Summary Background Babies with low birthweight (<2500 g) are at increased risk of early mortality. However, low birthweight includes babies born preterm and with fetal growth restriction, and not all these infants have a birthweight less than 2500 g. We estimated the neonatal and infant mortality associated with these two characteristics in low-income and middle-income countries. Methods For this pooled analysis, we searched all available studies and identified 20 cohorts (providing data for 2 015 019 livebirths) from Asia, Africa, and Latin America that recorded data for birthweight, gestational age, and vital statistics through 28 days of life. Study dates ranged from 1982 through to 2010. We calculated relative risks (RR) and risk differences (RD) for mortality associated with preterm birth (<32 weeks, 32 weeks to <34 weeks, 34 weeks to <37 weeks), small-for-gestational-age (SGA; babies with birthweight in the lowest third percentile and between the third and tenth percentile of a US reference population), and preterm and SGA combinations. Findings Pooled overall RRs for preterm were 6·82 (95% CI 3·56–13·07) for neonatal mortality and 2·50 (1·48–4·22) for post-neonatal mortality. Pooled RRs for babies who were SGA (with birthweight in the lowest tenth percentile of the reference population) were 1·83 (95% CI 1·34–2·50) for neonatal mortality and 1·90 (1·32–2·73) for post-neonatal mortality. The neonatal mortality risk of babies who were both preterm and SGA was higher than that of babies with either characteristic alone (15·42; 9·11–26·12). Interpretation Many babies in low-income and middle-income countries are SGA. Preterm birth affects a smaller number of neonates than does SGA, but is associated with a higher mortality risk. The mortality risks associated with both characteristics extend beyond the neonatal period. Differentiation of the burden and risk of babies born preterm and SGA rather than with low birthweight could guide prevention and management strategies to speed progress towards Millennium Development Goal 4—the reduction of child mortality. Funding Bill & Melinda Gates Foundation.

A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate, The Journal of Maternal-Fetal & Neonatal Medicine, 21:1, 9-23, DOI: 10.1080/14767050701830480 To link to this article: https://doi.org/10.1080/14767050701830480 Abstract Introduction. Accumulating evidence suggests that an imbalance between pro-angiogenic (i.e., vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)) and anti-angiogenic factors (i.e., soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1)) is involved in the pathophysiology of preeclampsia (PE). Endoglin is a protein that regulates the pro-angiogenic effects of transforming growth factor b, and its soluble form has recently been implicated in the pathophysiology of PE. The objective of this study was to determine if changes in maternal plasma concentration of these angiogenic and anti-angiogenic factors differ prior to development of disease among patients with normal pregnancies and those destined to develop PE (preterm and term) or to deliver a small for gestational age (SGA) neonate. Methods. This longitudinal nested case-control study included 144 singleton pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered appropriate for gestational age (AGA) neonates (n ¼ 46); (2) patients who delivered an SGA neonate but did not develop PE (n ¼ 56); and (3) patients who developed PE (n ¼ 42). Longitudinal samples were collected at each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. Plasma concentrations of soluble endoglin (s-Eng), sVEGFR-1, and PlGF were determined by specific and sensitive ELISA. Results. (1) Patients destined to deliver an SGA neonate had higher plasma concentrations of s-Eng throughout gestation than those with normal pregnancies; (2) patients destined to develop preterm PE and term PE had significantly higher concentrations of s-Eng than those with normal pregnancies at 23 and 30 weeks, respectively (for preterm PE: p 5 0.036 and for term PE: p ¼ 0.002); (3) patients destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma concentrations of PlGF than those with a normal pregnancy throughout gestation, and the maternal plasma concentration of this analyte became detectable later among patients with pregnancy complications, compared to normal pregnant women; (4) there were no significant differences in the plasma concentrations of sVEGFR-1 between patients destined to deliver an SGA neonate and those with normal pregnancies; (5) patients destined to develop preterm and term PE had a significantly higher plasma concentration of sVEGFR-1 at 26 and 29 weeks of gestation than controls (p ¼ 0.009 and p ¼ 0.0199, respectively); and (6) there was no significant difference in the increment of sVEGF...

