Objective
Ultrasound is widely regarded as an important adjunct to antenatal care (ANC) to guide practice and reduce perinatal mortality. We assessed the impact of ANC ultrasound use at health ...centres in resource‐limited countries.
Design
Cluster randomised trial.
Setting
Clusters within five countries (Democratic Republic of Congo, Guatemala, Kenya, Pakistan, and Zambia)
Methods
Clusters were randomised to standard ANC or standard care plus two ultrasounds and referral for complications. The study trained providers in intervention clusters to perform basic obstetric ultrasounds.
Main outcome measures
The primary outcome was a composite of maternal mortality, maternal near‐miss mortality, stillbirth, and neonatal mortality.
Results
During the 24‐month trial, 28 intervention and 28 control clusters had 24 263 and 23 160 births, respectively; 78% in the intervention clusters received at least one study ultrasound; 60% received two. The prevalence of conditions noted including twins, placenta previa, and abnormal lie was within expected ranges. 9% were referred for an ultrasound‐diagnosed condition, and 71% attended the referral. The ANC (RR 1.0 95% CI 1.00, 1.01) and hospital delivery rates for complicated pregnancies (RR 1.03 95% CI 0.89, 1.20) did not differ between intervention and control clusters nor did the composite outcome (RR 1.09 95% CI 0.97, 1.23) or its individual components.
Conclusions
Despite availability of ultrasound at ANC in the intervention clusters, neither ANC nor hospital delivery for complicated pregnancies increased. The composite outcome and the individual components were not reduced.
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Antenatal care ultrasound did not improve a composite outcome that included maternal, fetal, and neonatal mortality.
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Antenatal care ultrasound did not improve a composite outcome that included maternal, fetal, and neonatal mortality.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
Limited data are available from low‐ and middle‐income countries (LMICs) on the relationship of haemoglobin levels to adverse outcomes at different times during pregnancy. We evaluated the ...association of haemoglobin levels in nulliparous women at two times in pregnancy with pregnancy outcomes.
Design
ASPIRIN Trial data were used to study the association between haemoglobin levels measured at 6+0–13+6 weeks and 26+0–30+0 weeks of gestation with fetal and neonatal outcomes.
Setting
Obstetric care facilities in Pakistan, India, Kenya, Zambia, The Democratic Republic of the Congo and Guatemala.
Population
A total of 11 976 pregnant women.
Methods
Generalised linear models were used to obtain adjusted relative risks and 95% CI for adverse outcomes.
Main outcome measures
Preterm birth, stillbirth, neonatal death, small for gestational age (SGA) and birthweight <2500 g.
Results
The mean haemoglobin levels at 6+0–13+6 weeks and at 26–30 weeks of gestation were 116 g/l (SD 17) and 107 g/l (SD 15), respectively. In general, pregnancy outcomes were better with increasing haemoglobin. At 6+0–13+6 weeks of gestation, stillbirth, SGA and birthweight <2500 g, were significantly associated with haemoglobin of 70–89 g/l compared with haemoglobin of 110–129 g/l The relationships of adverse pregnancy outcomes with various haemoglobin levels were more marked at 26–30 weeks of gestation.
Conclusions
Both lower and some higher haemoglobin concentrations are associated with adverse fetal and neonatal outcomes at 6+0–13+6 weeks and at 26–30 weeks of gestation, although the relationship with low haemoglobin levels appears more consistent and generally stronger.
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Both lower and some higher haemoglobin concentrations were associated with adverse fetal and neonatal outcomes at 6–13 weeks and 26–30 weeks of gestation.
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Both lower and some higher haemoglobin concentrations were associated with adverse fetal and neonatal outcomes at 6–13 weeks and 26–30 weeks of gestation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
We sought to classify causes of stillbirth for six low‐middle‐income countries using a prospectively defined algorithm.
Design
Prospective, observational study.
Setting
Communities in ...India, Pakistan, Guatemala, Democratic Republic of Congo, Zambia and Kenya.
Population
Pregnant women residing in defined study regions.
Methods
Basic data regarding conditions present during pregnancy and delivery were collected. Using these data, a computer‐based hierarchal algorithm assigned cause of stillbirth. Causes included birth trauma, congenital anomaly, infection, asphyxia, and preterm birth, based on existing cause of death classifications and included contributing maternal conditions.
Main outcome measures
Primary cause of stillbirth.
