Customized versus population approach for evaluation of fetal overgrowth.

OBJECTIVE: To compare the ability of customized versus normalized population fetal growth norms in identifying neonates at risk for adverse perinatal outcomes (APOs) associated with fetal overgrowth and gestational diabetes (GDM). STUDY DESIGN: Secondary analysis of a multicenter treatment trial of mild GDM. The primary outcome was a composite of neonatal outcomes associated with fetal overgrowth and GDM. Birth weight percentiles were calculated using ethnicity- and gender-specific population and customized norms (Gardosi). RESULTS: Two hundred three (9.8%) and 288 (13.8%) neonates were large for gestational age by population (LGApop) and customized (LGAcust) norms, respectively. Both LGApop and LGAcust were associated with the primary outcome and neonatal hyperinsulinemia, but neither was associated with hypoglycemia or hyperbilirubinemia. The ability of customized and population birth weight percentiles for predicting APOs were poor (area under the receiver operating characteristic curve < 0.6 for six of eight APOs). CONCLUSION: Neither customized nor normalized population norms better identify neonates at risk of APOs related to fetal overgrowth and GDM.

Maternal insulin resistance and preeclampsia.

OBJECTIVE: The purpose of this study was to determine whether mid-trimester insulin resistance is associated with subsequent preeclampsia. STUDY DESIGN: This was a secondary analysis of 10,154 nulliparous women who received vitamin C and E or placebo daily from 9-16 weeks gestation until delivery. Of these, 1187 women had fasting plasma glucose and insulin tested between 22 and 26 weeks gestation. Insulin resistance was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index. RESULTS: Obese women were twice as likely to have a HOMA-IR result of ≥75th percentile. Hispanic and African American women had a higher percentage at ≥75th percentile for HOMA-IR than white women (42.2%, 27.2%, and 16.9%, respectively; P < .001). A HOMA-IR result of ≥75th percentile was higher among the 85 nulliparous women who subsequently had preeclampsia, compared with women who remained normotensive (40.5% vs 24.8%; adjusted odds ratio, 1.9; 95% confidence interval, 1.1-3.2). Quantitative insulin sensitivity check index results were similar to the HOMA-IR results. CONCLUSION: Midtrimester maternal insulin resistance is associated with subsequent preeclampsia.

The role of human decay-accelerating factor in the pathogenesis of preterm labor.

Complement activation is thought to contribute to the pathogenesis of preterm labor (PTL). Decay-accelerating factor (DAF) is a natural complement pathway inhibitor. Our hypothesis was that DAF expression on maternal white blood cells (WBCs) in women with preterm labor is elevated compared with women with no preterm labor. Our secondary objective was to determine if differences in upregulation of DAF levels correlated with clinical outcomes. Serial blood samples were obtained from 30 patients with a clinical diagnosis of PTL and a control group of 30 pregnant individuals (same gestational age range) to determine DAF expression in peripheral WBCs in both groups. DAF expression was higher in women with PTL (less than 37 weeks) compared with the control group without PTL. Subjects with PTL who delivered before 34 weeks had less DAF expression and different kinetics of expression compared with those carrying pregnancies beyond 34 weeks. These data suggest that women with a clinical diagnosis of preterm labor have increased DAF expression on peripheral WBCs. Furthermore, it appears that failure to elevate DAF expression is associated with a risk of early premature delivery.

Second-stage labor duration in nulliparous women: relationship to maternal and perinatal outcomes.

OBJECTIVE: The purpose of this study was to assess maternal and perinatal outcomes as a function of second-stage labor duration. STUDY DESIGN: We assessed outcomes in nulliparous laboring women who were enrolled in a trial of fetal pulse oximetry. RESULTS: Of 5341 participants, 4126 women reached the second stage of labor. As the duration of the second stage increased, spontaneous vaginal delivery rates declined, from 85% when the duration was <1 hour to 9% when it was > or =5 hours. Adverse maternal outcomes that were associated significantly with the duration of the second stage of labor included chorioamnionitis (overall rate, 3.9%), third- or fourth-degree perineal laceration (overall rate, 8.7%), and uterine atony (overall rate, 3.9%). Odds ratios for each additional hour of the second stage of labor ranged from 1.3-1.8. Among individual adverse neonatal outcomes, only admission to a neonatal intensive care unit was associated significantly with second stage duration (odds ratio, 1.4). CONCLUSION: The second stage of labor does not need to be terminated for duration alone.

