In vitro differentiation of villous trophoblasts from pregnancies complicated by intrauterine growth restriction with and without pre-eclampsia.

Highly purified (>99.99%) primary villous cytotrophoblasts from uncomplicated pregnancies and pregnancies complicated with intrauterine growth restriction (IUGR) alone, IUGR with pre-eclampsia (IUGR-PE) and PE alone were cultured for 5days and the extent of differentiation into syncytiotrophoblasts measured in terms of syncytialisation and secretion of chorionic gonadotropin (hCG) and placental lactogen (hPL). Three separate phenotypes were observed: (1) normal and IUGR-PE cells showed low syncytialisation and secretion of hCG and hPL, (2) IUGR cells showed the highest levels of syncytialisation and secretion and (3) PE cells showed high syncytialisation but low secretion. These results strongly suggest IUGR, IUGR-PE and PE to be distinct conditions in which villous cytotrophoblasts are either exposed to different environments or are genetically different.

Prostaglandin endoperoxide-H synthase (PGHS) activity and immunoreactive PGHS-1 and PGHS-2 levels in human amnion throughout gestation, at term, and during labor.

Prostaglandins (PGs) are of primary importance in the initiation and maintenance of labor in women. A major intrauterine source of prostaglandins is the amnion, which synthesizes increased amounts of PGE2 at term labor. Because PG endoperoxide-H synthase (PGHS) catalyzes the rate-limiting step of PG synthesis from arachidonic acid, we investigated the changes in amniotic PGHS specific activity during gestation and at term and preterm labor. Also, we determined the level of immunoreactive PGHS protein in the amnion to evaluate the mechanisms by which PGHS activity may be regulated. PGHS specific activity, measured at the amount of PGE2 produced by amnion microsomes under optimal conditions, was 18.2 +/- 3.7 pg PGE2/micrograms protein.min (mean +/- SE; n = 19) at term (37-42 weeks gestation) before the spontaneous onset of labor. PGHS specific activity was significantly higher after spontaneous term labor (38.9 +/- 6.0 pg PGE2/micrograms protein.min; n = 19; P < 0.05). Amnion samples from preterm (< 36 weeks gestation) nonlaboring patients contained low levels of PGHS specific activity (5.9 +/- 1.8 pg PGE2/micrograms protein.min; n = 9), which increased significantly with spontaneous preterm labor (28.3 +/- 6.8 pg PGE2/micrograms protein.min; n = 10; P < 0.05). Longitudinal analysis of the data showed that PGHS specific activity was low in the first and second trimesters of gestation, but increased dramatically before labor onset at term. We detected PGHS protein in all microsomal samples, with an antiovine PGHS antibody recognizing both PGHS-1 and -2 isoforms of the enzyme. However, there was no correlation between PGHS specific activity and the amount of immunoreactive PGHS protein. Using an antibody specific for PGHS-2, we detected immunoreactive protein in only 9 of the 25 tissues examined and found no correlation between PGHS specific activity and the amount of PGHS-2 protein. These results suggest that 1) PGHS specific activity in the amnion increases sharply before the onset of labor at term; 2) further increases in specific activity occur during term and preterm labor; and 3) the specific activity of PGHS in the amnion is not related directly to the amount of immunoreactive enzyme protein.

Gestational diabetes mellitus: prevalence, risk factors, maternal and infant outcomes.

OBJECTIVES: To study prevalence, risk factors, and maternal and infant outcomes of women with gestational diabetes mellitus (GDM). METHODS: A retrospective cohort study was performed based on 111563 pregnancies delivered between 1991 through 1997 in 39 hospitals in northern and central Alberta, Canada. Multivariate logistic regression was used to estimate the odds ratios with 95% confidence intervals, and to control for confounding variables. RESULTS: The prevalence of GDM was 2.5%. Risk factors for GDM included age >35 years, obesity, history of prior neonatal death, and prior cesarean section. Teenage mothers and women who drank alcohol were less likely to have GDM. Mothers with GDM were at increased risk of presenting with pre-eclampsia, premature rupture of membranes, cesarean section, and preterm delivery. Infants born to mothers with GDM were at higher risk of being macrosomic or large-for-gestational-age. CONCLUSIONS: Specific conditions predispose to GDM which itself is associated with a significantly increased risk of maternal and fetal morbidity.

Maternal smoking and preeclampsia.

