mean difference for binary and continuous outcomes, respectively. We also calculated absolute risk reduction with 98.3% confidence interval for primary and secondary outcomes at birth and 24 months. The final models were adjusted for place of birth, family possessing a below poverty line card, women’s height, and women’s body mass index which were potential confounders. We also adjusted the analysis for clustering due to twins. The intervention effect on secondary outcomes was assessed using the same models as for primary outcomes. We used Kernel weighted local polynomial smoothing technique to create length-for-age z score from birth to 24 months for all three comparisons. The relative measures of effect on key primary outcomes within each of the prespecified subgroup analyses were estimated and presented as forest plots. Data analysis was conducted with Stata version 16.0.We have been working in the study setting for over two decades and understand the study population well. Reduction in the proportion of LBW babies and better care during pregnancy are key priorities. We conducted formative research for a year to understand the needs and aspirations of the families, to assess their behaviour and perceptions about the interventions in different domains, and to determine the best way of delivering interventions at home. The interventions were finalised in consultation with the Study Technical Advisory Group which included representatives from the community who were familiar with the issues. We plan to organise dissemination meetings to share the findings with the community and policymakers.Of the 20 243 women screened between 1 July 2017 and 30 December 2019, 13 500 underwent first randomisation to receive preconception interventions (n=6722) or routine care (n=6778). Of the women randomised in the preconception intervention group, 2938 (43.7%) did not get pregnant during the 18 month follow-up period, 3594 reported pregnancies, and 190 were censored prematurely. Similarly, in the routine care group, 3562 (52.6%) women did not get pregnant during the follow-up period, 3098 reported pregnancy, and 118 were censored prematurely. Women with an ultrasound confirmed pregnancy—2652 (73.8%) in the preconception and 2269 (73.2%) in the routine care group—underwent a second randomisation to receive pregnancy and early childhood interventions or routine care. The number of live births was 1290 in group A (preconception and pregnancy and early childhood interventions), 1276 in group B (preconception interventions), 1093 in group C (pregnancy and early childhood interventions), and 1093 in group D (control). Children who reached 24 months of age by 30 June 2021 (DSMC decision) were included in the analysis for 24 month outcomes: 453 in group A, 439 in group B, 293 in group C, and 271 in group D .The baseline characteristics of women at both randomisations were similar except for women’s height, proportion underweight, families possessing a below poverty line card, and place of birth . The medCompliance with interventions was high. Around 90% of women were screened and received treatment for different morbidities during the preconception and pregnancy periods. Women and children consumed nutritional supplements for around 75% of the follow-up period . Around 97% of women received counselling on positive thinking and problem solving skills, and 98% of children on early child play and responsive care.At the time of the second randomisation after confirmation of pregnancy, the proportion of women with reproductive tract infections was lower , and mean haemoglobin was 0.56 g/dL higher  in the preconception intervention groups than in the groups that did not receive these interventions. The proportion of women with hypothyroidism  and body mass index <18.5  was lower in groups that received preconception interventions than in groups that did not receive preconception interventions, but the upper limit of the confidence interval crossed null effect .v B+D; At 35-37 weeks of gestation, haemoglobin concentration  was higher, and the proportion with moderate anaemia , severe anaemia , reproductive tract infection , preeclampsia or eclampsia  was lower. Gestational weight gain between enrolment and 35 weeks of gestation was 1.42 kg  higher in the pregnancy intervention groups than in the no pregnancy intervention groups  and the proportion SGA was also lower  in the preconception intervention groups (A+B) than in the groups that did not receive preconception interventions (C+D). Birth weight was higher  and birth length was also higher  in the preconception intervention than in the no preconception intervention groups. The proportion of preterm births did not differ between the groups . The proportion LBW  and proportion preterm birth  were also lower in the pregnancy intervention than in the no pregnancy intervention groups, and the mean birth weight was also lower , but the upper limit of the confidence interval crossed null effect  and the proportion SGA was also lower  in the group that received interventions during both preconception and