Results
Of 109 911 women who were enrolled and delivered (99% of those screened in pregnancy), 2847 had a stillbirth (a rate of 27.2 per 1000 births). Asphyxia was the cause of 46.6% of the stillbirths, followed by infection (20.8%), congenital anomalies (8.4%) and prematurity (6.6%). Among those caused by asphyxia, 38% had prolonged or obstructed labour, 19% antepartum haemorrhage and 18% pre‐eclampsia/eclampsia. About two‐thirds (67.4%) of the stillbirths did not have signs of maceration.
Conclusions
Our algorithm determined cause of stillbirth from basic data obtained from lay‐health providers. The major cause of stillbirth was fetal asphyxia associated with prolonged or obstructed labour, pre‐eclampsia and antepartum haemorrhage. In the African sites, infection also was an important contributor to stillbirth. Using this algorithm, we documented cause of stillbirth and its trends to inform public health programs, using consistency, transparency, and comparability across time or regions with minimal burden on the healthcare system.
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Major causes of stillbirth are asphyxia, pre‐eclampsia and haemorrhage. Infections are important in Africa.
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Major causes of stillbirth are asphyxia, pre‐eclampsia and haemorrhage. Infections are important in Africa.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
To describe the causes of maternal death in a population‐based cohort in six low‐ and middle‐income countries using a standardised, hierarchical, algorithmic cause of death (COD) ...methodology.
Design
A population‐based, prospective observational study.
Setting
Seven sites in six low‐ to middle‐income countries including the Democratic Republic of the Congo (DRC), Guatemala, India (two sites), Kenya, Pakistan and Zambia.
Population
All deaths among pregnant women resident in the study sites from 2014 to December 2016.
Methods
For women who died, we used a standardised questionnaire to collect clinical data regarding maternal conditions present during pregnancy and delivery. These data were analysed using a computer‐based algorithm to assign cause of maternal death based on the International Classification of Disease—Maternal Mortality system (trauma, termination of pregnancy‐related, eclampsia, haemorrhage, pregnancy‐related infection and medical conditions). We also compared the COD results to healthcare‐provider‐assigned maternal COD.
Main outcome measures
Assigned causes of maternal mortality.
Results
Among 158 205 women, there were 221 maternal deaths. The most common algorithm‐assigned maternal COD were obstetric haemorrhage (38.6%), pregnancy‐related infection (26.4%) and pre‐eclampsia/eclampsia (18.2%). Agreement between algorithm‐assigned COD and COD assigned by healthcare providers ranged from 75% for haemorrhage to 25% for medical causes coincident to pregnancy.
Conclusions
The major maternal COD in the Global Network sites were haemorrhage, pregnancy‐related infection and pre‐eclampsia/eclampsia. This system could allow public health programmes in low‐ and middle‐income countries to generate transparent and comparable data for maternal COD across time or regions.
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An algorithmic system for determining maternal cause of death in low‐resource settings is described.
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An algorithmic system for determining maternal cause of death in low‐resource settings is described.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The objective of this study was to investigate the effect of insulin and IGF-I on protein synthesis and translation initiation in C2C12 myotubes in nutrient-deprived Dulbecco’s phosphate buffered ...saline (DPBS). The results showed that insulin and IGF-I increased protein synthesis by 62% and 35% respectively in DPBS, and the effect was not affected by rapamycin, but was blocked by LY294002. Insulin and IGF-I stimulated eukaryotic initiation factor 4E (eIF4E) binding protein (4EBP1) phosphorylation in a dose-dependent manner, and the stimulation was independent of availability of external amino acids. Both LY294002 and rapamycin blocked the insulin and IGF-I-induced increases in 4EBP1 phosphorylation. The results also showed that insulin and IGF-I were able to stimulate PKB/Akt phosphorylation, glycogen synthase kinase (GSK) 3β phosphorylation and mTOR phosphorylation in DPBS. Insulin and IGF-I increased the amount of eIF4G associated with eIF4E in nutrient-deprived C2C12 myotubes. The amount of 4EBP1 associated with eIF4E was decreased after insulin or IGF-I stimulation. We conclude that in C2C12 myotubes, insulin and IGF-I may regulate protein synthesis and translation initiation independent of external amino acid supply via the phosphatidylinositol-3 kinase-PKB/Akt-mTOR pathway.
