Evidence of placental haemorrhage and preterm delivery.

OBJECTIVE: To evaluate evidence of placental haemorrhage (PH) obtained through maternal interviews, patient charts and placental pathology examinations as potential indicators of a 'bleeding pathway' to preterm delivery (PTD). DESIGN: Prospective cohort. SETTING: Fifty-two clinics in five communities in Michigan, USA (1998-2004). POPULATION: A subset (n = 996) of cohort participants with complete placental pathology data. METHODS: First-trimester bleeding and placental abruption were ascertained by mid-trimester interviews and chart review, respectively. Disc-impacting blood clot was defined as a gross placental examination finding of a blood clot impacting adjacent tissue. Microscopic haemorrhage was defined as 'high' (top quintile) scores on an aggregate measure of placental pathology findings suggestive of atypical maternal vessel haemorrhage. These four PH indicators were compared with one another and with risk of PTD assessed by logistic regression analyses. MAIN OUTCOME MEASURES: Preterm delivery and PTD subtypes (i.e. <35 weeks, 35-36 weeks; spontaneous, medically indicated) compared with term deliveries. RESULTS: Placental abruption cases had 2.3-fold to 5.5-fold increased odds of the other three PH indicators. Disc-impacting blood clots and microscopic haemorrhage were associated with one another (odds ratio [OR] = 4.6), but not with first-trimester bleeding. In a multivariable model that included all four PH indicators and confounders, risk of PTD < 35 weeks was elevated with first-trimester bleeding (OR = 1.9 [1.0, 3.4]), placental abruption (OR = 5.2 [1.7, 16.2]), disc-impacting blood clots (OR = 2.3 [1.0, 5.0]) and microscopic haemorrhage (OR = 2.4 [1.4, 4.2]). CONCLUSIONS: Multiple clinical and subclinical PH indicators are associated with PTD, particularly early PTD.

Early ultrasound dating of pregnancy: selection and measurement biases.

Can using early ultrasound examinations to date pregnancy introduce information bias in perinatal research? Our purpose was to identify determinants of early ultrasound examinations and to compare early ultrasound to menstrual history dating. Between January 1987 and June 1989, 1159 white, largely middle class, prenatal patients were contacted for a prospective observational study. 876 (76%) agreed to participate. Of these 764 (87%) met the eligibility criteria for this analysis, namely singleton pregnancy, delivered after 20 weeks (spontaneous or induced, vaginal or c-section), with prenatal chart abstracted. Selection factors for early ultrasound identified in multivariate analysis were: bleeding in early pregnancy, OR = 1.9 (1.0, 3.5), attendance at health maintenance organization OR = 7.2 (3.4, 15), no insurance or Medicaid only OR = 0.3 (0.1, 0.6), and increasing time from last menstrual period to first prenatal visit in weeks OR = 0.89 (0.85, 0.93). In conformity with previous results, ultrasound dating of pregnancy led to a higher estimate of preterm delivery (10 vs 7.6%), a higher estimate of term delivery (87.2 vs 82.7%) and a lower estimate of postterm delivery (2.8 vs 9.7%) than dating by menstrual history, p < 0.001. Selection factors and measurement issues, such as those described here, could introduce bias and should be carefully considered in the design, analysis and interpretation of perinatal research.

Imaging the fetal brain in the second and third trimesters using transvaginal sonography.

High-frequency transvaginal probes were used at 20-40 weeks' gestation to develop a systematic examination of the fetal brain. Modeling the procedure after the standard neonatal neurosonographic examination, we attempted to obtain three coronal sections (anterior, midline, posterior) and two sagittal sections (midsagittal, right or left parasagittal). In 70 normal patients, all planes were imaged with a similar frequency (74-76%) except for the posterior coronal plane, which was imaged 59% of the time. Among the first 35 cases, 17% had a complete study, compared with 71% of the second 35 cases. Transvaginal sonography established or changed the diagnosis in five of the 13 cases with central nervous system or other abnormalities. We recommend that a complete fetal neurosonographic examination include transvaginal sonography to complement and enhance the transabdominal examination, especially for cases in which a fetal abnormality is suspected.

Correlates of low thyroxine values at newborn screening among infants born before 32 weeks gestation.