OBJECTIVE: To study the relationship between maternal smoking and preeclampsia and whether this association differs between primiparous and multiparous women. STUDY DESIGN: We conducted a population-based, retrospective, cohort study of 58,216 singleton pregnancies from northern and central Alberta, Canada, between 1995 and 1997. Multivariate logistic regression was used to control for maternal alcohol consumption, drug dependence, maternal age, maternal weight, prior intrauterine growth restriction and other confounders. RESULTS: Maternal smoking was associated with a significantly reduced overall risk of preeclampsia (adjusted odds ratio [aOR]: .61; 95% confidence interval [CI]: .50-.75; P < .01). Stratified analyses showed that in primiparous pregnancies, maternal smoking was associated with a significantly decreased risk (aOR: .63; 95% CI: .50-.80; P < .01); in multiparous women, maternal smoking was not associated with a statistically significant decreased risk of preeclampsia (aOR: 0.72; 95% CI: .51-1.02; P > .05). CONCLUSION: Maternal smoking is protective against preeclampsia. Understanding the underlying biologic mechanisms of this protective effect may advance our knowledge of the pathogenesis of preeclampsia.

Vaginal probe ultrasound in malignancy involving the uterine cervix.

Current staging procedures in women with cancer of the cervix are inaccurate in up to one third of cases. The availability of vaginal probe ultrasound has prompted the authors to investigate its potential role in treatment of women with cervical cancer. In this preliminary report 22 women were evaluated by endovaginal scanning. A previously unreported sign consisting of dense bright echoes in the cervical stroma was observed. This sign was present in most patients with cervical involvement by cancer but the ultrasonographic distribution of echoes did not always match accurately the extension of the disease. Despite the interesting nature of this new findings, its role is going to be limited based on this small sample size.

Endogenous tumor necrosis factor alpha mediates enhanced apoptosis of cultured villous trophoblasts from intrauterine growth-restricted placentae.

Tumor necrosis factor alpha (TNFalpha) has been implicated in the abnormally high levels of trophoblast apoptosis seen in placentae from pregnancies complicated by small births. We examined the hypothesis that at physiological (35-50 mmHg) oxygen tensions, the production of TNFalpha stimulates the apoptosis of placental trophoblasts associated with infants that are intrauterine growth-restricted (IUGR). Highly purified cytotrophoblasts (CT) from IUGR-complicated pregnancies spontaneously underwent a higher rate of apoptosis after 24 h of culture at a normoxic (for villous CT) tension of 38 mmHg than did CT from normal placentae. Real-time PCR analysis of TNFalpha mRNA revealed approximately threefold higher levels in IUGR trophoblasts after culturing at a pO2 of 38 mmHg. A higher level of TNFalpha receptor p55 (which mediates apoptosis) was found in IUGR CT by western blot analysis at pO2 of <10, 38, and 140 mmHg. Neutralizing antibody to TNFalpha significantly inhibited the apoptosis of IUGR trophoblasts cultured at 38 mmHg and addition of TNFalpha significantly elevated apoptosis of normal and IUGR trophoblasts but less in IUGR cells cultured at <10 mmHg. We conclude that at physiological oxygen tensions (38 mmHg), villous CT from IUGR pregnancies, when compared with uncomplicated pregnancies, undergo more TNFalpha-induced apoptosis both because of elevated expression of TNFalpha and TNF receptor p55.

Gestational diabetes mellitus. Unresolved issues and future research directions.

OBJECTIVE: To summarize the controversial aspects of gestational diabetes (GDM) and introduce readers to possible relevant research questions that could be examined to provide clinicians with good-quality data on which to base decisions about this relatively common pregnancy-related issue. DATA SOURCES AND STUDY SELECTION: Ongoing review of the English literature related to GDM. Sources were not restricted to prospective, controlled trials, as these are severely limited in number. SYNTHESIS: Controversial issues include the relevance of GDM to clinically meaningful outcomes in the index pregnancy, the effectiveness of current therapy in altering these outcomes, and the resultant questionable relevance of routine screening and diagnosis of an entity with as yet uncertain significance in pregnancy. CONCLUSIONS: Suggested questions to be addressed in multicentre controlled trials include randomization with respect to screening and with respect to treatment. Until such trials are completed, continuing with a standard approach to screening, diagnosis, and treatment, such as that suggested by the third international workshop on GDM, is recommended.

Trial of labor after previous cesarean section: prognostic indicators of outcome.