SummaryBackgroundNational estimates for the numbers of babies born small for gestational age and the comorbidity with preterm birth are unavailable. We aimed to estimate the prevalence of term and preterm babies born small for gestational age (term-SGA and preterm-SGA), and the relation to low birthweight (<2500 g), in 138 countries of low and middle income in 2010.MethodsSmall for gestational age was defined as lower than the 10th centile for fetal growth from the 1991 US national reference population. Data from 22 birth cohort studies (14 low-income and middle-income countries) and from the WHO Global Survey on Maternal and Perinatal Health (23 countries) were used to model the prevalence of term-SGA births. Prevalence of preterm-SGA infants was calculated from meta-analyses.FindingsIn 2010, an estimated 32·4 million infants were born small for gestational age in low-income and middle-income countries (27% of livebirths), of whom 10·6 million infants were born at term and low birthweight. The prevalence of term-SGA babies ranged from 5·3% of livebirths in east Asia to 41·5% in south Asia, and the prevalence of preterm-SGA infants ranged from 1·2% in north Africa to 3·0% in southeast Asia. Of 18 million low-birthweight babies, 59% were term-SGA and 41% were preterm. Two-thirds of small-for-gestational-age infants were born in Asia (17·4 million in south Asia). Preterm-SGA babies totalled 2·8 million births in low-income and middle-income countries. Most small-for-gestational-age infants were born in India, Pakistan, Nigeria, and Bangladesh.InterpretationThe burden of small-for-gestational-age births is very high in countries of low and middle income and is concentrated in south Asia. Implementation of effective interventions for babies born too small or too soon is an urgent priority to increase survival and reduce disability, stunting, and non-communicable diseases.FundingBill & Melinda Gates Foundation by a grant to the US Fund for UNICEF to support the activities of the Child Health Epidemiology Reference Group (CHERG).

Inflammation has been implicated in the mechanisms responsible for preterm and term parturition, as well as fetal injury. Out of all of the suspected causes of preterm labour and delivery, infection and/or inflammation is the only pathological process for which both a firm causal link with preterm birth has been established and a molecular pathophysiology defined. Inflammation has also been implicated in the mechanism of spontaneous parturition at term. Most cases of histopathological inflammation and histological chorioamnionitis, both in preterm and term labour, are sub-clinical in nature. The isolation of bacteria in the amniotic fluid, known as microbial invasion of the amniotic cavity, is a pathological finding; the frequency of which is dependent upon the clinical presentation and gestational age. There is a window of time during which it may be possible to detect a 'molecular signature of inflammation' by analysis of the transcriptome before histological evidence is observed. This article reviews the role of inflammation in preterm and term parturition. It is possible that modulation of inflammation using anti-inflammatory cytokines, corticoids, antioxidants and/or other factors may complement antibiotic therapy and limit fetal injury.

