Despite the reduction of neonatal morbidity and mortality, is one of the third Sustainable Development Goal to end the death of children, the burden of the problem still the major challenge in Ethiopia. Globally, the most common causes of neonatal morbidity and mortality are adverse fetal outcomes . Therefore this systematic review and meta-analysis aimed to estimate the pooled prevalence of adverse fetal outcomes and its associated factors in Ethiopia.2 statistic was computed to check the heterogeneity of studies. Subgroup analysis was performed for the evidence of heterogeneity.International databases  were searched. Seventeen articles were included, among these, fourteen were cross-sectional and three of them were case-control studies. Publication bias was employed using a funnel plot and eggers test. The IA total of 11,280 study participants were used to estimate the pooled prevalence of adverse fetal outcomes. The overall pooled prevalence of adverse fetal outcomes in Ethiopia was 26.88% . Low birth weight 10.06%  and prematurity 8.76%  were the most common adverse birth outcome at the national level. Rural in residency , lack of antenatal care follow up , pregnancy-induced hypertension , advanced maternal age ≥ 35 were the factors associated with adverse birth outcome.The pooled prevalence of adverse fetal outcomes in Ethiopia was high. Rural in residency, lack of antenatal care follow up, pregnancy-induced hypertension, advanced maternal age ≥ 35, and having current complications of pregnancy were the factors associated with adverse fetal outcomes.CRD42020149163. Adverse fetal outcome is the major challenge both in low and middle-income countries. Globally, adverse birth outcomes such as preterm birth, low birth weight, stillbirth, and congenital defect are some of the common problems. Neonatal morbidities and mortalities are one of the most common contributing factors for 11.8 million deaths. Even though neonatal mortality is declined globally, highest in sub-Saharan Africa and South Asia, with each estimated at 27 deaths per 1000 live births in 2017 , Pakistan [56.9%] and Guatemala [19.9%] , 39. ThiThis review was estimated the overall prevalence of preterm (prematurity) among adverse fetal outcomes in Ethiopia. Hence, the overall pooled prevalence of preterm was 8.76% (5.4–12.11). This study finding is in line with the study done in Asia [10.4%], North America [11.2%], Sub-Saharan Africa [12%], Nigeria [11.4%], South Korea [7.1%], Nebraska [5.54%] and Indonesia [10.4%] –42. ThisThis review was estimated the overall prevalence of congenital defects among adverse fetal outcomes in Ethiopia. Hence, the overall pooled prevalence of congenital defects was 2.55% (2.41–3.69). This review finding is lower than the study done in sub-Saharan Africa [20%], and Nigeria [6.3%] , 44. TheThis review was estimated the overall prevalence of low birth weight among adverse birth outcomes in Ethiopia. Hence, the overall pooled prevalence of low birth weight was 10.06% (7.21–12.91). This study finding is in line with the study done in Indonesia [12.9%], Armenia  and lower than the study done in Kenya [12.3%], Tanzania (13.9%), South Africa [38.54%] –48. Low The odds of having advanced maternal age ≥ 35 years nearly three times to have adverse fetal outcomes. This finding is in line with the study done in Cameroon , low incThe odds of having pregnancy-induced hypertension were nearly three times to have adverse birth outcomes. This finding is in line with the study done in Cameroon , Kenya , India , NigeriaPregnancy complication is one of the associated risk factors in this meta-analysis. Having pregnancy complications was almost five times more likely to develop adverse fetal outcomes. This study finding is in line with the study done in Bangladesh . Brazil Lack of antenatal care follow up is the associated risk factor for adverse fetal outcomes in this meta-analysis. Having no ANC follow up was four times more likely to develop adverse birth outcomes. This study finding is in line with the study done in Tanzania , and Gamp value = 0.522) of the polled estimated prevalence of adverse fetal outcomes.The odds of living in rural were two times more likely to develop adverse fetal outcomes. This study finding is in line with the study done in China , and BraIncluding papers only published by the English language and accessing only hospital-based studies was the restraint of the study. It might lack national representativeness because no data were from all regions.In this study, the overall pooled prevalence of adverse fetal outcomes in Ethiopia was high. Rural in residency, lack of antenatal care follow up, pregnancy-induced hypertension, advanced maternal age ≥ 35, and having a current complication of pregnancy were the factors associated with adverse fetal outcomes. Therefore, based on the study findings, the authors recommend particular emphasis shall be given to have regular antenatal care follow up, health education, early detection, and intervention of obstetric complications. Creating awareness of women on the effect of pregnancy at an advanced age, and providing timely and focused antenatal care (ANC) follow up to all pregnant women are very crucial to reduce the magnitude of the problem.


While there is increasing evidence on the safety of artemisinin-based combination therapy (ACT) for the case management of malaria in early pregnancy, little is known about the association between exposure to ACT during the first trimester and the effect on fetal growth.Data were analysed from prospective studies of pregnant women enrolled in Mozambique, Burkina Faso and Kenya designed to determine the association between anti-malarial drug exposure in the first trimester and pregnancy outcomes, including low birth weight (LBW) and small for gestational age (SGA). Exposure to anti-malarial drugs was ascertained retrospectively by record linkage using a combination of data collected from antenatal and adult outpatient clinic registries, prescription records and self-reported medication usage by the women. Site-level data synthesis (fixed effects and random effects) was conducted as well as individual-level analysis (fixed effects by site).Overall, 1915 newborns were included with 92 and 26 exposed to ACT (artemether–lumefantrine) and quinine, respectively. In Burkina Faso, Mozambique and Kenya at recruitment, the mean age (standard deviation) was 27.1 (6.6), 24.2 (6.2) and 25.7 (6.5) years, and the mean gestational age was 24.0 (6.2), 21.2 (5.7) and 17.9 (10.2) weeks, respectively. The LBW prevalence among newborns born to women exposed to ACT and quinine (QNN) during the first trimester was 10/92 (10.9%) and 7/26 (26.9%), respectively, compared to 9.5% (171/1797) among women unexposed to any anti-malarials during pregnancy. Compared to those unexposed to anti-malarials, ACT and QNN exposed women had the pooled LBW prevalence ratio (PR) of 1.13  0.62–2.05, p-value 0.700) and 2.03 , respectively. Compared to those unexposed to anti-malarials ACT and QNN-exposed women had the pooled SGA PR of 0.85  and 1.41 , respectively. Whereas compared to ACT-exposed, the QNN-exposed had a PR of 2.14  for LBW and 8.60  for SGA. The level of between sites heterogeneity was moderate to high.ACT exposure during the first trimester was not associated with an increased occurrence of LBW or SGA. However, the data suggest a higher prevalence of LBW and SGA for children born to QNN-exposed pregnancies. The findings support the use of ACT (artemether–lumefantrine) for the treatment of uncomplicated malaria during the first trimester of pregnancy. Malaria in pregnancy is an important public health problem in malaria-endemic countries where pregnant women and their offspring have a higher risk of infection and sequelae. Malaria infection during pregnancy is associated with maternal anaemia and intra-uterine growth restriction (IUGR), leading to poor pregnancy outcomes such as low birth weight (LBW) and small for gestational age (SGA) , 2. LBW P. falciparum malaria in pregnant women in their second or third trimester. ACT is presently only recommended by WHO in the first trimester if quinine cannot be used or in case of severe malaria where the benefit outweighs the potential risk. Quinine is recommended for uncomplicated malaria in the first trimester of pregnancy [Cohort studies in malaria-endemic areas show an association between malaria infection at an earlier gestational age, i.e., in the first trimester, and adverse fetal growth, pregnancy outcome, duration of pregnancy, and placental weight at term , 11. Walregnancy . Howeverregnancy , 14.Findings from preclinical studies have reported that artemisinins are embryotoxic and teratogenic in multiple animal species –18. In sP. falciparum is the main species. All three ASAP sites have a health and demographic surveillance system (HDSS) [ASAP was a prospective cohort study of pregnant women, conducted under a single multi-centre study protocol at three SSA sites as part of Malaria in Pregnancy Consortium activities as previously published . The sitm (HDSS) –28. WithPregnant women were identified through household visits, community key informants, and at antenatal care visits in a health facility within the HDSS catchment area. All identified pregnant women were invited to the antenatal care (ANC) clinics and assessed for eligibility. Following written consent, baseline information was collected and data entered into a pregnancy register. Electronic records from outpatient and inpatient visits were recorded through the HDSS platform and linked to the study records to identify possible exposure to ACT and other anti-malarials during the first trimester of the pregnancy. For this analysis, only singleton newborns with birth weight collected within the first 7 days of life are included. Multiple methods were used for the ascertainment of gestational age, including date of last menstrual period, fundal height, ultrasound, and Ballard Score as explained elsewhere . Women wThe ascertainment of drug exposure included both prospective and retrospective self-reported medication usage and linkage to treatment records at local health facilities of drug prescribing and dispensing. The process of drug identification, self-reporting and record linkage with health facility data has been described elsewhere . Two or The present analysis is restricted to birth weight, LBW and SGA among live births. LBW was defined as a birth weight of < 2500 g collected within the first 24 h of life . Birth w2 statistic was used [Baseline characteristics were compared by site and by anti-malarial exposure to assess imbalances across sites and exposure groups. Frequencies