Neonatal Genetic Variation in Steroid Metabolism and Key Respiratory Function Genes and Perinatal Outcomes in Single and Multiple Courses of Corticosteroids.

OBJECTIVE: The aim of the study is to evaluate the association of steroid metabolism and respiratory gene polymorphisms in neonates exposed to antenatal corticosteroids (ACS) with respiratory outcomes, small for gestational age (SGA), and response to repeat ACS. STUDY DESIGN: This candidate gene study is a secondary analysis of women enrolled in a randomized controlled trial of single versus weekly courses of ACS. Nineteen single nucleotide polymorphisms (SNPs) in 13 steroid metabolism and respiratory function genes were evaluated. DNA was extracted from placenta or fetal cord serum and analyzed with TaqMan genotyping. Each SNP was evaluated for association via logistic regression with respiratory distress syndrome (RDS), continuous positive airway pressure (CPAP)/ventilator use (CPV), and SGA. RESULTS: CRHBP, CRH, and CRHR1 minor alleles were associated with an increased risk of SGA. HSD11B1 and SCNN1B minor alleles were associated with an increased likelihood of RDS. Carriage of minor alleles in SerpinA6 was associated with an increased risk of CPV. CRH and CRHR1 minor alleles were associated with a decreased likelihood of CPV. CONCLUSION: Steroid metabolism and respiratory gene SNPs are associated with respiratory outcomes and SGA in patients exposed to ACS. Risks for respiratory outcomes are affected by minor allele carriage as well as by treatment with multiple ACS.

Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population?

OBJECTIVE: To determine if change in maternal angiogenic biomarkers between the first and second trimesters predicts pre-eclampsia in low-risk nulliparous women. DESIGN: A nested case-control study of change in maternal plasma soluble Flt-1 (sFlt-1), soluble endoglin (sEng) and placenta growth factor (PlGF). We studied 158 pregnancies complicated by pre-eclampsia and 468 normotensive nonproteinuric controls. SETTING: A multicentre study in 16 academic medical centres in the USA. POPULATION: Low-risk nulliparous women. METHODS: Luminex assays for PlGF, sFlt-1 and sEng performed on maternal EDTA plasma collected at 9-12, 15-18 and 23-26 weeks of gestation. Rate of change of analyte between first and either early or late second trimester was calculated with and without adjustment for baseline clinical characteristics. MAIN OUTCOME MEASURES: Change in PlGF, sFlt-1 and sEng. RESULTS: Rates of change of PlGF, sEng and sFlt-1 between first and either early or late second trimesters were significantly different in women who developed pre-eclampsia, severe pre-eclampsia or early-onset pre-eclampsia compared with women who remained normotensive. Inclusion of clinical characteristics (race, body mass index and blood pressure at entry) increased sensitivity for detecting severe and particularly early-onset pre-eclampsia but not pre-eclampsia overall. Receiver operating characteristics curves for change from first to early second trimester in sEng, PlGF and sFlt-1 with clinical characteristics had areas under the curve of 0.88, 0.84 and 0.86, respectively, and for early-onset pre-eclampsia with sensitivities of 88% (95% CI 64-99), 77% (95% CI 50-93) and 77% (95% CI 50-93) for 80% specificity, respectively. Similar results were seen in the change from first to late second trimester. CONCLUSION: Change in angiogenic biomarkers between first and early second trimester combined with clinical characteristics has strong utility for predicting early-onset pre-eclampsia.

Vitamin D status and recurrent preterm birth: a nested case-control study in high-risk women.

