Genetic effects on the timing of parturition and links to fetal birth weight.

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.

Large maternal waist circumference in relation to height is associated with high glucose concentrations in an early-pregnancy oral glucose tolerance test: A population-based study.

INTRODUCTION: To explore the role of maternal anthropometric characteristics in early-pregnancy glycemia, we analyzed the associations and interactions of maternal early-pregnancy waist circumference (WC), height and pre-pregnancy body mass index (BMI) with plasma glucose concentrations in an oral glucose tolerance test (OGTT) at 12-16 weeks' gestation. MATERIAL AND METHODS: A population-based cohort of 1361 pregnant women was recruited in South Karelia, Finland, from March 2013 to December 2016. All participants had their WC, weight, height, HbA1c , and blood pressure measured at 8-14 weeks' gestation and subsequently underwent a 2-h 75-g OGTT, including assessment of fasting insulin concentrations, at 12-16 weeks' gestation. BMI (kg/m2 ) was calculated using self-reported pre-pregnancy weight. Maternal WC ≥80 cm was defined as large. Maternal height ≥166 cm was defined as tall. Data on gestational diabetes treatment was extracted from hospital records. RESULTS: In the total cohort, 901 (66%) of women had an early-pregnancy WC ≥80 cm, which was associated with higher early-pregnancy HbA1c, higher concentrations of  fasting plasma glucose and serum insulin, higher post-load plasma glucose concentrations, higher HOMA-IR indices, higher blood pressure levels, and higher frequencies of pharmacologically treated gestational diabetes, than early-pregnancy WC <80 cm. Maternal height ≥166 cm was negatively associated with 1- and 2-h post-load plasma glucose concentrations. Waist-to-height ratio (WHtR) >0.5 was positively associated with both fasting and post-load plasma glucose concentrations at 12-16 weeks' gestation, even when adjusted for age, smoking, nulliparity, and family history of type 2 diabetes. The best cut-offs for WHtR (0.58 for 1-h plasma glucose, and 0.54 for 2-h plasma glucose) were better predictors of post-load glucose concentrations >90th percentile than the best cut-offs for BMI (28.1 kg/m2 for 1-h plasma glucose, and 26.6 kg/m2 for 2-h plasma glucose), with areas-under-the-curve (95% confidence interval) 0.73 (0.68-0.79) and 0.73 (0.69-0.77), respectively, for WHtR, and 0.68 (0.63-0.74) and 0.69 (0.65-0.74), respectively, for BMI. CONCLUSIONS: In our population-based cohort, early-pregnancy WHtR >0.5 was positively associated with both fasting and post-load glucose concentrations at 12-16 weeks' gestation and performed better than BMI in the prediction of post-load glucose concentrations >90th percentile. Overall, our results underline the importance of evaluating maternal abdominal adiposity in gestational diabetes risk assessment.

Higher pulse wave velocity in young adult offspring of mothers with type 1 diabetes: a case-control study.

BACKGROUND: Offspring of mothers with type 1 diabetes have an increased risk for acquiring early onset cardiovascular disease (CVD). Arterial stiffness, measured as pulse wave velocity (PWV), is a non-invasive biomarker for CVD risk assessment. Our aim is to determine whether PWV is increased in young adult offspring of mothers with type 1 diabetes. METHODS: This is a case-control study carried out in the hospital district of Helsinki and Uusimaa, Finland. 75 offspring of mothers with type 1 diabetes (cases) and 84 offspring of mothers without diabetes (controls), aged 18-23 years, were enrolled in this study. All participants attended clinical assessments, including questionnaires and laboratory tests. Carotid-femoral PWV (cfPWV), carotid-radial PWV (crPWV), and PWV ratio were measured from each participant using the Complior Analyse mechanotransducer (Alam Medical, France). Student's t-test and chi-squared test were used to assess differences between the groups. Stata 17.0, StataCorp LP (College Station, TX, USA) statistical package was used for the analysis. RESULTS: We did not observe any differences in conventional CVD risk factors: systolic blood pressure, LDL, HbA1c, and smoking between cases and controls. We detected higher cfPWV in cases 6.5 (SD ± 1.2) m/s than in controls 6.2 (SD ± 0.7) m/s, p = 0.049, after adjustments for BMI, smoking, mean arterial pressure, height, and pulse rate was made. We did not observe any difference between cases and controls regarding crPWV or PWV ratio. Additionally, we detected no sex differences. CONCLUSIONS: We report a novel finding of signs of increased arterial stiffness already in young adult offspring of mothers with type 1 diabetes compared to matched offspring of mothers without diabetes. Our finding suggests that exposure to an adverse intrauterine environment of type 1 diabetes mothers may affect the vascular health of offspring already in young adulthood. Additional research within this topic is warranted.