We assessed the relation of perinatal factors to severe hypothyroxinemia of prematurity, defined as thyroxine value more than 2.6 standard deviations below the mean for newborns. The 365 survivors of birth before 32 weeks gestation were enrolled in a population-based study of the correlates of neonatal brain injury. In this historical cohort study, mothers were interviewed; perinatal data were abstracted from medical records and neonatal data were collected prospectively. Neonatal thyroxine screening values were retrieved from the New Jersey State Department of Health. Associated with severe hypothyroxinemia were: gestational age 23-27 weeks vs. 31 weeks (OR = 5.1, 95% CI 1.7, 15.2), later age at thyroxine test (OR = 1.6 per day, 95% CI 1.2, 2.1), fraction inspired oxygen at age 24 h > 40% (OR = 3.2, 95% CI 1.1, 8.8), mechanical ventilation (OR = 5.1, 95% CI 1.3, 19.4), diastolic blood pressure < 20 mmHg (OR = 2.3, 95% CI 1.2, 4.3), and > 12 years of maternal education (OR = 0.4, 95% CI 0.22, 1.0). Infants with severe hypothyroxinemia had higher mortality, more days of oxygen supplementation, ventilation and hospitalization and were 11 times more likely to require oxygen supplementation at the postnatal age equivalent to 36 weeks gestational age (odds ratio 10.6, 95% CI 2.3, 48.8). In preterm infants, neonatal thyroxine levels obtained at newborn screening in the first week of life may convey important prognostic information about mortality, morbidity, and the risk for bronchopulmonary dysplasia.

Increased fetal heart rate variability with acute hypoxia in chronically instrumented sheep.

Fetal heart rate (FHR) and oxygen consumption were determined in 45 studies in 20 chronically instrumented, normoxic sheep. FHR variability was measured by a template device to determine amplitude range, and oscillatory frequency was manually counted over 5-min periods. During 26 min of isocapnic hypoxia, fetal O2 consumption decreased 39% and FHR decreased 18%, and FHR variability increased, the changes being maintained over the treatment period. It is suggested that the maintenance of FHR variability during this profound hypoxia denotes adequate cardiorespiratory compensatory mechanisms during the short period; prolongation of the hypoxia would probably result in fetal cerebral or myocardial decompensation, and disappearance of FHR variability. The increased variability may be due to increased alpha-adrenergic activity.

Smoking, alcohol and caffeine in relation to ovarian age during the reproductive years.

BACKGROUND: We sought to determine whether smoking, alcohol and caffeine are related to four indicators of ovarian age: antral follicle count (AFC), follicle stimulating hormone (FSH), inhibin B and estradiol. METHODS: Analyses drew on ultrasound scans and sera from 188 women, aged 22-49. We used least squares regression to estimate differences in AFC and hormone levels for women who smoke cigarettes or who drink alcohol or caffeine. RESULTS: Current smoking is related to elevated FSH (beta for ln(FSH) = 0.21, 95% CI 0.04, 0.39), but not to AFC, inhibin B or estradiol. Neither alcohol nor caffeine is related to any ovarian age indicator. Exploratory analyses suggest that the association of current smoking with FSH varies with age: comparing current with never smokers, at ages 30, 35, 40 and 45, estimated differences in mean FSH are 0.3, 1.3, 3.2 and 6.9 mIU/ml. CONCLUSIONS: The association of current smoking with FSH may reflect accelerated oocyte atresia, impaired follicle quality or dysregulation of the hypothalamic-pituitary-ovarian axis. Identification of the causal mechanism has implications for prevention or treatment of conception delay, infertility and morbidity associated with early menopause.

Predictors of antral follicle count during the reproductive years.

BACKGROUND: We sought to identify indicators of antral follicle count which would be serviceable to clinicians seeking to estimate the number of ovarian follicles without relying on sonographic counts. METHODS: We examined the relations of chronological age and four potential indicators of ovarian age-ovarian volume, FSH, dimeric inhibin B and estradiol-to antral follicle count in 176 recently pregnant women. We identified the regression models which best predict low antral follicle count (< or =10 follicles). RESULTS: Chronological age, ovarian volume, FSH and inhibin B were each significantly associated with antral follicle count. Fifty-three (30.1%) women had < or =10 antral follicles. In the total sample, at the cutpoint corresponding to 80% sensitivity, the positive predictive value for a regression model with all four variables was 60%. All regression models performed less well in women <35 years (13.9% with low count) than in women > or =35 years (52.0% with low count). In older women, the positive predictive value for the model with all four variables was 79%, compared with 60% for a model with chronological age alone. CONCLUSIONS: Our models provide a basis for advising women aged > or =35 years who are either trying to conceive or wish to learn whether they may postpone childbearing.

