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.

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.

Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study.

BACKGROUND: Preterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known. METHODS: To identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance. RESULTS: Maternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case-control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors. CONCLUSIONS: Our study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302 and rs237902 may have gestational age-dependent effects on prematurity. Most of the OXTR rare variants identified do not appear to significantly contribute to the risk of PTB, but those shown to affect receptor function in our in vitro study warrant further investigation. Future studies with larger sample sizes are needed to confirm the findings of this study.

50gram oral glucose challenge test combined with risk factor-based screening for gestational diabetes.

OBJECTIVE: Our aim was to study whether universal screening of all pregnant women by Oral Glucose Challenge Test (OGCT) would identify a higher number of women with Gestational Diabetes (GDM) than risk factor based screening. STUDY DESIGN: A 50 g OGCT test was performed prospectively in 532 unselected women at 26-28 weeks of gestation. The 1-h venous plasma glucose concentration of >7.3 mmol/l was considered as a positive screening result. Patients with a positive OGCT underwent a 75 g 2-h OGTT, which was used as the actual diagnostic test for GDM. When two or all three of the glucose concentrations in OGTT (measured at fasting state and 1 and 2 h after the 75 g glucose load) were above the 97.5th percentile the patient was considered as having GDM. In addition, women with risk factors for GDM also underwent a 75 g OGTT regardless of the result of the OGCT. RESULTS: A positive 50 g OGCT was obtained in 123 (23%) of the women. In 15 (12%) of these, a diagnosis of GDM was established by the subsequent OGTT. Out of the 409 remaining women with a normal OGCT, 148 (36%) had risk factors for GDM. An OGTT performed in these patients identified 4 additional women with a GDM. Seventy-nine percent of GDM was thus found with 50g OGCT without regarding risk factors. Forty-seven percent of the women with GDM would have been missed in screening by risk factors only. CONCLUSIONS: In our population 50 g OGCT appears to identify a higher number of GDM than risk factor based screening. Combined with risk factor screening a few more cases of GDM would be found.

Endothelium-derived nitric oxide metabolites and soluble intercellular adhesion molecule-1 in diabetic and normal pregnancies.

OBJECTIVE: Endothelial dysfunction has been demonstrated in adult subjects with diabetes. We studied if maternal diabetes is associated with altered endothelial function in the fetus, as this might shed light on mechanisms by which adult diseases are programmed in utero. STUDY DESIGN: Total nitrate/nitrite (NOx) concentration was measured spectrophotometrically with the Griess reagent method. Soluble intercellular adhesion molecule-1 (sICAM-1) concentration was measured by enzyme-linked immunoassay. RESULTS: Venous cord serum NOx concentration at birth was highest in pregnancies complicated by type 1 diabetes (29.5+/-1.8 micromol/l, n=63) (P<0.0001 versus controls) and lowest in normal pregnancies (19.0+/-1.0 micromol/l, n=56). The concentration was intermediate in pregnancies complicated by gestational diabetes (23.9+/-2.7 micromol/l, n=24), but not significantly higher than in normal pregnancies (P=0.172). Venous cord serum sICAM-1 concentration did not differ between the three groups (P=0.191). Maternal serum NOx concentration in the third trimester was higher in pregnancies complicated by type 1 diabetes (22.9+/-3.4 micromol/l, n=22) than in normal pregnancies (15.4+/-1.4 micromol/l, n=21) (P=0.049). CONCLUSIONS: : Increased cord serum NOx but unaltered sICAM-1 concentration in diabetic pregnancies indicates that maternal diabetes does not cause a general alteration in fetal endothelial function. The increase in cord serum and maternal serum NOx concentration in diabetic pregnancies may be due to abnormalities in insulin-induced nitric oxide release or to a diminished reactivity of the vasculature to the effects of nitric oxide.

Endogenous and recombinant erythropoietin levels decline in human amniotic fluid and fetal plasma in vitro at 37 degrees C.

OBJECTIVE: To determine the in vitro stability of endogenous and recombinant erythropoietin (EPO) incubated at 37 degrees C in amniotic fluid (AF) and fetal plasma. STUDY DESIGN: Endogenous and recombinant EPO in AF, fetal plasma and phosphate buffer were incubated in vitro for 21 days at 37 degrees C. Serial aliquots were analyzed for EPO and the rates of EPO decline were compared within and between groups. RESULTS: Endogenous and recombinant EPO declined significantly in plasma and AF at 37 degrees C. Endogenous EPO displayed a similar linear rate of decline in AF and plasma, with nearly 70% of the initial hormone concentration remaining at 21 days. Recombinant EPO incubated in buffer did not change. CONCLUSIONS: Using the rate of decline in endogenous EPO we observed, EPO levels measured in AF or plasma within 21 days of fetal demise can be extrapolated back to the level likely present at fetal death.

