17-Hydroxyprogesterone caproate in triplet pregnancy: an individual patient data meta-analysis.

BACKGROUND: Preterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective. OBJECTIVE: To determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-hydroxyprogesterone caproate (17OHPc). SEARCH STRATEGY: We searched literature databases, trial registries and references in published articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies. DATA COLLECTION AND ANALYSIS: Investigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32 weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at <24, <28 and <34 weeks of gestation. MAIN RESULTS: Three RCTs of 17OHPc versus placebo included 232 mothers with triplet pregnancies and their 696 offspring. Risk-of-bias scores and between-study heterogeneity were low. Baseline characteristics were comparable between 17OHPc and placebo groups. The rate of the composite adverse perinatal outcome was similar among those treated with 17OHPc and those treated with placebo (34 and 35%, respectively; risk ratio [RR] 0.98, 95% confidence interval [95% CI] 0.79-1.2). The rate of birth at <32 weeks was also similar in the two groups (35 and 38%, respectively; RR 0.92, 95% CI 0.55-1.56). There were no significant between-group differences in perinatal mortality rate, randomisation-to-delivery interval, or other specified outcomes. CONCLUSION: Prophylactic 17OHPc given to mothers with triplet pregnancies had no significant impact on perinatal outcome or pregnancy duration. TWEETABLE ABSTRACT: 17-Hydroxyprogesterone caproate had no significant impact on the outcome or duration of triplet pregnancy.

Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.

BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB). OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA). SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles. SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB. MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75). AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

Impact of duration of rupture of membranes on outcomes of premature infants.

OBJECTIVE: The primary aim of the study was to determine how the risk of adverse outcomes was related to the duration of the latency period and gestational age at birth following preterm premature rupture of the fetal membranes (PPROM). STUDY DESIGN: Retrospective review of infants discharged from 330 neonatal intensive care units. We defined four subgroups based on gestational age: 23 to 25, 26 to 28, 29 to 31 and 32 to 34 weeks. Each gestational age group was evaluated by duration of ROM: <24 h, 1 to 7 days, 8 to 14 days, 15 to 21 days, 21 to 28 days and >28 days and compared with a referent group (PPROM of >24 h but <7 days). RESULT: In all, 239 808 non-anomalous infants 23 to 34 weeks' gestational age were identified; 37 233 (15.5%) had rupture of membranes (ROM) >24 h. Compared with a reference group (PPROM of >24 h but <7 days), the risk of mortality for PPROM of 8 to 14, 15 to 21 and 21 to 28 days varied depending on gestational age at birth. Only PPROM >28 days was consistently associated with increased mortality and decreased likelihood of survival without morbidity in all gestational age subgroups. CONCLUSION: PPROM for >28 days is associated with an increased risk of death and morbidity.

The fetal heart monitor tracing in pregnancies complicated by a spontaneous umbilical cord hematoma.

The objective of this study is to present and describe the fetal heart rate appearance in pregnancies complicated by an antenatal spontaneous umbilical cord hematoma that resulted in a live birth. Three cases of antenatal spontaneous umbilical cord hematoma are described. All three patients presented with a complaint of decreased fetal movement. The fetal heart monitor tracings on admission are depicted and discussed. In all three cases, the fetal heart rate pattern showed decreased variability with an absence of accelerations. Decelerations were noted but were identified in 25% or less of the contractions and primarily with contractions that exceeded 90 s. Absent accelerations with minimal to absent variability, if caused by uteroplacental insufficiency, usually develop in the presence of recurrent decelerations. Absent accelerations with minimal to absent variability in the absence of recurrent decelerations may suggest other causes including aneuploidy or congenital cardiac or neurologic anomalies. Though rare, spontaneous umbilical cord hematoma can be added to the differential.

The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system.