The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age, The Journal of Maternal-Fetal & Neonatal Medicine, 21:5, 279-287, DOI: 10.1080 AbstractIntroduction. An imbalance between angiogenic and anti-angiogenic factors has been proposed as central to the pathophysiology of preeclampsia (PE). Indeed, patients with PE and those delivering small-for-gestational age (SGA) neonates have higher plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and the soluble form of endoglin (s-Eng), as well as lower plasma concentrations of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) than do patients with normal pregnancies. Of note, this imbalance has been observed before the clinical presentation of PE or the delivery of an SGA neonate. The objective of this study was to determine if changes in the profile of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters are associated with a high risk for the subsequent development of PE and/or delivery of an SGA neonate. Methods. This longitudinal case-control study included 402 singleton pregnancies in the following groups: (1) normal pregnancies with appropriate for gestational age (AGA) neonates (n ¼ 201); (2) patients who delivered an SGA neonate (n ¼ 145); and (3) patients who developed PE (n ¼ 56). Maternal plasma samples were obtained at the time of each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. In this study, we included two samples per patient: (1) first sample obtained between 6 and 15 weeks of gestation ('first trimester' sample), and (2) second sample obtained between 20 and 25 weeks of gestation ('second trimester' sample). Plasma concentrations of s-Eng, sVEGFR-1, and PlGF were determined by specific and sensitive immunoassays. Changes in the maternal plasma concentrations of these angiogenesis-related factors were compared among normal patients and those destined to develop PE or deliver an SGA neonate while adjusting for maternal age, nulliparity, and body mass index. General linear models and polytomous logistic regression models were used to relate the analyte concentrations, ratios, and product to the subsequent development of PE and SGA. Results.(1) An increase in the maternal plasma concentration of s-Eng between the first and second trimesters conferred risk for the development of preterm PE and SGA (OR 14.9, 95% CI 4.9-45.0 and OR 2.9, 95% CI 1.5-5.6, respectively).(2) An increase in the maternal plasma concentration of sVEGFR-1 between the first and second trimester conferred risk for the development of preterm PE (OR 3.9, 95% CI 1.2-12.6). (3) A subnormal increase in maternal plasma PlGF concentration between the first and the second trimester was a risk factor for the subsequent development of preterm and term PE (OR 4....

Objectives To estimate small for gestational age birth prevalence and attributable neonatal mortality in low and middle income countries with the INTERGROWTH-21st birth weight standard. Design Secondary analysis of data from the Child Health Epidemiology Reference Group (CHERG), including 14 birth cohorts with gestational age, birth weight, and neonatal follow-up. Small for gestational age was defined as infants weighing less than the 10th centile birth weight for gestational age and sex with the multiethnic, INTERGROWTH-21st birth weight standard. Prevalence of small for gestational age and neonatal mortality risk ratios were calculated and pooled among these datasets at the regional level. With available national level data, prevalence of small for gestational age and population attributable fractions of neonatal mortality attributable to small for gestational age were estimated. Setting CHERG birth cohorts from 14 population based sites in low and middle income countries. Main outcome measures In low and middle income countries in the year 2012, the number and proportion of infants born small for gestational age; number and proportion of neonatal deaths attributable to small for gestational age; the number and proportion of neonatal deaths that could be prevented by reducing the prevalence of small for gestational age to 10%. Results In 2012, an estimated 23.3 million infants (uncertainty range 17.6 to 31.9; 19.3% of live births) were born small for gestational age in low and middle income countries. Among these, 11.2 million (0.8 to 15.8) were term and not low birth weight (≥2500 g), 10.7 million (7.6 to 15.0) were term and low birth weight (<2500 g) and 1.5 million (0.9 to 2.6) were preterm. In low and middle income countries, an estimated 606 500 (495 000 to 773 000) neonatal deaths were attributable to infants born small for gestational age, 21.9% of all neonatal deaths. The largest burden was in South Asia, where the prevalence was the highest (34%); about 26% of neonatal deaths were attributable to infants born small for gestational age. Reduction of the prevalence of small for gestational age from 19.3% to 10.0% in these countries could reduce neonatal deaths by 9.2% (254 600 neonatal deaths; 164 800 to 449 700). Conclusions In low and middle income countries, about one in five infants are born small for gestational age, and one in four neonatal deaths are among such infants. Increased efforts are required to improve the quality of care for and survival of these high risk infants in low and middle income countries

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The combination of abnormal UADV and maternal plasma PlGF concentration of < 280 pg/mL in the second trimester is associated with a high risk for preeclampsia and early onset and/or severe preeclampsia in a low-risk population. Among those with abnormal UADV, a maternal plasma concentration of PlGF of < 280 pg/mL identifies most patients who will experience early onset and/or severe preeclampsia.