Increased variability of fetal heart rate during labour: a review of preclinical and clinical studies.

Increased fetal heart rate variability (FHRV) in intrapartum cardiotocographic recording has been variably defined and poorly understood, limiting its clinical utility. Both preclinical (animal) and clinical (human) evidence support that increased FHRV is observed in the early stage of intrapartum fetal hypoxaemia but can also be observed in a subset of fetuses during the preterminal stage of repeated hypoxaemia. This review of available evidence provides data and expert opinion on the pathophysiology of increased FHRV, its clinical significance and a stepwise approach regarding the management of this pattern, and propose recommendations for standardisation of related terminology.

Late-Pregnancy Fetal Hypoxia Is Associated With Altered Glucose Metabolism and Adiposity in Young Adult Offspring of Women With Type 1 Diabetes.

Objective: To investigate associations between exposure to fetal hypoxia and indicators of metabolic health in young adult offspring of women with type 1 diabetes (OT1D). Methods: 156 OT1D born between 7/1995 and 12/2000 at Helsinki University Hospital, Finland, were invited for follow-up between 3/2019 and 11/2019. A control group of 442 adults born from non-diabetic pregnancies, matched for date and place of birth, was obtained from the Finnish Medical Birth Register. In total, 58 OT1D and 86 controls agreed to participate. All OT1D had amniotic fluid (AF) sampled for erythropoietin (EPO) measurement within two days before delivery in order to diagnose fetal hypoxia. In total, 29 OTID had an AF EPO concentration <14.0 mU/l, defined as normal, and were categorized into the low EPO (L-EPO) group. The remaining 29 OT1D had AF EPO ≥14.0 mU/ml, defined as fetal hypoxia, and were categorized into the high EPO (H-EPO) group. At the age of 18-23 years, participants underwent a 2-h 75g oral glucose tolerance test (OGTT) in addition to height, weight, waist circumference, body composition, blood pressure, HbA1c, cholesterol, triglyceride, high-sensitivity CRP and leisure-time physical activity measurements. Results: Two OT1D were diagnosed with diabetes and excluded from further analyses. At young adult age, OT1D in the H-EPO group had a higher BMI than those in the L-EPO group. In addition, among female participants, waist circumference and body fat percentage were highest in the H-EPO group. In the OGTTs, the mean (SD) 2-h post-load plasma glucose (mmol/L) was higher in the H-EPO [6.50 (2.11)] than in the L-EPO [5.21 (1.10)] or control [5.67 (1.48)] offspring (p=0.009). AF EPO concentrations correlated positively with 2-h post-load plasma glucose [r=0.35 (95% CI: 0.07 to 0.62)] and serum insulin [r=0.44 (95% CI: 0.14 to 0.69)] concentrations, even after adjusting for maternal BMI, birth weight z-score, gestational age at birth and adult BMI. Control, L-EPO and H-EPO groups did not differ with regards to other assessed parameters. Conclusions: High AF EPO concentrations in late pregnancy, indicating fetal hypoxia, are associated with increased adiposity and elevated post-load glucose and insulin concentrations in young adult OT1D.

Intrapartal cardiotocographic patterns and hypoxia-related perinatal outcomes in pregnancies complicated by gestational diabetes mellitus.

