Brian M. Casey

A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes

BACKGROUND It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes. METHODS Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus (i.e., an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [5.3 mmol per liter]) were randomly assigned to usual prenatal care (control group) or dietary intervention, self-monitoring of blood glucose, and insulin therapy, if necessary (treatment group). The primary outcome was a composite of stillbirth or perinatal death and neonatal complications, including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma. RESULTS A total of 958 women were randomly assigned to a study group--485 to the treatment group and 473 to the control group. We observed no significant difference between groups in the frequency of the composite outcome (32.4% and 37.0% in the treatment and control groups, respectively; P=0.14). There were no perinatal deaths. However, there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes, including mean birth weight (3302 vs. 3408 g), neonatal fat mass (427 vs. 464 g), the frequency of large-for-gestational-age infants (7.1% vs. 14.5%), birth weight greater than 4000 g (5.9% vs. 14.3%), shoulder dystocia (1.5% vs. 4.0%), and cesarean delivery (26.9% vs. 33.8%). Treatment of gestational diabetes mellitus, as compared with usual care, was also associated with reduced rates of preeclampsia and gestational hypertension (combined rates for the two conditions, 8.6% vs. 13.6%; P=0.01). CONCLUSIONS Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications, it did reduce the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and hypertensive disorders. (ClinicalTrials.gov number, NCT00069576.)

Birth Weight in Relation to Morbidity and Mortality among Newborn Infants

BACKGROUND At any given gestational age, infants with low birth weight have relatively high morbidity and mortality. It is not known, however, whether there is a threshold weight below which morbidity and mortality are significantly greater, or whether that threshold varies with gestational age. METHODS We analyzed the neonatal outcomes of death, five-minute Apgar score, umbilical-artery blood pH, and morbidity due to prematurity for all singleton infants delivered at Parkland Hospital, Dallas, between January 1, 1988, and August 31, 1996. A distribution of birth weights according to week of gestation at birth was created. Infants in the 26th through 75th percentiles for weight served as the reference group. Data on preterm infants (those born at 24 to 36 weeks of gestation) were analyzed separately from data on infants delivered at term (37 or more weeks of gestation). RESULTS A total of 122,754 women and adolescents delivered singleton live infants without malformations between 24 and 43 weeks of gestation. Among the 12,317 preterm infants who were analyzed, there was no specific birth-weight percentile at which morbidity and mortality increased. Among 82,361 infants who were born at term and whose birth weights were at or below the 75th percentile, however, the rate of neonatal death increased from 0.03 percent in the reference group (26th through 75th percentile for weight) to 0.3 percent for those with birth weights at or below the 3rd percentile (P<0.001). The incidence of five-minute Apgar scores of 3 or less and umbilical-artery blood pH values of 7.0 or less was approximately doubled for infants at or below the 3rd birth-weight percentile (P=0.003 and P<0.001, respectively). The incidence of intubation at birth, seizures during the first day of life, and sepsis was also significantly increased among term infants with birth weights at or below the 3rd percentile. These differences persisted after adjustment for the mothers race and parity and the infants sex. CONCLUSIONS Mortality and morbidity are increased among infants born at term whose birth weights are at or below the 3rd percentile for their gestational age.

Subclinical hypothyroidism and pregnancy outcomes.