pregnancy periods (A) than in the control group (D). Birth weight was 77.67 g higher ; birth length  and proportion of preterm births  did not differ in groups A and D .The proportion stunted at birth was lower  in the preconception intervention groups (A+B) than in the groups that did not receive preconception interventions (C+D). Head circumference  and still births  did not differ between the groups.The proportion stunted at birth was lower  and head circumference was 0.12 cm higher  in the pregnancy intervention groups (A+C) than in the groups that did not receive pregnancy interventions (B+D). Still births  did not differ between the groups .The proportion stunted at birth was lower  and head circumference was 0.18 cm higher  in the preconception and pregnancy intervention group (A) than in the control group (D). Still births  did not differ between the groups .v B+D), from 6 months of age in the groups that received preconception, pregnancy and early childhood interventions (A v D), but did not differ in the groups that received or did not receive preconception interventions  and the mean length-for-age z score  did not differ in the preconception intervention groups (A+B) and the groups that did not receive preconception interventions C+D; . The proAt 24 months of age, weight-for-length z score  and weight-for-age z score  did not differ in the preconception intervention groups (A+B) and the groups that did not receive preconception interventions (C+D). Similarly, wasting , underweight , and head circumference  did not differ between these groups .The mean weight-for-length z score was 0.33 standard deviation higher , the mean weight-for-age z score was 0.45 standard deviation higher (0.31 to 0.59), and the head circumference was 0.34 cm higher (0.15 to 0.53) in the pregnancy and early childhood intervention groups (A+C) than in the groups that did not receive these interventions (B+D). Similarly, the proportion who were wasted was lower  and the proportion underweight was lower  in groups A+C than in groups B+D .The mean weight-for-length z score was 0.40 standard deviation higher , the mean weight-for-age z score was 0.54 standard deviation higher (0.33 to 0.75), and the head circumference was 0.46 cm higher (0.19 to 0.74) in the group that received interventions during preconception, pregnancy and early childhood (A) than in the control group (D). Similarly, the proportion who were wasted was lower  and the proportion underweight was lower  in group A than in group D .We assessed the interaction between preconception interventions and pregnancy and early childhood interventions for all primary outcomes and present comparisons of individual groups . We did After post hoc adjustment for seven primary outcomes in addition to the three comparisons using the Holm-Bonferroni method, statistically significant differences remained for all measures except mean birth length in the preconception intervention groups (A+B) compared with the groups that did not receive these interventions .The subgroup analyses for primary outcomes for all prespecified comparisons did not show any significant effect modification . The intervention impact at birth and at 24 months was similar for short (<150 cm) and tall (≥150 cm) women.v B+D), and in the group that received interventions in both periods .Findings of other secondary outcomes related to the mothers and their children are shown in the supplementary appendix . One noteworthy finding was that the proportion of infants exclusively breastfed at 5 months of age was higher  in the pregnancy and early childhood intervention groups  compared with the standard of care in a network meta-analysis.Several mechanisms in the WHO framework on childhood stunting explain our findings related to LBW and stunting.While the preconception interventions were at least as important as pregnancy interventions for birth outcomes, the effect was diluted two years after birth when preconception interventions only had a marginal additional benefit to pregnancy and early childhood interventions on the outcomes at 24 months. One possible explanation could be that intensive breastfeeding counselling, provision of high quality complementary food, and early child play stimulation after birth could play critical parts in improving child growth. Delivering interventions using several home visits might also have contributed to high compliance rates. We hypothesise that a complex, multifactorial problem like stunting could only be addressed by a complex intervention addressing key health, nutrition, psychosocial care, and environment issues at the same time. This theory is shown by the larger impact of our intervention compared with that seen in studies examining simple interventions. Our results are particularly generalisable to low and middle income populations in South Asia.The strengths include a rigorous study design, large sample size, high compliance for most interventions, well standardised outcome measurements, early pregnancy ultrasound based gestation assessment, and generalisability to low and middle income