AIMS: In previous reports, cardiotocographic (CTG) fetal heart rate (FHR) monitoring has shown only limited benefits in decreasing adverse perinatal outcomes in pregnancies complicated by gestational diabetes mellitus (GDM). The aim of the present study was to evaluate whether an association exists between the recently reported ZigZag pattern (FHR baseline amplitude changes of > 25 bpm with a duration of 2-30 min) and asphyxia-related neonatal outcomes in GDM pregnancies. METHODS: Intrapartal CTGs were recorded in a one-year cohort of 5150 singleton childbirths. The following CTG changes were evaluated: ZigZag pattern, saltatory pattern, late decelerations, episodes of tachycardia and bradycardia, reduced variability, and uterine tachysystole. The cohort was divided into three groups: women with GDM, women with normal oral glucose tolerance test (OGTT), and women with no OGTT performed. Umbilical artery (UA) blood gases, Apgar scores, neonatal respiratory distress, and neonatal encephalopathy were used as outcome variables. RESULTS: GDM was diagnosed in 624 (12.1%), OGTT was normal in 4115 (79.9%), and OGTT was not performed in 411 (8.0%) women. Hypoxia-related ZigZag patterns (OR 1.94, 95% CI 1.64-2.34) and late decelerations (OR 1.65, 95% CI 1.27-2.13) of FHR, as well as a greater risk of fetal asphyxia (UA pH < 7.10 and/or UA BE < -12.0 meq/L and/or Apgar scores < 7 at 5-min) (OR 6.64, 95% CI 1.84-12.03) were observed in those with GDM compared with those without GDM. CONCLUSIONS: GDM is associated with intrapartal ZigZag pattern and late decelerations, cord blood acidemia and low 5-min Apgar scores at birth indicating increased occurrence of fetal hypoxia in GDM pregnancies.

Factors associated with intrapartum ZigZag pattern of fetal heart rate: A retrospective one-year cohort study of 5150 singleton childbirths.

OBJECTIVES: Recent studies suggest that intrapartum ZigZag pattern of fetal heart rate (FHR) is significantly associated with cord blood acidaemia and neonatal complications. For the clinical significance of this pattern, it is mandatory that ZigZag episodes in cardiotocographic (CTG) recording are correctly identified. The aim of the present study was to examine maternal, fetal and delivery-related factors that could explain the occurrence of ZigZag pattern of FHR during the last 2 h of labour in a large obstetric cohort. STUDY DESIGN: CTG recordings from 5150 singleton childbirths at ≥33 weeks of gestation during one year were evaluated retrospectively and blinded to pregnancy and neonatal outcomes in a university hospital in Helsinki, Finland. All women in the cohort were in the active phase of labour with regular uterine contractions. ZigZag FHR pattern was defined as FHR baseline amplitude changes of >25 bpm with a duration of 2-30 min. The following maternal, fetal and labour/delivery-related variables were determined: maternal age, obesity (prepregnancy BMI ≥ 30.0 kg/m2), parity, preeclampsia, maternal fever ≥38.0 °C, smoking, gestational age at delivery, fetal sex, birth weight z-score, mode of delivery, and type of onset of labour. RESULTS: ZigZag pattern occurred in 582/5150 (11.3 %) cases, and only in childbirths after 37 weeks of gestation. Fetal male gender (OR 3.29; 95 % CI 2.70-4.02), nulliparous pregnancy (OR 2.60; 95 % CI 2.15-3.15) and post-term gestational age (≥42 weeks) (OR 1.92; 95 % CI 1.47-2.48) were independently associated with the occurrence of ZigZag pattern. Among the three significant risk factors, clustering of two or three factors was associated with an increase of the ZigZag pattern occurrence risk to 5.0-16.4-fold (95 % CI 3.16-31.60). CONCLUSIONS: ZigZag pattern occurred in term pregnancies after 37 weeks of gestation only. Fetal male gender, nulliparity and post-term pregnancy are significantly associated with ZigZag FHR pattern during the last two hours of labour. Identification of maternal, fetal and delivery-related variables are imperative in order to interpret correctly the findings of CTG and to prevent adverse neonatal outcome.