BACKGROUND: Clinical thyroid dysfunction has been associated with pregnancy complications such as hypertension, preterm birth, low birth weight, placental abruption, and fetal death. The relationship between subclinical hypothyroidism and pregnancy outcomes has not been well studied. We undertook this prospective thyroid screening study to evaluate pregnancy outcomes in women with elevated thyrotropin (thyroid-stimulating hormone, TSH) and normal free thyroxine levels. METHODS: All women who presented to Parkland Hospital for prenatal care between November 1, 2000, and April 14, 2003, had thyroid screening using a chemiluminescent TSH assay. Women with TSH values at or above the 97.5th percentile for gestational age at screening and with free thyroxine more than 0.680 ng/dL were retrospectively identified with subclinical hypothyroidism. Pregnancy outcomes were compared with those in pregnant women with normal TSH values between the 5th and 95th percentiles. RESULTS: A total of 25,756 women underwent thyroid screening and were delivered of a singleton infant. There were 17,298 (67%) women enrolled for prenatal care at 20 weeks of gestation or less, and 404 (2.3%) of these were considered to have subclinical hypothyroidism. Pregnancies in women with subclinical hypothyroidism were 3 times more likely to be complicated by placental abruption (relative risk 3.0, 95% confidence interval 1.1–8.2). Preterm birth, defined as delivery at or before 34 weeks of gestation, was almost 2-fold higher in women with subclinical hypothyroidism (relative risk, 1.8, 95% confidence interval 1.1–2.9). CONCLUSION: We speculate that the previously reported reduction in intelligence quotient of offspring of women with subclinical hypothyroidism may be related to the effects of prematurity. LEVEL OF EVIDENCE: II-2

Pregnancy Outcomes in Women With Gestational Diabetes Compared With the General Obstetric Population

Objective To compare pregnancy outcome in a homogeneous group of women glucose with that of women without this disorder. Methods This was retrospective study of all women with singleton cephalic-presenting pregnancies delivered at University of Texas Southwestern Medical Center during the period January 1, 1991, through december 31, 1995. During this period, women were screened selectively for glucose intolerance and National Diabetes Data Group thresholds were used to diagnose gestational diabetes. Women with class A1 gestational diabetes were compared with nondiabetic women within the cohort. Effects of confouding variables were analyzed using multiple logistic regression and a matched-control comparison. Controls were matched according to ethnicity, maternal age, maternal weight, and parity. Results A total of 61,209 nondiabetic women with singleton caphalic pregnancies were delivered during the study period, and 874 were diagnosd with class A, gestational diabetes. Women with class A1 gestational diabetes wee significantly older, heavier, of greater parity, and more often of Hispanic ethnicity. Hypertension (17 vérsus 12%), caesarean delivery (30 versus 17%), and shoulder dystocia (3 versus 1%) were significantly increased (all P < .001) in these women compared with the general obstetric population. Infants born to women with class A1 gestational diabetes were significantly larger (mean birth weight 3581 ± 616 versus 3290 ± 546 g, P < .001), and this accounted for the increased incidence of dystocia. The attributable risk for large for gestational age (LGA) infants due to class A1 gestational diabetes was 12%. Conclusion The main consequence of class A1 gestational diabetes is excessive fetal size leading to increased risk of difficult labor and delivery. We estimate that approximately one of eight women with class A1 gestational diabetes mellitus delivers an LGA infant attributable to glucose intolerance.

Subclinical hyperthyroidism and pregnancy outcomes.

OBJECTIVE: Subclinical hyperthyroidism has long-term sequelae that include osteoporosis, cardiovascular morbidity, and progression to overt thyrotoxicosis or thyroid failure. The objective of this study was to evaluate pregnancy outcomes in women with suppressed thyroid-stimulating hormone (TSH) and normal free thyroxine (fT4) levels. METHODS: All women who presented to Parkland Hospital for prenatal care between November 1, 2000, and April 14, 2003, underwent thyroid screening by chemiluminescent TSH assay. Women with TSH values at or below the 2.5th percentile for gestational age and whose serum fT4 levels were 1.75 ng/dL or less were identified to have subclinical hyperthyroidism. Those women screened and delivered of a singleton infant weighing 500 g or more were analyzed. Pregnancy outcomes in women identified with subclinical hyperthyroidism were compared with those in women whose TSH values were between the 5th and 95th percentiles. RESULTS: A total of 25,765 women underwent thyroid screening and were delivered of singleton infants. Of these, 433 (1.7%) were considered to have subclinical hyperthyroidism, which occurred more frequently in African-American and/or parous women. Pregnancies in women with subclinical hyperthyroidism were less likely to be complicated by hypertension (adjusted odds ratio 0.66, 95% confidence interval 0.44–0.98). All other pregnancy complications and perinatal morbidity or mortality were not increased in women with subclinical hyperthyroidism. CONCLUSION: Subclinical hyperthyroidism is not associated with adverse pregnancy outcomes. Our results indicate that identification of subclinical hyperthyroidism and treatment during pregnancy is unwarranted. LEVEL OF EVIDENCE: II-2

