AbstractBackgroundHuman birthweight is a complex, multifactorial trait. Maternal characteristics contribute to birthweight variation by influencing the intrauterine environment. Variation explained by genetic effects is also important, but their contributions have not been assessed alongside other key determinants. We aimed to investigate variance in birthweight explained by genetic scores in addition to easily-measurable clinical and anthropometric variables.MethodsWe analysed 549 European-ancestry parent-offspring trios. We investigated variance explained in birthweight (adjusted for sex and gestational age) in multivariable linear regression models including genetic scores, routinely-measured maternal characteristics and parental anthropometric variables. We used R-Squared (R2) to estimate variance explained, adjusted R-squared (Adj-R2) to assess improvement in model fit from added predictors, and F-tests to compare nested models.ResultsMaternal and fetal genetic scores together explained 6.0% variance in birthweight. A model containing maternal age, weight, smoking, parity and 28-week fasting glucose explained 21.7% variance. Maternal genetic score explained additional variance when added to maternal characteristics (Adj-R2 =0.233 vs Adj-R2=0.210, p<0.001). Fetal genetic score improved variance explained (Adj-R2=0.264 vs 0.248, p<0.001) when added to maternal characteristics and parental heights.ConclusionsGenetic scores account for variance explained in birthweight in addition to easily measurable clinical variables. Parental heights partially capture fetal genotype and its contribution to birthweight, but genetic scores explain additional variance. While the genetic contribution is modest, it is comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.Key messagesKnown contributors to variation in birthweight include (i) factors associated with the maternal intrauterine environment (e.g. maternal glycaemia or smoking), and (ii) parental heights, which capture some of the genetic contribution to fetal growth. However, the added contribution of genetic scores composed of common birthweight-associated variants has not been assessed.We showed, using 549 parent-offspring trios, that maternal and fetal genetic scores explained additional variation in sex-and gestational age-adjusted birthweight, when added to maternal variables that are easily obtained in a clinical setting (age, weight, smoking, parity and 28-week fasting glucose).Parental heights explained variance in birthweight independently of routinely measured maternal clinical variables, but the maternal and fetal (or paternal) genetic scores made additional, independent contributions to birthweight variance.The genetic score contribution was modest, but it was comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.Since this work was limited to a UK sample of European ancestry, it will, however, be important to test the relative contributions of genetics and other factors to birthweight variation in diverse populations.

Background: Using genetic scores for fasting plasma glucose (FPG GS) and type 2 diabetes (T2D GS), we investigated whether the fasting, 1-hour and 2-hour glucose thresholds from the WHO 2013 criteria for gestational diabetes (GDM) have different implications for genetic susceptibility to raised fasting glucose and type 2 diabetes in women from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and Atlantic Diabetes in Pregnancy (DIP) studies. Methods: Cases were divided into three subgroups: (i) FPG ≥5.1 mmol/L only, n=222; (ii) 1-hour glucose post 75 g oral glucose load ≥10 mmol/L only, n=154 (iii) 2-hour glucose ≥8.5 mmol/L only, n=73; and (iv) both FPG ≥5.1 mmol/L and either of a 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, n=172. We compared the FPG and T2D GS of these groups with controls (n=3,091) in HAPO and DIP separately. Results: in HAPO and DIP, the mean FPG GS in women with a FPG ≥5.1 mmol/L, either on its own or with 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, was higher than controls (all P <0.01). Mean T2D GS in women with a raised FPG alone or with either a raised 1-hour or 2-hour glucose was higher than controls (all P <0.05). GDM defined by 1-hour or 2-hour hyperglycaemia only was also associated with a higher T2D GS than controls (all P <0.05). Conclusions: the different diagnostic categories that are part of the WHO 2013 criteria for GDM identify women with a genetic predisposition to type 2 diabetes as well as a risk for adverse pregnancy outcomes.

Heterozygous mutations in GCK result in a persistent, mildly raised glucose from birth, but it is usually diagnosed in adulthood as maturity-onset diabetes of the young (MODY), where hyperglycemia is often an incidental finding. The hyperglycemia of GCK-MODY is benign and does not require treatment, but is important to be aware of, particularly in females where it has implications for managing pregnancy. We present three cases of neonatal hyperglycemia resulting from a heterozygous mutation in GCK, illustrating its clinical presentation and evolution in early life. In summary, as with adults, neonatal hyperglycemia is an incidental finding, does not require treatment and has no adverse consequences for health. Neonates and their parents should be referred for genetic testing to confirm the diagnosis, avoid a label of diabetes and enable pregnancy counseling for females found to be affected.