Adverse early experience, including prenatal maternal psychosocial stress, has the potential to negatively influence developmental processes through both physiological and behavioral mechanisms. This in turn may have adverse consequences for the mental and physical health, well-being and aging of the individual throughout the entire life-span. We have initiated a program of research on humans to examine the consequences of maternal stress and related factors in pregnancy on the length of gestation, fetal growth, and brain development. We have also investigated the physiological mechanisms that are involved. In this chapter we outline the theoretical rationale for this work and give an overview of our findings to date. These findings support a significant and independent role for behavioral processes such as maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal-placental-fetal neuroendocrine axis; specifically by placental corticotropin-releasing hormone. Using a fetal challenge paradigm as a novel method for quantifying fetal neurologic maturity in utero, we have found that the maternal environment exerts a significant influence on the fetal autonomic nervous system and on central nervous system processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first 3 years of postnatal life. The implications of these studies for life-span development and health are discussed.

Stress, infection and preterm birth: a biobehavioural perspective.

Preterm birth is currently the most important problem in maternal-child health in the United States. Epidemiological studies have suggested that two factors, maternal stress and maternal urogenital tract infection, are significantly and independently associated with an increased risk of spontaneous preterm birth. These factors are also more prevalent in the population of sociodemographically disadvantaged women who are at increased risk for preterm birth. Studies of the physiology of parturition suggest that neuroendocrine and immune processes play important roles in the physiology and pathophysiology of normal and preterm parturition. However, not all women with high levels of stress and/or infection deliver preterm, and little is understood about factors that modulate susceptibility to pathophysiological events of the endocrine and immune systems in pregnancy. We present here a comprehensive, biobehavioural model of maternal stress and spontaneous preterm delivery. According to this model, chronic maternal stress is a significant and independent risk factor for preterm birth. The effects of maternal stress on preterm birth may be mediated through biological and/or behavioural mechanisms. We propose that maternal stress may act via one or both of two physiological pathways: (a) a neuroendocrine pathway, wherein maternal stress may ultimately result in premature and/or greater degree of activation of the maternal-placental-fetal endocrine systems that promote parturition; and (b) an immune/inflammatory pathway, wherein maternal stress may modulate characteristics of systemic and local (placental-decidual) immunity to increase susceptibility to intrauterine and fetal infectious-inflammatory processes and thereby promote parturition through pro-inflammatory mechanisms. We suggest that placental corticotropin-releasing hormone may play a key role in orchestrating the effects of endocrine and inflammatory/immune processes on preterm birth. Moreover, because neuroendocrine and immune processes extensively cross-regulate one another, we further posit that exposure to both high levels of chronic stress and infectious pathogens in pregnancy may produce an interaction and multiplicative effect in terms of their combined risk for preterm birth. Finally, we hypothesise that the effects of maternal stress are modulated by the nature, duration and timing of occurrence of stress during gestation. A discussion of the components of this model, including a theoretical rationale and review of the available empirical evidence, is presented. A major strength of this biobehavioural perspective is the ability to explore new questions and to do so in a manner that is more comprehensive than has been previously attempted. We expect findings from this line of proposed research to improve our present state of knowledge about obstetric risk assessment for preterm birth by determining the characteristics of pregnant women who are especially susceptible to stress and/or infection, and to broaden our understanding of biological (endocrine, immune, and endocrine-immune interactions) mechanisms that may translate social adversity during pregnancy into pathophysiology, thereby suggesting intervention strategies.

A comparison of echocardiography and pulmonary artery catheterization for evaluation of pulmonary artery pressures in pregnant patients with suspected pulmonary hypertension.

