Use of biomarkers to assess tissue specific androgen adequacy: defining male hypogonadism.

PURPOSE: The criteria for normal testosterone have been established by expert consensus rather than by evidence. We determined whether a cutoff point for normal could be established using biomarkers. MATERIALS AND METHODS: We performed an exploratory investigation of 1,492 hypogonadal men pooled from 7 registration trials. Serum testosterone, prostate specific antigen and hematocrit were measured at baseline and after 90 days of continuous testosterone replacement therapy. RESULTS: Baseline prostate specific antigen, percent change in prostate specific antigen and hematocrit appeared to be most strongly related to baseline serum testosterone. Subgroup analysis and visual inspection of linear spline fit of these data suggested an approximate serum testosterone cutoff for normal of 300 ng/dl for percent change in hematocrit, and 200 ng/dl for baseline prostate specific antigen and percent change in prostate specific antigen. CONCLUSIONS: This exploratory study revealed considerable variation among individuals and target tissues in individuals. Further study should be performed using standardized assays in a broader population.

Frequency of uterine contractions and the risk of spontaneous preterm delivery.

BACKGROUND: The measurement of the frequency of uterine contractions has not been useful for reducing the rate of preterm delivery in randomized trials. Nonetheless, ambulatory monitoring of contractions continues to be used in clinical practice. METHODS: We assessed the frequency of uterine contractions as a predictor of the risk of spontaneous preterm delivery before 35 weeks of gestation. We enrolled women with singleton pregnancies between 22 and 24 weeks of gestation. The women used a contraction monitor at home to record contraction frequency twice daily on 2 or more days per week from enrollment to delivery or 37 weeks of gestation. RESULTS: We obtained 34,908 hours of successful monitoring recordings from 306 women. Although more contractions were recorded from women who delivered before 35 weeks than from women who delivered at 35 weeks or later, we could identify no threshold frequency that effectively identified women who delivered preterm infants. The sensitivity and positive predictive value of a maximal hourly frequency of contractions of four or more between 4 p.m. and 3:59 a.m. were 9 percent and 25 percent, respectively, at 22 to 24 weeks and 28 percent and 23 percent at 27 to 28 weeks. Other proposed screening tests, such as digital and ultrasound evaluations of the cervix and assays for fetal fibronectin in cervicovaginal secretions, also had low sensitivity and positive predictive value for preterm labor. CONCLUSIONS: Although the likelihood of preterm delivery increases with an increased frequency of uterine contractions, measurement of this frequency is not clinically useful for predicting preterm delivery.

The NICHD-MFMU antibiotic treatment of preterm PROM study: impact of initial amniotic fluid volume on pregnancy outcome.

OBJECTIVE: The purpose of this study was to evaluate the associations between measured amniotic fluid volume and outcome after preterm premature rupture of membranes (PROM). STUDY DESIGN: This was a secondary analysis of 290 women, with singleton pregnancies, who participated in a trial of antibiotic therapy for preterm PROM at 24(0) to 32(0) weeks. Each underwent assessment of the 4 quadrant amniotic fluid index (AFI) and a maximum vertical fluid pocket (MVP) before randomization. The impact of low AFI (< 5.0 cm) and low MVP (< 2.0 cm) on latency, amnionitis, neonatal morbidity, and composite morbidity (any of death, RDS, early sepsis, stage 2-3 necrotizing enterocolitis, and/or grade 3-4 intraventricular hemorrhage) was assessed. Logistic regression controlled for confounding factors including gestational age at randomization, GBS carriage, and antibiotic study group. RESULTS: Low AFI and low MVP were identified in 67.2% and 46.9% of women, respectively. Delivery occurred by 48 hours, 1 and 2 weeks in 32.4%, 63.5% and 81.7% of pregnancies, respectively. Both low AFI and low MVP were associated with shorter latency (P < .001), and with a higher rate of delivery at 48 hours, 1, and 2 weeks (P = .02 for each). However, neither test offered significant additional predictive value over the risk in the total population. Low AFI and low MVP were not associated with increased amnionitis. After controlling for other factors, both low MVP and low AFI were associated with shorter latency (P < or = .002), increased composite morbidity (P = .03), and increased RDS (P < or = .01), but not with increased neonatal sepsis (P = .85) or pneumonia (P = .53). Alternatively, after controlling for fluid volume, gestational age, and GBS carriage, the antibiotic study group had longer latency, and suffered less common primary outcomes and neonatal sepsis. CONCLUSION: Oligohydramnios should not be a consideration in determining which women will be candidates for expectant management or antibiotic treatment when it is identified at initial assessment of preterm PROM remote from term.

Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women.

OBJECTIVE: To estimate the rate of congenital varicella zoster virus syndrome in neonates born to women developing varicella zoster virus infections during pregnancy. METHODS: Pregnant women with clinical varicella zoster virus infection were enrolled at ten perinatal centers. Maternal and fetal immunoglobulin (Ig) G and IgM by fluorescent antibody confirmed 74.3% of cases. Specialists examined neonates at 0-6 months, 7-18 months, and 19-30 months after delivery to detect abnormalities of their eyes, hearing, and physical and developmental features. A hierarchical set of criteria was used to define congenital varicella syndrome. A jury of four investigators assigned the classification of all findings. RESULTS: In 362 women enrolled from 1993 to 1996, 15 had herpes zoster, and 347 had primary varicella zoster virus infection. Varicella zoster virus affected 140 women (38.7%) in the first trimester, 122 (33.7%) in the second trimester, and 100 (27.6%) in the third trimester. Five twin pairs were included. Only one case (0.4%) of definite congenital varicella syndrome was found, a 3360-g female infant having a left retinal macular lesion with typical skin scars after maternal varicella at 24 weeks. The maternal blood sample at birth was negative for IgG antibodies to toxoplasmosis and cytomegalovirus. Two cases involved fetal death at 20 weeks and fetal hydrops at 17 weeks after maternal varicella at 11 and 5 weeks, respectively. We found no cases of limb hypoplasia, microcephalus, or cataract. CONCLUSION: The frequency of congenital varicella syndrome is very low (0.4%) in a prospectively studied cohort. Eye examinations of exposed infants had a low yield.

Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women.

OBJECTIVE: To estimate whether antibiotic treatment of asymptomatic women with a positive cervical or vaginal fetal fibronectin test in the second trimester would reduce the risk of spontaneous preterm delivery. METHODS: Women were screened between 21 weeks 0 days and 25 weeks 6 days of gestation with cervical or vaginal swabs for fetal fibronectin. Women with a positive test (50 ng/mL or more) were randomized to receive metronidazole (250 mg orally three times per day) and erythromycin (250 mg orally four times per day) or identical placebo pills for 10 days. The primary outcome was spontaneous delivery before 37 weeks' gestation after preterm labor or premature membrane rupture. RESULTS: A total of 16,317 women were screened for fetal fibronectin, and 6.6% had a positive test; 715 fetal fibronectin test-positive women consented to randomization. Outcome data were available for 703 women: 347 in the antibiotic group and 356 in the placebo group. The antibiotic and placebo groups were not significantly different for maternal age (P =.051), ethnicity (P =.849), marital status (P =.127), education (P =.244), and bacterial vaginosis (P =.236). No difference was observed in spontaneous preterm birth before 37 weeks' (odds ratio [OR] 1.17, 95% confidence interval [CI] 0.80, 1.70), less than 35 weeks' (OR 0.92, 95% CI 0.54, 1.56), or less than 32 weeks' (OR 1.94, 95% CI 0.83, 4.52) gestation in antibiotic- compared with placebo-treated women. Among women with a prior spontaneous preterm delivery, the rate of repeat spontaneous preterm delivery at less than 37 weeks' gestation was significantly higher in the active drug compared with the placebo group (46.7% versus 23.9%, P =.039). CONCLUSION: Treatment with metronidazole plus erythromycin of asymptomatic women with a positive cervical or vaginal fetal fibronectin test in the late second trimester does not decrease the incidence of spontaneous preterm delivery.

Asthma during pregnancy.