OBJECTIVE: To determine whether vitamin D status is associated with recurrent preterm birth, and any interactions between vitamin D levels and fish consumption. DESIGN: A nested case-control study, using data from a randomised trial of omega-3 fatty acid supplementation to prevent recurrent preterm birth. SETTING: Fourteen academic health centres in the USA. POPULATION: Women with prior spontaneous preterm birth. METHODS: In 131 cases (preterm delivery at <35 weeks of gestation) and 134 term controls, we measured serum 25-hydroxyvitamin D [25(OH)D] concentrations by liquid chromatography-tandem mass spectrometry (LC-MS) from samples collected at baseline (16-22 weeks of gestation). Logistic regression models controlled for study centre, maternal age, race/ethnicity, number of prior preterm deliveries, smoking status, body mass index, and treatment. MAIN OUTCOME MEASURES: Recurrent preterm birth at <37 and <32 weeks of gestation. RESULTS: The median mid-gestation serum 25(OH)D concentration was 67 nmol/l, and 27% had concentrations of <50 nmol/l. Serum 25(OH)D concentration was not significantly associated with preterm birth (OR 1.33; 95% CI 0.48-3.70 for lowest versus highest quartiles). Likewise, comparing women with 25(OH)D concentrations of 50 nmol/l, or higher, with those with <50 nmol/l generated an odds ratio of 0.80 (95% CI 0.38-1.69). Contrary to our expectation, a negative correlation was observed between fish consumption and serum 25(OH)D concentration (-0.18, P < 0.01). CONCLUSIONS: In a cohort of women with a prior preterm birth, vitamin D status at mid-pregnancy was not associated with recurrent preterm birth.

Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord blood, placenta and breast milk.

Treatment of maternal chronic myeloid leukemia with imatinib mesylate is avoided because of potential fetal effects. Two women with progression of disease during pregnancy required imatinib therapy. Concentrations of imatinib in maternal blood, placenta, umbilical cord blood and breast milk were 886, 2452, 0 to 157, and 596 ng/ml, respectively. Concentrations of the active metabolite CGP74588 in maternal blood, placenta, umbilical cord blood and breast milk were 338, 1462, 0 and 1513 ng/ml, respectively. As Imatinib and CGP74588 cross the mature placenta poorly, use of the drug after the first trimester may be reasonable under some circumstances. Imatinib and CGP74588 are found in breast milk, and therefore avoidance of breastfeeding is advisable.

Amniotic fluid insulin at 14-20 weeks' gestation: association with later maternal glucose intolerance and birth macrosomia.

OBJECTIVE: To examine the hypothesis that early second trimester amniotic fluid (AF) insulin concentration is elevated and later fetal growth is augmented in gravidas demonstrating later oral glucose intolerance. RESEARCH DESIGN AND METHODS: In this prospective observational cohort study, AF was sampled at 14-20 weeks' gestation in 247 subjects, and 1-h 50-g oral glucose challenge tests (GCTs) were performed at > or = 24 weeks. AF insulin was assayed by an automated immuno-chemiluminometric assay (8). Macrosomia was defined as birth weight above the 90th centile. RESULTS: AF insulin concentration (range 1.4-44.5 pmol/l) correlated positively with gestational age and maternal weight. A logistic regression analysis, adjusted for maternal age and midpregnancy weight, showed increased AF insulin multiples of gestational age-specific medians to be associated with subsequently diagnosed gestational diabetes mellitus (GDM) (OR 1.9, CI 1.3-2.4, P = 0.029). Among 60 subjects with GCT values > 7.2 mmol/l, each unit increase in AF insulin multiple of median (MOM) was associated with a threefold increase in fetal macrosomia incidence (3.1, 1.3-4.9, P = 0.048). CONCLUSIONS: An elevated AF insulin concentration at 14-20 weeks' gestation is associated with subsequently documented maternal glucose intolerance. Among gravidas with GCT values > 7.2 mmol/l, elevated early AF insulin concentration is associated with fetal macrosomia. Maternal glucose intolerance may affect fetal insulin production before 20 weeks' gestation.

Midpregnancy serum C-peptide concentration and subsequent pregnancy-induced hypertension.