urban populations.Some limitations need consideration. We could not use community mobilisation to promote interventions because of the individually randomised design. Intensity of delivery of a few interventions such as psychosocial support, management of chronic disease in women, and common illnesses in children was lower than desired. Anthropometry outcomes were assessed at day 7 (+6 days) after birth to ensure similar outcome assessment across study groups given the greater access of study teams to intervention group mothers immediately after birth. Lockdowns due to the covid-19 pandemic affected intervention delivery and delayed outcome assessment in a few instances.Additionally, the study could not be blinded because of the nature of interventions; however, study outcomes were assessed by an independent team not involved in delivering interventions or informed of the group allocation before measurements. We do not believe that the higher proportion of live births in the preconception intervention group compared with the no preconception intervention group caused any appreciable bias. It is possible that this might have attenuated the effect of preconception interventions because women in the preconception interventions group became pregnant earlier  than those in the no preconception intervention group . The desired sample size at 24 months could not be achieved because the DSMB recommended stopping the study based on strong evidence for the beneficial effects for 24 month outcomes.The feasibility of implementing this impactful but complex intervention in routine programme settings needs to be carefully considered. While most interventions provided during pregnancy and early childhood are part of several national programmes, they need to be high quality. Research on how to implement these interventions within routine systems to improve adverse growth outcomes like stunting seems necessary and should be a priority.Our findings provide evidence that preconception interventions have major benefits for reducing the burden of infants with LBW and SGA. Strengthening the existing antenatal and early childhood programmes would reduce the risk of preterm births, SGA, and stunting at 24 months. Implementation research studies are important in other low and middle income countries to assess the feasibility of delivering intervention packages effectively, identify context specific barriers, monitor quality and coverage of programmes, and improve community awareness and rollout. Integrating preconception interventions into current health systems coupled with early identification and management of pregnant women and infants who are at high risk should be a priority. These findings provide an opportunity for policymakers and managers to review and improve current programmes to improve women’s health and reduce adverse pregnancy outcomes and the burden of undernutrition in children younger than 24 months of age.Evidence suggests no clear impact of preconception interventions on low birth weight, preterm birth, and small for gestational age or stunting at 24 months of ageMost studies have tested the effect of individual interventions after identifying pregnancy up to two years after birthThese interventions covered health, nutrition, water, sanitation and hygiene, and psychosocial health, with modest effects on birth weight and linear growth at 24 months of ageThis study shows that a package of health, nutrition, psychosocial care, and water, sanitation and hygiene interventions delivered during preconception, pregnancy, and early childhood reduces the risk of low birth weight and stunting at 24 months of agePreconception interventions had an important impact on birth outcomes but not on outcomes at 24 months of agePreconception and pregnancy interventions improved several maternal outcomes—higher haemoglobin concentration and gestational weight gain, and reduced risk of reproductive tract infections, moderate to severe anaemia, and pregnancy induced hypertension


Premature infants require special care, and clinical feeding methods for this patient group are generally divided into breastfeeding and formula milk. This retrospective study investigated the effects of these two feeding methods on premature infants admitted to the neonatal intensive care unit between 2017 and 2018. Data regarding the duration of complete enteral feeding, weight gain, and postnatal infections were collected, categorized, and compared. Pearson’s correlation coefficient was used to determine the correlation between the intestinal flora and clinical outcomes. Results revealed no differences between the two feeding methods, and neither had significant effects on clinical indicators in premature infants, although the gut microbiota may be an important factor influencing many clinical indicators. Results of this study suggest an important role for the gut microbiota in the care of premature infants and provide a basis for promoting the healthy development of this patient population. Nutrition in early life is a critical factor for neonatal growth and long-term