were used for categorical variables and for numeric variables means and standard deviations. The prevalence of LBW and of SGA and the mean birth weight by exposure group in each site were computed. As measure of association, the mean difference (MD) was used for birth weight outcome and prevalence ratios (PR) for the prevalence of LBW and SGA. Two types of data synthesis of effect were performed. One is the site-level aggregated through the use of both fixed effects and random effects meta-analysis. Inverse variance based weights were used and for zero events study, 0.5 continuity correction was employed. To assess the heterogeneity between sites the Iwas used .The other data synthesis is based on patient-level data whereby linear (for MD) and log-binomial (for PR) regressions were used. All models included the site indicator as covariates. The age at recruitment, gravidity, marital status, and education level were included in the adjusted analysis. The log-binomial regressions had convergence failure and data spasticity issues. Thus, a Bayesian implementation of the log-binomial with posterior distributions approximated through Markov Chain Monte Carlo (MCMC) was performed in JAGS software –39. UninThe protocol was reviewed and approved by the Ethical Review Boards of the Kenya Medical Research Institute (KEMRI), US Centers for Disease Control and Prevention (CDC), National Bioethics Committee in Mozambique, Centre Muraz Institutional Ethics committee and National Ethics committee in Burkina Faso, Liverpool School of Tropical Medicine in the UK, and the Institutional Review Board of the University of Washington.A total of 2836 recruited women representing 2930 pregnancy outcomes and 1915 live births were included in the analysis .Newborns at Burkina Faso’s site had on average a weight of 2875.9 g, compared to Mozambique’s and Kenya’s site with 3093.3 g and 3175.2 g, respectively. Figure Table 2 below 15%.The prevalence of LBW was 15.9% (104/656), 6.1% (41/669) and 7.2% 43/590) in Burkina Faso, Mozambique and Kenya, respectively. Figure /590 in BTable The prevalence of SGA was 19.1% 124/648), 5.0% (33/659) and 19.6% (114/581), respectively in Burkina Faso, Mozambique and Kenya. Figure /648, 5.0Table The prevalence of prematurity was 6.6% 43/656), 9.8% (65/665) and 3.2% 19/590) respectively in Burkina Faso, Mozambique and Kenya. Figure 6, 9.8%  for 7 days , 44, creThere was no evidence of an increased prevalence of SGA with exposure to ACT. This finding is consistent with Manyando et al. who reported a similar prevalence of SGA among newborns exposed to ACT compared to exposed to sulfadoxine–pyrimethamine (9.0 vs 7.7%) in a cohort in Zambia and using a more restrictive definition of SGA . Also, there was no evidence of an increased prevalence of pre-term with exposure to ACT. However, quinine is possibly associated with a higher prevalence of SGA compared to those unexposed to anti-malarials or ACT in the first trimester of gestation. Previous literature comparing these risks is limited; this is the first study to investigate this association using the recently available world reference growth curves during gestation , 33.Although malaria in pregnancy is common in SSA, it can be easily confused with many other febrile diseases that may occur during pregnancy. It has been shown in Mozambique that only 27% of pregnant women presenting with fever had parasitaemia detected . MoreoveP. falciparum infection was reported among pregnant women from the Thailand Myanmar border [The prevalence of SGA found in this study varied between 5.0% among infants born in Mozambique and 19.6% among infants born in Kenya. These estimates are consistent with recent estimates of SGA based on 22 birth cohort studies from the SGA-Preterm Birth working group . Howeverr border . In thisr border , 51. HowThis study included only pregnancies ending as singleton live birth and with birth weight collected within 7 days of life in the analysis. This could lead to some bias because SGA is associated with a lower probability of survival. Thus, the inclusion in the data analysis is conditioning on the outcome. However, it is not expected to be an important source of bias because the neonatal mortality rate in these sites is small (fewer than 30 per 1000 live-births). Compared to other study sites, Asembo (Kenya) had a higher proportion of missing information of weight at birth variable, representing 12% of all pregnancies recruited (Fig. Regarding birth weight, some newborns who were delivered in home settings had their weight assessed post-24 h of birth. If such non-differential misclassification occurred, it would have biased the estimates toward the null . NeverthP. falciparum malaria during the first trimester of pregnancy. The existence of the HDSS platform greatly facilitated active safety surveillance of anti-malarials used during pregnancy.No evidence was found of an increased risk of LBW, SGA or prematurity among infants born to women with confirmed first-trimester exposure to an ACT. The findings add support for the use of ACT for uncomplicated Additional file 1. Additional Figures S1–S3, Tables S1–S16.


A 2 × 2 repeated-measures ANOVA analyzed best potentiated performance. Partial correlations controlling for sex calculated relationships between the 1RM BHT and 505 COD speed test percent potentiation. There was a significant main effect for time (p < 0.001), but not for condition (p = 0.271) or condition × time (p = 0.295). There were no significant correlations between 1RM BHT and potentiation. The 85% 1RM BHT did potentiate the 505 4–16 min post-CA but no more than the CC. Nonetheless, a heavy BHT could be programmed prior to COD drills as COD speed could be potentiated and performance improved in men and women.This study investigated whether the barbell hip thrust (BHT) enhanced change-of-direction (COD) speed measured by the 505 COD speed test. Forty recreationally trained individuals completed three sessions. Session 1 included one-repetition maximum (1RM) BHT testing to measure absolute and relative strength. Sessions 2 and 3 involved two counter-balanced conditioning activities (CAs): 3 sets × 5 repetitions of the BHT at 85% 1RM and a control condition . The 505 COD speed test was performed 5 and 2.5 min pre-CA, and 4, 8, 12, and 16 min post-CA in each session. A 2 × 5 repeated-measures ANOVA ( Agility is an essential quality of many athletes and has been defined as an action that features an initiation of body movement, change-of-direction (COD), or rapid acceleration or deceleration in response to a stimulus . In addiPAPE is where a muscle’s contractile history contributes to enhanced power-based actions . SpecifiThe overload provided by the CA, in addition to the biomechanical specificity between the CA and power-based exercise, is an important factor in determining whether PAPE occurs ,12. For Training history can also influence whether an individual experiences PAPE ,18,19,20Therefore, the purpose of this research was to determine whether 3 sets of 5 repetitions at 85% 1RM of the BHT could potentiate COD speed measured by the 505 COD speed test in college-aged men and women. It was hypothesized that the BHT would lead to a faster 505 performance compared to a control condition (CC) of 6 min rest. Lastly, it was hypothesized that there would be significant relationships between absolute and relative BHT load and percent potentiation in the 505 COD speed test ,18.A convenience sample of 40 subjects  were recruited for this study, including 20 males  and 20 females . Similar to Orjalo et al. , G*PowerTesting was conducted over three days with 48–72 h separating each session. Each subject completed the testing sessions at the same time of day, dependent upon their availability ,22,24,25During session one, the subject’s age, height, and body mass were taken. A stadiometer  was used to measure height, while electronic scales  were used to measure the body mass of each subject. All subjects completed the same warm-up, which consisted of 5 min of jogging at a self-selected pace on a treadmill, followed by 10 min of dynamic stretching. Following this, subjects performed two trials of the 505 COD test to familiarize themselves for the next two sessions . Once the 505 COD performances were completed, they performed the 1RM BHT test in an indoor weight room. During sessions 2 and 3, the subjects completed the same standardized dynamic warm-up as previously outlined, then at 5 and 2.5 min prior to the CA performed two trials of the 505 COD test (one per leg). The order of the trials was determined by the subject’s dominant leg  . The tesDuring session one, subjects performed a 1RM BHT to measure absolute and relative strength, and to determine the weight that was used for the 85% 1RM PAPE condition. To perform the BHT, subjects were instructed to start by sitting on the ground with their legs flat on the floor, feet shoulder-width apart, and their upper back against a padded exercise bench. A standard Olympic barbell and weight plates , with a pad positioned on the bar for comfort , was plaThe procedures for finding the 1RM BHT were as follows. After the standard dynamic warm-up, the BHT warm-up sets completed by the subject consisted of 3 sets × 8 repetitions at 30%, 40%, and 50% of the subject’s perceived 1RM, with 2 min of rest provided between sets . Once thThe 505 COD speed test incorporates two 5 m sprints separated by a 180° turn . The proAs stated, following the dynamic warm-up, subjects performed two trials of the 505 COD speed test at 5 and 2.5 min prior to the CA with the mean of all CAs calculated to provide baseline data ,27,28,29The following equation was utilized to calculate Post-CA COD performance percentage change: % Potentiation = Potentiated Variable  ÷ Unpotentiated Variable (average baseline) × 100. To interpret the Post-CA performance percentage change; a value less than 100 indicated a faster 505 COD speed performance ; a value greater than 100 indicated a slower 505 COD speed performance ; and a value equal to 100 indicated no change in 505 COD speed performance  ,22,24,25F ratio was detected in any ANOVA calculations, post hoc pairwise tests were conducted using the Bonferroni adjustment procedure for multiple comparisons. The individual results of all participants were also described to allow for a more detailed examination of the effects of PAPE via the BHT upon COD speed, which may provide pertinent information to the strength and conditioning practitioner not possible via grouped analysis. All analyses were determined via the Statistics Package for Social Sciences . Descriptive statistics (mean ± standard deviation (SD)) were calculated