Skin Autofluorescence in Young Adult Offspring of Women with Type 1 Diabetes: A Cross-Sectional Case-Control Study.

INTRODUCTION: Offspring born to women with type 1 diabetes pregnancies have an elevated risk for early-onset obesity and type 2 diabetes compared with offspring born to women without diabetes. Skin autofluorescence (SAF) is a marker of accumulated advanced glycation end products (AGEs) and it has been shown to predict type 2 diabetes, cardiovascular disease, and mortality in the general population. The aim of this study was to evaluate whether maternal type 1 diabetes influences the SAF value in young adult offspring. METHODS: This cross-sectional case-control study included 78 offspring of women with type 1 diabetes (cases) and 85 control participants (controls). All study participants, aged 18-23 years, were invited to participate in a clinical assessment including laboratory tests and questionnaires. SAF was assessed using the AGE reader from the dominant forearm of each participant. RESULTS: The mean SAF value did not differ between the cases (1.61 [standard deviation (SD) 0.37]) arbitrary units [AU]) and the controls (1.64 [SD 0.41] AU) (p = 0.69). After adjusting for glycated hemoglobin A1c, body fat percentage, smoking, and season the mean SAF value did not differ between the cases and the controls (p = 0.49) but differed between men and women (p = 0.008), without any interaction observed (p = 0.78). CONCLUSION: SAF values did not differ between the young adult offspring of women with type 1 diabetes and offspring born to mothers without diabetes. Surprisingly, young adult women showed higher SAF values than men in both case and control groups.

Intrapartum zigzag pattern of fetal heart rate is an early sign of fetal hypoxia: A large obstetric retrospective cohort study.

INTRODUCTION: The aim of the present study was to identify possible associations of fetal heart rate (FHR) patterns during the last 2 hours of labor with fetal asphyxia expressed by umbilical artery acidemia at birth and with neonatal complications in a large obstetric cohort. MATERIAL AND METHODS: Cardiotocographic recordings from 4988 singleton term childbirths over 1 year were evaluated retrospectively and blinded to the pregnancy and neonatal outcomes in a university teaching hospital in Helsinki, Finland. Umbilical artery pH, base excess and pO2 , low Apgar scores at 5 minutes, need for intubation and resuscitation, early neonatal hypoglycemia, and neonatal encephalopathy were used as outcome variables. According to the severity of the neonatal complications at birth, the cohort was divided into three groups: no complications (Group 1), moderate complications (Group 2) and severe complications (Group 3). RESULTS: Of the 4988 deliveries, the ZigZag pattern (FHR baseline amplitude changes of >25 bpm with a duration of 2-30 minutes) occurred in 11.7%, late decelerations in 41.0%, bradycardia episodes in 52.9%, reduced variability in 36.7%, tachycardia episodes in 13.9% and uterine tachysystole in 4.6%. No case of saltatory pattern (baseline amplitude changes of >25 bpm with a duration of >30 minutes) was observed. The presence of the ZigZag pattern or late decelerations, or both, was associated with cord blood acidemia (odds ratio [OR] 3.3, 95% confidence interval [CI] 2.3-4.7) and severe neonatal complications (Group 3) (OR 3.3, 95% CI 2.4-4.9). In contrast, no significant associations existed between the other FHR patterns and severe neonatal complications. ZigZag pattern preceded late decelerations in 88.7% of the cases. A normal FHR preceded the ZigZag pattern in 90.4% of the cases, whereas after ZigZag episodes, a normal FHR pattern was observed in only 0.9%. CONCLUSIONS: ZigZag pattern and late decelerations during the last 2 hours of labor are significantly associated with cord blood acidemia at birth and neonatal complications. The ZigZag pattern precedes late decelerations, and the fact that normal FHR pattern precedes the ZigZag pattern in the majority of the cases suggests that the ZigZag pattern is an early sign of fetal hypoxia, which emphasizes its clinical importance.