health . PrematuIn the mother’s body, in which the uterine environment is essentially sterile, the fetus is not exposed to microorganisms. During and after birth, however, they are exposed to the environment of the birth canal and surrounding microorganisms, causing the intestines to quickly colonize a wide variety of bacteria . It has Some published studies have addressed the use of BM or FM powder for premature infant nutrition fortification , 18; howData from 31 infants admitted to the neonatal intensive care unit (NICU) at Peking University Third Hospital  between September 2017 and September 2018, were collected. The present study was approved by the Human Research Protection Office. Newborn infants with a gestational age within 32 weeks or birth weight <2.0 kg were eligible for inclusion in the study; those who had congenital malformations and a survival time <7 days were excluded. Umbilical vein catheterization was performed in all premature infants who were treated with protective ventilation strategies, nutritional support, and prevention of infections based on clinical medical practice. Informed consent was obtained from the parents or legal guardians of all subjects before enrollment.In accordance with previous methods , all prePreterm infant formula for initial EN was used in cases of insufficient maternal milk. When developing to a plateau of 10–20 ml per day, premature infants were given priority to breastfeeding for successive feeding or continued formula feeding if BM was not available. According to the proportion of FM powder intake, >50% were assigned to the FM group, while the others were assigned to the BM group.Weight gain, NEC, postnatal infections, duration of NICU hospitalization, complete EN, and parenteral nutrition (PN) were defined as the major clinical outcomes. The secondary outcomes included blood biochemistry and routine blood tests. The duration of NICU hospitalization, EN, and PN were calculated from the day of birth. Weight gain was defined as the mean daily weight change during the NICU stay. Umbilical vein catheterization was performed in all preterm infants, and peripherally inserted central catheterization was performed according to the development of preterm infants, which commonly contributes to PN. The internationally revised Bell-NEC classification standard  was usedPneumonia was clinically diagnosed in the presence of respiratory distress, except for other factors , as well as significantly augmented leukocyte counts and C-reactive protein levels in the blood, accompanied by new infiltrates on chest radiographs and positive pneumonia bacterial culture .t-test or the chi-squared test and presented as the mean ± standard deviation (SD). Differences with p< 0.05 were considered to be statistically significant. Pearson’s correlation coefficient was used to determine the correlation between the intestinal flora and clinical outcomes.Data regarding major morbidities, including NEC, late-onset sepsis, and types of infections, were collected from the medical charts of each preterm infant. Categorical data were compared using a two-tailed unpaired Student’s A total of 31 infants, with a birth weight between 820 and 2,010 g  and gestational age between 25 and 32 weeks  fulfilled the inclusion criteria. Sixteen (52%) infants received BM and 15 (48%) received FM. The groups had similar baseline characteristics , with nop = 0.004). Most premature infants had a hospital stay of 14–57 days , and alanine aminotransferase (ALT), which were significantly higher in BM-fed infants than in those who were FM-fed, as shown in However, owing to the difference between premature and normal infants, the reference ranges of various indicators have not yet been determined. Therefore, nutritional indicators for premature infants should be further explored.The authors previously explored different effects of FM and BM on the development of intestinal microecology in premature infants . The resBifidobacteriaceae and Propionibacteriaceae largely explained the correlation between Actinobacteria and PLT, and Enterobacteriaceae largely contributed to the negative correlation between Proteobacteria and PLT indicators. In addition, Xanthomonadaceae in Proteobacteria exhibited a significant positive correlation with monocytes, which may represent pathogens.The relationship between the gut microbiota and blood indices at the family level was also explored. As shown in Enterococcaceae may best contribute to the blood biochemical indicators. Enterococcaceae and Peptostreptococcaceae were the main factors that caused the increase in ALT, AST, and urea levels  can be found below: ENA; The studies involving human participants were reviewed and approved by the Peking University Third Hospital Medical Science Research Ethics Committee. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.HC: conceptualization. CC and ML: data curation. ML, CC, and SK: formal analysis. HC, J-IK, and JJ: funding acquisition. ML, CC, and HC: writing–review and editing. All authors contributed to the article and approved the submitted version.