Obstetrical judgments of viability and perinatal survival of extremely low birthweight infants.

OBJECTIVES: The purpose of the study was to determine whether the obstetrical judgment of viability makes a difference to fetal and neonatal survival of extremely low birthweight infants (500-749 g). METHODS: We assessed the effect of the antenatal judgment of viability in a group of 66 infants born weighing from 500 to 749 g. These infants were alive at maternal hospital admission and were subsequently live-born or stillborn between January 1, 1984, and December 31, 1985. We related the antepartum assessment of viability and other factors recorded in the medical record to fetal survival and to postneonatal survival to hospital discharge. RESULTS: The obstetrical judgement of viability was strongly associated with outcome. After birthweight and gestational age were controlled, fetuses considered viable were 18 times more likely to survive (95% confidence interval = 2, 175) than those considered nonviable. CONCLUSIONS: The effects of obstetrical practices on perinatal mortality must be taken into consideration in estimating the survival potential of very small fetuses and in evaluating the relationship between survival and disability.

Association of maternal, antenatal and perinatal complications with suicide in adolescence and young adulthood.

The aim of the present study was to investigate whether maternal, antenatal and perinatal complications are associated with adolescent or young adulthood suicide in offspring. Cases consisted of individuals, aged 15-22 years, born in New York City and committing suicide in New York City between 1985 and 1991 (n = 189). Two controls were selected for each case, constituting the hospital birth immediately preceding and following that of the case, matched with the case with regard to sex and ethnicity. Cases were compared with controls using an index that summed a range of maternal, antenatal and perinatal complications and also with regard to the frequency of individual complications. In the total sample, cases and controls did not differ either in the mean number of all complications combined or in the proportions with specific complications. This lack of association between complications and outcome also obtained in separate analyses by sex, ethnicity, socio-economic status and age at suicide. These results fail to replicate the findings of two previous reports implicating maternal, antenatal and perinatal complications in risk of youth suicide. At present, epidemiological evidence that adverse reproductive events increase the risk for suicide in offspring remains inconclusive.

PIP: The hypothesis that maternal, antenatal, and perinatal complications are associated with adolescent and young adult suicide in offspring was investigated in a case-control study conducted in New York City, New York (US). 189 youths 15-22 years old, born in New York City and committing suicide in New York City in 1985-91, served as cases. Two sex- and ethnicity-matched controls, constituting the hospital birth immediately before and after that of the case, were enrolled for each case. Cases and controls did not differ either in the mean number of all maternal, antenatal, and perinatal complications combined or in the proportions with specific complications. This lack of association between complications and outcome persisted in separate analyses by sex, ethnic group, socioeconomic status, and age at suicide. Two previous studies found significantly elevated suicide rates in youth who experienced respiratory distress at birth lasting more than 1 hour and whose mothers had a chronic illness during pregnancy or did not enter prenatal care before 20 weeks gestation.

Distribution and recirculation of umbilical and systemic venous blood flow in fetal lambs during hypoxia.