OBJECTIVE: To test the hypothesis that elevated midpregnancy serum insulin (IRI) and C-peptide (CP) concentrations are associated with later development of pregnancy-induced hypertension (PIH), independent of prepregnancy obesity and midpregnancy blood pressure. RESEARCH DESIGN AND METHODS: In this prospective study, a cohort of normotensive women, ages > or = years performed a 50-g glucose challenge test at 24-30 weeks' gestational age. Blood samples were collected after an overnight fast and 1 h after glucose ingestion. Serum IRI and CP concentrations were measured in each sample. Maternal height, blood pressure and proteinuria were measured at the time of glucose challenge testing and after 36 weeks' gestational age. RESULTS: Of 320 subjects enrolled 44 women (13.8%) had subsequent PIH. Crude odds ratios (ORs) for devevelopment of PIH associated with each 1 U rise in log fasting IRI, log lasting CP. and glucosed-induced increase in CP (expressed as log [postprandial CP/fasting CP]) were 2.0 (95% CI 1.3-3.3), 1.8 (CI 1.2-2.7), and 2.3 (CI 1.1-4.9) respectively. After controlling for prepregnancy BMI, gestational age, and midpregnancy mean arterial pressure, adjusted ORs corresponding to log fastig IRI and CP for the development of PIH were 1.3 (95% CI 0.7-2.3) and 1.7 (CI 1.1-2.7) respectively, and, afterq adjustment for fasting CP, the adjusted OR of the glucose-induced rise in log CP was 3.7 (CI 1.5-9.3). CONCLUSIONS: Mid-pregnancy tasting and postoral glucose CP levels are associated with subsequent development of PIH, independent of maternal obesity and midpregnancy baseline blood pressure. These findings many reflect an amplified beta3-cell response to glycemic stimulus, similar to that found in states of insulin resistance, that appears to be independently associated with PIH.

Outcome of very low birth weight infants with histopathologic chorioamnionitis.

OBJECTIVE: To determine neonatal outcome at 7 months of corrected age in very low birth weight (VLBW) infants with placental chorioamnionitis. METHODS: We conducted a cohort study of 287 VLBW infants delivered as a result of preterm premature rupture of membranes (PROM) or preterm labor. Control subjects (n = 123) had placentas with absent umbilical cord inflammation and absent or low-grade membrane inflammation. Case subjects (n = 164) had moderate membrane inflammation or any umbilical cord inflammation. Neonatal and 7-month outcomes were compared. A power analysis showed that 98 total subjects were needed to reject the two-sided null hypothesis with a difference in mean Bayley index scores of at least 8. RESULTS: Infants in the study group had significantly more preterm PROM, antenatal antibiotics, lower birth weight, lower gestational age, longer duration of ruptured membranes, and clinical chorioamnionitis. Intraventricular hemorrhage occurred more commonly in infants with placentas demonstrating chorioamnionitis (relative risk = 1.6, 95% confidence interval 1.1, 2.4, P =.013). One hundred sixty-seven (69%) of the 243 surviving infants had 7-month follow-up. There was no difference between cases and controls in mean Bayley mental developmental index (93 compared with 90, P =.25), psychomotor developmental index (89 compared with 90, P =.68), or in the number of infants that were developmentally delayed. CONCLUSION: Despite a higher frequency of intraventricular hemorrhage, no difference in developmental scores was detected at 7 months of corrected age in VLBW infants with histologic chorioamnionitis.

Lethal fetal renal anomalies and obstetric outcome.

The incidence of prenatal and intrapartum complications was examined among 33 pregnancies complicated by lethal fetal renal abnormalities (cases) and compared to 200 contemporaneous control pregnancies (controls) by retrospective record review. Cases experienced higher rates of antepartum bleeding (29% vs. 6%, p<0.0001) stillbirth (15% vs. 0%, p<0.0001), preterm birth (34.3+/-4.1 vs. 39.7+/-1.8, p<0. 0001) and breech presentation (48% vs. 4%, p<0.0001). Twenty-six of 33 cases had lung weights

Glucocorticoid-associated maternal hyperglycemia: a randomized trial of insulin prophylaxis.

OBJECTIVES: To study the degree and timing of maternal hyperglycemia following betamethasone therapy in nondiabetic patients and establish a prophylactic dose of insulin. METHODS: Forty-five patients receiving betamethasone 12 mg i.m. at 7 AM on two consecutive days were randomized to no insulin (n = 20), low-dose insulin (n = 18), and high-dose insulin (n = 7) protocols. Each treatment group received s.c. insulin at 7 AM on the 2 days of betamethasone therapy (20 units NPH/10 units regular, and 40 units NPH/20 units regular, respectively). Capillary plasma glucose measurements were obtained at fasting and 2 h after meals for 3 days. A multivariate normal regression model was used to estimate and compare mean glucose levels. RESULTS: Eighty-five percent of patients who did not receive insulin exhibited hyperglycemia at levels previously associated with fetal acidosis. Significant differences in mean postprandial plasma glucose levels were found between the no-treatment and insulin groups on days 1 and 2. No significant differences were noted between groups on day 3. CONCLUSIONS: Transient maternal hyperglycemia occurs in a consistent pattern in nondiabetic patients receiving betamethasone, which can be limited by the concurrent use of insulin. Further studies to assess fetal acidosis in this setting are warranted.