In utero programming of adult vascular function in transgenic mice lacking low-density lipoprotein receptor.

OBJECTIVE: The objective of this study was to examine the role of maternal hypercholesterolemia in fetal programming of adult vascular function using transgenic mice lacking the low-density lipoprotein receptor (LDLR). STUDY DESIGN: Homozygous LDLR knockout mice (B6.129S7-Ldlr(tm1Her)/J, LDLR(-/-KO)) and their wild-type controls (C57BL/6J, LDLR(+/+WT)) were cross-bred to produce 4 litter groups: LDLR(-/-KO), maternally derived heterozygous (LDLR(+/-Mat)), paternally derived heterozygous (LDLR(+/-Pat)) and LDLR(+/+WT). Female and male offspring were killed at 10-12 weeks of age, and carotid arteries were used for in vitro experiments. RESULTS: The dose responses to phenylephrine were significantly higher in LDLR(-/-KO) and LDLR(+/-Mat) male offspring. The contractile responses to phenylephrine in female mice were significantly increased only in the LDLR(-/-KO) offspring. Maximal Ca(2+) contraction was higher in LDLR(-/-KO) male and female offspring. CONCLUSION: Despite being genomically similar, heterozygous offspring that developed in a hypercholesterolemic maternal environment had abnormal vascular responses later in life compared with those that developed in a normal environment.

Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo.

OBJECTIVE: To assess whether there are evident adverse effects of 17 alpha-hydroxyprogesterone caproate after in utero exposure. METHODS: This study evaluated surviving children of mothers who participated in a multicenter placebo-controlled trial of weekly intramuscular 17 alpha-hydroxyprogesterone caproate, with a 2:1 allocation to 17 alpha-hydroxyprogesterone caproate and placebo, respectively. The guardian was interviewed about the child's general health. Children underwent a physical examination and developmental screen with the Ages and Stages Questionnaire. Gender-specific roles were assessed with the Preschool Activities Inventory. RESULTS: Of 348 eligible surviving children, 278 (80%) were available for evaluation (194 in the 17 alpha-hydroxyprogesterone caproate group and 84 in the placebo group). The mean age at follow-up was 48 months. No significant differences were seen in health status or physical examination, including genital anomalies, between 17 alpha-hydroxyprogesterone caproate and placebo children. Scores for gender-specific roles (Preschool Activities Inventory) were within the normal range and similar between 17 alpha-hydroxyprogesterone caproate and placebo groups. CONCLUSION: 17 alpha-hydroxyprogesterone caproate seems to be safe for the fetus when administered in the second and third trimesters.

The effect of the postnatal environment on altered fetal programming of adult vascular function in mice that lack endothelial nitric oxide synthase.

OBJECTIVE: The purpose of this study was to investigate vascular reactivity in heterozygous and homozygous offspring with a genetic predisposition for hypertension after postnatal cross-fostering to mothers with the opposite genetic inheritance of the NOS3 knockout allele. STUDY DESIGN: Homozygous NOS3 knockout (C57BL/6J-NOS3(-/-KO)) and wild-type mice (NOS3(+/+WT)) were bred to obtain heterozygous litters with a paternally derived (NOS3(+/-pat)) or maternally derived (NOS3(+/-mat)) knockout allele. After delivery, heterozygous and homozygous litters were cross-fostered to a mother with the opposite NOS3 gene status. Carotid arteries were placed in a wire myograph for isometric tension recording with the use of contractile and relaxant agents. Statistical analysis with 1-way analysis of variance and Neuman-Keuls post-hoc testing was performed. RESULTS: Increased sensitivity to phenylephrine and absent relaxation to acetylcholine in NOS3(+/-mat) was reversed with cross-fostering, and vasorelaxation to isoproterenol was increased. Contraction to calcium was increased in the cross-fostered paternally derived and wild-type litters. CONCLUSION: Postnatal interventions may alter the adult vascular profile favorably that is the result of an abnormal intrauterine environment.