AbstractIn 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease.
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Background: Using genetic scores for fasting plasma glucose (FPG GS) and type 2 diabetes (T2D GS), we investigated whether the fasting, 1-hour and 2-hour glucose thresholds from the WHO 2013 criteria for gestational diabetes (GDM) have different implications for genetic susceptibility to raised fasting glucose and type 2 diabetes in women from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and Atlantic Diabetes in Pregnancy (DIP) studies. Methods: Cases were divided into three subgroups: (i) FPG ≥5.1 mmol/L only, n=222; (ii) 1-hour glucose post 75 g oral glucose load ≥10 mmol/L only, n=154 (iii) 2-hour glucose ≥8.5 mmol/L only, n=73; and (iv) both FPG ≥5.1 mmol/L and either of a 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, n=172. We compared the FPG and T2D GS of these groups with controls (n=3,091) in HAPO and DIP separately. Results: in HAPO and DIP, the mean FPG GS in women with a FPG ≥5.1 mmol/L, either on its own or with 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, was higher than controls (all P <0.01). Mean T2D GS in women with a raised FPG alone or with either a raised 1-hour or 2-hour glucose was higher than controls (all P <0.05). GDM defined by 1-hour or 2-hour hyperglycaemia only was also associated with a higher T2D GS than controls (all P <0.05). Conclusions: the different diagnostic categories that are part of the WHO 2013 criteria for GDM identify women with a genetic predisposition to type 2 diabetes as well as a risk for adverse pregnancy outcomes.

Background: Using genetic scores for fasting plasma glucose (FPG GS) and type 2 diabetes (T2D GS), we investigated whether the fasting, 1-hour and 2-hour glucose thresholds from the WHO 2013 criteria for gestational diabetes (GDM) have different implications for genetic susceptibility to raised fasting glucose and type 2 diabetes in women from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and Atlantic Diabetes in Pregnancy (DIP) studies. Methods: Cases were divided into three subgroups: (i) FPG ≥5.1 mmol/L only, n=222; (ii) 1-hour glucose post 75 g oral glucose load ≥10 mmol/L only, n=154 (iii) 2-hour glucose ≥8.5 mmol/L only, n=73; and (iv) both FPG ≥5.1 mmol/L and either of a 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, n=172. We compared the FPG and T2D GS of these groups with controls (n=3,091) in HAPO and DIP separately. Results: in HAPO and DIP, the mean FPG GS in women with a FPG ≥5.1 mmol/L, either on its own or with 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, was higher than controls (all P <0.01). Mean T2D GS in women with a raised FPG alone or with either a raised 1-hour or 2-hour glucose was higher than controls (all P <0.05). GDM defined by 1-hour or 2-hour hyperglycaemia only was also associated with a higher T2D GS than controls (all P <0.05). Conclusions: the different diagnostic categories that are part of the WHO 2013 criteria for GDM identify women with a genetic predisposition to type 2 diabetes as well as a risk for adverse pregnancy outcomes.

Context: Previous studies have shown reduced placental levels of 11-hydroxysteroid dehydrogenase type 2 (11HSD2) in preeclampsia (PE). However, it is unknown if the maternal cortisol-to-cortisone ratio is predictive of placental complications of pregnancy. Objective: to determine the relationship between the maternal serum cortisol-to-cortisone ratio at different stages of pregnancy and the risk of PE or fetal growth restriction (FGR). Design: Women from the Pregnancy Outcome Prediction Study experiencing PE (n = 194) or FGR (n = 185), plus a random sample of healthy controls (n = 279), were studied. Steroids were measured at;12,;20,;28, and;36 weeks of gestational age (wkGA). Separate analyses were performed for outcomes with term or preterm delivery. Associations were modeled using logistic regression. Results: at 28 wkGA, the cortisol-to-cortisone ratio was negatively associated (OR per 1 SD increase, 95% CI)] with preterm PE (OR 0.33, 95% CI 0.19 to 0.57), term PE (OR 0.61, 95% CI 0.49 to 0.76), and preterm FGR (OR 0.50, 95% CI 0.29 to 0.85). At 36 wkGA, the cortisol-to-cortisone ratio was negatively associated with term PE (OR 0.42, 95% CI 0.32 to 0.55) but not term FGR (OR 1.07, 95% CI 0.87 to 1.31). Associations were not materially affected by adjustment for maternal characteristics. Conclusions: a lower maternal serum cortisol-to-cortisone ratio precedes clinical manifestation of PE and preterm FGR by many weeks, despite previous reports of reduced levels of placental 11bHSD2 in these conditions. Our observations implicate enhanced maternal 11bHSD2 activity or reduced 11bHSD type 1 activity in the pathophysiology of PE.