Dietary diversity scores can be used as a proxy for dietary intakes and for assessment of nutrient adequacy. Studies from low-resource settings have found maternal dietary diversity scores to be associated with neonatal birth size. We here investigated the relationship between the dietary diversity score among pregnant mothers and birth size of their offspring across quantiles of the birth size variables; birth weight, length, abdominal circumference, and head circumference. We also investigated if seasonality affects birth size across different quantiles.Dietary intake and anthropometric data were collected from 190 pregnant women and their neonates in rural Malawi through two agricultural seasons. Dietary data was collected using 24-hour recall interviews and was categorized into the 10-food group dietary diversity score proposed for women by the Food and Agriculture Organization. Neonatal anthropometrics were collected upon delivery at health facilities. Quantile regression analyses were used to investigate associations between dietary diversity scores and birth size, as well as between seasonality and birth size.We found that neonatal abdominal circumference was 0.9 cm larger during the post-harvest season compared to the pre-harvest season among neonates in the 25th quantile. Birth weight was 281.4 g higher for those born during the post-harvest season in the 90th quantile. For a one-unit increase in maternal dietary diversity score, birth weight increased by 56.7 g among those in the 25th quantile and neonatal head circumference increased by 0.2 cm for those in the 70th quantile. However, these findings did not remain significant when considering the cluster effect of the neonatal anthropometric data.Our findings indicate that the relationship between seasonality and birth size differs across the distribution of birth size. Investigating the effect of seasonality across the distribution of birth size could be important to identify vulnerable subgroups and develop better, targeted interventions to improve maternal and child nutrition and health.The online version contains supplementary material available at 10.1186/s12884-022-04924-4. Dietary diversity score (DDS), which is the count of food groups consumed over a defined time period, can be used as a simple tool for measuring diet adequacy . The minPrevious studies have usually analyzed associations between DDS and birth outcomes assuming a constant linear relationship between DDS and birth outcomes, and thus only the average effect of DDS on birth outcomes has been examined. However, when conducting interventions to improve diet and birth outcomes it is important to know the full extent of the relationship between the studied variables. Thus more informatively, one can investigate whether the relationships between DDS and the birth size variables change across the entire distribution of the birth size variables . This coIn farming communities in low-income countries, the seasonal changes in food availability and access, such as those caused by agricultural production cycles and variation in household income, may affect the adequacy of maternal dietary intake . SeasonaUsing the standard DDS with ten food groups suggested by FAO, as a proxy for maternal dietary intake, we here aimed to investigate the effect of maternal DDS on the distributions of birth weight, length, abdominal circumference and head circumference. Moreover, the association between MDD-W (a dichotomous variable) and the same four indicators for birth size was determined. We also wanted to examine whether there is a seasonal effect on birth size in the Malawian setting, and whether it differs across the distribution of birth size.A cross-sectional study was conducted in the Nankumba Traditional Authority (TA) of Mangochi District. This is a rural area with a population of about 150,000 at the time of the study. The most common occupations are subsistence farming and fishing. There is only one rainy season occurring from November to May , 11. ThePregnant women were selected into the survey using a one-stage randomized sampling procedure. Initially, 76 clusters, defined by geographic areas (villages) were randomly selected. Only women between 28 and 35 weeks of gestation were recruited because we wanted to study participants in their last trimester, but who would not give birth before the 10-days required for data collection. Gestational age was derived from last menstruation cycle or through assessment of fundal length. Women who were bedridden due to illness or had not been residents in the study area for the previous 6 months, were excluded. From each cluster, 4–6 participants were recruited. To avoid selection bias in the recruitment, all potential participants in the geographical cluster were identified by local health volunteers or health surveillance assistants. In most cases, all the eligible pregnant women within a cluster were invited to participate.Results from this paper are part of a cross-sectional pre-study study aiming to inform a planned food-based intervention trial to improve maternal diet and birth size in the study area. The sample size was calculated to detect the prevalence of iron deficiency of 26% to within ±10%, with a power of 80%, at a 95% confidence level, assuming a design effect of 1.5 and a 35% rate of attrition. A design effect of 1.5 was added to account for similarities between participants recruited from the same geographic clusters . The calTo sensitize the local community to the project, chiefs from all villages of the Nankumba TA were invited to an information meeting held by the study coordinator. Soap was given as incentives after each interview, and participants received a bag of sugar after the last interview. Money to cover transportation to the health clinic was also provided.Dietary data were collected from pregnant women between August and September 2013, when food availability was sufficient for most households, and between February and March 2014, when food was limited. Some participants