Maternal Diabetes mellitus and infant malformations

OBJECTIVE To investigate the effects of pregestational, as opposed to gestational, diabetes on infant malformations. METHODS All women delivering infants at Parkland Hospital between January 1, 1991, and December 31, 2000, were ascertained. Screening for gestational diabetes was methodically employed throughout the study period using National Diabetes Data Group criteria for diagnosis of pregestational and gestational diabetes. Standardized definitions of major infant malformations were specified before data analysis and subdivided according to the organ systems involved. RESULTS A total of 145,196 women were delivered during the study period, and 2687 (1.9%) were diagnosed to have diabetes mellitus. Gestational diabetes was diagnosed in 2277 (1.6%) of whom 230 (10%) had fasting hyperglycemia diagnosed, and the remainder consistently demonstrated fasting serum levels less than 105 mg/dL. Pregestational diabetes was diagnosed in 410 (0.3%) women. Infant malformations occurred in 1.5% of nondiabetic women compared with 1.2% of women with normal fasting glucose gestational diabetes, 4.8% in women with gestational diabetes plus fasting hyperglycemia, and 6.1% in those with pregestational diabetes (P < .001, for comparison of the latter two groups with the nondiabetic population). CONCLUSION Women with pregestational diabetes or gestational diabetes plus fasting hyperglycemia have a three‐to four‐fold increased risk of infant malformations, whereas women with mild gestational diabetes have malformation rates no different than the general nondiabetic obstetric population.

Thyroid-stimulating Hormone in Singleton and Twin Pregnancy: Importance of Gestational Age–specific Reference Ranges

OBJECTIVE: To estimate a normal reference range for thyroid-stimulating hormone (TSH) at each point in gestation in singleton and twin pregnancies. METHODS: All women enrolling for prenatal care from December 2000 through November 2001 underwent prospective TSH screening at their first visit. Separate nomograms were constructed for singleton and twin pregnancies using regression analysis. Values were converted to multiples of the median (MoM) for singleton pregnancies at each week of gestation. RESULTS: Thyroid-stimulating hormone was evaluated in 13,599 singleton and 132 twin pregnancies. Thyroid-stimulating hormone decreased significantly during the first trimester, and the decrease was greater in twins (both P < .001). Had a nonpregnant reference (0.4–4.0 mU/L) been used rather than our nomogram, 28% of 342 singletons with TSH greater than 2 standard deviations above the mean would not have been identified. For singleton first-trimester pregnancies, the approximate upper limit of normal TSH was 4.0 MoM, and for twins, 3.5 MoM. Thereafter, the approximate upper limit was 2.5 MoM for singleton and twin pregnancies. CONCLUSION: If thyroid testing is performed during pregnancy, nomograms that adjust for fetal number and gestational age may greatly improve disease detection. Values expressed as multiples of the median may facilitate comparisons across different laboratories and populations. LEVEL OF EVIDENCE: II-2

Perinatal Significance of Isolated Maternal Hypothyroxinemia Identified in the First Half of Pregnancy