Effect of a previous pregnancy on vascular function in endothelial nitric oxide synthase 3 knockout mice.

OBJECTIVE: Nitric oxide deficiency has been implicated in adverse pregnancy outcomes. Mice that lack endothelial nitric oxide synthase (NOS3) have abnormal in vitro vascular reactivity. Our objective was to assess the effect of a previous pregnancy on the abnormal vascular function of NOS3 knockout mice. STUDY DESIGN: Carotid arteries from pregnant NOS3 knockout (NOS3(-/-KO)) and wild-type control mice (NOS3(+/+WT)) from first and second pregnancy were obtained for in vitro vascular reactivity studies. Vascular responses to cumulative concentrations of the vasoconstrictors phenylephrine, serotonin, and thromboxane and the vasorelaxants acetylcholine, sodium nitroprusside, and isoproterenol were determined. RESULTS: In the first pregnancy, contractile responses were exaggerated in the knockout animals, compared with the wild-type animals. However, the second pregnancy in knockout animals was associated with normalization of responses to phenylephrine and serotonin and increased responses to the endothelium-independent relaxants. CONCLUSION: The vascular function of NOS3 knockout mice improves with subsequent pregnancy becoming comparable to wild-type animals.

Gender-specific effect of overexpression of sFlt-1 in pregnant mice on fetal programming of blood pressure in the offspring later in life.

OBJECTIVE: The purpose of this study was to determine whether fetal programming of adult blood pressure is altered in a previously characterized mouse model of preeclampsia that was induced by sFlt-1. STUDY DESIGN: CD-1 mouse mothers at day 8 of gestation were injected with an adenovirus carrying Flt 1-3 (10(9) plaque-forming units) or with an adenovirus carrying mFc as control (10(9) plaque-forming units). The resulting pups were followed until 6 months of age, at which time blood pressure (BP) was recorded continuously for 6 days. The offspring weight was also recorded from weaning until adulthood. RESULTS: BP was significantly higher in the male offspring that were born to sFlt-1-treated mothers compared with the controls. Male offspring from sFlt-1-treated mothers were significantly smaller from weaning until adulthood. However, there were no significant differences in BP and postweaning weight in female offspring between the 2 groups. CONCLUSION: Our findings highlight the role of the intrauterine environment in the developmental origin of adult disease.

The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice.

OBJECTIVE: It has been shown that the level of soluble fms-like tyrosine kinase-1 (sFlt-1) is elevated in pregnant women who are destined to have preeclampsia, and a role for sFlt-1 in its pathogenesis has been suggested. Our objective was to determine the effect of the over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in pregnant mice. STUDY DESIGN: At day 8 of gestation CD-1 mice were allocated randomly to an injection of an adenovirus carrying sFlt-1 (10(9) plaque-forming units; sFlt-1 group), adenovirus carrying the murine immunoglobulin G2alpha Fc fragment (10(9) plaque-forming units; mFc group used as a control for the virus) or saline solution (100 microL; saline group). At day 10 of gestation, blood pressure catheters were inserted through the left carotid artery into the aortic arch and tunneled to a telemetric transmitter. Blood pressure was monitored continuously in the conscious unrestrained animals until day 18. Blood was collected from the pregnant mice at different gestational times, and plasma sFlt-1 was measured by enzyme-linked immunosorbent assay. Pups and placentae were weighed, and maternal platelet counts were determined at death on day 18. RESULTS: Plasma levels of sFlt-1 increased significantly in the sFlt-1 mice and were significantly higher than the 2 control groups. The mean blood pressure in the sFlt-1 mice was significantly higher on days 17 and 18 of gestation, compared with the mFc and saline solution groups. The time-course of blood pressure rise mirrored that of the sFlt-1 levels. The average pup weight, placental weight, and maternal platelet counts were significantly lower in the sFlt-1 group, compared with the controls. CONCLUSION: SFlt-1 induces hypertension and fetal growth restriction in pregnant mice, which supports its hypothesized role in the pathogenesis of preeclampsia. This animal model minimizes the need for manipulation or the administration of various compounds to induce the condition.