for all subjects. Q–Q plot analysis was utilized to determine the normality of the data ,41,42. Ir between 0 to ±0.3 was small; ±0.31 to ±0.49, moderate; ±0.5 to ±0.69, large; ±0.7 to ±0.89, very large; and ±0.9 to ±1, near perfect, for relationship prediction [p < 0.05.To investigate relationships between absolute and relative strength measured by the 1RM BHT with percent 505 potentiation, partial correlations were used. Due to the established differences between women and men with regard to strength, power, and speed tests, partial correlations controlling for sex were utilized ,47,48. Sediction . For all1,39 = 3.402, p = 0.073, partial η2 = 0.183) or condition × time . There was a significant main effect for time . Post hoc analyses indicated that the pooled 505 data at 4 min (p = 0.005), 8 min (p = 0.014), 12 min (p = 0.005), and 16 min (p = 0.001) were all significantly faster than at baseline. Regarding the best potentiated 505 time, there was again no significant main effect for condition  or condition × time . There was a significant main effect for time , with the best potentiated 505 time significantly (p < 0.001) faster than the baseline. The individual results of each subject across each condition and time point are presented in The Q–Q plot analysis determined that all assessed variables were normally distributed. All assessed variables demonstrated acceptable levels of reliability (ICC ≥ 0.70 and CV < 10%). −1 . The mean 1RM BHT (absolute strength) for the subjects in this study was 156.26 ± 64.17 kg . Accordingly, the mean relative strength measure equaled 1.44 ± 0.24 kg·BMThe purpose of this study was to determine whether 3 sets × 5 repetitions of BHT with 85% 1RM could potentiate COD performance as measured by the 505 COD speed test in college-aged men and women. Previous research has shown the benefit of this exercise and load for enhancing linear sprint performance ,18. The Previous research has shown that 3 sets × 5 repetitions of BHT with 85% 1RM can enhance sprinting speed over 15 m in male handball players  and overWhat is notable is that even if 3 sets × 5 repetitions of BHT with 85% 1RM was not significantly different from the CC, it did lead to a faster 505 COD test performance at multiple time points. Especially in college-aged athletes, training time and exposure can be limited . This puPrevious research has suggested that stronger individuals could experience greater PAPE ,17,18,20There are several limitations to this study that should be acknowledged. As noted, the subject population were recreational athletes. Higher-level athletes may respond differently to a CA , and theThe current study revealed that 3 sets × 5 repetitions of BHT with 85% 1RM was able to enhance COD speed as measured by the 505 COD speed test in college-aged, recreationally trained men and women. This occurred at multiple time points from 4 to 16 min post-CA, but the changes in 505 time were not different from a those due to a CC of 6 min rest. Additionally, there were no significant relationships between absolute and relative lower-body strength measured by the 1RM BHT with 505 percent potentiation. Although the data may have been influenced by the training history of the participants, there are useful implications that can be drawn from this analysis of college-aged men and women. To improve training efficiency in college-aged men and women, strength exercises could be positioned before COD drills that feature actions such as those in the 505 COD test. COD speed could also be potentiated as long as the recovery time is appropriate.


Are specific phenotypes in preterm newborns associated with clinical, growth, and neurodevelopmental differences at age 2 years compared with term newborns?In this cohort study of 6529 preterm and term newborns who were followed up from birth to age 2 years, 8 preterm-birth phenotypes were identified: no main maternal, fetal, or placental condition detected (35%); infections (21%); preeclampsia (12%); fetal distress (10%); intrauterine growth restriction (8%); severe maternal disease (6%); bleeding (5%); and congenital anomaly (4%). Each phenotype was associated with substantial differences in neonatal morbidity and infant outcomes.The study’s findings support the use of phenotypic classification for preterm births. The etiologic complexities of preterm birth remain inadequately understood, which may impede the development of better preventative and treatment measures.To examine the association between specific preterm-birth phenotypes and clinical, growth, and neurodevelopmental differences among preterm newborns compared with term newborns up to age 2 years.The INTERBIO-21st study included a cohort of preterm and term newborn singletons enrolled between March 2012 and June 2018 from maternity hospitals in 6 countries worldwide who were followed up from birth to age 2 years. All pregnancies were dated by ultrasonography. Data were analyzed from November 2019 to October 2020.Preterm-birth phenotypes.Infant size, health, nutrition, and World Health Organization motor development milestones assessed at ages 1 and 2 years; neurodevelopment evaluated at age 2 years using the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) tool.A total of 6529 infants (3312 boys [50.7%]) were included in the analysis. Of those, 1381 were preterm births . Among 1381 preterm newborns, 8 phenotypes were identified: no main maternal, fetal, or placental condition detected (485 infants [35.1%]); infections (289 infants [20.9%]); preeclampsia (162 infants [11.7%]); fetal distress (131 infants [9.5%]); intrauterine growth restriction (110 infants [8.0%]); severe maternal disease (85 infants [6.2%]); bleeding (71 infants [5.1%]); and congenital anomaly (48 infants [3.5%]). For all phenotypes, a previous preterm birth was a risk factor for recurrence. Each phenotype displayed differences in neonatal morbidity and infant outcomes. For example, infants with the no main condition detected phenotype had low neonatal morbidity but increased morbidity and hospitalization incidence at age 1 year . Compared with term newborns, the highest risk of scoring lower than the 10th centile of INTER-NDA normative values was observed in the fine motor development domain among newborns with the fetal distress  phenotype.Results of this study suggest that phenotypic classification may provide a better understanding of the etiologic factors and mechanisms associated with preterm birth than continuing to consider it an exclusively time-based entity. This cohort study, part of the INTERBIO-21st Newborn Study, an extension of the INTERGROWTH-21st Project, examines the association between preterm-birth phenotypes and clinical, growth, and neurodevelopmental differences among preterm newborns compared with term newborns up to age 2 years. The present INTERBIO-21st Newborn Study6 comprised phase 2 of the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Project, a population-based research initiative involving almost 70 000 mothers and infants worldwide that was conducted from 2008 to 2015. In this study, we investigated whether preterm-birth phenotypes were associated with clinical, epidemiological, growth, and neurodevelopmental differences among preterm and term infants up to age 2 years.Preterm birth is a heterogeneous syndrome, which has been previously described in terms of 3 factors: spontaneous or medically induced labor, presence or absence of preterm premature rupture of membranes, and mode of delivery.STROBE) reporting guideline for cohort studies.The INTERBIO-21st Newborn Study included a cohort of preterm and term newborns who were enrolled from March 2012 to June 2018 and followed up from birth to age 2 years. The study was approved by the Oxfordshire Research Ethics Committee C, institutional research ethics committees at participating sites, and corresponding regional authorities. All mothers provided written informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  or head circumference at less than 24 weeks 0 days’ gestation (25% of newborns) using INTERGROWTH-21st standards.9 Given the design of the INTERBIO-21st study, we selected a higher proportion of newborns with lower birth weight .In brief, the study enrolled preterm newborns who were live born at 23 weeks 0 days’ to 36 weeks 6 days’ gestation and term newborns who were live born at 37 weeks 0 days’ to 41 weeks 6 days’ gestation.6 with software oversampling at lower gestational ages to increase statistical power for studying the highest-risk subgroups by producing a higher proportion of exposures and adverse neonatal outcomes. To correct for the oversampling of newborns who were small for gestational age (defined as birth weight <10th centile based on INTERGROWTH-21st standards) in the present analysis, we generated a term newborn group consisting of term infants who were appropriately grown for gestational age (defined as birth weight ≥10th centile based on INTERGROWTH-21st standards); approximately 10% of the term newborn group included randomly selected term infants who were small for gestational age to reflect the incidence of newborns who are small for gestational age in the general population.Deliveries were screened daily using a tablet computer ,10 which produced the WHO Child Growth Standards.11 In brief, newborn measures were obtained within 12 hours of birth (and no later than 24 hours after birth) using identical equipment at all sites. An electronic scale  was used to measure birth weight, and an infantometer  was used to measure recumbent length.10 Head circumference was measured using metallic nonextendable tape (Chasmors). The anthropometrists independently took all measures twice and compared values using maximum allowable differences of 50 g for weight, 7 mm for length, and 4 mm for head circumference. If any difference exceeded those values, both observers independently performed the relevant measurement a second time and, if necessary, a third time.13 The Oxford Anthropometric Standardization Unit regularly monitored staff performance and recommended retraining if measurements consistently exceeded the maximum allowable differences.The anthropometric measurement protocols, training materials, and quality control procedures were based on the World Health Organization (WHO) Multicentre Growth Reference Study,14Standardized care and feeding practices were implemented using INTERGROWTH-21st protocols. Exclusive breastfeeding until age 6 months was encouraged, with standard supplementation for preterm newborns.15 We used an unweighted composite neonatal outcome score comprising a severe neonatal morbidity index that included 1 or more of the following severe