Introduction: Low maternal serum levels of pregnancy-associated plasma protein a (PAPP-A) measured in the first trimester and high levels of alpha fetoprotein (AFP) measured in the second trimester have been associated with adverse pregnancy outcomes reflective of placental insufficiency, and there is a synergistic relationship between the two. We investigated the utility as a screening test of a simple ratio of maternal serum AFP to PAPP-A (AFP:PAPP-A) measured in the first trimester. Methods: We studied 4057 nulliparous women with a singleton pregnancy from the Pregnancy Outcome Prediction (POP) study. We studied the predictive ability for adverse outcome of the AFP:PAPP-A ratio measured in the first trimester with and without correction for maternal weight and gestational age at measurement. We compared the AFP:PAPP-A ratio with corrected AFP and PAPP-A on their own and in combination. Results: an AFP:PAPP-A ratio >10 was associated with placentally-related adverse outcomes, including fetal growth restriction (risk ratio (RR) 3.74, 95% confidence interval (CI) 2.30–6.09), severe preeclampsia (RR 2.12, 95% CI 1.39–3.25) and stillbirth (RR 5.05, 95% CI 1.48–17.18). The ratio performed favorably in predicting adverse pregnancy outcomes when compared with corrected measurements of either AFP or PAPP-A, and was equivalent to a model combining the two. Its predictive ability was not affected by correction for maternal weight or gestational age at measurement. Discussion: an elevated maternal AFP:PAPP-A ratio in the first trimester is associated with placentally-related adverse outcomes in a cohort of unselected nulliparous women.

Maternal glycemia is a key determinant of birth weight, but recent large-scale genome-wide association studies demonstrated an important contribution of fetal genetics. It is not known whether fetal genotype modifies the impact of maternal glycemia or whether it acts through insulin-mediated growth. We tested the effects of maternal fasting plasma glucose (FPG) and a fetal genetic score for birth weight on birth weight and fetal insulin in 2,051 European mother-child pairs from the Exeter Family Study of Childhood Health (EFSOCH) and the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The fetal genetic score influenced birth weight independently of maternal FPG and impacted growth at all levels of maternal glycemia. For mothers with FPG in the top tertile, the frequency of large for gestational age (birth weight ≥90th centile) was 31.1% for offspring with the highest tertile genetic score and only 14.0% for those with the lowest tertile genetic score. Unlike maternal glucose, the fetal genetic score was not associated with cord insulin or C-peptide. Similar results were seen for HAPO participants of non-European ancestry (n = 2,842 pairs). This work demonstrates that for any level of maternal FPG, fetal genetics has a major impact on fetal growth and acts predominantly through independent mechanisms.

We evaluated the impact of placental micro (≤50 mg) and macro (∼200 mg) explants, oxygen concentration and culture method on placental RNA quality after long-term culture. Our findings show that micro explants cultured at 8% oxygen have the best RNA quality and tissue structure. Macro explants were less viable after long-term culture. Macro explants and explants undergoing syncytial degeneration produced poor quality RNA and should be avoided.

We compared the neonatal and infant outcomes at one year (Bayley mental and psychomotor development index, and physical growth) of babies who were (n = 63) or were not (n = 100) delivered prior to 37 weeks in women admitted in threatened late preterm labor (34-35+6 weeks) with a cervix ≤15 mm. The women were part of a clinical trial to investigate the tocolytic effect of the oxytocin antagonist barusiban. Babies born late preterm (34-36 +6 weeks) had a significantly increased risk of short-term morbidity (hepatobiliary disorders, respiratory disorders, metabolic disorders, nervous system disorders, infection; p < 0.05 for each) compared with those born at term, but there were no significant differences in the neurodevelopmental and physical outcomes at one year (p > 0.05 for both one-year outcomes). © 2013 Nordic Federation of Societies of Obstetrics and Gynecology.

We compared the neonatal and infant outcomes at one year (Bayley mental and psychomotor development index, and physical growth) of babies who were (n = 63) or were not (n = 100) delivered prior to 37 weeks in women admitted in threatened late preterm labor (34-35(+6) weeks) with a cervix ≤15 mm. The women were part of a clinical trial to investigate the tocolytic effect of the oxytocin antagonist barusiban. Babies born late preterm (34-36(+6) weeks) had a significantly increased risk of short-term morbidity (hepatobiliary disorders, respiratory disorders, metabolic disorders, nervous system disorders, infection; p < 0.05 for each) compared with those born at term, but there were no significant differences in the neurodevelopmental and physical outcomes at one year (p > 0.05 for both one-year outcomes).

Preterm birth may be spontaneous or medically indicated for maternal or fetal reasons. Around 20-25% of preterm births (PTB) follow preterm premature rupture of the membranes (PPROM), however the cause of preterm labour is often unknown. It may represent early maturation and activation of the normal labour process or it may be precipitated by pathological causes. The normal process of labour has a diurnal variation with more deliveries occurring at night. Evidence demonstrating that the diurnal variation persists in preterm deliveries suggest that at least a proportion are due to early maturation of the normal process and the logical assumption is that these may be amenable to prevention or effective treatment. Whatever the cause of preterm delivery, there appears to be a common pathway resulting in activation of inflammatory processes. It is important to distinguish the physiological and pathological causes of preterm labour and not to assume that all inflammation is pathological. The distinction is clinically important since pathological causes may be associated with an adverse intrauterine environment, which would be a contraindication to delaying delivery.