A cross-sectional analytic survey of 92 patients permitted to attempt vaginal delivery after previous lower segment cesarean section ("trial of scar") is reported. Variables which may predict mode of delivery were assessed. Fifty patients (54.3%) were delivered vaginally; 42 patients (45.7%) had repeat cesarean sections in labor. There were three cases of scar dehiscence (3.2%). There were no maternal or fetal mortality. When the cervix was less than 3 cm dilated at initial examination in labor, 10 of 37 patients (27%) were delivered vaginally, compared to 38 of 55 patients (69%) who were delivered vaginally when the cervix was greater than 3 cm dilated. Assessment of cervical dilatation on admission in labor proved to be the most significant prognostic factor at the onset of labor, with regard to successful vaginal delivery in a patient with a lower segment cesarean section scar.

Successful outcome in a case of cystic adenomatoid malformation of the lung complicated by fetal hydrops, using extracorporeal membrane oxygenation.

Severe fetal hydrops associated with cystic adenomatoid malformation of the lung inexplicably resolved spontaneously at 33-34 weeks' gestation. Following postnatal resection of the lesion which was of the macrocystic variety, the infant's respiratory status deteriorated, requiring 1 week of complicated support with extracorporeal membrane oxygenation. The baby survived and was discharged.

Prenatal diagnosis of holoprosencephaly (HPE) in a fetus with a recombinant (18)dup(18q)inv(18)(p11.31q11.2)mat.

Alobar holoprosencephaly (HPE) was identified by ultrasonography at 18 weeks' gestation in a fetus of a 29-year-old G2P0A1 woman. HPE has been described in association with various chromosomal anomalies. Amniocentesis was performed and a rearrangement of chromosome 18 resembling an isochromosome for the long arm of chromosome 18 was found. Subsequently, the mother was found to have a pericentric inversion of chromosome 18 with breakpoints at p11.31 and q11.2. The karyotype of the fetus was re-interpreted as 46,XX, rec(18)dup(18q)inv(18)(p11.31q11.2)mat. This is the first case of a parental inversion leading to a deficiency of 18p11.31 to 18pter associated with HPE.

Myometrial electrophysiologic activity and gap junctions in the pregnant rabbit.

Electromyographic activity of the myometrium, intrauterine pressure, and myometrial gap junctions were examined in rabbits at various stages of pregnancy and during parturition. Electromyographic activity occurred throughout pregnancy and was characterized by electromyographic bursts lasting up to 5 minutes at a frequency of one to four per hour. The gap junction area of plasma membrane showed a significant increase at delivery at a time when electromyographic activity changed to rhythmic bursts of short duration at a frequency of about one per minute. This study shows that the rabbit uterus is active throughout pregnancy; furthermore, the development of large numbers of gap junctions between myometrial cells occurs at a time when uterine activity changes to the expulsive activity required for labor.

Relationship between plasma glucose levels in glucose-intolerant women and newborn macrosomia.

The purpose of this study was to examine the relationship between newborn macrosomia and plasma glucose profile in both a "glucose challenge test (GCT)-positive oral glucose tolerance test (OGTT)-negative" group (n = 113) and a gestational diabetes mellitus (GDM) group (n = 50). We examined 1) plasma glucose concentrations following a positive screen 50-g GCT (n = 163), 2) glucose concentrations following a 100-g OGTT (n = 163), and 3) the average fasting (AF) and 2-hour postprandial (APP) plasma glucose concentrations in the treated GDM group (n = 46). It was a case-control study with macrosomia vs. non-macrosomia in the ratio of 1:4. Macrosomia was analyzed by both birthweight > 4,000 g and gender-specific birthweight > 90th percentile for gestational age criteria. The GCT and the OGTT were performed between 26 and 30 weeks of pregnancy. The results demonstrated no significant impact of plasma glucose values from GCT, OGTT, AF, or APP on macrosomia in both "GCT-positive OGTT-negative" and GDM (treated) groups. Further, the screening and diagnostic plasma glucose concentrations were not related to macrosomia in both "GCT-positive OGTT-negative" and GDM groups. We found a difference of 0.6 mmol/liter in the maternal AF and APP glucose concentrations between mothers of macrosomic versus non-macrosomic newborns in the treated (diet or diet+insulin) GDM group. The clinical relevance of this difference remains to be explored. Our study provides a different methodological and analytic perspective in examining macrosomia versus non-macrosomia in the "GCT-positive OGTT-negative" and the GDM groups using univariate and multivariate analyses.