OBJECTIVE: This study was undertaken to compare the accuracy of echocardiography versus pulmonary artery catheterization to estimate pulmonary artery pressures in pregnant women with suspected pulmonary hypertension. STUDY DESIGN: A retrospective chart review was performed between January 1990 and February 2000 for all pregnant patients with cardiac disease. Patients with pulmonary artery pressure values estimated by cardiac catheterization and echocardiography during pregnancy were included. Pulmonary hypertension is defined as pulmonary artery systolic pressure >30 mm Hg. RESULTS: Twenty-seven patients were included in the study. There was a significant overestimation of the mean pulmonary artery pressure with echocardiography compared with catheterization (55.4 vs 51.1 mm Hg; P <.005). Of the 20 patients, pulmonary artery pressure was significantly greater when estimated by echocardiography than when measured by catheterization (59.6 vs 54.8 mm Hg; P <.004). Thirty-two percent (8/25) of the patients had pulmonary hypertension when estimated by echocardiography but had normal pulmonary artery pressures on subsequent catheterization. CONCLUSION: Echocardiography significantly overestimated pulmonary artery pressures compared with catheterization in pregnant patients with suspected pulmonary hypertension. Patients with structural cardiac defects appear to have a significantly greater difference in pulmonary artery pressures. Thirty-two percent of pregnant patients with normal pulmonary artery pressures may be misclassified as having pulmonary artery hypertension when measured by echocardiography alone.

Pregnancy outcome in Hispanic patients with unexplained positive triple marker screening for Down syndrome.

OBJECTIVE: The objective of this study was to compare pregnancy outcomes in Hispanic patients with a positive serum triple marker screen for Down syndrome and normal fetal karyotype with Hispanic women who had a negative triple marker screen. METHODS: This prospective investigation involved Hispanic gravidas who underwent maternal serum screening. A power analysis was performed to determine the sample size. Fifty women with false-positive screens for Down syndrome were matched with a control group of 100 women with a negative screen. Adverse pregnancy outcomes were compared between the two groups. RESULTS: An adverse pregnancy outcome occurred in 14% of the study group and in 13% of controls. There were no statistically significant differences between the two groups in the incidence of preterm labor (p > 0.5), pre-eclampsia (p > 0.1), intrauterine growth restriction (p > 0.5), or fetal demise (p > 0.5). CONCLUSION: Hispanic patients with unexplained positive triple marker screen for Down syndrome do not appear to be at increased risk for adverse pregnancy outcomes.

Management of premature rupture of membranes.

The management of patients with PROM, regardless of gestational age, remains controversial. Generally, when patients are in labor, have infection, or there is irreversible fetal distress, there are few options other than delivery. For those not in labor, especially in premature gestational ages, the complexities of the many combinations of decisions to be made regarding the best methods for evaluating patients, prolonging gestation, reducing complications of prematurity, and choosing the timing and route of delivery make studying and solving the problem of the best option for management difficult at best. The administration of corticosteroids and broad-spectrum antibiotics of those patients in the very early premature gestational age groups has now been shown clearly to improve outcome. Beyond that, the remainder of these problems are somewhat unresolved and several reasonable options often exist and are likely to remain so for some time to come.

A randomized controlled trial of the effect of increased intravenous hydration on the course of labor in nulliparous women.

OBJECTIVE: One variable that has the potential to affect the course of labor but has not been evaluated previously is the adequacy of maternal hydration. Typical orders provide for 125 mL of intravenous fluids per hour in patients taking limited oral fluids. Many such patients are clinically dehydrated. Physiologists have shown that increased fluids improve skeletal muscle performance in prolonged exercise. This study was designed to determine whether increased intravenous fluids affect the progress of labor. STUDY DESIGN: Nulliparous women with uncomplicated singleton gestations at term, in spontaneous active labor with dilatation between 2 and 5 cm, and with a cephalic presentation were included. Patients who gave consent were randomly selected to receive either 125 mL or 250 mL of intravenous fluids per hour. RESULTS: One hundred ninety-five patients were randomly selected, 94 to the 125-mL group and 101 to the 250-mL group. Prerandomization variables were well matched between the 2 groups. The mean volume of total intravenous fluids was significantly greater in the 250-mL group (2008 mL vs 2487 mL; P =.002), as was the mean hourly rate (152 mL/h in the 125-mL group vs 254 mL/h in the 250-mL group; P =.001). The frequency of labor lasting >12 hours was statistically higher in the 125-mL group (20/78 [26%] vs 12/91 [13%]; P =.047). In addition, there was a trend favoring longer mean duration of the first stage and total duration of labor in patients delivered vaginally in the 125-mL group, by 70 and 68 minutes, respectively (P =.06). There was a trend toward a lower frequency of oxytocin administration for inadequate labor progress in the higher fluid rate group (61 [65%] in the 125-mL group vs 51 [49%] in the 250-mL group; P =.06). Cesarean deliveries were more frequent in the 125-mL group (n = 16) than in the 250-mL group (n = 10) but did not reach statistical significance. CONCLUSION: This study presents the novel finding that increasing fluid administration for nulliparous women in labor above rates commonly used is associated with a lower frequency of prolonged labor and possibly less need for oxytocin. Thus inadequate hydration in labor may be a factor contributing to dysfunctional labor and possibly cesarean delivery. Consideration of this factor in clinical management and in future studies considering variables that affect labor is warranted.