neonatal complications: bronchopulmonary dysplasia, hypoxic-ischemic encephalopathy, sepsis, anemia (requiring transfusion), periventricular hemorrhage or leukomalacia, retinopathy, necrotizing enterocolitis (Bell stage 2 or higher), and patent ductus arteriosus (requiring intervention).18 At ages 1 and 2 years, we assessed (1) hospital admission (≥1 admission); (2) diagnosis and treatment for infections requiring antibiotic medication (≥3 regimens), otitis media, pneumonia, bronchiolitis, parasitosis, diarrhea, vomiting, exanthema, skin disease, fever lasting 3 or more days (≥3 episodes), and meningitis; (3) neurologic disorders, including seizures and cerebral palsy; and (4) severe clinical conditions, including cardiovascular problems, gastroesophageal reflux, hemolytic conditions, trauma from injury, or any condition requiring surgery.Each mother provided detailed information about the infant’s health and severe morbidities at birth, age 1 year, and age 2 years using project-specific forms.10 Motor development was assessed using the chronological age of the child by comparing parental information with 4 WHO developmental milestones: sitting without support, crawling on hands and knees, standing alone, and walking alone.19At birth, we measured weight, length, and head circumference following INTERGROWTH-21st protocols. At ages 1 and 2 years, we measured weight, length, and head circumference following WHO protocols.20 The INTER-NDA is implemented by nonspecialists21 and uses mixed methods to measure cognition, language development, fine and gross motor skills, and positive and negative behavior. The tool has been validated against the Bayley Scales of Infant Development22 and has indicated good interrater and test-retest reliability.20 Vision was assessed using the Cardiff Visual Acuity and Contrast Sensitivity tests.23 We estimated the proportion of children scoring lower than the 10th centile on the INTER-NDA and on visual tests using international standards.24We assessed neurodevelopment at age 2 years using the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA), which measures multiple dimensions of early development among children aged 22 to 30 months.4 that were empirically tested.5 The same definitions of maternal, fetal, and placental conditions and the same analytical strategy using a 2-step cluster analysis  were then applied to the data collected for the present study.5 This approach allowed us to compare the distribution of clusters and their proportional contribution across populations.To construct the preterm-birth phenotypes  because each infection had low statistical power when analyzed separately .To assess associations between maternal risk factors and phenotypes, we performed multinomial logistic regression analyses to model nominal outcome variables. Odds ratios (ORs) for each phenotype  compared with the term newborn group were estimated based on multinomial modeling. Model 1 was adjusted for maternal age, height, first trimester and prepregnancy body mass index , years of education, presence of prepregnancy mental illness, length of menstrual cycle, and smoking during pregnancy. Model 2 was adjusted for all variables included in model 1 plus the number of previous pregnancies, miscarriages, and terminations. Model 3 was adjusted for all variables included in model 2 plus the number of previous births, low birth weight (defined as <2500 g) and preterm infants, and neonatal deaths. We found no data that violated the independence of irrelevant alternatives assumption in our models.z scores for weight, length, head circumference, weight for length, and percentage of newborns lower than the 10th centile compared with INTERGROWTH-21st standards7 and preterm reference charts.26 At ages 1 and 2 years, similar z scores and centiles for weight, length, and head circumference were generated compared with the WHO Child Growth Standards.11 We used 1-way analysis of variance to test whether the means of each z score were different across the phenotypes and the term newborn group. Phenotypic analyses at age 2 years used chronological rather than corrected age.27For all newborns, we generated age- and sex-specific We performed logistic regression analysis to assess associations between phenotypes and neonatal, 1-year, and 2-year morbidity indices, presented as ORs with 95% CIs adjusted for study site. For the neonatal morbidity analyses, we compared individual preterm-birth phenotypes with the phenotype for no main maternal, fetal, or placental condition detected. Unadjusted and adjusted analyses were conducted for gestational age. Robust SEs were estimated in all logistic association models using the vce (cluster clustvar) package in Stata software, version 15 (StataCorp).We used a Kruskal-Wallis nonparametric test to examine the equality of age distribution at the achievement of gross motor development milestones among phenotypes and the term newborn group. All analyses were performed using Stata software, version 15. Data were analyzed from November 2019 to October 2020.We prospectively enrolled 7540 women between 2012 and 2019; of those, 202 women were lost to follow-up or withdrew consent. After excluding 27 infants with missing birth weights, 7311 newborns  remained  to 25.0% . For the preterm group, each site’s contribution ranged from 6.7%  to 27.0% . Sociodemographic characteristics were similar across groups from different sites.Among 1381 preterm newborns, the largest phenotype was no main maternal, fetal, or placental condition detected . Cluster selection also derived phenotypes with 1 main condition , indicating that preterm birth was a heterogeneous syndrome. These phenotypes comprised infections (289 infants [20.9%]), preeclampsia (162 infants [11.7%]), fetal distress (131 infants [9.5%]), intrauterine growth restriction (110 infants [8.0%]), bleeding (71 infants [5.1%]), and congenital anomaly (48 infants [3.5%])  and among preterm newborns with specific phenotypes, such as preeclampsia (124 of 162 infants [76.5%]), bleeding (61 of 71 infants [85.9%]), fetal distress (123 of 131 infants [93.9%]), and severe maternal disease (55 of 85 infants [64.7%])  were small for gestational age and most were associated with the intrauterine growth restriction (73 infants [66.0%]), preeclampsia (42 infants [26.1%]), and fetal distress (33 infants [24.9%]) phenotypes , bleeding , and congenital anomaly  phenotypes. The lowest risk of severe neonatal morbidity was observed in newborns with the intrauterine growth restriction phenotype ; however, newborns with this phenotype had the highest risk of neonatal and postnatal growth restriction . There wThe phenotypes associated with different morbidities at age 1 year among preterm newborns compared with the term newborn group are shown in eTable 5 in the 29 Newborns with the phenotypes for intrauterine growth restriction, bleeding, and congenital anomaly were considerably slower in reaching this milestone, with median ages at achievement of 15.0 months , 15.0 months , and 15.2 months , respectively, representing a 3-month delay compared with the median age of 12 months reported by the WHO.29 Newborns with other phenotypes experienced a 1- to 2-month delay.24 according to phenotype and compared with the term newborn group. Heterogeneity was observed, which would have been missed if all preterm newborns had been considered as a single entity. For example, excluding newborns with the congenital anomaly phenotype, those with the fetal distress phenotype had the highest risk of cognitive , fine motor , gross motor , and language  development problems. Newborns with the preeclampsia phenotype had a high risk of cognitive , fine motor , and gross motor  development problems. Compared with term newborns, the highest risk of scoring lower than the 10th centile based on INTER-NDA normative values was observed in the fine motor development domain among newborns with the fetal distress  and congenital anomaly  phenotypes. The risk of fine motor delay was high among all preterm-birth phenotypes.5The study’s findings indicated that, among an international sample selected to maximize the inclusion of high-risk pregnancies, differential patterns existed with regard to maternal risk factors, the incidence of newborns who were small for gestational age, neonatal and childhood growth, neonatal and childhood severe morbidity, and neurodevelopment across preterm-birth phenotypes. These differential patterns are likely associated with specific pathologic factors that have implications for the growing fetus, as previously reported for early neonatal outcomes.The postnatal patterns varied across phenotype and age. For example, newborns with the intrauterine growth restriction phenotype had lower neonatal morbidity but more growth restriction and neurodevelopmental delay in childhood. Newborns with the no main condition phenotype who were not small for their gestational age had lower neonatal morbidity but increased morbidity at age 2 years. Those with the infections phenotype had lower gestational ages at birth and a low risk of being small for gestational age but a high risk of morbidity and postnatal growth restriction.1The association between preterm birth and the phenotype for intrauterine growth restriction, which was observed in 8.0% of all preterm infants, would not have emerged had the syndrome’s heterogeneity not been recognized. Notably, some preterm newborns with the intrauterine growth restriction phenotype were not included in that phenotype group for this study because they had other pathologic characteristics, such as preeclampsia or congenital anomalies. Other etiologic factors were likely associated with fetal growth restriction  that were associated with the dominant condition and preterm birth 4; (2) it was designed to explore a priori hypotheses associated with the heterogeneity of preterm birth; (3) it accurately estimated gestational age in all newborns; (4) it oversampled newborns with low gestational ages to maximize the number of subgroups considered very high risk; (5) it achieved a 1:4 ratio for enrolled preterm and term newborns, substantially exceeding the 1:1 target; (6) it monitored growth, morbidity, and neurodevelopment from birth to age 2 years using standardized data collection systems; and (7) it assessed neurodevelopment compared with international normative values using a validated psychometric tool.30The present study is distinct because (1) it has a firm conceptual basis31 and to avoid the use of low birth weight  as a factor.32 It has been asserted that low birth weight is a necessary factor to include because, in many regions of the world, gestational age