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth.

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWASs), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of functional genomic annotations in human cell types relevant to pregnancy and PTB. We generated transcriptome (RNA-seq), epigenome (ChIP-seq of H3K27ac, H3K4me1, and H3K4me3 histone modifications), open chromatin (ATAC-seq), and chromatin interaction (promoter capture Hi-C) annotations of cultured primary decidua-derived mesenchymal stromal/stem cells and in vitro differentiated decidual stromal cells and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. Using these resources, we uncovered additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

Dissecting maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes, and adult phenotypes: A mendelian-randomization and haplotype-based genetic score analysis in 10,734 mother-infant pairs.

BACKGROUND: Many maternal traits are associated with a neonate's gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations are unresolved. METHODS AND FINDINGS: Based on 10,734 mother-infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, we constructed haplotype genetic scores using single-nucleotide polymorphisms (SNPs) known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). Using these scores as genetic instruments, we estimated the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes. We also used infant-specific birth weight genetic scores as instrument and examined the effects of fetal growth on pregnancy outcomes, maternal BP, and glucose levels during pregnancy. The maternal nontransmitted haplotype score for height was significantly associated with gestational duration (p = 2.2 × 10-4). Both maternal and paternal transmitted height haplotype scores were highly significantly associated with birth weight and length (p < 1 × 10-17). The maternal transmitted BMI scores were associated with birth weight with a significant maternal effect (p = 1.6 × 10-4). Both maternal and paternal transmitted BP scores were negatively associated with birth weight with a significant fetal effect (p = 9.4 × 10-3), whereas BP alleles were significantly associated with gestational duration and preterm birth through maternal effects (p = 3.3 × 10-2 and p = 4.5 × 10-3, respectively). The nontransmitted haplotype score for FPG was strongly associated with birth weight (p = 4.7 × 10-6); however, the glucose-increasing alleles in the fetus were associated with reduced birth weight through a fetal effect (p = 2.2 × 10-3). The haplotype scores for T2D were associated with birth weight in a similar way but with a weaker maternal effect (p = 6.4 × 10-3) and a stronger fetal effect (p = 1.3 × 10-5). The paternal transmitted birth weight score was significantly associated with reduced gestational duration (p = 1.8 × 10-4) and increased maternal systolic BP during pregnancy (p = 2.2 × 10-2). The major limitations of the study include missing and heterogenous phenotype data in some data sets and different instrumental strength of genetic scores for different phenotypic traits. CONCLUSIONS: We found that both maternal height and fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: taller maternal stature, higher maternal BMI, and higher maternal blood glucose are associated with larger birth size through maternal effects; in the fetus, the height- and metabolic-risk-increasing alleles are associated with increased and decreased birth size, respectively; alleles raising birth weight in the fetus are associated with shorter gestational duration and higher maternal BP. These maternal and fetal genetic effects may explain the observed associations between the studied maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes.

Oral glucose tolerance test results in early pregnancy: A Finnish population-based cohort study.

AIMS: To analyze early-pregnancy oral glucose tolerance test (OGTT) results and differences between early- and late-pregnancy OGTT results in a population-based cohort. METHODS: From 3/2013 to 12/2016, pregnant women in South Karelia, Finland, were invited to undergo a 2-hour 75 g OGTT at 12-16 weeks' gestation (OGTT1) and, if normal, repeat testing at 24-28 weeks (OGTT2). Early and late gestational diabetes (GDM) were diagnosed using the same nationally endorsed criteria (fasting [FPG], 1- or 2-hour plasma glucose ≥5.3, ≥10.0 or ≥8.6 mmol/L, respectively). RESULTS: In OGTT1 (n = 1401), the mean (SD) FPG, 1- and 2-hour values were 4.85 (0.34), 6.63 (1.73) and 5.60 (1.28) mmol/L, respectively. Early GDM was diagnosed in 209 (14.9%). In OGTT2 (n = 1067), late GDM was diagnosed in 114 (10.6%). In women without GDM (n = 953), the mean FPG values were higher and post-load values lower in OGTT1 vs. OGTT2. No interaction effects of gestational timepoint and maternal BMI on OGTT results were detected, except for the 2-hour value. In women with late GDM, both mean FPG and post-load values were lower in OGTT1 vs. OGTT2. Results were similar employing the IADPSG GDM criteria. CONCLUSIONS: Our findings suggest that gestational-age specific OGTT thresholds for early GDM diagnosis need to be generated.