A multicenter controlled trial of fetal pulse oximetry in the intrapartum management of nonreassuring fetal heart rate patterns.

OBJECTIVE: Recent developments permit the use of pulse oximetry to evaluate fetal oxygenation in labor. We tested the hypothesis that the addition of fetal pulse oximetry in the evaluation of abnormal fetal heart rate patterns in labor improves the accuracy of fetal assessment and allows safe reduction of cesarean deliveries performed because of nonreassuring fetal status. STUDY DESIGN: A randomized, controlled trial was conducted concurrently in 9 centers. The patients had term pregnancies and were in active labor when abnormal fetal heart rate patterns developed. The patients were randomized to electronic fetal heart rate monitoring alone (control group) or to the combination of electronic fetal monitoring and continuous fetal pulse oximetry (study group). The primary outcome was a reduction in cesarean deliveries for nonreassuring fetal status as a measure of improved accuracy of assessment of fetal oxygenation. RESULTS: A total of 1010 patients were randomized, 502 to the control group and 508 to the study group. There was a reduction of >50% in the number of cesarean deliveries performed because of nonreassuring fetal status in the study group (study, 4. 5%; vs. control, 10.2%; P =.007). However, there was no net difference in overall cesarean delivery rates (study, n = 147 [29%]; vs. control, 130 [26%]; P = .49) because of an increase in cesarean deliveries performed because of dystocia in the study group. In a blinded partogram analysis 89% of the study patients and 91% of the control patients who had a cesarean delivery because of dystocia met defined criteria for actual dystocia. There was no difference between the 2 groups in adverse maternal or neonatal outcomes. In terms of the operative intervention for nonreassuring fetal status, there was an improvement in both the sensitivity and the specificity for the study group compared with the control group for the end points of metabolic acidosis and need for resuscitation. CONCLUSION: The study confirmed its primary hypothesis of a safe reduction in cesarean deliveries performed because of nonreassuring fetal status. However, the addition of fetal pulse oximetry did not result in an overall reduction in cesarean deliveries. The increase in cesarean deliveries because of dystocia in the study group did appear to result from a well-documented arrest of labor. Fetal pulse oximetry improved the obstetrician's ability to more appropriately intervene by cesarean or operative vaginal delivery for fetuses who were actually depressed and acidotic. The unexpected increase in operative delivery for dystocia in the study group is of concern and remains to be explained.

Fetal fibronectin detection as a predictor of preterm birth in actual clinical practice.

OBJECTIVE: This study was undertaken to determine whether fetal fibronectin determination is more useful for predicting preterm delivery in clinical practice than it has appeared to be in prospective blinded studies. STUDY DESIGN: Charts of 151 patients with fetal fibronectin tests performed during 2 years were reviewed. Patients were included if they had symptoms of preterm labor, a singleton pregnancy at 24 to 35 weeks' gestation, intact membranes, and cervical dilatation < or =3 cm. RESULTS: Complete data were available for 85 tests. For delivery within 7 days after specimen collection the sensitivity, specificity, positive predictive value, and negative predictive value were 89%, 84%, 40%, and 98%, respectively. The positive predictive value was greater (P <.002) than those reported in three prospective studies evaluating delivery within 7 days in patients with symptoms. Gestational age at delivery and birth weight were lower for patients with positive results (P <. 0001 and P <.006, respectively). Patients with positive results were also treated more with tocolysis, corticosteroid use, and hospitalization than were patients with negative results. For direct comparison with studies of patients with cervical dilatation <3 cm, only 4 patients with cervical dilatation of 3 cm were enrolled. All 4 had negative results of fetal fibronectin testing, and their outcomes therefore did not affect the positive predictive value. CONCLUSION: The positive predictive value of fetal fibronectin measured in actual clinical practice was significantly greater for delivery within 7 days than has been reported in blinded prospective studies.