cannot be reliably estimated. However, actions to minimize the incidence of preterm birth may nonetheless be taken and are warranted for a syndrome that occurs in at least 10% to 12% of all births worldwide and has serious implications for human developmental capacity. Governments, international organizations, and donors can work to improve antenatal care so that every woman receives adequate evaluation early in pregnancy.31The study’s results have implications for research and clinical practice. Preterm birth is a distinct syndrome in the medical field because it is defined by time . Hence, it is important to estimate the gestational age as accurately as possible, consistent with the 2016 WHO guidelines,33 as some sites were located in rural or semiurban areas. This limitation was considered when the INTERBIO-21st study was designed, but we concluded that the loss of follow-up at such sites was offset by the enrollment of a high-risk population with accurate gestational ages and a higher number of more severe exposures . Nevertheless, the risk of systematic loss to follow-up bias according to phenotype is unlikely because, with the exception of the intrauterine growth restriction phenotype, the follow-up rates across phenotypes were similar.This study has several limitations. The loss to follow-up at age 2 years was higher than that of previous studies,We could not include multiple births because we focused, for several logistical and sample size reasons, on singletons. In addition, we did not include stillbirths or late terminations because the childhood follow-up component was fundamental to the study. We also did not document the ways in which urinary tract infections were specifically diagnosed or record whether prophylactic antibiotic medications were prescribed for the treatment of group B streptococcus colonization. We categorized congenital anomaly as a separate phenotype to reinforce the integrity of preterm birth as a distinct syndrome. However, given the small sample of infants with the congenital anomaly phenotype , we could not draw meaningful conclusions.5 using identical methods but a data set with a different risk profile, supports our hypothesis that these phenotypes occur systematically across populations. However, the phenotype prevalence changes depending on which factors predominate.Although cluster methods are susceptible to nuances in the data, the fact that we obtained clusters that were similar to those acquired in a previous study,34 which were highlighted by Lee et al.35 Our study was designed to explore the preterm and intrauterine growth restriction syndromes in parallel. This overlapping approach was required because intrauterine growth restriction is an equally complex syndrome that has multiple etiologic characteristics and presentations. However, our focus on developmental outcomes precluded including stillbirths. Future research may explore these associations in detail.We recognize that there are competing etiologic characteristics and risk factors among the preterm birth, intrauterine growth restriction, and stillbirth syndromes,In this study, the preterm birth syndrome was composed of well-defined phenotypes with differential neonatal morbidity, early childhood morbidity, growth, and neurodevelopment up to age 2 years. Therefore, the concept of preterm birth as an exclusively time-based entity may no longer be appropriate. Phenotypic classification of preterm newborns is likely to provide a better understanding of the etiologic factors and mechanisms associated with preterm birth. Although the study’s findings indicated that approximately 35% of phenotypes were not associated with distinct clinical conditions, newborns with preterm-birth phenotypes nevertheless remain at a higher risk of growth and developmental problems.


Several studies in humans indicate that low birth weight predisposes individuals to obesity in later life. Despite the constant increase in prevalence of obesity in the canine population and the major health consequences of this affection, few investigations have been carried out on the association between birth weight and the development of overweight in dogs. The purpose of the current study was to examine the association between birth weight and some other neonatal characteristics and overweight at adulthood in a population of purebred Labrador dogs. Information was collected about the sex, age, neuter status, birth weight, and growth rates (between 0–2 days and 2–15 days of age) in 93 Labrador dogs raised under similar environmental conditions until two months old. The body condition scores  of these dogs at adulthood were recorded, with BCS equal to or greater than 6 classified as overweight. Dogs were split into two groups based on the median birth weight in the population: lower than the median (LTM) and higher than the median (HTM). A logistic regression model was applied to analyse associations between the general characteristics of the dogs , early life parameters  and overweight at adulthood. Birth weight was the only early-life parameter found to be associated with overweight  with a prevalence of overweight of 70% among the dogs with LTM birth weight vs. 47% in dogs born with HTM birth weight. Overweight was also associated with age and neuter status . Our results suggest that, as in humans, dogs with the lowest birth weights are more likely to become overweight at adulthood. More studies are needed to further examine this relationship and to explore the underlying mechanisms. A subsequent objective could be to identify preventive strategies such as an adapted early nutrition programme for at-risk individuals. Excessive bodyweight (overweight and obesity) is a growing global health problem in dogs, the prevalence ranging between 20–40% all over the world –3. MultiDiseases in adulthood are increasingly associated with early life events  and numeThus, the purpose of this study was to analyse the association between neonatal parameters (birth weight and early growth) and overweight at adulthood in a Labrador dog population.The study was conducted in a guide dog breeding kennel , a nonprofit organization affiliated to the French Federation of Guide Dog Associations (FFAC). Only breeding bitches and retired dogs of Labrador breed born at the CESECAH and over one year of age were included. Outside the reproduction period (breeding bitches), or once retired (bitches and sires), the dogs are housed in volunteer families. Breeding bitches included in the reproduction program are housed in the maternity room at the CESECAH’s facility, from two weeks before whelping until the separation from the puppies at around 9 weeks after birth. Each puppy is routinely weighed during this period. After weaning, the bitches go back to their volunteer families, and the puppies are transferred to different French Guide Dog Schools, where they are selected and trained to become guide dogs.All volunteer families were asked to bring their dogs for an examination session (one exam per dog at adult age in September 2017 or in June 2018). Body fat mass was estimated from the body condition score (BCS). Two operators, using palpation and visual observation, assigned a score to each dog, based on the 9‐point scale developed by Laflamme et al. : 1 emaciThe interplay between neonatal parameters and the risk of overweight was investigated by fitting a logistic regression which took the general parameters into account.The outcome was a binary variable based on the BCS. Dogs with a BCS of 5 or less were classed as “not overweight” and those with a BCS of 6 or more, as “overweight”. The reference category was dogs that were not overweight. Explanatory variables included sex , age , neuter status (neutered/entire), birth weight, growth rate 0–2 days [(weight at 2 days–weight at birth) ÷ weight at birth x 100] and growth rate 2–15 days [(weight at 15 days–weight at 2 days) ÷ weight at 2 days x 100]. The three last parameters were categorised into two groups based on the median .BCS category ~ Birth weight + Growth rate 2d + Growth rate 15d + Neuter status + Sex + Age), a backward selection based on the Akaike's Information Criterion (AIC) was applied to select the most parsimonious model. At the end of the backward selection, interactions were tested by running models with and without the interaction term. A Chi-square test was then performed to examine the statistical significance of the residuals sum of squares difference between the two models (with vs. without interaction term). The final model was assessed by Pearson residuals test. Moreover, the area under the receiver operating characteristic curve (AUROC) was used to assess the ability of the models to differentiate overweight and non-overweight dogs.Starting with the full model . Sex distribution was 6 (6.5%) entire males, 36 (38.7%) entire females, 18 (19.4%) neutered males and 33 (35.5%) neutered females. The overall prevalence of overweight (BCS ≥ 6) was 58.1% . The results indicated that neutering, LTM birth weight and older age were related to the prevalence of overweight , Fig 2. The results of the present study in a Labrador dog cohort suggest that birth weight, in addition to age and neuter status, was associated with the risk of becoming overweight at adulthood.2O) dilution, which are difficult to conduct in the field , but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.3.2. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc.  http://journals.plos.org/plosone/s/competing-interests). If this adherence statement is not accurate and  there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” . The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: This manuscript is about the association between birth weight and overweight in Labrador dogs.The manuscript is well written, the statistical analysis seems appropriate to me as well as the conclusions, according to the results. However, the work has some limitations and needs some clarification.1) Since the age of the included dogs ranged from 1 to 9 years of age, it is assumed that this is a retrospective study. Authors are asked to explain how puppies were raised under similar environmental conditions over such a long period of time2) Body fat was estimated only by BCS. Despite the fact that BCS may correlate well with more accurate methods, this is a limitation of the study3) Authors have mentioned other limitations of the study, including the number of dogs, the lack of information about their health status and lifestyle, and the fact that dogs belonged to a single breed4) Potential correlation between low weight at birth and overweight in adulthood is nicely discussed but none of the mentioned hypotheses has been verified in the present study5) In my opinion, Figure 1 may be deleted and BCS distribution of dogs may be reported in the textReviewer #2: The manuscript is well written and the results and conclusions are interesting. The overall presentation is sound.Please add % behind the numbers in parenthesis in Table 1 "Neonatal and adult characteristics of overweight and not-overweight Labradors"Please change "racial predisposition" in line 166 into "breed predisposition"**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  18 Nov 2020Journal requirementshttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf• Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdfand We have added the corresponding initials in brackets after the email address of the corresponding author and we have modified the layout of the first page. Next, we checked the overall style of the manuscript but we regret that we did not identify other areas of non-compliance with the guidelines. Could you be more specific about the problems identified?