Labor-associated gene expression in the human uterine fundus, lower segment, and cervix.

BACKGROUND: Preterm labor, failure to progress, and postpartum hemorrhage are the common causes of maternal and neonatal mortality or morbidity. All result from defects in the complex mechanisms controlling labor, which coordinate changes in the uterine fundus, lower segment, and cervix. We aimed to assess labor-associated gene expression profiles in these functionally distinct areas of the human uterus by using microarrays. METHODS AND FINDINGS: Samples of uterine fundus, lower segment, and cervix were obtained from patients at term (mean +/- SD = 39.1 +/- 0.5 wk) prior to the onset of labor (n = 6), or in active phase of labor with spontaneous onset (n = 7). Expression of 12,626 genes was evaluated using microarrays (Human Genome U95A; Affymetrix) and compared between labor and non-labor samples. Genes with the largest labor-associated change and the lowest variability in expression are likely to be fundamental for parturition, so gene expression was ranked accordingly. From 500 genes with the highest rank we identified genes with similar expression profiles using two independent clustering techniques. Sets of genes with a probability of chance grouping by both techniques less than 0.01 represented 71.2%, 81.8%, and 79.8% of the 500 genes in the fundus, lower segment, and cervix, respectively. We identified 14, 14, and 12 those sets of genes in the fundus, lower segment, and cervix, respectively. This enabled networks of co-regulated and co-expressed genes to be discovered. Many genes within the same cluster shared similar functions or had functions pertinent to the process of labor. CONCLUSIONS: Our results provide support for many of the established processes of parturition and also describe novel-to-labor genes not previously associated with this process. The elucidation of these mechanisms likely to be fundamental for controlling labor is an important prerequisite to the development of effective treatments for major obstetric problems--including prematurity, with its long-term consequences to the health of mother and offspring.

Tenure of academic chairs in obstetrics and gynecology: a 25-year perspective.

OBJECTIVE: To assist in predicting future leadership needs, this longitudinal study examines turnover and net retention rates among chairs at university obstetrics and gynecology departments between 1981 and 2005. METHODS: A database of appointment dates and tenure of chairs at each of 125 Association of American Medical Colleges-approved United States medical schools was collated using membership listings from the Association of Professors of Gynecology and Obstetrics and from the Council of University Chairs in Obstetrics and Gynecology. Complete data from 118 departments were confirmed by selective correspondence at individual departments and further review by the investigators. RESULTS: A total of 260 individuals (232 men, 28 women) became new chairs between 1981 and 2005. The annual turnover rate increased gradually from 6.0% to 12.7%. Five-year net retention rates remained steady between 1982 and 1997 but dropped after 1997 (85.6% compared with 63.2%; P=.03). A chair's tenure ranged widely (1 to 23 years; median 8 years), regardless of gender or school type, size, or location. Approximately one half of interim chairs became permanent chairs, usually at their own institution. The number of new women chairs increased from none in 1981 to 17 (15.2% of total chairs) in 2005. CONCLUSION: Academic chair positions in obstetrics and gynecology experienced a doubling in annual turnover rates, while retention rates declined. The proportion of chairs occupied by women increased progressively. LEVEL OF EVIDENCE: II-2.

A patient-centered health care delivery system by a university obstetrics and gynecology department.