Isolated mental developmental delay in very low birth weight infants: association with prolonged doxapram therapy for apnea.

OBJECTIVE: We investigated factors associated with isolated mental delay in infants weighing < 1250 g at birth. STUDY DESIGN: With a case-control design, matching variables for 40 cases included gestation, birth weight, sex, grade of intraventricular hemorrhage, and socioeconomic status. Case subjects had a mental developmental index < 70, and controls had a mental developmental index > or = 85, according to the Bayley Scales of Infant Development II at 18 months' corrected age. RESULTS: There were no differences between the case and control subjects for neonatal complications and antenatal or postnatal steroid use. There was a marked difference in the cumulative dosage and duration of doxapram therapy used for apnea of prematurity (total dose 2233 +/- 1927 mg vs 615 +/- 767 mg, P < .001; duration 45.2 +/- 32.5 days vs 19.4 +/- 23.4 days, P < .001 for case subjects and control subjects, respectively). Multivariate analysis did not identify additive predictive variables. CONCLUSION: Isolated mental delay in infants weighing < 1250 g at birth was associated with the total dosage and duration of doxapram therapy for severe apnea. Although this may be a marker for cerebral dysfunction manifesting as apnea of prematurity, possible adverse effects of doxapram or its preservative, benzyl alcohol, on the developing brain deserve further study.

Anemia during pregnancy and birth outcome: a meta-analysis.

To determine the relationship between maternal anemia [hemoglobin (Hgb) < 10-11 g/dL] and various birth outcomes, a meta-analysis was conducted based on published literature identified by MEDLINE and manual search from 1966 through 1999. Odds ratios (OR) from selected studies were pooled according to the gestational age at anemia diagnosis. The meta-analysis shows that maternal anemia during early pregnancy was associated with slightly increased preterm birth [pooled adjusted OR (aOR): 1.32, 95% confidence interval (CI): 1.01-1.74], and nonstatistically significant increased low birth weight [pooled aOR: 1.39 (0.70-2.74)], and was not associated with fetal growth restriction [pooled aOR: 1.01 (0.73-1.38)]. However, there was a nonstatistically significant inverse relationship between anemia during late pregnancy and preterm birth [pooled aOR: 0.92 (0.54-1.84)] and low birth weight [pooled aOR: 0.80 (0.64-1.00)]. Anemia was not statistically significantly associated with hypertensive disorders of pregnancy regardless of stage of pregnancy [pooled OR: 0.80 (0.53-1.20)]. The relationship between anemia and perinatal mortality was inconclusive. A few studies indicated that severe maternal anemia (Hgb < 8-8.5 g/dL) was associated with increased risk of poor outcomes. We conclude that early pregnancy anemia is associated with slightly increased risk of preterm birth. The trend toward an inverse association of anemia determined during late pregnancy with preterm birth and low birth weight may reflect the benefit of plasma volume expansion.

Prostaglandin endoperoxide H synthase mRNA expression in the fetal membranes correlates with fetal fibronectin concentration in the cervico-vaginal fluids at term: evidence of enzyme induction before the onset of labour.

OBJECTIVE: To determine the relationship of prostaglandin endoperoxide H synthase (PGHS) expression in the gestational tissues and fetal fibronectin in cervico-vaginal fluids before the onset of labour at term. DESIGN: Cross-sectional, observational study. SAMPLES: Amnion, chorion laeve and decidua were collected from 24 term pregnant women following elective caesarean section. Samples of cervico-vaginal secretions were obtained from the same women immediately before caesarean section. METHODS: PGHS-1 and PGHS-2 mRNA levels in tissues were determined by specific ribonuclease protection assays. Fetal fibronectin concentrations in the cervico-vaginal fluids were measured by enzyme-linked immunosorbent assay. The abundance of PGHS mRNA was compared between groups of patients with the same mean gestational age but different cervico-vaginal fetal fibronectin levels. Linear regression analysis was used to determine the association between PGHS levels and fetal fibronectin. RESULTS: Two groups of women were identified who had significantly different fetal fibronectin values but the same gestational ages. The group with the higher fetal fibronectin concentrations had significantly higher PGHS- 1 and PGHS-2 mRNA levels in the chorion laeve and higher PGHS-2 mRNA levels in the amnion, than the group with lower fetal fibronectin concentrations. PGHS- 1 and PGHS-2 mRNA levels in the chorion laeve and PGHS-2 mRNA in the amnion showed an overall significant association with fetal fibronectin levels. CONCLUSIONS: High concentrations of fetal fibronectin in cervico-vaginal secretions before the onset of spontaneous labour at term are associated with high levels of PGHS-2 mRNA in the chorion laeve and the amnion and of PGHS- 1 mRNA in the chorion laeve. Increased expression of PGHS in these tissues may therefore be involved in the events leading to term birth.