Saltatory Pattern of Fetal Heart Rate during Labor Is a Sign of Fetal Hypoxia.

BACKGROUND: While late decelerations and major bradycardia episodes in intrapartum cardiotocography (CTG) recordings are known to correlate with fetal distress,little is known of the importance of the saltatory pattern. OBJECTIVE: The aim of the study was to examine whether the fetal heart rate (FHR) saltatory pattern in intrapartum CTG registration is associated with fetal hypoxia during the last 2 h of labor. DESIGN: The study group consisted of CTG recordings from 194 births with a 1-min Apgar score of <8 (birth weight 3,614 ± 512 g; gestational age 40.6 ± 0.7 weeks). The comparison group included 51 infants with a 1-min Apgar score of ≥9 (birth weight 3,624 ± 400 g; gestational age 40.5 ± 0.4 weeks). FHR patterns were evaluated blindly by 2 experienced perinatologists. The pH, base excess (BE), pO2 and erythropoietin (EPO) were measured from umbilical cord blood at birth as outcome variables. RESULTS: Saltatory pattern occurred in 31/194 (16.0%) of the study group and in 1/51 (2.0%) of the comparison group. Umbilical artery pH, BE, and pO2 were lower and umbilical vein (UV) EPO higher in the study group than in the comparison group. In the study group, UV EPO level was significantly higher in cases where the saltatory pattern was present (median 241 mU/mL, 95% CI 39.4-16,484), than in those without the saltatory pattern (median 39.4 mU/mL, 95% CI 11-282) (p < 0.0001, for difference). In the study group, no differences in EPO levels were found in cases where episodes of bradycardia, tachycardia, reduced variability, or uterine tachysystole were present or absent. In the study group, saltatory pattern preceded late decelerations in 82.8%. CONCLUSION: Saltatory pattern in an intrapartum FHR recording is an early sign of fetal hypoxia.

Fetal chronic hypoxia and oxidative stress in diabetic pregnancy. Could fetal erythropoietin improve offspring outcomes?

Oxidative stress is responsible for microvascular complications (hypertension, nephropathy, retinopathy, peripheral neuropathy) of diabetes, which during pregnancy increase both maternal and fetal complications. Chronic hypoxia and hyperglycemia result in increased oxidative stress and decreased antioxidant enzyme activity. However, oxidative stress induces also anti-oxidative reactions both in pregnant diabetes patients and in their fetuses. Not all type 1 diabetes patients with long-lasting disease develop microvascular complications, which suggests that some of these patients have protective mechanisms against these complications. Fetal erythropoietin (EPO) is the main regulator of red cell production in the mother and in the fetus, but it has also protective effects in various maternal and fetal tissues. This dual effect of EPO is based on EPO receptor (EPO-R) isoforms, which differ structurally and functionally from the hematopoietic EPO-R isoform. The tissue protective effects of EPO are based on its anti-apoptotic, anti-oxidative, anti-inflammatory, cell proliferative and angiogenic properties. Recent experimental and clinical studies have shown that EPO has also positive metabolic effects on hyperglycemia and diabetes, although these have not yet been fully delineated. Whether the tissue protective and metabolic effects of EPO could have clinical benefits, are important topics for future research in diabetic pregnancies.

Amniotic fluid and umbilical cord serum erythropoietin in term and prolonged pregnancies.