A high-sensitivity assay for amniotic fluid insulin at 14-20 weeks' gestation.

OBJECTIVE: To examine sensitivity, precision, and sample stability of an immunochemiluminomimetric insulin assay in 14-20 week amniotic fluid (AF) and fetal age distribution of second-trimester AF insulin concentrations. METHODS: We assayed fresh specimens from 576 gravidas who had amniocentesis at 14-20 weeks' gestation because of maternal age. In a preliminary study, samples were divided into aliquots and stored at 4C and -20C for 24 hours to assess freezing effect. Some samples stored at 4C were assayed repeatedly during a 14-day period and others, stored at -20C, were assayed after a 70-day period. RESULTS: This assay reliably measured AF insulin to a detection limit of 0.03 microIU/mL. Insulin could be measured in all amniotic fluid samples and demonstrated a log10 Gaussian distribution, ranging from 0.24 to 7.41 microIU/mL. Interassay coefficients of variation ranged from 4.4 to 8.9% at concentrations of 0.4-2.0 microIU/mL. Linearity of dilution from 1.5 to 10 times was 99.2 +/- 8.6%. Spike recovery of 10 microIU/mL was from 92-109%. Recovery after freezing to -20C for 24 hours (101%) and 70 days (97%) and after storage at 4C for 14 days (97%) demonstrated no significant loss. CONCLUSION: A two-site, dual monoclonal, immunochemiluminomimetric insulin assay was sufficiently sensitive and precise within the lower range of measured AF insulin concentrations to investigate clinical associations of 14-20 week AF insulin with maternal and fetal conditions. The insulin stability in this matrix suggests that assays can be reliable on specimens stored up to 70 days.

Influence of chorioamnionitis on developmental outcome in very low birth weight infants.

OBJECTIVE: To determine the effect of exposure to chorioamnionitis on developmental outcome in very low birth weight (VLBW) infants. METHODS: Five hundred four maternal charts (97% of all VLBW infants delivered from 1990 to 1994) were reviewed. A historical cohort study of the 330 infants delivered secondary to preterm premature rupture of membranes or preterm labor was performed. Case subjects (71) were delivered of mothers with chorioamnionitis by clinical criteria; control subjects (259) were delivered of mothers without chorioamnionitis. Bayley index scores at 7 months' corrected age and special care nursery outcomes were compared. One hundred seventy-three subjects were necessary to reject the two-sided null hypothesis with 80% power with a difference in mean Bayley index scores of at least 8. RESULTS: Neonatal sepsis (8.5% compared with 1.9%; odds ratio [OR] = 4.7, 95% confidence interval [CI] 1.4, 15.9, P = .015) and a low 5-minute Apgar (72% compared with 55%; OR = 2.1, CI 1.2, 3.8, P = .012) occurred more frequently in the chorioamnionitis group. One hundred eighty-seven (68%) of 273 surviving neonates had follow-up. Cases and controls were similar in mean Bayley mental developmental index (91.2 compared with 91.8, P = .84), Bayley psychomotor developmental index (89.8 compared with 89.1, P = .82), and number of infants developmentally delayed. Duration of exposure to chorioamnionitis did not affect neonatal outcome. CONCLUSION: Despite higher rates of sepsis and low Apgar scores, no difference in outcome at 7 months of corrected age was detected in VLBW infants exposed to chorioamnionitis. Contemporary neonatal management may reduce the adverse effects of this exposure.

The diagnosis of gestational diabetes.