OBJECTIVE: To establish pregnancy-specific free thyroxine thresholds and to assess perinatal effects associated with isolated maternal hypothyroxinemia identified in the first half of pregnancy. METHODS: Stored serum samples from 17,298 women who previously underwent thyroid-stimulating hormone (TSH) screening in the first half of pregnancy were analyzed for free thyroxine (T4) concentrations and thyroid peroxidase antibodies. Women with a free T4 below 0.86 ng/dL but a normal-range TSH were identified to have isolated maternal hypothyroxinemia. Pregnancy outcomes in these women were compared to those with a normal TSH and free T4. Thyroid peroxidase antibody status and the relationship between TSH and free T4 were analyzed for these women and women with subclinical hypothyroidism. RESULTS: Isolated maternal hypothyroxinemia was identified in 233 women (1.3%). There were not any excessive adverse pregnancy outcomes in these women. Positive thyroid peroxidase antibody assays (greater than 50 international units/mL) were similar in normal women (4%) and those with isolated hypothyroxinemia (5%) but were greater in women with subclinical hypothyroidism (31%, P<.001). There was a negative correlation between TSH and free T4 in normal women (rs=–0.19, P<.001) and those with subclinical hypothyroidism (rs=–0.11, P=.007). The correlation in women with isolated hypothyroxinemia was not significant. CONCLUSION: Isolated maternal hypothyroxinemia has no adverse effects on perinatal outcome. Moreover, unlike subclinical hypothyroidism, there was a low prevalence of thyroid peroxidase antibodies and no correlation between TSH and free T4 levels in women with hypothyroxinemia, leading us to question its biological significance. LEVEL OF EVIDENCE: II

Antenatal Betamethasone for Women at Risk for Late Preterm Delivery

BACKGROUND Infants who are born at 34 to 36 weeks of gestation (late preterm) are at greater risk for adverse respiratory and other outcomes than those born at 37 weeks of gestation or later. It is not known whether betamethasone administered to women at risk for late preterm delivery decreases the risks of neonatal morbidities. METHODS We conducted a multicenter, randomized trial involving women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gestation who were at high risk for delivery during the late preterm period (up to 36 weeks 6 days). The participants were assigned to receive two injections of betamethasone or matching placebo 24 hours apart. The primary outcome was a neonatal composite of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery. RESULTS The primary outcome occurred in 165 of 1427 infants (11.6%) in the betamethasone group and 202 of 1400 (14.4%) in the placebo group (relative risk in the betamethasone group, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P=0.02). Severe respiratory complications, transient tachypnea of the newborn, surfactant use, and bronchopulmonary dysplasia also occurred significantly less frequently in the betamethasone group. There were no significant between-group differences in the incidence of chorioamnionitis or neonatal sepsis. Neonatal hypoglycemia was more common in the betamethasone group than in the placebo group (24.0% vs. 15.0%; relative risk, 1.60; 95% CI, 1.37 to 1.87; P<0.001). CONCLUSIONS Administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications. (Funded by the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01222247.).

Human Myometrial Gene Expression Before and During Parturition

Abstract Identification of temporal and spatial changes in myometrial gene expression during parturition may further the understanding of the coordinated regulation of myometrial contractions during parturition. The objective of this study was to compare the gene expression profiles of human fundal myometrium from pregnant women before and after the onset of labor using a functional genomics approach, and to further characterize the spatial and temporal expression patterns of three genes believed to be important in parturition. Fundal myometrial mRNA was isolated from five women in labor and five women not in labor, and analyzed using human UniGEM-V microarrays with 9182 cDNA elements. Real-time polymerase chain reaction using myometrial RNA from pregnant women in labor or not in labor was used to examine mRNA levels for three of the genes; namely, prostaglandin-endoperoxide synthase 2 (PTGS2), calgranulin B (S100A9), and oxytocin receptor (OXTR). The spatial expression pattern of these genes throughout the pregnant uterus before and after labor was also determined. Immunolocalization of cyclooxygenase-2 (also known as PTGS2) and S100A9 within the uterine cervix and myometrium were analyzed by immunohistochemistry. Few genes were differentially expressed in fundal myometrial tissues at term with the onset of labor. However, there appears to be a subset of genes important in the parturition cascade. The cellular properties of S100A9, its spatial localization, and dramatic increase in cervix and myometrium of women in labor suggest that this protein may be very important in the initiation or propagation of human labor.