gave birth in another agricultural season than the dietary interview took place. Participants were classified according to post-harvest (food plenty) and pre-harvest season (food poor) dependent on the season in which they gave birth to assess seasonality of birth outcomes. Infant weight, length, head circumference and abdominal circumference were measured at birth. All data were collected by trained Malawian interviewers with a university degree in nutrition or agriculture who were fluent in both English and the local language Chichewa.During a 10-day period, we collected multiple quantified and semi-quantified dietary recall data from the participants in their own homes in order to encourage participation and improve recall of the foods consumed . More coDDS is defined as the number food groups consumed over a reference period and used as a qualitative proxy for an individual’s dietary adequacy . The fooA pre-coded questionnaire developed and used in rural Malawi, was administered at the first visit to collect socio-demographic data on both participant and household level, such as age, education (i.e. completed at least primary school), occupation, number of children, number of people in the household, and food security. As a proxy for household economic status a household asset index was calculated based on 11 household items given scores according to their monetary value .Anthropometric measurements of the newborn infants were collected at health facilities by trained nurses within one hour after birth. Birth weight (nude) was measured to the nearest gram using Seca 376 digital pediatric scales . Length was measured to the nearest 0.1 cm using Seca 233 infantometer. Both head and abdominal circumference were measured to the nearest 0.1 cm using Seca 212 non-stretchable measuring tape. All neonatal anthropometric measurements were collected according to the International Fetal and Newborn Growth Standards for the twenty-first Century and World Health Organization standard procedures , 21.We applied independent t-test and test of proportions (chi-square test of association) to compare background characteristics between participants with and without neonatal data, and to compare background characteristics between participants in the two seasons. Mean birth weight, length, head circumference and abdominal circumference are presented for each season, and differences between seasons were compared using independent t tests. To visualize distributions of birth outcomes by birth seasons, Kernel density curves were made using kdensity syntax in Stata. Barnard’s exact test was applied to compare proportions of low birth weight between the two seasons.P < 0.05.Quantile regression, as introduced by Koenker and Basset , was useIn total 362 participants were invited to participate Fig. . Of thesn = 8) in the post-harvest season, whereas none of the infants in the pre-harvest season were born with low birth weight (P > 0.05).The distributions of birth size by birth seasons are shown as Kernel density curves Fig. . There wWe found that DDS was positively associated with birth weight in the 25th quantile, when adjusted for covariates Table : A one-uIn a rural Malawian setting, we investigated the effects of seasonality on birth size , and the potential associations between DDS and the same four indicators of birth size using quantile regression.In adjusted analyses, we found that babies in the 90th quantile who were born during the post-harvest season were 281 g heavier than those born during the pre-harvest season. Our results support previous findings, e.g. from the Pune Maternal Nutrition Study where babies exposed to the season with greatest food availability in late gestation were heavier than those exposed to food lean season in late gestation . We founThe national prevalence of low birth weight in Malawi around the time of our study was 12% . We founExamining associations between dietary diversity and birth size is important when developing nutrition education interventions, as dietary advice is given on food level, and not on single nutrients. Few studies have examined DDS in association with other birth outcomes than birth weight. Moreover, to our knowledge, quantile regression has not been applied when investigating the relationship between DDS and birth outcomes among rural pregnant women. We did not find any associations between DDS and birth outcomes when adjusting for covariates, including the geographical clustering effect of neonatal anthropometry, nor between MDD-W as a dichotomous variable and birth outcomes. Several studies have found that dietary diversity is positively associated with birth weight and with reduced risk of low birth weight , 24, 25.A major methodological strength of this study is the use of quantile regression, which enables a more comprehensive picture of the relationship between the independent and dependent variables. Whereas the ordinary least square method only provides the average effect of the independent variable on the dependent variable, quantile regression allows for the differential effect across the distribution of the dependent variables . This coThere are some limitations to this study. Around the time of the study, the proportion of Malawian women giving birth at health facilities was around 73%, although lower in rural than in urban areas . To ensuIn conclusion, we found abdominal circumference and birth weight to be associated with seasonality in adjusted models. Our findings indicate a differential effect of seasonality across the distribution of birth size. We did not detect any statistically significant associations between DDS and birth size in the fully adjusted models. Larger studies should be conducted to investigate the effect of season and DDS on quantiles of birth size, as this method could help identify vulnerable subgroups and better target dietary interventions to improve birth outcomes.Additional file 1: Table S1. Association between birth seasons (pre-harvest vs post-harvest) and birth size.