Association of preeclampsia with high birth weight for age.

OBJECTIVE: The purpose of this study was to examine the effect of gestational hypertension and preeclampsia on fetal growth. STUDY DESIGN: A retrospective cohort study was conducted on the basis of 97,270 pregnancies delivered between 1991 and 1996 in 35 hospitals in northern and central Alberta, Canada. Univariate and multivariate logistic analyses were performed to examine the impact of preeclampsia and gestational hypertension on high-birth-weight (> or =4200 g), large-for-gestational-age, low-birth-weight (<2500 g), and small-for-gestational-age babies. RESULTS: The rate of high-birth-weight fetuses in women with gestational hypertension (7. 3%) was higher than in those with normal blood pressure (5.6%). After we controlled for confounders, the adjusted odds ratio of high birth weight was 1.44 (95% confidence interval, 1.21-1.70) in women with gestational hypertension. Preeclampsia was also associated with a statistically nonsignificant (P =.054) increased risk of high birth weight (adjusted odds ratio, 1.40; 95% confidence interval 0. 99-1.98). The rate of large-for-gestational-age babies was significantly higher in women with gestational hypertension (4.5%) and preeclampsia (4.7%) than in those with normal blood pressure (2. 2%), with adjusted odds ratios of 1.50 (95% confidence interval, 1. 22-1.85) for gestational hypertension and 1.87 (95% confidence interval, 1.31-2.67) for preeclampsia. Concurrently, women who had gestational hypertension were also at higher risk of having low-birth-weight (adjusted odds ratio, 2.4; 95% confidence interval, 2.13-2.93) and small-for-gestational-age (adjusted odds ratio, 2.04; 95% confidence interval, 1.68-2.48) babies. Women with preeclampsia were also at markedly higher risk of having low-birth-weight (adjusted odds ratio, 4.14; 95% confidence interval, 3.32-5.15) and small-for-gestational-age (adjusted odds ratio, 2.56; 95% confidence interval, 1.92-3.41) babies. CONCLUSIONS: There is a significant association of preeclampsia and gestational hypertension with large-for-gestational-age infants, in addition to a significant association with low-birth-weight and small-for-gestational-age infants. This study challenges the currently held belief that reduced uteroplacental perfusion is the unique pathophysiologic process in preeclampsia.

Impact of pregnancy-induced hypertension on fetal growth.

OBJECTIVE: The purpose of this study was to evaluate the effect of different types of pregnancy-induced hypertension on fetal growth. STUDY DESIGN: A retrospective cohort study was conducted on the basis of 16,936 births from January 1, 1989, through December 31, 1990, by means of data from a population-based perinatal database in Suzhou, China. Pregnancy-induced hypertension was classified as gestational hypertension, preeclampsia, or severe preeclampsia-eclampsia. Univariate and multivariate regression analyses were performed to examine the effect of the various types of pregnancy-induced hypertension on gestational age, preterm birth, birth weight, low birth weight, and intrauterine growth restriction. RESULTS: Gestation was 0.6 week shorter in women with severe preeclampsia than in normotensive women (P <.01). However, the risk of preterm birth was not increased with any classification of pregnancy-induced hypertension (for severe preeclampsia: adjusted odds ratio 1.75; 95% confidence interval, 0.88-3.47). After adjustment for duration of gestation and other confounders, preeclampsia and severe preeclampsia increased the risk of intrauterine growth restriction and low birth weight. The adjusted odds ratios of low birth weight were 2.65 (1.73-4.39) for preeclampsia and 2.53 (1.19-4.93) for severe preeclampsia. However, the risk of low birth weight was not increased significantly for gestational hypertension (adjusted odds ratio 1.56 [1.00-2.41]). CONCLUSION: Preeclampsia increases the risk of intrauterine growth restriction and low birth weight.