The presence of vascular shunts in the fetal circulation results in mixture of oxygenated blood returning from the placenta with venous blood returning from the fetal body. In fetal sheep with chronically implanted vascular catheters we found during normal oxygenation that 22% of umbilical venous blood recirculated to the placenta without being presented to the fetal tissues (left-to-right shunt analogue) while about half of systemic venous blood recirculated to the fetal body and not to the placenta for oxygenation (right-to-left shunt analogue). These shunts comprised 34% of cardiac output and increase the workload on the fetal heart, as they are ineffective in terms of oxygen uptake and delivery. In normally-oxygenated fetuses, 11% of cardiac output was comprised of umbilical venous blood recirculating to the placenta (left-to-right shunt analogue) whereas 23% of cardiac output consisted of systemic venous blood circulating to the fetal body (right-to-left shunt analogue). During induced maternal-fetal hypoxia (10% O2 to ewe), although the percentage of ineffective cardiac output did not change (31%), the left-to-right shunt analogue increased to 19% and the right-to-left shunt analogues decreased to 12% of cardiac output. Hypoxia also resulted in an increase in the percentage of umbilical venous blood which bypassed the liver through the ductus venosus (control 57 +/- 12%; hypoxia 65 +/- 12%, P < 0.02), causing the proportion of umbilical venous blood contributing to the fetal cardiac output to increase from 27 +/- 10% during normoxia to 39 +/- 9% during hypoxia (P < 0.005). This factor, together with the redistribution of cardiac output during hypoxia, resulted in a 100% increase in oxygen delivery from umbilical venous blood to the myocardium and a maintenance of the umbilical vein derived oxygen supplied to the brain and placenta, despite a 40% reduction in total available oxygen in umbilical venous blood.

Phasic blood flow patterns in the superior and inferior venae cavae and umbilical vein of fetal sheep.

Measurements of phasic blood flow in the inferior and superior venae cavae and umbilical vein of fetal sheep (gestational age, 121 to 140 days) were made with chronically implanted electromagnetic flow transducers. In the venae cavae blood flow was inversely related to phasic changes in venous and/or intrathoracic pressure. During fetal apnea a forward surge of flow occurred during ventricular systole (systolic surge) and ventricular diastole (diastolic surge). Slower fetal heart rates were associated with a more prominent diastolic surge. Reductions in afterload caused by acetylcholine administration augmented the peak diastolic venous flow. In contrast, increased afterload caused by hypoxia and norepinephrine administration was associated with increased peak systolic flow. During regular fetal breathing movements the phasic flow pattern was determined largely by the respiratory cycle with the effect of the cardiac cycle superimposed. There was minimal venous pulsation in the intra-abdominal umbilical vein, compared with that of the intrathoracic venae cavae of the apneic fetus. Our findings demonstrate that fetal systemic vascular resistance profoundly influences right atrioventricular filling patterns.

Transvaginal ultrasonography in gynecologic office practice: assessment in 663 premenopausal women.

OBJECTIVES: We describe transvaginal ultrasonographic evaluation of 663 premenopausal women with signs or symptoms of gynecologic problems and compare the findings of transvaginal ultrasonography with those of antecedent bimanual examination. STUDY DESIGN: In this retrospective descriptive study, data on age, menstrual history, results of bimanual examination, and subsequent surgical and pathologic findings were abstracted from the medical record and linked to indications and results on transvaginal ultrasonography reports from May 1991 through October 1993. RESULTS: The result of bimanual examination of the uterus was normal in 125 of 347 women with transvaginal ultrasonography-diagnosed fibroids (36.0%). Findings were normal at bimanual examination of the corresponding adnexa in 134 of the 190 adnexa with transvaginal ultrasonography findings (70.5%). Among the subjects with normal results of bimanual examination of the adnexa, surgical procedures documented 12 endometriomas, 2 adnexal abscesses, and 5 benign and 1 malignant neoplasm. CONCLUSION: Given the apparent considerable limitations of the bimanual examination, the utility of routine in-office transvaginal ultrasonography screening of both women with and women without symptoms should be prospectively investigated.

Efficiency of sampling: birthweight and gestational age distributions in two cohorts, < 31 weeks and 500-1499 grams.

We studied the efficiency of two common sampling strategies used to assemble cohorts to study the long-term problems of preterm infants: infants with birthweights of 500-1499 g, and infants with gestational ages (GA) of < 31 weeks. Birthweight, GA and 2-year outcome data from a population based study of infants < 2001 g, the Central New Jersey Brain Hemorrhage Study (NBH), were used to define the birthweight and GA distributions, at enrollment and at the age of 2 years, of overlapping subsets: infants 500-1499 g (n = 599) and infants < 31 weeks of age (n = 522). Using frequencies from the NBH study, we estimated that 1000 infants of 500-1499 g enrolled at birth would produce 712 infants at the age of 2 years, 498 below 31 weeks and 214 above. Enrolling 1000 infants < 31 weeks would produce a cohort of 697 infants at the age of 2, all of whom were < 31 weeks. Neither sampling strategy maximised the statistical power to investigate the pathophysiological determinants of long-term outcomes associated with short GA. Both methods oversampled older GAs. A stratified sampling technique based on GA, designed to produce equal numbers of subjects at each week of GA, would improve statistical power to study long-term outcomes. As we move from descriptive to analytical studies of preterm infants, we need to devise efficient, GA-based, sampling strategies that maximise statistical power to test pathophysiological hypotheses.