Elimination of public funding of prenatal care for undocumented immigrants in California: a cost/benefit analysis.

OBJECTIVE: We compared the perinatal outcomes and costs of undocumented women with and without prenatal care and inferred the impact of denial of prenatal benefits to undocumented immigrants in California. STUDY DESIGN: We retrospectively reviewed the delivery records of a cohort of 970 undocumented immigrants. The effects of prenatal care on low birth weight and prematurity were evaluated by means of logistic regression. The difference in the costs of postnatal care between neonates with and without prenatal care was compared with the cost of prenatal care. This ratio was extrapolated to calculate the net cost to the state. Long-term morbidity costs were also considered. RESULTS: Nearly 10% of undocumented women had no prenatal care. These women were nearly 4 times as likely to be delivered of low birth weight infants (relative risk, 3.8; 95% confidence interval, 2.03-7.05) and >7 times as likely to be delivered of premature infants (relative risk, 7.4; 95% confidence interval, 4.35-12.59) as were undocumented women who had prenatal care. The cost of postnatal care for a neonate without prenatal care was $2341 more initially and $3247 more when incremental long-term morbidity cost was added than that for a neonate with prenatal care. For every dollar cut from prenatal care we expect an increase of $3. 33 in the cost of postnatal care and $4.63 in incremental long-term cost. Elimination of publicly funded prenatal care for undocumented women could save the state $58 million in direct prenatal care costs but could cost taxpayers as much as $194 million more in postnatal care, resulting in a net cost of $136 million initially and $211 million in long-term costs. CONCLUSIONS: Elimination of public funding of prenatal care for undocumented immigrants in California could substantially increase low birth weight, prematurity, and postnatal costs.

A randomized clinical trial of daily nonstress testing versus biophysical profile in the management of preterm premature rupture of membranes.

OBJECTIVE: Our purpose was to evaluate the ability of 2 different antepartum testing modalities to predict infectious morbidity in patients with preterm premature rupture of membranes. STUDY DESIGN: During a 36-month period, patients with preterm premature rupture of membranes (at 23 to 34 weeks of gestation) were randomly assigned to either a daily nonstress test or a biophysical profile, after a 24-hour observational period. We used the original scoring system of Manning et al for the biophysical profile, with a score of

High reliability perinatal units: an approach to the prevention of patient injury and medical malpractice claims.

Perinatal units differ in their ability to prevent patient injury and medical malpractice litigation. Obstetrical units with favorable performance are distinguished by common organizational and clinical features. Organizationally, they resemble what behavioral scientists define as "high-reliability organizations" (i.e., the ability to operate technologically complex systems essentially without error over long periods). Clinically, practices are based on nationally recognized guidelines and/or an operational philosophy of "safety first." These organizational and clinical features are described so that physicians, nurses, and administrators might view their own clinical environments in the context of this perspective.

The incidence and severity of shoulder dystocia correlates with a sonographic measurement of asymmetry in patients with diabetes.