OBJECTIVE: Erythropoietin - a hormone regulating erythropoiesis - is a biomarker of chronic fetal hypoxia. High erythropoietin levels in fetal plasma and amniotic fluid are associated with increased risk of adverse neonatal outcome. Since the risk of perinatal morbidity and mortality is increased in pregnancies beyond 41 gestational weeks, we evaluated erythropoietin levels in amniotic fluid and umbilical cord serum in apparently low-risk term (≥ 37 gestational weeks) and prolonged pregnancies (≥ 41 gestational weeks) with labor induction. STUDY DESIGN: This prospective cohort study comprised 93 singleton pregnancies at 37+0-42+1 gestational weeks, of which prolonged pregnancies numbered 63 (67.7%). Amniotic fluid samples were collected at time of labor induction by amniotomy. Umbilical cord blood samples for evaluation of pH, base excess, and umbilical cord serum erythropoietin were collected at birth. Erythropoietin levels were measured by immunochemiluminometric assay. Normal value of amniotic fluid erythropoietin level was defined as ≤ 3 IU/L, and abnormal value as ≥ 27 IU/L. Normal umbilical cord serum erythropoietin was defined as < 40 IU/L. Data on maternal pregnancy and delivery characteristics and short-term neonatal outcomes such as Apgar score were obtained from the hospital charts. Associations were calculated using Spearman's rank correlation coefficient. The Chi-square test, Fisher's exact test and the Mann-Whitney U test were utilized to determine differences in the study groups. RESULTS: Amniotic fluid erythropoietin levels correlated with gestational age (r = 0.261, p = 0.012) and were higher among prolonged pregnancies as compared to term pregnancies (p = 0.005). There were 78 (83.9%) vaginal deliveries, and among these erythropoietin levels in amniotic fluid correlated with the levels in umbilical cord serum (r = 0.513, p < 0.000). Umbilical cord serum erythropoietin levels correlated with gestational age among vaginal deliveries (r = 0.250, p = 0.027). Erythropoietin levels in amniotic fluid and umbilical cord serum did not correlate with umbilical artery pH or base excess, or other adverse pregnancy outcome. CONCLUSIONS: In vaginal deliveries erythropoietin levels in amniotic fluid correlated with the levels in umbilical cord serum. Erythropoietin levels correlated with gestational age, probably due to weakening placental function and relative hypoxemia occurring in advanced gestation. However, in this relatively low-risk study population erythropoietin was not related to adverse delivery outcome.

Correction: Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.

[This corrects the article DOI: 10.1371/journal.pgen.1007394.].

Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.

Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2-4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB.

Robust increases in erythropoietin production by the hypoxic fetus is a response to protect the brain and other vital organs.

Fetal erythropoietin (EPO), in addition to regulating erythropoiesis, has also tissue-protective properties based on its anti-inflammatory, anti-apoptotic, antioxidant, and neurotrophic effects. Notably, EPO concentrations needed for tissue protection are 100-1000 times higher than concentrations needed for regulating erythropoiesis. This dual effect of EPO is based on EPO-receptor (EPO-R) isoforms, which differ structurally and functionally. We hypothesize in this Integrated Mechanism Review that during severe fetal hypoxia the observed, but poorly understood, marked increases of fetal plasma EPO concentrations occur to protect the brain, heart, and other vital fetal organs. We further hypothesize that the concurrent marked increases of EPO in the amniotic fluid during fetal hypoxia, occur to protect newborn infants from necrotizing enterocolitis. This review presents experimental and clinical evidence in support of these hypotheses and points out unknown or poorly understood functions of EPO in the fetus. If these novel hypotheses are correct, the importance of fetal EPO as an antenatal hypoxia biomarker will become apparent. It will also likely point the way to important diagnostic and therapeutic fetal and neonatal interventions.

Genetic Associations with Gestational Duration and Spontaneous Preterm Birth.

BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10-8) or an association with suggestive significance (P<1.0×10-6) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.).