Thyroxine values from newborn screening of 919 infants born before 29 weeks' gestation.

OBJECTIVES: Severe transient hypothyroxinemia in premature infants is associated with cerebral palsy and mental retardation: this study assessed its prevalence in very premature infants. METHODS: Congenital hypothyroidism screening programs in three states provided thyroxine values for 919 newborn infants younger than 29 weeks who were enrolled in a multicenter study. RESULTS: Thyroxine values were lower than 4.0 micrograms/dL in 21% of survivors and increased each week by 0.6 microgram/dL (95% confidence interval [CI] = 0.4, 0.7). At tests done 1 to 2 days after birth, levels were 2.5 micrograms/dL higher (95% CI = 1.8, 3.3) than at tests done at 8 to 14 days. In New York, levels were 1.0 microgram/dL higher (95% CI = 0.3, 1.6) than elsewhere. The levels of infants who died were 1.3 micrograms/dL lower (95% CI = 0.6, 2.0) than those of survivors. CONCLUSIONS: Severe transient hypothyroxinemia is common in very premature infants and deserves further study.

Selective distribution of microspheres injected into the umbilical veins and inferior venae cavae of fetal sheep.

To investigate the extent of streaming of umbilical venous blood in the venous and arterial circulations of normal and hypoxic sheep fetuses and to experimentally determine its effect on determinations of blood flow by means of the microsphere method, we injected 15 mu microspheres labeled with different radionuclides into the umbilical veins (UVs) and distal inferior venae cavae (DIVC) of 21 chronically catheterized near-term sheep fetuses. We determined the ratio of the radioactive counts from the UV-injected microspheres to the radioactive counts from the DIVC-injected microspheres (UV/DIVC count ratio) in each fetal tissue in 40 experiments. In 75% of the normal fetuses and 58% of the hypoxic fetuses, UV-injected microspheres streamed preferentially through the foramen ovale to the left atrium and ventricle when compared with DIVC-injected microspheres. Fetal hypoxia was associated with a significant decrease in the extent of preferential streaming. In the arterial circulation, we found no evidence for preferential streaming of UV-injected and DIVC-injected microspheres.

The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age.

BACKGROUND: Transient hypothyroxinemia, a common finding in premature infants, is not thought to have long-term sequelae or to require treatment. We investigated whether hypothyroxinemia in premature infants is a cause of subsequent motor and cognitive abnormalities. METHODS: In this historical cohort study, we retrieved blood thyroxine values, obtained on routine screening in the first week of life, from state screening records on children who weighted 2000 g or less at birth, who were born at 33 weeks' gestation or earlier, and who were enrolled in a population-based study of the late sequelae of neonatal brain hemorrhage. We investigated the relation of these values to the odds for disabling cerebral palsy among 463 subjects for whom data were available and to the mental-development score on the Bayley Scales of Infant Development or the Stanford-Binet Intelligence Scales for Children at the age of two years in 400 subjects. The effects of severe hypothyroxinemia, defined as a blood thyroxine value more than 2.6 SD below the mean for New Jersey newborns, were assessed before and after adjustment for gestational age and potentially confounding variables. RESULTS: In analyses adjusted for gestational age, infants with severe hypothyroxinemia had a risk of disabling cerebral palsy that was nearly 11 times that of infants without hypothyroxinemia (odds ratio, 10.8; 95 percent confidence interval, 3.0 to 39.3) and a mean mental-development score at the age of two that was 15.4 points lower (95 percent confidence interval, 8.1 to 22.6 points) than the mean score of children with normal neonatal blood thyroxine concentrations. After adjustment for gestational age and multiple prenatal, perinatal, and early and last neonatal variables, severe hypothyroxinemia was still associated with an increased risk of disabling cerebral palsy (odds ratio, 4.4; 95 percent confidence interval, 1.0 to 18.6) and a reduction of nearly 7 points (95 percent confidence interval, 0.3 to 13.2 points) in the mental-development score. CONCLUSIONS: Severe hypothyroxinemia in preterm infants may be an important cause of problems in neurologic and mental development detected at the age of two years.