At the University of Texas Medical Branch at Galveston, we developed an off-site clinic system that offers a wide array of services to low-income women and their infants over a large geographic area. These clinics strove toward cultural sensitivity and competency. This patient-centered approach was well accepted and appreciated by our patients. The clinics offered unique, value-added services including combined location with other needed services, on-site laboratory and antepartum testing, the option for delivery at the University of Texas Medical Branch at Galveston in a Birth Center by certified nurse midwives from the clinics, 2 high-level ultrasound "hub" centers in the outlying region that offer level II ultrasound and maternal-fetal medicine specialist consultation on site, and linkage of all sites to our electronic medical record, telemedicine, and telegenetics consultation. We also developed an off-site domiciliary facility at the University of Texas Medical Branch at Galveston. From 1989 to 2004, our clinics grew from 12 to 38 (now serving 123 Texas counties). Annual patient visits increased from approximately 34,000 to 342,926. Deliveries at the University of Texas Medical Branch at Galveston grew from 3,959 in 1990 to an estimated 6,400 in 2004. Underscoring this increase was the probable loss of at least 1,500 deliveries to local hospitals that had previously denied or discouraged admission to Medicaid-eligible pregnant women. Many women chose to deliver in our hospital even although they had to travel a longer distance to reach our facility. Our experience has shown that patient-centered care can be a viable business strategy to maintain and expand patient volumes and will work even where there are serious geographic disadvantages.

In situ analysis of interleukin-1-induced transcription of cox-2 and il-8 in cultured human myometrial cells.

The specific binding of transcription factors to DNA has been shown to be inhibited by chromatin structure and increased by cooperative interactions with other proteins. Consequently, in situ analysis using chromatin immunoprecipitation offers the most accurate view of transcriptional control. Transient transfection studies and in vitro analyses of IL-1-induced cox-2 transcription in a number of cell types have indicated regulation by either nuclear factor kappa B (NF-kappa B) or CCAAT/enhancer binding protein (C/EBP beta), or both acting cooperatively. To determine the mechanisms of COX-2 (cyclooxygenase or prostaglandin endoperoxide synthase) induction in cultured human myometrial cells in situ, we examined the cross-linking of the RelA subunit of NF-kappa B and C/EBP beta to the cox-2 promoter and flanking sequences. As a control, we inspected the interaction of these transcription factors with the IL-8 gene, which has been shown in other cell types to be activated by the cooperative interaction of NF-kappa B and C/EBP beta. Indeed, both transcription factors were cross-linked to the il-8 promoter after IL-1 treatment, but only RelA was cross-linked to cox-2 DNA. The il-8 promoter was also found to physically interact with proteins cross-linked to sites further upstream. IL-1 treatment also increased polymerase II cross-linking to both promoters and increased histone H4 acetylation at specific sites. These results indicate that modification of chromatin structure is part of the response to IL-1 stimulation. Chromatin immunoprecipitation thus provides critical insight into the mechanisms of COX-2 and IL-8 expression in human myometrial cells.

Cloning, characterization, and expression of the rat relaxin gene.

Relaxin, a hormone in the insulin superfamily, is synthesized by the corpus luteum of the rat ovary. Expression of relaxin precursor mRNA in rats is sharply induced after day 10 of pregnancy and plateaus on days 15 to 20 (parturition occurs on day 23). In an effort to understand this induction, we cloned the gene and carried out promoter analyses by transient transfection and chromatin immunoprecipitation methods. The single gene is 2.9 kilobases and is composed of two exons and one intron. There are alternative splice acceptor sites, 3 base pairs apart, which account for the inclusion of an extra codon in about 10% of the transcripts. The induction of transcription by day 15 was observed by the binding of polymerase II and histone H3 acetylation at the promoter region. There is a functional STAT binding site, about 3.8 kb upstream from the transcriptional start site, that is occupied by STAT3 on day 6 of pregnancy, when relaxin expression is minimal; on day 15, when expression is maximal, STAT3 is replaced by STAT5a. These data are consistent with STAT5 playing a role in the induction of relaxin expression.

Neonatal organ system injury in acute birth asphyxia sufficient to result in neonatal encephalopathy.