OBJECTIVE: To determine neonatal and maternal outcomes stratified by asthma severity during pregnancy by using the 1993 National Asthma Education Program Working Group on Asthma and Pregnancy definitions of asthma severity. The primary hypothesis was that moderate or severe asthmatics would have an increased incidence of delivery at <32 weeks of gestation compared with nonasthmatic controls. METHODS: This was a multicenter, prospective, observational cohort study conducted over 4 years at 16 university hospital centers. Asthma severity was defined according to the National Asthma Education Program Working Group on Asthma and Pregnancy classification and modified to include medication requirements. This study had 80% power to detect a 2- to 3-fold increase in delivery less than 32 weeks of gestation among the cohort with the moderate or severe asthma compared with controls. Secondary outcome measures included obstetrical and neonatal outcomes. RESULTS: The final analysis included 881 nonasthmatic controls, 873 with mild asthma, 814 with moderate, and 52 with severe asthma. There were no significant differences in the rates of preterm delivery less than 32 weeks (moderate or severe 3.0%, mild 3.4%, controls 3.3%; P =.873) or less than 37 weeks of gestation. There were no significant differences for neonatal outcomes except discharge diagnosis of neonatal sepsis among the mild group compared with controls, adjusted odds ratio 2.9, 95% confidence interval 1.2, 6.8. There were no significant differences for maternal complications except for an increase in overall cesarean delivery rate among the moderate-or-severe group compared with controls (adjusted odds ratio 1.4, 95% confidence interval 1.1, 1.8). CONCLUSION: Asthma was not associated with a significant increase in preterm delivery or other adverse perinatal outcomes other than a discharge diagnosis of neonatal sepsis. Cesarean delivery rate was increased among the cohort with moderate or severe asthma. LEVEL OF EVIDENCE: II-2

Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy.

OBJECTIVE: This study was undertaken to compare the efficacy of inhaled beclomethasone dipropionate to oral theophylline for the prevention of asthma exacerbation(s) requiring medical intervention. STUDY DESIGN: A prospective, double-blind, double placebo-controlled randomized clinical trial of pregnant women with moderate asthma was performed. RESULTS: There was no significant difference (P=.554) in the proportion of asthma exacerbations among the 194 women in the beclomethasone cohort (18.0%) versus the 191 in the theophylline cohort (20.4%; risk ratio [RR]=0.9, 95% CI=0.6-1.3). The beclomethasone cohort had significantly lower incidences of discontinuing study medications caused by side effects (RR=0.3, 95% CI=0.1-0.9; P=.016), and proportion of study visits with forced expiratory volume expired in 1 second (FEV1) less than 80% predicted (0.284+/-0.331 vs 0.284+/-0.221, P=.039). There were no significant differences in treatment failure, compliance, or proportion of peak expiratory flow rate less than 80% predicted. There were no significant differences in maternal or perinatal outcomes. CONCLUSION: The treatment of moderate asthma with inhaled beclomethasone versus oral theophylline resulted in similar rates of asthma exacerbations and similar obstetric and perinatal outcomes. These results favor the use of inhaled corticosteroids for moderate asthma during pregnancy because of the improved FEV1 and because theophylline had more side effects and requires serum monitoring.

Asthma morbidity during pregnancy can be predicted by severity classification.

BACKGROUND: The 1993 National Asthma Education Program Working Group on Asthma and Pregnancy defined asthma severity as mild, moderate, or severe on the basis of symptoms and spirometry, but no studies have evaluated the relationship between this classification system and subsequent asthma morbidity during pregnancy. OBJECTIVE: The objective of this study was to evaluate the relationship between asthma severity classification during pregnancy and gestational asthma exacerbations. METHODS: Asthma severity was defined according to the 1993 classification, adjusted to include medication requirements, in a volunteer sample of 1739 pregnant asthmatic patients who were less than 26 weeks' gestation. RESULTS: Initial asthma classification (mild, moderate, or severe) was significantly related to subsequent asthma morbidity during pregnancy (hospitalizations, unscheduled visits, corticosteroid requirements, and asthma symptoms during labor and delivery). Exacerbations during pregnancy occurred in 12.6% of patients initially classified as mild, 25.7% of patients classified as moderate, and 51.9% of patients classified as severe (P <.001). Asthma morbidity was similar, whether patients were classified as moderate or severe by symptoms and spirometry or by medication requirement. Thirty percent of initially mild patients were reclassified as moderate-severe during pregnancy, and 23% of the initially moderate-severe patients were reclassified as mild later in pregnancy; asthma morbidity in these patients changed accordingly. CONCLUSION: The National Asthma Education Program Working Group on Asthma and Pregnancy classification of asthma severity, adapted to include medication use, predicts subsequent asthma morbidity during pregnancy.