Kenneth Higby

Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety

OBJECTIVE Our aim was to determine the efficacy and safety of tocolytic agents currently used to treat premature labor. STUDY DESIGN We carried out a comprehensive review of tocolytic agents in the treatment of premature labor. Three hundred twenty-eight studies published between 1933 and 1992 were analyzed. RESULTS An analysis of randomized, placebo-controlled, clinical trials showed that magnesium sulfate is not better than placebo in the treatment of premature labor. beta-Adrenergic receptor agonists effectively stop premature labor for only 24 to 48 hours. Calcium channel blockers and oxytocin antagonists inhibit uterine contractions, but their role in stopping labor is undefined. Prostaglandin inhibitors appear to be effective in treating premature labor and have few adverse side effects. CONCLUSIONS The only tocolytic drugs that might be effective are the prostaglandin inhibitors. Tocolytic agents should be used only between 24 and 32 completed weeks of gestation. Magnesium sulfate should not be used to treat premature labor. Oxytocin antagonists should be used only in experimental clinical trials. Calcium channel blockers and beta-adrenergic receptor agonists inhibit uterine contractions but do not prolong gestation for longer than 48 hours.

Normal values of urinary albumin and total protein excretion during pregnancy

OBJECTIVE Our purpose was to determine the normal 24-hour excretion values of urinary albumin and total protein in healthy pregnant women. STUDY DESIGN We evaluated 270 healthy pregnant women < or = 35 years old without a history of diabetes, hypertension, pyelonephritis, preeclampsia, or renal or connective tissue disease. Adequacy of 24-hour collection was determined by creatinine excretion. RESULTS The mean protein excretion in 24 hours was 116.9 mg, upper 95% confidence limit 259.4 mg. The mean albumin excretion in 24 hours was 11.8 mg, upper 95% confidence limit 28.7 mg. Both protein and albumin excretion increased after 20 weeks of gestation. No patient had evidence of microalbuminuria, defined as urinary albumin excretion > 30 mg/L. CONCLUSION These data support 260 mg per 24 hours of urinary protein and 29 mg per 24 hours of albumin as the upper limit of normal in pregnancy. Albumin accounts for a small fraction of total urinary protein excretion.

Accuracy and intraobserver variability of simulated cervical dilatation measurements

OBJECTIVE Our purpose was to assess the accuracy and intraobserver variability of clinical cervical diameter measurements among obstetric health care providers. STUDY DESIGN Polyvinyl chloride pipes 1 to 10 cm in diameter were mounted in cardboard boxes and used to simulate cervical examinations. The boxes were designed so that the examiner had to rely solely on proprioception to determine the inner diameter. RESULTS A total of 1574 simulated cervical diameter measurements were obtained from 102 different examiners in a two-part study. The overall accuracy for determining the exact diameter was 56.3%, which improved to 89.5% when an error of +/- 1 cm was allowed. Intraobserver variability for a given diameter measurement was 52.1%, which decreased to 10.5% when an error of +/- 1 cm was allowed. CONCLUSIONS Cervical diameter measurements obtained by digital examination are precise when an error of +/- 1 cm is allowed for. Intraobserver variability is > 50% and is an important consideration when evaluating dysfunctional labor.

A Risk-Benefit Assessment of Therapies for Premature Labour

Prematurity is the leading cause of neonatal morbidity and mortality, yet the incidence of preterm birth has not declined despite the use of multiple pharmacological agents to treat preterm labour. After reviewing the literature we conclude the following.β-Agonists have been shown to prolong gestation for 24 to 48 hours; however, these agents have not been shown to decrease neonatal morbidity or mortality. Adverse effects are inevitable and can be life-threatening. There are no proven benefits to mother or fetus with long term therapy.More data are needed regarding the tolerability and efficacy of calcium antagonists before routine clinical use can be recommended. Oxytocin antagonists should be considered investigational drugs and further studies are needed to evaluate their effectiveness in the treatment of preterm labour. Furthermore, the tolerability of Oxytocin antagonists in both mother and fetus has not been adequately established.Indomethacin, a Prostaglandin inhibitor, has been shown to delay delivery in a limited number of randomised placebo-controlled clinical trials. Sulindac appears promising but has never been evaluated in a well controlled trial. Neonatal adverse effects appear to be minimal with Prostaglandin inhibitors as long as the duration of treatment is short (<48 to 72 hours) and the gestational age is <32 weeks.Magnesium sulfate appears to inhibit myometrial contractility but is ineffective at prolonging gestation or preventing preterm birth. Furthermore, magnesium has not been shown to decrease neonatal morbidity or mortality; in fact, some investigators have shown an increase in infant mortality with this agent.There are no data to support adjunctive antimicrobial therapy for the treatment of preterm labour. Oral maintenance therapy with any of these tocolytic agents has not been shown to decrease the rate of preterm birth or recurrent preterm labour.

A comparison between two screening methods for detection of microproteinuria.