The insulin-like growth factors (IGF) are important anabolic hormones in the mammalian fetus; their anabolic actions are potentially modulated by alterations in the IGF-binding proteins (IGFBP). We ...have previously shown that the nutritional state of the fetus affects both IGF-I and the IGFBP concentrations. The present study was designed to determine the effect of alterations in insulin and IGF-I circulating concentrations on the IGFBPs. Because both insulin and IGF-I elicit decreases in glucose and amino acid concentrations, the concentrations of these substrates were clamped during the hormone infusions. Sixteen ovine fetuses were chronically catheterized at approximately 115 days of gestation, and experimental procedures performed at approximately 130 days of gestation. Insulin, IGF-I or both were infused for an 8-h period. Baseline concentrations of hormones and binding proteins were obtained, and concentrations were also obtained at the end of the infusion. Hepatic IGFBP-1 mRNA expression was also determined. Intravenous infusion of IGF-I significantly increased IGF-I concentrations in plasma in the ovine fetus. Intravenous infusion of insulin inhibited hepatic IGFBP-1 gene expression when amino acids and glucose were clamped. In contrast, intravenous infusion of recombinant human IGF-I (rhIGF-I) enhanced hepatic IGFBP-1 gene expression. Neither insulin nor rhIGF-I treatment had an effect on hepatic IGFBP-3 gene expression. Insulin did not alter plasma IGFBP-1 significantly, but it increased IGFBP-3 in plasma. rhIGF-I increased both IGFBP-1 and IGFBP-3 protein levels in plasma. The responses of IGFBP-1 and IGFBP-3 to increased plasma IGF-I and insulin may serve to protect the fetus from exaggerated anabolic effects and to blunt the hypoglycemic potential of circulating IGFs and insulin.
This study was conducted to investigate fasting-induced alterations in insulin signaling to the regulatory components of the translation machinery. Insulin (890 mIU/h) and IGF-I (40 nM/h) were ...infused into a chronically catheterized ovine fetus (0.85 gestation) for 7 h following a 5-d maternal fast. Amino acid and glucose concentrations were clamped to minimize the effects of alterations in circulating substrate concentrations. The IGF-I induced increase in 4E-BP1 phosphorylation (percentage in the gamma form) increased from 28% in control to 44% (NS). The insulin-induced increase in 4E-BP1 phosphorylation was more pronounced, and the gamma percentage was 56% on average in the insulin group. The insulin-induced increase in 4E-BP1 phosphorylation was lower than in fed animals and did not result in significant changes in eIF4E.4E-BP1 binding or eIF4E.eIF4G binding. Insulin increased PKB/Akt phosphorylation and p70S6K phosphorylation to a similar extent as in fed animals. We conclude that maternal fasting resulted in reduced insulin sensitivity of 4E-BP1 phosphorylation and eIF4F formation. This reduced insulin-induced 4E-BP1 phosphorylation was not due to a global defect in insulin signaling; the defects underlying the reduced basal phosphorylation and insulin-responsiveness of 4E-BP1 in fasted animals may be in signaling components other than, or downstream of, PKB/Akt. Selective inhibition of downstream components of insulin signaling allows fetuses to adapt to nutritional stress by decreasing the anabolic response to insulin and other growth factors, so that more amino acids can be used as oxidative substrate to compensate for shortage of energy due to reduced glucose supply.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Section of Neonatal-Perinatal Medicine, Department of Pediatrics,
Indiana University School of Medicine, James Whitcomb Riley
Hospital for Children, Indianapolis, Indiana 46202
To determine whether ...increased amino acid availability can
reduce proteolysis in premature neonates and to assess the capacity of
infants born prematurely to acutely increase the irreversible catabolism of the essential amino acids leucine (via oxidation) and
phenylalanine (via hydroxylation to form tyrosine), leucine and
phenylalanine kinetics were measured under basal conditions and in
response to a graded infusion of intravenous amino acids (1.2 and 2.4 g · kg 1 · day 1 ) in
clinically stable premature (~32 wk gestation) infants in the 1st wk
of life. In contrast to the dose-dependent suppression of proteolysis
seen in healthy full-term neonates, the endogenous rates of appearance
of leucine and phenylalanine (reflecting proteolysis) were unchanged in
response to amino acids (297 ± 21, 283 ± 19, and 284 ± 31 µmol · kg 1 · h 1 for
leucine and 92 ± 6, 92 ± 4, and 84 ± 7 µmol · kg 1 · h 1 for
phenylalanine). Similar to full-term neonates, leucine oxidation (40 ± 5, 65 ± 6, and 99 ± 7 µmol · kg 1 · h 1 ) and
phenylalanine hydroxylation (12 ± 1, 16 ± 1, and 20 ± 2 µmol · kg 1 · h 1 )
increased in a stepwise fashion in response to graded amino acids. This
capacity to increase phenylalanine hydroxylation may be crucial to meet
tyrosine needs when exogenous supply is limited. Finally, to determine
whether amino acids stimulate glucose production in premature neonates,
glucose rate of appearance was measured during each study period. In
response to amino acid infusion, rates of endogenous glucose production
were unchanged (and near zero).