Obstetric problems in diabetic pregnancy - The role of fetal hypoxia.

Perinatal mortality has not decreased over the last two decades in pregestational diabetic pregnancies. Stillbirth rate is 4-6 times and neonatal mortality 2-4 times higher in diabetic than in non-diabetic pregnancies despite modern electronic fetal surveillance methods. Majority of late stillbirths are "unexplained", many of which are presumably caused by fetal hypoxia. Both experimental and clinical studies have shown that fetal hyperglycaemia and hyperinsulinaemia can independently cause fetal hypoxia, which ultimately can lead to fetal death. Poor glycaemic control is associated with perinatal complications. Sharp increases in amniotic fluid erythropoietin levels indicate fetal hypoxia in diabetic pregnancy. Fetal erythropoietin concentrations correlate directly with maternal HbA(1c) levels. It is therefore important to maintain near-normal glycaemic level throughout pregnancy. Measurement of amniotic fluid erythropoietin level is a new way to detect fetal hypoxia antenatally. Sufficiently large controlled studies are needed before definitive answer of the clinical utility of amniotic fluid erythropoietin measurements in diabetic pregnancies can be determined.

Increased fetal plasma and amniotic fluid erythropoietin concentrations: markers of intrauterine hypoxia.

Tissue hypoxia is the major stimulus of erythropoietin (EPO) synthesis in fetuses and adults. Since EPO does not cross the placenta and is not stored, fetal plasma and amniotic fluid levels indicate EPO synthesis and elimination. Acutely, the rate and magnitude of the increase in plasma EPO levels correlate with the intensity of hypoxia. Amniotic fluid EPO levels correlate with cord plasma levels in normal and abnormal pregnancies, with fetal plasma EPO levels in humans averaging 2.6 times higher than the corresponding amniotic fluid EPO levels. Recent experimental and clinical studies demonstrate that EPO has neuroprotective effects related to its anti-apoptotic and vascular growth-promoting properties. Although under basal conditions the fetal kidneys are the main site of EPO production, during hypoxia recent experimental data indicate an important role of the placenta. Amniotic fluid EPO levels have been shown to increase exponentially during fetal hypoxia in preeclamptic, diabetic and Rh-immunized pregnancies, to correlate inversely with cord blood pH, pO(2) and base excess and to predict neonatal morbidities and NICU admission. As an indicator of chronic intrauterine hypoxia, fetal EPO measurements have increased our knowledge about the pathogenesis and importance of intrauterine growth restriction, macrosomia, diabetic pregnancy, prolonged pregnancy, meconium staining, fetal hemorrhage, fetal anemia, maternal smoking and alcohol consumption, abnormal fetal heart rate and abnormal Doppler flow patterns. While the clinical utility of fetal amniotic fluid and plasma EPO measurements in the management of high-risk pregnancies and their offspring is promising, adequately powered clinical trials are urgently needed.

Amniotic fluid erythropoietin concentrations differentiate between acute and chronic causes of fetal death.

BACKGROUND: Increased fetal plasma erythropoietin concentration is an indicator of chronic fetal hypoxia. Amniotic fluid erythropoietin levels correlate highly significantly with fetal erythropoietin levels before labor. We studied AF erythropoietin levels after fetal death in order to determine whether this could differentiate between stillbirths from acute or chronic causes. METHODS: Amniotic fluid was obtained after fetal death for erythropoietin measurement following fetal death in 21 pregnancies. Two of the pregnancies had twins, of which one infant was born alive. All 22 stillborn fetuses had an autopsy. None had malformations. Without prior knowledge of the results of the erythropoietin analyzes, the causes of fetal death were divided into acute, chronic or unknown groups. RESULTS: Eight pregnancies had an acute cause of fetal death (e.g. cord complication or placental abruption), eight pregnancies had a chronic cause (intrauterine growth restriction or erythroblastosis) and in five pregnancies the cause of fetal death could not be determined. In all eight pregnancies with an acute cause of fetal death, AF erythropoietin levels were normal (< 20 mU/mL). In contrast, six of the eight pregnancies with a chronic cause had AF erythropoietin levels above normal (range from 49.9 mU/mL to 391 mU/mL). In the five pregnancies with an unknown cause of fetal death, AF erythropoietin levels were normal in three and elevated in two. CONCLUSIONS: Elevated AF erythropoietin levels, identified after fetal death, suggest that the fetus died from a chronic hypoxic event, whereas normal AF erythropoietin levels suggest that the fetus died from an acute event.