The concept of gestational diabetes goes back at least to 1946. Over the years, sophistication has increased regarding the pathophysiology of this condition. However, there is not universal agreement on how to diagnose gestational diabetes. The most widely used diagnostic criteria in the U.S. were validated by their predictive value for subsequent diabetes in the mother, rather than by their ability to identify risk to the fetus and newborn. The best available evidence supports the notion that the relationship between carbohydrate intolerance in pregnancy and adverse perinatal outcomes is a continuous one, and no single cutoff can separate pregnant women into those with high risk and those with no risk at all. Suggestions are made for arriving at appropriate, albeit arbitrary, diagnostic criteria.

The effect of pregnancy on the natural history of diabetic retinopathy and nephropathy.

Retinopathy and nephropathy are complications of diabetes mellitus that can affect women of reproductive age. This article focuses on the effect of pregnancy on the risk of progression of microvascular disease, both during gestation and at long-term follow-up. Fortunately, with intensive medical surveillance and appropriate interventions, most women with types 1 and 2 diabetes mellitus can be offered an optimistic prognosis for child bearing.

The relationship between second-trimester amniotic fluid insulin and glucose levels and subsequent gestational diabetes.

Associations between elevated amniotic fluid glucose and insulin levels in the second trimester and the subsequent development of gestational diabetes have been reported. We conducted a case-control study to determine which analyte best predicts future maternal glucose intolerance. Thirty-nine women diagnosed with gestational diabetes (criteria of Carpenter and Coustan, Am. J. Obstet. Gynecol., 144, 768, 1982) who had undergone genetic amniocentesis for advanced maternal age were matched with euglycaemic controls. Glucose and insulin concentrations were determined by analysis of stored amniotic fluid samples. No significant difference was detected between cases and controls for amniotic fluid glucose concentrations. Amniotic fluid insulin concentrations were significantly higher in cases (mean rank 4.44, P < 0.01, using matched rank analysis of variance, where 1 is the lowest and 6 is the highest rank). After conversion to multiples of the median, 20 per cent of women with subsequent gestational diabetes were found to have amniotic fluid glucose levels at or above the 90th centile, while 35 per cent of cases had similarly elevated amniotic fluid insulin levels. We conclude that second-trimester amniotic fluid insulin is a more sensitive predictor of impending glucose intolerance than amniotic fluid glucose, although neither is sufficiently powerful to use alone as a screening test.

Positional effects on maternal cardiac output during labor with epidural analgesia.

OBJECTIVE: Our purpose was to test the hypothesis that the supine versus the lateral position is associated with a greater decrement in cardiac output after epidural analgesia in labor. STUDY DESIGN: Twenty-one normal term subjects were randomized to the left lateral or supine position in early labor. Cardiac output measured by the acetylene rebreathing method, stroke volume, heart rate, mean arterial pressure, and systemic vascular resistance were obtained at 5-minute intervals, beginning before a 500 ml intravenous fluid bolus (baseline) and ending 45 minutes after epidural injection. RESULTS: Mean baseline supine versus lateral group differences were significant for 21% lower cardiac output, 21% lower stroke volume, 19% higher mean arterial pressure, 50% higher systemic vascular resistance, and equivalent heart rate. In the supine group fluid bolus resulted in significantly increased cardiac output and stroke volume, decreased mean arterial pressure and systemic vascular resistance, and unchanged heart rate. In the supine group cardiac output and stroke volume decreased significantly after epidural injection. The lateral position group exhibited no hemodynamic alterations after fluid bolus or epidural. CONCLUSIONS: In contrast to the lateral position, the supine position is associated with a significant postepidural decrement in cardiac output, not identified by a change in heart rate. This likely reflects an inability to maintain stable preload volume in the supine position.

Exercise fails to improve postprandial glycemic excursion in women with gestational diabetes.