OBJECTIVE We compared two screening tests for microproteinuria with 24-hour quantitative measurements to determine which method is better at predicting clinically significant proteinuria. STUDY DESIGN We obtained 690 24-hour urine collections from both low- and high-risk patients seen for prenatal care. Qualitative screening for microproteinuria on the basis of the protein-error-of-indicators principle (Ames Multistix 10SG and Micro-bumintest, Miles Diagnostic Division, Elkhart, Ind.) was done by the same investigator (C.S.). Quantitative assay was done by use of pyrogallol red-molybdate for total protein and by radioimmunoassay for albumin. RESULTS The Micro-bumintest had a sensitivity of 87% compared with 36% for the Multistix 10SG. It also had a higher specificity and higher positive and negative predictive values. The Micro-bumintest was a better screening test in patients with significant protein excretion (> 300 mg/24 hours). CONCLUSION The Micro-bumintest has a much higher sensitivity and a lower false-negative rate than does the Multistix 10SG. Our data support the Micro-bumintest as a better screening test for clinically significant proteinuria.

Transvaginal cervical length scans to prevent prematurity in twins: a randomized controlled trial

BACKGROUND Twin pregnancies are associated with an increased risk of perinatal morbidity and mortality primarily due to spontaneous preterm deliveries. The mean gestational age for delivery is 35.3 weeks and twins account for 23% of preterm births <32 weeks. A number of strategies have been proposed to prevent preterm deliveries: tocolytics, bed rest, hospitalization, home uterine activity monitoring, cerclage, and most recently, progesterone. Unfortunately, none have proven effective. Recent metaanalyses and reviews suggest that transvaginal cervical length (TVCL) ultrasound in the second trimester is a powerful predictor of preterm birth among asymptomatic women. Indeed, TVCL has the highest positive and negative predictive values for determining the risk of spontaneous preterm delivery in twin pregnancies. It follows that TVCL assessment may allow identification of a subset of twin pregnancies that re better candidates for interventions intended to prevent prematurity. OBJECTIVE We sought to determine whether use of TVCL prolongs gestation in twin pregnancies. STUDY DESIGN This is a multicenter, randomized, controlled trial of 125 dichorionic or monochorionic/diamniotic twin pregnancies without prior preterm birth <28 weeks. The study group (n = 63) had TVCL and digital exams monthly from 16-28 weeks and were managed with a standard algorithm for activity restriction and cerclage. The control group (n = 62) had monthly digital cervical examinations but no routine TVCL ultrasound examinations. The primary outcome was gestational age at delivery. Secondary outcomes included percentage of deliveries <35 weeks, and maternal and neonatal outcomes. RESULTS The mean gestational age at delivery was 35.7 weeks (95% confidence interval [CI], 35.2-36.2) among those managed with TVCL and 35.5 weeks (95% CI, 34.7-36.4) among the control patients. The Kaplan-Meier estimates of deliveries <38 weeks were not significantly different between groups. This was true whether we compared curves with a log-rank test (P = .67), Breslow test (P = .67), or Tarone-Ware test (P = .64). The percentage of deliveries <35 0/7 weeks did not differ: 27.4% for subjects managed with routine TVCL and 28.6% for control subjects (relative risk, 0.96; 95% CI, 0.60-1.54). Our study had an 80% power to detect a 12-day difference in the gestational age at delivery with 95% confidence. CONCLUSION The overall mean length of gestation and the percentage of women delivering <35 weeks did not differ between twin gestations managed with TVCL and digital exams monthly from 16-28 weeks with a standard algorithm for activity restriction and cerclage and controls who had monthly digital cervical examinations but no routine TVCL. Routine second-trimester transvaginal ultrasound assessment of cervical length is not associated with improved outcomes when incorporated into the standard management of otherwise low-risk twin pregnancies.

Human Placental Transfer of the Prostaglandin Inhibitor Sulindac Using an In Vitro Model

Objective: We determined whether the prostaglandin inhibitor sulindac crosses the human placenta. Methods: The recirculating single-cotyledon placenta model was used to characterize the matenal-to-fetal and fetal-to-maternal transport of 14C-labeled sulindac in normal term placentas perfused immediately after delivery. Antipyrine was added as a standard for simple diffusion. Serial samples were taken from bth reservoirs during each 3-hour perfusion. Transport was calculated using liquid scitntillation spectrometry for 14C-labeled sulindac and high-performance liquid chromatography for antipyrine. Results: There was significant maternal-to-fetal transfer of sulindac. The mean (±SD) transfer at 2 hours was 7.22 ± 2.57%. The fetal-to-maternal transfer was similar at 10.75 ± 3.80%. The mean maternal/fetal concentration ratio of sulindac was 0.42 at 3 hours. Placental uptake ranged from 24-45 ng/g of placenta. Conclusions: Sulindac crosses the human placenta in small but significant amounts. The transport is similar in both directions, implying simple diffusion.