Sphincter rupture and anal incontinence after first vaginal delivery.

BACKGROUND: The aim of this prospective study was to establish the incidence of anal incontinence and sphincter defects after first vaginal delivery. METHODS: A total of 99 nulliparous and pregnant women were examined prospectively 4 weeks (mean) before delivery and 4 months (mean) after delivery. Of the study population, 75 (76%) women had vaginal delivery and 24 (24%) had cesarean section. Vacuum extraction was necessary in 20 (20%) cases. The symptoms of anal incontinence were asked about using a standard questionnaire. Clinical examination, endoanal ultrasound (EAUS) and anal manometry were performed before and after delivery. RESULTS: The symptoms of mild anal incontinence, mainly gas incontinence, increased after vaginal delivery more than after cesarean section (P < 0.032). Occult anal sphincter defects were noted in 17 (23%) of the 75 women after vaginal delivery by using EAUS. After vacuum extraction, anal sphincter defects were noted in nine (45%) out of 20 women. No new sphincter defects were found in the cesarean section group. The maximal squeezing pressures were significantly decreased in the patients with external anal sphincter (EAS) defects (P = 0.0025). Vacuum extraction leads to more sphincter defects but does not significantly increase anal incontinence or decrease mean anal sphincter pressures. CONCLUSIONS: The first vaginal delivery can result in occult sphincter defects and the use of vacuum extraction increases the risk.

Amniotic fluid and cord plasma erythropoietin levels in pregnancies complicated by preeclampsia, pregnancy-induced hypertension and chronic hypertension.

AIMS: The purpose of the present study was to compare fetal and neonatal outcomes with amniotic fluid erythropoietin (EPO) levels obtained in the antepartum period in pregnancies complicated by preeclampsia, pregnancy-induced hypertension or chronic hypertension. METHODS: Erythropoietin concentrations were measured in amniotic fluid within 2 days before delivery and in cord blood at birth in 75 hypertensive women and in 23 healthy controls delivered by cesarean section before labor contractions. Erythropoietin levels did not influence clinical decisions. RESULTS: Amniotic fluid erythropoietin levels correlated highly significantly with cord plasma EPO levels and were significantly higher in pregnancies complicated by hypertension than in control pregnancies. Umbilical arterial pH, acid-base and blood gas values at birth were not different from controls. Both cord plasma and amniotic fluid erythropoietin levels correlated with cord blood pH, acid-base and blood gas values at birth in the study group. Newborn infants admitted to the newborn intensive care unit had significantly higher fetal erythropoietin levels and were more acidotic, hypoxemic and hypoglycemic than infants admitted to the normal care nursery. CONCLUSIONS: Our findings suggest that elevated amniotic fluid erythropoietin levels are markers of chronic or subchronic fetal hypoxia and are associated with neonatal morbidity in pregnancies complicated by hypertension.

Primary sphincter repair: are the results of the operation good enough?

PURPOSE: This study was designed to evaluate the clinical outcome of primary anal sphincter repair caused by obstetric tears and to analyze possible risk factors associated with sphincter rupture during vaginal delivery. METHODS: A total of 52 females with a third-degree or fourth-degree perineal laceration during vaginal delivery were examined. The symptoms of anal incontinence were obtained by a standard questionnaire. In addition to a clinical examination, endoanal ultrasound, anal manometry, and pudendal nerve terminal motor latency examinations were performed. A control group consisted of 51 primiparous females with no clinically detectable perineal laceration after vaginal delivery. RESULTS: After primary sphincter repair, 31 females (61 percent) had symptoms of anal incontinence. Fecal incontinence occurred in 10 females (20 percent). According to Hardcastle and Parks' and Jorge and Wexner's classifications, the study group had more severe symptoms of anal incontinence than the control group (P<0.001 in both classification groups). In endoanal ultrasound examination, a persistent defect of the external anal sphincter was found in 39 females (75 percent) in the rupture group compared with 10 females (20 percent) in the control group (P<0.001). Anal sphincter pressures were significantly lower in the rupture group than in the control group. An abnormal presentation was the only risk factor for anal sphincter rupture during vaginal delivery. CONCLUSIONS: After primary sphincter repair, persistent external anal sphincter defect and symptoms of anal incontinence are common in females who have had a primary sphincter repair after vaginal delivery. The means of improving the results of primary repair should be studied further.