The effect of an acute period of moderate intensity exercise on maternal glycemic excursion following a mixed nutrient meal was studied. Five normal (NL) and six gestational diabetic (GDM) subjects were enrolled. A randomized crossover design was used to compare fasting glucose and insulin levels, peak glucose and insulin levels and incremental area of the glycemic and insulin curves following a mixed nutrient meal with or without an exercise stress that took place 14 h earlier. Exercise consisted of upright stationary cycling for 30 min at a heart rate consistent with 60% VO2max. The clinical characteristics of normal and gestational diabetic subjects were comparable. Mean values (+/-SEM) with, versus without, exercise for fasting glucose (NL: 78.9 +/- 2.6 vs. 80.0 +/- 2.6 mg/dl; GDM: 86.4 +/- 2.0 vs. 82.1 +/- 3.5 mg/ dl), peak glucose (NL: 132.3 +/- 10.4 vs. 139.1 +/- 15.6 mg/dl; GDM: 165.8 +/- 5.5 vs. 160.3 +/- 7.8 mg/dl), the area under the glycemic curve (NL: 5758 +/- 1038 vs. 6393 +/- 1281 mg/dl.min; GDM: 8,178 +/- 890 vs. 8,331 +/- 563 mg/dl.min) did not differ. Similarly, plasma insulin levels did not differ between protocols for either group of subjects. Exercise has been proposed as a treatment to reduce glycemia in gestational diabetes. Results from this study indicate a single bout of exercise did not blunt the glycemic response observed following a mixed nutrient meal.

Glucose and lactate kinetics during a short exercise bout in pregnancy.

Pregnancy is considered diabetogenic. Although exercise has been advocated to assist in metabolic control of the nonpregnant diabetic individual, there is a paucity of data about the metabolic effects of exercise during pregnancy. To examine whether moderate exertion may be beneficial in the maintenance of maternal carbohydrate homeostasis, glucose and lactate kinetics were measured in the third trimester in five pregnant nondiabetic women (gestational age, 34.2 +/- 0.1 weeks [mean +/- SE]) by infusion of 45 microg x kg(-1) x min(-1) [6,6-2H2]glucose and 70 microg x kg(-1) x min(-1) [U-13C]lactate tracers. Subjects were observed at rest for determination of baseline steady-state kinetics over a 30-minute period, and then they exercised for 30 minutes at 60% maximum oxygen consumption (VO2max) and were evaluated for 30 minutes postexercise. Glucose and lactate kinetics and lactate oxidation were measured throughout the exercise protocol. This study was repeated postpartum in all individuals at least 6 weeks after delivery. Compared with the steady-state preinfusion period, plasma glucose concentration was not elevated during exercise in either group, nor was plasma lactate concentration significantly different in either group. Glucose kinetics did not change during exercise, but lactate kinetics increased in both groups. V02 and percent of lactate C contribution to CO2, an indication of lactate oxidation, increased proportionally in both groups during exercise. Metabolic perturbations, as measured by glucose and lactate kinetics, do not appear to be different during the third trimester of pregnancy during a relatively short bout of exercise compared with the nonpregnant state.

Fetal hyperinsulinism at 14-20 weeks and subsequent gestational diabetes.

OBJECTIVE: To examine the predictive value of amniotic fluid (AF) insulin at 14-20 weeks' gestation for subsequent gestational diabetes and macrosomia in unselected gravidas 35 years or older at time of genetic amniocentesis. METHODS: We identified 296 pregnancies through stored AF samples from genetic amniocenteses (collected March 1987 through August 1992) in women meeting the following criteria: age 35 years or older, amniocentesis at 14-20 weeks, performance of a 50-g glucose challenge test, and adequate delivery data. RESULTS: A modified double-antibody radioimmunoassay reliably measured AF insulin with a detection limit of 0.35 microU/mL. Pregnant women in whom gestational diabetes was later diagnosed had higher median AF insulin levels than women who did not (0.60 versus 0.42 microU/mL, respectively; P = .026). A stepwise logistic regression analysis of gestational age at amniocentesis, maternal second-trimester weight, maternal age, and log AF insulin value on gestational diabetes showed only AF insulin to have a significant association with gestational diabetes (P = .004). Seven of 21 cases of gestational diabetes had AF insulin values exceeding the 95th percentile (1.33 microU/mL) compared with only 14 of 275 women with normal glucose tolerance (P < .001). Amniotic fluid insulin did not predict macrosomia in either nondiabetic or gestational diabetic pregnancies. CONCLUSION: Gestational diabetes is associated with increased AF insulin at 14-20 weeks, suggesting augmentation of fetal insulin production in the early fetal period in at least some cases of gestational diabetes.