• Thank you for stating in your Funding Statement: "This study was partially funded by Royal Canin SAS . AAL, JLhttp://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.and JF participated in the analyses of the data and in the reviewing of the paper." Please provide an amended statement that declares *all* the funding or sources of support  received during this study, as detailed online in our guide for authors at We have added the requested sentence at the Funding statement. • Thank you for stating the following in the Competing Interests section: "The authors have declared that no competing interests exist." We note that one or more of the authors have an affiliation to the commercial funders of this research study : Royal Canin.Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form. Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.We have provided this explanation and added the roles of authors affiliated to Royal Canin in Funding Statement.Line 251 « This study was partially funded by Royal Canin SAS . The funder provided support in the form of salaries for AM. Moreover, AAL, JL and JF participated in the analyses of the data and in the reviewing of the paper. There was no additional external funding received for this study. »Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. As noted earlier, there are no competing interests in this study. Royal Canin partially funded this study but that did not interfere with the full and objective publication of this research article.http://journals.plos.org/plosone/s/competing-interests). If this adherence statement is not accurate and there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” . This is why we wrote that « The study was conducted on Labradors raised under similar environmental conditions until two months of age which meant that the breed and breeding conditions were homogeneous. » (line 157). Even if, indeed, some environmental parameters such as hygrometry or temperature could not be controlled in the field and have probably varied over time.• Body fat was estimated only by BCS. Despite the fact that BCS may correlate well with more accurate methods, this is a limitation of the study. Authors have mentioned other limitations of the study, including the number of dogs, the lack of information about their health status and lifestyle, and the fact that dogs belonged to a single breedThank you for this comment. We added the following sentence to clarify this limitation. Line 164 « Nevertheless, despite this good correlation, further studies with an assessment of adiposity by quantitative measures should be conducted. »• Potential correlation between low weight at birth and overweight in adulthood is nicely discussed but none of the mentioned hypotheses has been verified in the present studyThat’s true. This study is a first step in the investigation of the relationship between low birth weight and overweight in adulthood. As we mentioned in the discussion « further studies are needed to explore and identify the precise mechanisms explaining the association between low birth weight and adult overweight in the canine species » (line 204). • In my opinion, Figure 1 may be deleted and BCS distribution of dogs may be reported in the textThank you for this suggestion. We have chosen to converse the figure that provides a visual representation of the distribution of BCS in our population.Reviewer #2The manuscript is well written and the results and conclusions are interesting. The overall presentation is sound.• Please add % behind the numbers in parenthesis in Table 1 "Neonatal and adult characteristics of overweight and not-overweight Labradors"Thank you for this suggestion which clearly improves the readibility of the table. We have added %’s behind the figures in the table under consideration.• Please change "racial predisposition" in line 166 into "breed predisposition"Thank you for this suggestion. We modified this sentence.Line 170 « In addition to breed predisposition, this may be explained by […] ».AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 27 Nov 2020Association between birth weight and risk of overweight at adulthood in Labrador dogsPONE-D-20-33064R1Dear Dr. Mugnier,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Simon Clegg, PhDAcademic EditorPLOS ONEAdditional Editor Comments:Many thanks for resubmitting your manuscript to PLOS OneAs you have addressed all the reviewer points, and the manuscript reads well, I have recommended it for publicationYou should hear from the Editorial Office soonIt was a pleasure working with you and I wish you all the best for the futureHope you are keeping safe and well in these difficult timesThanksSimon 2 Dec 2020PONE-D-20-33064R1 Association between birth weight and risk of overweight at adulthood in Labrador dogs Dear Dr. Mugnier:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofDr. Simon Clegg Academic EditorPLOS ONE


To the editor:The COVID‐19 pandemic has drastically strained the American healthcare system.It remains unclear how the pandemic has influenced maternal care choices, in particular how women have altered their birth plans. Data on common birth plan changes are needed to help providers better understand factors shaping care decisions, information that can be used to address patient concerns and tailor care recommendations. Here, we use an online convenience survey to assess how American women's birth plans (eg intended labour support and delivery location) have changed in response to the COVID‐19 pandemic.The COVID‐19 And Reproductive Effects (CARE) study was posted on social media platforms  and distributed via email to contacts working in maternity care and public health. Pregnant women over the age of 18 and living in the United States were invited to participate in a survey assessing how the pandemic was impacting their medical care and birth plans. The data presented here were collected between 16 and 20 April 2020.In addition to providing basic demographic data, gestational week and intended delivery facility, participants were asked whether ‘any aspect of your birth plan changed due to COVID‐19’ (yes/no). If they answered yes, they were then asked why and how their plans changed. These analyses were limited to participants who completed the entire survey (n = 1400). A subset of this sample also answered an open‐ended question describing the specific changes to their birth plans (n = 592); these qualitative responses were assessed for common patterns.The average participant age was 31.4 years old. The majority of participants were married/in domestic partnerships (94.5%), White (85.9%), had completed at least a bachelor's degree (77.3%), were employed full‐time (61.1%) and reported having not experienced any COVID‐19‐like symptoms (89.4%). Most participants planned on giving birth in a hospital .Overall, 45.2% of respondents reported changing some aspect of their birth plans because of COVID‐19, due in part to their own concerns (53.9% of respondents), their partner's concerns (21.9%), the concerns of friends or family members (13.8%) and comments from medical providers (60.8%). The prevalence of women changing their birth plans varied by trimester. Approximately 28.6% of women in their first trimester (36/126) reported changing their plans due to COVID‐19, compared to 37.0% of women in their second trimester (228/617 women) and 56.2% of women in their third trimester (369/657 women).Commonly provided COVID‐related birth plan changes—from a subset of 592 respondents—are outlined in Table Many participants planned to remain with their current provider, but were preparing for a very different birth experience with fewer support persons during labour (n = 367/592) and no visitors to meet their baby or care for their other children during delivery (n = 186/592). Some women worried they might have to labour alone if childcare could not be arranged and their partner had to watch their other children instead of attending the birth. Several women reported opting to no longer give birth in a hospital due to restrictions on who would be allowed in the delivery room, the possibility of forced separation from their newborn and fear of virus exposure (n = 81/592).Pregnant American women face a variety of care‐related challenges related to COVID‐19, and our results demonstrate that this has led to altered birth plans. Yet, the reasons behind the changes appear to be individual‐dependent. While several participants reported that they now preferred an out of hospital birth because they feared COVID‐19 exposure, a handful of women reported choosing a hospital instead of a home birth because they feared suffering COVID‐related complications during delivery if they were unknowing carriers, or because they worried they would not be admitted to an overcrowded hospital should they need to transfer.Notably, the women in this sample exhibited a much higher preference for out of hospital births than the national average before the COVID‐19 pandemic .It is important to note that due to the use of convenience sampling these data are not representative of the whole US population. Additional work is needed using more diverse samples to identify additional issues influencing maternal care decisions. The diverse factors influencing maternal birth plan choices highlighted here may serve as reference providers can use to explore the specific concerns of each patient, ultimately leading to more productive provider‐patient conversations about the maternal care and delivery options available to best address any given situation.The authors declare that they have no competing interests.