The objective of this paper is to examine the relationship between fetal asymmetry measured sonographically and the incidence and severity of shoulder dystocia in diabetic patients. Ultrasound data were collected retrospectively from examinations of women with gestational and pregastational diabetes who delivered at University of California, Irvine Medical Center from 1993-1995. Sonographic fetal asymmetry was quantified by calculating the difference between the abdominal diameter and the biparietal diameter in centimeters (AD-BPD). The residual AD-BPD was a patient's actual AD-BPD at the time of the ultrasound minus the mean AD-BPD obtained in our population at the patient's gestational age. The correlations between fetal asymmetry and the incidence and severity of shoulder dystocia were assessed using an analysis of variance as well as a logistic regression analysis. Mild shoulder dystocia was defined as a delivery requiring McRobert's maneuver and/or suprapubic pressure, while severe shoulder dystocia was assessed when delivery of the posterior arm with Wood's corkscrew maneuver was required. One hundred twenty-three women met the inclusion criteria for the study. Dividing the cohort into three groups based on AD-BPD residual values resulted in the following AD-BPD residual ranges and incidences of shoulder dystocia: Group I, -1.80 to -0.32 cm (9.8%), Group II, -0.31 to 0.32 cm (19.5%), and Group III .33 to 2.0 cm (34.1%), (p <0.03). The residual AD-BPD difference correlated with the incidence of shoulder dystocia after controlling for maternal age, weight, parity, birth weight, and the gestational age at ultrasound (P <0.03). Similar results were found with regards to dystocia severity as the mean residual AD-BPD difference between those with no dystocia, mild dystocia, and severe shoulder dystocia was -0.09, 0.23, and 0.46 cm, respectively, (p <0.006). The residual AD-BPD correlated with the severity of shoulder dystocia after controlling for the above-mentioned confounding variables (p <0.05) in a regression analysis. There is a direct correlation in diabetic patients between the level of fetal truncal asymmetry measured sonographically and the incidence and severity of shoulder dystocia.

Management of fetal distress.

Since its introduction more than 20 years ago, continuous electronic FHR monitoring has become the standard in most modern obstetric units. Practitioners well versed in FHR pattern interpretation do not question the value of fetal monitoring. Not only does this modality detect hypoxia early in its evolution, but also it allows the opportunity to understand the physiology of the hypoxia and to intervene if necessary. Although nonrandomized studies demonstrate an improvement in the perinatal death rate with continuous monitoring, most randomized studies have failed to confirm this observation. Continuous fetal monitoring has been associated in several studies with an increase in the CS rate; however, concomitant changes in obstetric practice have also raised the incidence of CS, making the interpretation of to what degree fetal monitoring is responsible for this increase difficult. Other than this association with an increased CS rate, fetal monitoring seems to present few risks. A thorough understanding of basic fetal heart abnormalities is crucial to prevent unnecessary intervention; however, although quite sensitive, FHR monitoring remains nonspecific in predicting fetal metabolic acidosis. Fetal pulse oximetry is a recent development still undergoing investigation. The ability to measure fetal oxygen saturation during labor adds critical information about fetal status and refines the interpretation of abnormal FHR patterns. If approved by the US Food and Drug Administration, it has the potential to affect dramatically the practice of obstetrics.

Maternal corticotropin-releasing hormone and habituation in the human fetus.

Elevated concentrations of maternal corticotrophin-releasing hormone (CRH) during the 2nd and early 3rd trimester of human pregnancy are associated with spontaneous preterm birth, but the effects of maternal CRH on the fetus are unknown. Maternal plasma was collected for analysis of CRH concentration, m = 156.24 +/- 130.91 pg/ml, from 33 pregnant women during Weeks 31-33 of gestation. Immediately after collection of plasma, fetal heart rate (FHR) measures were obtained in response to a challenge with a series of vibroacoustic stimuli. Fetuses of mothers with highly elevated CRH did not respond significantly to the presence of a novel stimulus in a repeated series, p = 0.016. These effects on the FHR response were not related to parity, fetal gender, medical (antepartum) risk, or eventual birth outcomes. Impaired dishabituation in these fetuses of mothers with high concentrations of CRH suggests that neurological systems rich with CRH receptors that support learning and memory, such as parahippocampal regions, may be targets for maternal/placental CRH, with implications for fetal neurological development.

Corticotrophin-releasing hormone and fetal responses in human pregnancy.