premature newborns; leucine; phenylalanine; protein turnover; stable isotope tracers
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
Submitted 17 November 2004
; accepted in final form 5 January 2005
Fetal nutritional stress ...may result in intrauterine growth restriction and postnatal insulin resistance. To determine whether insulin resistance can begin in utero, we subjected late-gestation (130135 days) ewes to 120 h of complete fasting and compared the results with our previous work in fed ewes (38). We determined the effect of insulin and/or recombinant human (rh)IGF-I infusion on ovine fetal phenylalanine kinetics, protein synthesis, and phenylalanine accretion. Experimental infusates were 1 ) saline, 2 ) rhIGF-I plus a replacement dose of insulin (40 nmol IGF-I/h + 16 mIU insulin/h), 3 ) insulin (890 mIU/h), and 4 ) IGF-I plus insulin (40 nmol IGF-I/h + 890 mIU insulin/h). During hormone infusion, both glucose and amino acid concentrations were clamped at basal concentrations. Amino acid infusion was required during infusion of either hormone to maintain plasma concentrations constant. However, the amount required during insulin infusion was less than during IGF-I infusion and 40% less than the amount required during identical studies in nonfasted animals. Phenylalanine used for protein synthesis and accretion was increased compared with control animals but again less so than in the nonfasted animals. In contrast to nonfasted animals, neither hormone increased the fractional synthetic rate of skeletal muscle protein nor that of plasma albumin. These results indicate that a short but severe nutritional stress can significantly alter the fetal anabolic response to insulin even when both glucose and amino acid substrate supplies are restored. Therefore, adaptive responses characterized by insulin resistance begin in utero when the fetus is subjected to sufficient nutritional stress.
protein synthesis; skeletal muscle; phenylalanine kinetics; fetal programming
Address for reprint requests and other correspondence: E. A. Liechty, Riley Hospital R208, 699 West Dr., Indianapolis, IN 46202 (E-mail: eliecht{at}iupui.edu )
Herman B. Wells Center for Pediatric Research, Indiana
University School of Medicine, Indianapolis, Indiana 46202
The mechanisms by which insulin-like
growth factor I (IGF-I) and insulin regulate ...eukaryotic initiation
factor (eIF)4F formation were examined in the ovine fetus. Insulin
infusion increased phosphorylation of eIF4E-binding protein
(4E-BP1) in muscle and liver. IGF-I infusion did not alter
4E-BP1 phosphorylation in liver. In muscle, IGF-I increased
4E-BP1 phosphorylation by 27%; the percentage in the -form in
the IGF-I group was significantly lower than that in the insulin group.
In liver, only IGF-I increased eIF4G. Both IGF-I and insulin increased
eIF4E · eIF4G binding in muscle, but only insulin decreased the
amount of 4E-BP1 associated with eIF4E. In liver, only IGF-I
increased eIF4E · eIF4G binding. Insulin increased the
phosphorylation of p70 S6 kinase (p70 S6k ) in both muscle
and liver and protein kinase B (PKB/Akt) in muscle, two indicative
signal proteins in the phosphatidylinositol (PI) 3-kinase pathway.
IGF-I increased PKB/Akt phosphorylation in muscle but had no effect on
p70 S6k phosphorylation in muscle or liver. We conclude that
insulin and IGF-I modulate eIF4F formation; however, the two hormones have different regulatory mechanisms. Insulin increases phosphorylation of 4E-BP1 and eIF4E · eIF4G binding in muscle, whereas
IGF-I regulates eIF4F formation by increasing total eIF4G. Insulin, but
not IGF-I, decreased 4E-BP1 content associated with eIF4E. Insulin
regulates translation initiation via the PI 3-kinase-p70 S6k
pathway, whereas IGF-I does so mainly via mechanisms independent of the
PI 3-kinase-p70 S6k pathway.
insulin; insulin-like growth factor I; fetus; eukaryotic initiation
factors; p70 S6 kinase
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