Birth prevalence of cerebral palsy (CP) is declining in high‐income countries, to as low as 1.4 per 1000 live births in the most recent international reports. This represents a 35% reduction in birth prevalence over a 15‐year period. This reduction is underpinned by a heightened focus of attention towards all aspects of CP, including: increased awareness, better data collection, development of national networks and registries, an explosion of research in basic science, perinatal care, neonatal neurology, public health, early detection, and targeted early intervention. Quick uptake of evidence into practice has ensued and overall improvements in clinical care occurred concurrently. It is anticipated that with continued partnerships with families, ongoing research driving further clinical improvement and vice versa, birth prevalence and severity of CP will further decline and the focus will shift to prevention in low‐ and middle‐income countries.Research in the field of perinatal care and cerebral palsy (CP) prevention has increased significantly.In high‐income countries, increased awareness of CP and scientific advances have improved clinical care.Population‐based registers have limitations but remain the best mechanism to quantify birth prevalence of CP and accurately track trends.There have been recent reductions in the birth prevalence of CP. Research in the field of perinatal care and cerebral palsy (CP) prevention has increased significantly.In high‐income countries, increased awareness of CP and scientific advances have improved clinical care.Population‐based registers have limitations but remain the best mechanism to quantify birth prevalence of CP and accurately track trends.There have been recent reductions in the birth prevalence of CP. NICUNeonatal intensive care unitCerebral palsy (CP) is a condition that essentially, but not exclusively, involves the motor system – originally thought to result from a static brain lesion resulting in a dynamic motor impairment that evolved and often deteriorated with advancing growth and development. Historically the condition had an associated sense of ‘fait accompli' that left clinicians focused on managing the complications of the condition. At that stage, we understood that brain injury was permanent; that the brain differed from other organs in the body because of its inability to regenerate and repair. The notion that the condition, rather than the symptoms, could be improved was beyond comprehension for many. However, the last two decades have seen exciting developments in the field of CP research that have largely been driven and recognized by data collected into population‐based registers. These include genome studies, preventive strategies such as antenatal magnesium sulphate, neuronal rescue strategies such as therapeutic hypothermia, and the increased uptake of early detection enabling rigorous early intervention research. Improved understanding of risk factors and clinical phenotype alongside advances in perinatal care have been the foundation for this dramatic increase in CP research, which is now reaping rewards.CP can be classified into two broad groups based on timing of the injury responsible for causing CP: individuals whose brain injury occurred in the prenatal/perinatal period and those that acquire a brain injury postnatally. One of the most exciting developments has been the significant decrease in the rate of prenatal/perinatal CP that has been reported recently by CP registers. The decrease was seen first in Europe when birth prevalence declined from 1.9 in 1000 live births in 1980 to 1.7 in 1000 live births in 2003.Around 45% of people diagnosed with CP were born preterm . There has been a dramatic drop in the rate of CP among infants born extremely preterm ,Greater experience with infants born preterm has enabled staff to provide better care over time with improved resuscitation, less intubation, and increased use of nasal continuous positive airway pressure around the time of birth.In the most recent international report, the Australian Cerebral Palsy Register identified a considerable drop in the rate of CP among term born infants who account for over half of the infants with CP.A proportion of term born infants who experience intrapartum hypoxia have benefitted from therapeutic hypothermia which has become the standard of care in NICUs in high‐income countries.Rates of postnatally acquired CP have also decreased.must be maintained. Ongoing scrutiny of this data will also stimulate the next waves of research to further reduce the incidence and impact of CP, and stay on top of any unexpected increases.While these results are heartening, history tells us that we must avoid being complacent about both our current practice and these results. Recently in Australia there were reports of increased numbers of infants with kernicterus related to delayed detection of hyperbilirubinaemia. Infants from diverse cultural backgrounds seemed most at risk. This observation followed widespread implementation of policies recommending early discharge home from maternity hospitals.With preterm birth associated with 45% of cases of CP, it follows that reducing the rate of preterm birth will likely decrease the rate of CP further. A recent Cochrane Review recommends four key interventions to reduce preterm birth: midwife‐led continuity models of care, screening for lower genital tract infections, zinc supplementation for pregnant females without systemic illness, and cervical cerclage for females with a singleton at high risk of preterm birth.The Western Australian Preterm Birth Initiative has reduced preterm birth by 8% using a combination of health professional advice, public health and social media campaigns, and a preterm birth prevention clinic.The immediate perinatal period is a time of extreme vulnerability for infants born preterm. There is an increasing amount of research interrogating optimization of resuscitation and ventilation. A recent study by Tracy et al. revealed that resuscitation equipment often does not meet the desired standardsOnce admitted to the NICU, newborn infants are highly dependent on technology and engineering skills. There is increasing recognition of neuromonitoring alongside cardio‐respiratory monitoring in the NICU. Amplitude integrated electroencephalogram is now commonplace in NICUs in high‐income countries. Newer neuromonitoring modalities such as near infra‐red spectroscopy provide insights into cerebral oxygen saturation, and are currently being interrogated for their ability to predict outcome, and perhaps aid in improving survival and neurodevelopmental outcomes. Vesoulis et al.Beyond monitoring, specific neuroprotective strategies such as erythropoietin have shown early promiseAntenatal factors such as intrauterine growth restriction, congenital anomalies, and infections are some of the biggest risk factors for term newborn encephalopathyFor the small proportion of term born infants who suffer a lack of oxygen or cerebral blood flow around the time of birth, therapeutic hypothermia is an important neuro‐rescue therapy reducing both mortality and morbidity amongst survivors of birth asphyxia.There is emerging evidence that targeted early intervention including cognitive input may also improve neurodevelopmental outcomes.www.icpgc.org). Large numbers of DNA and clinical information from affected infants, children, and their parents will be necessary to better understand these complex inter‐relationships, and a database is currently being built (The CP Commons) which will mean genomic and clinical data can be shared across the world, to maximize efficiency and outcomes. One other area that demands more investigation is perinatal stroke in term born infants. Rates of hemiplegia have not declined in the registers,Congenital anomalies are found in nearly 25% of people with CP and this group have largely been excluded from research.We should also embrace the technologies and strategies that our engineering and computer science colleagues are beginning to provide. The use of artificial intelligence has potential to further improve our diagnostic capacity and management of conditions that are currently susceptible to the variation in human opinion. Machine learning to predict fetal health statusWe have presented a very focused high‐income country view describing rates of CP and advances in management particularly where CP registers exist.For research investigating prevention and reduction of severity of CP to proceed as quickly as possible, we must ensure that families and individuals with CP are integrally involved in research development and conduct, and the translation of findings into clinical practice. Consumer generated priorities have driven a great deal of the research that has occurred over the last 10 years. One of the most important priorities for family members and people with CP is the prevention of CP.We describe a decline in the birth prevalence of CP that results from a number of different strategies and interventions. In the first instance, better knowledge about the true birth prevalence and trends of CP, through the development of population‐based registers, has promoted and focused research in a way that has driven interrogation of preventive strategies, improvements in clinical care from conception into childhood, earlier detection of CP, and implementation of early intervention strategies. With ongoing endeavours in this area, we anticipate further reductions in the birth prevalence of CP and continued improvements in quality of life for those living with CP.


Per- and polyfluoroalkyl substances (PFASs) have been detected in drinking water supplies around the world and are the subject of intense regulatory debate. While they have been associated with several illnesses, their effects on reproductive outcomes remains uncertain.We analyzed birth outcomes in the east Minneapolis-St. Paul metropolitan area from 2002 to 2011, where a portion of the population faced elevated exposure to PFASs due to long-term contamination of drinking water supplies from industrial waste disposal. Installation of a water filtration facility in the highly contaminated city of Oakdale, MN at the end of 2006 resulted in a sharp decrease in exposure to PFASs, creating a “natural experiment”. Using a difference-in-differences approach, we compare the changes in birth outcomes before and after water filtration in Oakdale to the changes over the same period in neighboring communities where the treatment of municipal water remained constant.Average birth weight and average gestational age were statistically significantly lower in the highly exposed population than in the control area prior to filtration of municipal water supply. The highly exposed population faced increased odds of low birth weight  and pre-term birth  relative to the control before filtration, and these differences moderated after filtration. The general fertility rate was also significantly lower in the exposed population  prior to filtration and appeared to be rebounding post-2006.Our findings provide evidence of a causal relationship between filtration of drinking water containing high levels of exposure to PFASs and improved reproductive outcomes. Per- and polyfluoroalkyl substances (PFASs) are a class of industrial chemicals that have been manufactured in the U.S. since the 1950s. PFASs have been used in a variety of consumer and industrial products, including water repellant fabric treatments, non-stick cookware, and fire-fighting foams, for their surfactant properties and resistance to degradation , 3. In tPerfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are the most widely studied compounds within the class of PFASs and have been associated with a range of adverse health effects, including cancer . Some stATSDR also concludes that elevated exposures to PFOS and PFOA are associated with decreased fertility, as some human epidemiological studies have reported a negative association between serum-PFAS concentrations and fecundity, measured through time-to-pregnancy (TTP) , 16, altThis paper provides new evidence of the effect of PFOA and PFOS exposure on reproductive outcomes. Our study focused on residents of Oakdale, Minnesota in the east Minneapolis-St. Paul metropolitan area, where elevated concentrations of PFOA and PFOS were detected in municipal water supplies as a result of industrial disposal in nearby landfills beginning in the 1950’s   for the