During human pregnancy, maternal and fetal compartments of the human placenta produce and release corticotrophic-releasing hormone (CRH). Elevations of placental CRH are associated with decreased gestational length (including preterm delivery). The effects of elevated placental CRH on human fetal neurological development are not known. Pregnant women in the 31st and 32nd week of gestation consented to procedures for collection of blood and measurement of fetal heart rate (FHR) in response to a series of 40 vibro-acoustic stimuli (VAS). Measures of habituation and dishabituation were calculated from the FHR. All subjects were followed to delivery. Fetuses (N = 33) of women with highly elevated CRH were least responsive (p < .03) to stimulation after presentation of a novel (dishabituating) stimulus with control for parity, fetal gender, medical (antepartum) risk, and gestational length at term. In a larger sample (N = 156) a polynomial model predicted the pattern of FHR reactivity for the first 15 trials. Placental CRH concentration significantly predicted FHR reactivity after controlling for the effects of trial number, baseline FHR, inter-trial interval, and presence of uterine contractions. Increased maternal CRH levels were significantly related to the length of gestation after controlling for the effects of fetal gender, parity, and medical risk (p = .05). The relationship between length of gestation and FHR was not significant suggesting separate actions of CRH on these events. Elevated placental CRH appears to accelerate certain developmental events (gestational length) and may influence the fetal nervous system. The impaired fetal responses to novelty and increased arousal observed in this study suggest that neurological systems may be targets for placental CRH during sensitive developmental periods.

Maternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancy.

OBJECTIVE: Corticotropin releasing hormone, a hypothalamic neuropeptide, plays a major role in regulating pituitary-adrenal function and the physiologic response to stress. During pregnancy corticotropin-releasing hormone is synthesized in large amounts by the placenta and released into the maternal and fetal circulations. Various endocrine, autocrine, and paracrine roles have been suggested for placental corticotropin-releasing hormone. The aim of this study was to prospectively assess the relationship between maternal plasma concentrations of corticotropin-releasing hormone in the early third trimester of pregnancy and the length of gestation in two groups of deliveries, with and without spontaneous labor. STUDY DESIGN: In a sample of 63 women with singleton intrauterine pregnancies, maternal plasma samples were collected between 28 and 30 weeks' gestation and corticotropin-releasing hormone concentrations were determined by radioimmunoassay. Each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, antepartum risk conditions, presence or absence of spontaneous labor, and birth outcomes were abstracted from the medical record. RESULTS: Maternal corticotropin-releasing hormone levels between 28 and 30 weeks' gestation significantly and negatively predicted gestational length (P < .01) after adjustment for antepartum risk. Moreover, subjects who were delivered preterm had significantly higher corticotropin-releasing hormone levels in the early third trimester (P < .01) than did those who were delivered at term. In deliveries preceded by spontaneous onset of labor, maternal third-trimester corticotropin-releasing hormone levels significantly and independently predicted earlier onset of labor (P < .01) and preterm labor (P < .05), whereas in deliveries effected by induction of labor or cesarean delivery, maternal corticotropin-releasing hormone levels were a marker of antepartum risk but not a statistically independent predictor of gestational length. CONCLUSION: These findings support the premise that placental corticotropin-releasing hormone is potentially implicated in the timing of human delivery in at least two ways. First, placental corticotropin-releasing hormone may play a role in the physiology of parturition. Premature or accelerated activation of the placental corticotropin-releasing hormone system, as reflected by precocious elevation of maternal corticotropin-releasing hormone levels, may therefore be associated with earlier onset of spontaneous labor and resultant delivery. Second, placental corticotropin-releasing hormone may be a marker of antepartum risk for preterm delivery and therefore an indirect predictor of earlier delivery. The implications of these findings are discussed in the context of the neuroendocrinology of placental corticotropin-releasing hormone and human parturition. Furthermore, the role of corticotropin-releasing hormone as a possible effector of prenatal stress in producing alterations in the timing of normal delivery is detailed.