Emergency room use of transvaginal ultrasonography by obstetrics and gynecology residents.

OBJECTIVE: The objective of this study was to evaluate the feasibility and diagnostic value of the emergency room use of transvaginal ultrasonography operated by the obstetrics and gynecology residents. STUDY DESIGN: One hundred sixty-eight patients scanned in the emergency room constituted the study group and were compared with 61 patients for whom emergency room scanning was not available. Scanning and no-scanning days alternated for a 6-month period. The Student t test was used in the analysis. RESULTS: By comparing the two patient groups a statistically significant (p less than 0.0001) difference was seen in the time spent by the group of patients scanned in the emergency room (40 minutes) when compared with that of the patients for whom no emergency room scanning was available (215 minutes). The residents expressed high confidence in the scanning procedure. There were six misdiagnosed cases, three of them nonruptured ectopic gestations. However, none of these patients was discharged without adequate treatment. CONCLUSION: The study confirmed our hypothesis that obstetrics and gynecology residents can operate and should have available ultrasonography machines in the emergency departments to render quicker and better patient care.

Variation in use of corticosteroids among infants < or = 1,500 grams across hospitals in three states.

We identified factors associated with no antenatal corticosteroid treatment among 1,369 women who delivered infants < or = 1,500 g and < 34 weeks gestation, 1991-1993. At four hospitals, infants weighing 500-1,500 g were enrolled. Information regarding corticosteroid use, maternal characteristics, and perinatal events were obtained. Factors associated with no corticosteroid treatment were examined in unadjusted and adjusted logistic regression models. Overall, 693 (50.6%) women did not receive corticosteroids. Two hospitals had higher rates of no corticosteroid usage (89% and 75%) as compared with the other two (32% and 50%). Black, Hispanic, and poor women were more likely to receive care at the hospitals where the rates of corticosteroid utilization were lower. Factors in the multivariate model included: < 1 or 1 day of hospitalization, vs. delivery on > or = 2 days of hospitalization (21.4: 14.5, 97.2; 4.7: 3.2, 6.9); gestational age < 26 weeks (2.7: 1.8, 4.1) or > 28 weeks (1.8: 1.3, 2.6) vs. 26-28 weeks; < 12 hours of labor vs. > 12 hours (1.7: 1.2, 2.4); delivering at hospital 2, 3, 4 vs. hospital 1 (1.6: 1.1, 2.5; 24.3: 13.6, 43.4; 10.2: 6.8, 15.3). We conclude that variations in hospital practice limit widespread use of this important antenatal treatment.

Hemodynamic effects of alpha-adrenergic blockade during hypoxia in fetal sheep.

During hypoxemia there is a redistribution of cardiac output in the sheep fetus associated with increased vascular resistance in some fetal organs. The role of the alpha-adrenergic blocking drug to eight chronically instrumented hypoxemic sheep fetuses. We measured arterial blood pressure and heart rate, determined cardiac output and organ blood flows by means of radionuclide-labeled microspheres, and calculated vascular resistances in fetuses before and during hypoxia, and after injection of phenoxybenzamine 15 mg into the inferior vena cava of the hypoxemic fetus. Hypoxemia resulted in an increased vascular resistance in certain vascular beds. Alpha-adrenergic blockade during hypoxia abolished the increase in vascular resistance of the fetal body and caused an increase in the blood flow to some tissues which had a hypoxia-induced vasoconstriction. After alpha-adrenergic blockade during hypoxia, mean arterial blood pressure decreased from 48 +/- 6 to 42 +/- 6 mm Hg (p less than 0.05) and heart rate increased from 128 +/- 19 to 235 +/- 51 beats per minute (p less than 0.001). Cardiac output increased 23% and blood flow to the brain was maintained. We conclude that the alpha-adrenergic system is important in maintaining the redistribution of cardiac output that occurs in hypoxic fetal sheep.