entirety of Washington County and portions of neighboring counties. A summary of maternal and newborn characteristics, as well as zip code level demographics, for our study population is provided in Table We relied on individual-level birth record data for over 48,000 births collected by the Minnesota Department of Health (MDH), representing all singleton live births between 2002 and 2011 in all zip codes contained at least partially within Washington county – the county in which Oakdale resides – excluding certain communities for which information regarding PFAS concentrations was insufficient. The birth data included mother’s age, marital status, and educational attainment at time of birth; birth month and year, gestational age, birth weight, and infant sex; and zip codes of maternal residence address.To account for socioeconomic factors not represented in the birth data itself, we introduced demographic variables from the U.S. Census Bureau’s decennial census and the American Community Survey (ACS). Average household income and racial composition were included at the zip-code level and served as proxies for individual-level maternal characteristics. Values for the years 2002–2009 were linearly interpolated from the 2000 and 2010 censuses, while 2011 values were taken directly from the ACS. While individual-level data would enable more accurate control of demographic changes in the study area over time, these data are unavailable due to privacy concerns.Exposure to PFAS is approximated by the residential zip code of a mother at the time of birth combined with birth year. Approximately 99% of Oakdale’s population of 27,000 residents were served by the city’s municipal water system. According to 2005 testing, among Oakdale’s nine municipal wells, PFOA concentrations ranged from 0.07 to 0.70 μg/L and PFOS concentrations ranged from a non-detectable concentration to 1.04 μg/L . For refDrinking water in certain other nearby communities, including Cottage Grove, Lake Elmo, and Woodbury, are also known to have been contaminated by PFAS but did not install municipal GAC filtration during our study period. Exposure was also less consistent in these other affected communities due to greater reliance on private domestic wells. These communities were therefore considered separately in our analyses. The communities used as our control area have not been found to have detectable levels of PFAS  and 35.9 ng/mL  respectively, according to volunteer samples obtained in 2008, 2 years after GAC was installed . These mWe first evaluated birth weight and gestational age as continuous outcomes, and then studied binary adverse outcomes of birth weight < 2500 g and < 1500 g, and gestational age at birth < 37 weeks and < 32 weeks. The analysis of binary adverse outcomes was made feasible from a statistical standpoint by our relatively large sample size. Table Taking advantage of the Oakdale-wide changes in PFAS exposure, we used a difference-in-differences approach to evaluate all outcomes , both coWe estimated all models both with and without individual-level characteristics  and with and without zip-code level characteristics . Indicators for maternal drug use and medical risk factors were included as robustness checks, but since these data appear inconsistent over time, results from these estimations are provided in the additional files. Our primary estimating equations are all similarly defined as:β1 and β2, which indicate the difference in mean or probability of an outcome in Oakdale relative to the control communities before and after filtration respectively. The difference between these two coefficients is therefore indicative of the effect of filtration. The vectors of individual maternal characteristics and zip code-level characteristics control for time-variant differences across communities. The vectors of birth month and birth year effects control for changes over time and season that are common across communities.The coefficients of interest are Continuous birth outcomes were modeled using ordinary least squares regression with standard errors clustered at the zip-code level. Binary individual-level outcomes  were modeled using logistic regression estimated via maximum likelihood, with standard errors clustered at the zip-code level. For binary individual-level outcomes, results are reported as odds ratios, which reflect the increased or decreased odds of the specified birth outcome for mothers living in Oakdale relative to the control areas.General and age-specific fertility rates were estimated by Poisson regression via maximum likelihood using robust standard errors . The nump < 0.01 level, and significantly different from one another. Average birth weights in the other affected communities were 7.0 g lower than those in the control area but with a p-value of 0.23. The inclusion of individual and zip-code level characteristics reduced the estimated standard errors and the magnitude of the Oakdale post-filtration coefficient. Inclusion of these covariates also changed the sign of the coefficient estimated for the other affected communities, likely due to differences in socioeconomic characteristics across communities.The coefficients on the community indicator variables for our continuous birth outcomes are illustrated in Fig. p < 0.01 and p < 0.05 levels, respectively. As indicated by comparison across the three models, estimated coefficients were insensitive to the inclusion of covariates but more precisely estimated with these additional controls.Estimates for gestational age demonstrated a similar pattern. Infants born in Oakdale before filtration were born an average of 0.1 weeks earlier than those in the control area, but the difference dissipated in the post-filtration period. Gestational age at birth was 0.09 weeks lower in the other affected communities than in the control area over the entire study period. Again, while these differences were small in magnitude, they were statistically significant at In both the birth weight and gestational age regressions, the coefficients on the individual and zip-code level characteristics had the anticipated signs . These materials also include results from two additional regressions where maternal drug use and medical risk factors are included in the individual controls. These results are omitted from Fig. We further estimated the effects of PFAS exposure on the probability of binary birth outcomes known to be associated with adverse long-term developmental consequences. Figure The same models were also estimated for the probability of pre-term birth  and early pre-term birth . Similar patterns hold for pre-term births  and early pre-term births , as were observed for low and very low birth weight. As with the birth weight and gestational age regressions, coefficients on individual and zip-code level characteristics, when included, had the anticipated signs  or preterm birth < 37 weeks), outcomes which have been associated with adverse long-term developmental consequences for the child , 37. How weeks, oOur analyses suggest that high levels of PFOA and PFOS exposure may lead to substantially increased odds of low birth weight, very low birth weight, pre-term birth, early pre-term birth, and a lower GFR. All of these outcomes are of substantial public health relevance –38. We nMethodologically, the present study differs from the existing literature in several ways . First, Second, with the exception of one C8 Science Panel study , prior sThird, the majority of prior studies are based on samples from general populations with more modest background levels of exposure to PFAS, limiting the range over which any relationships may be identified. Other studies that have estimated associations with high levels of PFAS exposure have been based on populations exposed primarily to PFOA , 40. ResFourth, our use of all singleton live births in our study communities over the relevant time period enables a novel evaluation of the effects of PFAS exposure on fertility through analysis of the GFR and age-specific fertility rates. Unlike prior studies of TTP (time-to-pregnancy) that follow a self-selected set of individuals that succeed in conceiving, the research design in the present study does not implicitly omit the impact of PFAS exposure on infertility. Our results provide the first epidemiological evidence that elevated PFAS exposure affects fertility; the GFR in Oakdale was 15 to 25% lower among women in fertile age groups than rates observed in the control communities. While the post-filtration recovery in Oakdale appears to be slower or more modest for the general fertility rate than for the individual adverse birth outcomes evaluated, the estimated coefficients are still higher for the 2007–2011 period than for the 2002–2006 period. The rebound appears to be driven by 25–34-year-old women who represent the largest age category for mothers in our study.While our study of the GFR cannot disentangle the particular mechanisms through which PFOA and/or PFOS exposure may affect the birth rate, it reflects the outcome of public health interest. Our study is, however, limited by lack of information on contraceptive use and other important choice-based determinants of fertility. To the extent that these variables are not captured by the demographic information included in the analysis and changed differently over time in Oakdale relative to the control communities, our estimates may be subject to confounding.Fifth, the installation of the GAC filtration facility in Oakdale in 2006 effectively eliminated Oakdale residents’ exposure to non-background concentrations of PFAS. This population-wide change in exposure allows a difference–in-differences comparison that provides a stronger basis for causal inference than a standard cross-sectional cohort-based study, as all confounding factors that do not change over time are implicitly controlled for. A type I error will arise only if omitted factors change at the same time as the intervention. One conceivable confounding factor could be the presence of other contaminants in Oakdale’s municipal water supply with concentrations that were also reduced by GAC filtration. However, extensive monitoring and remediation to address the presence of known contaminants in groundwater in Washington County was undertaken in the 1980s .Given the limitations on demographic information included in our data due to privacy concerns, it could also be the case that the composition of Oakdale’s population changed relative to the surrounding areas pre- and post-installation of the filtration system. Table Lastly, the present study is distinct due to the long study period. Exposure outcomes must be evaluated over a relatively long timeframe due to the fact that the half-lives of PFOA and PFOS in human blood have been estimated to be in the range of 2 to 4 years . MaternaThere are several important limitations of the present study. First, our data do not allow for the estimation of a dose-response relationship. Precise individual-level maternal exposure to PFAS in our study population is unknown, and our proxy for exposure is binary, although supported by analyses of serum samples thought to be representative for the community , 43. SecPFAS exposure from contaminated drinking water in Oakdale, MN during 2001–2006 was associated with increased odds of low birth weight, pre-term birth and lowered general fertility relative to uncontaminated control populations. Moreover, these differences moderated after installation of a water filtration facility at the end of 2006. This study provides new evidence of a causal relationship between an intervention to reduce elevated levels of exposure to PFASs through drinking water and improved reproductive outcomes.Additional file 1: Figure A1. Map of Study Area and PFAS Source Locations.Additional file 2: Figure A2. Current Extent of PFOS and PFOA Contamination of Groundwater in East Metro Area.Additional file 3: Table A1. All Regression Coefficients for Continuous Birth Outcomes.Additional file 4: Table A2. All Regression Coefficients for Low Birth Weight (< 2500 g) and Very Low Birth Weight (< 1500 g) Models, Reported as Odds Ratios.Additional file 5: Table A3. All Regression Coefficients for Pre-term Births (< 37 weeks) and Early Pre-term Births (< 32 weeks) Models, Reported as Odds Ratios.Additional file 6: Table A4. All Regression Coefficients for General and Age Group-Specific Fertility Rate Models, Reported as Incidence Rate Ratios.