OBJECTIVE: To identify the proportion of major organ system injury in cases of acute intrapartum asphyxia that result in neonatal encephalopathy. METHODS: A prospectively maintained database was cross-referenced using medical record coding to identify diagnoses of acute intrapartum asphyxia, acute birth asphyxia, or neonatal encephalopathy over a 6-year period. An acute intrapartum asphyxial antecedent was validated with emphasis on excluding long-standing or chronic conditions where injury likely occurred before presentation. Injury pattern was evaluated using routinely available laboratory and imaging tests. RESULTS: Forty-six cases of acute peripartum asphyxia sufficient to result in the diagnosis of neonatal encephalopathy were identified. Clinical central nervous system injury resulting in encephalopathy was present in 100% of cases as it was an entry criteria; of these, 49% had electroencephalogram and 40% had imaging studies diagnostic of acute injury. Liver injury based on elevated aspartate transaminase or alanine transaminase levels occurred in 80%. Heart injury, as defined by pressor or volume support beyond 2 hours of life or elevated cardiac enzymes, occurred in 78%. Renal injury, defined by an elevation of serum creatinine to greater than 1.0 mg/dL, persistent hematuria, persistent proteinuria, or clinical oliguria, occurred in 72%. An elevation in nucleated red blood cell counts exceeding 26 per 100 white blood cells occurred in 41%. CONCLUSION: Using common diagnostic tests as markers of acute asphyxial injury, we noted that multiple organs suffer damage during an acute intrapartum asphyxial event sufficient to result in a neonatal encephalopathy.

Change in mononuclear leukocyte responsiveness in midpregnancy and subsequent preterm birth.

OBJECTIVE: To estimate the associations of change in immune response with preterm delivery, omega-3 supplementation, and fish diet. METHODS: This was an ancillary study to a randomized trial of omega-3 fatty acid supplementation for the prevention of recurrent preterm birth. In vitro maternal peripheral blood mononuclear leukocyte production of the anti-inflammatory cytokine, interleukin-10, and the proinflammatory cytokine, tumor necrosis factor-α, in response to stimulation with lipopolysaccharide, was measured at 16-22 weeks of gestation (baseline) and again at 25-28 weeks of gestation (follow-up) among women with prior spontaneous preterm birth. Changes in concentrations from baseline to follow-up ([INCREMENT]) were compared separately among groups defined by gestational age category at delivery, fish diet history, and omega-3 compared with placebo treatment assignment with Kruskal-Wallis tests. RESULTS: Interleukin-10 [INCREMENT] differed by gestational age category among 292 women with paired assays. Concentrations increased less in women delivering between 35 and 36 6/7 weeks of gestation (48.9 pg/mL) compared with women delivering at term (159.3 pg/mL) and decreased by 65.2 pg/mL in women delivering before 35 weeks of gestation (P=.01). Tumor necrosis factor-α Δ also differed by gestational age category among 319 women, but the pattern was inconsistent. Those delivering between 35 and 36 6/7 weeks of gestation exhibited decreased concentrations of tumor necrosis factor-α at follow-up compared with baseline (-356.0 pg/mL); concentrations increased among women delivering before 35 weeks of gestation and those delivering at term, 132.1 and 86.9 pg/mL (P=.03). Interleukin-10 Δ and tumor necrosis factor-α Δ were unaffected by either omega-3 supplementation or fish diet. CONCLUSION: Recurrent preterm birth was associated with decreased peripheral blood mononuclear leukocyte production of interleukin-10 in response to a stimulus during the second trimester. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00135902. LEVEL OF EVIDENCE: II.

The utility of uterine artery Doppler velocimetry in prediction of preeclampsia in a low-risk population.

OBJECTIVE: The underlying pathophysiology of preeclampsia is thought to be abnormal trophoblast invasion of the spiral arteries leading to maldevelopment of uteroplacental perfusion. We estimated whether uterine artery Doppler measurements made in the early second trimester would predict the subsequent development of preeclampsia. METHODS: Uterine artery Doppler measurements before 21 weeks of gestation (median 16.6 weeks) were correlated with subsequent development of preeclampsia in a cohort of 2,188 low-risk nulliparous women in a randomized control trial of antioxidant supplementation for prevention of preeclampsia. Preeclampsia developed in 165 (7.5%) women. RESULTS: Development of preeclampsia overall was associated with increased resistance index, pulsatility index, a pulsatility index or resistance index multiple of the median at or above the 75th percentile but not the presence of a notch or a bilateral notch before 21 weeks of gestation. The sensitivity was 43% (95% confidence interval [CI] 35-51) and specificity 67% (95% CI 65-69) for prediction of preeclampsia overall. The presence of a notch or bilateral notch, resistance index, and pulsatility index multiple of the median was significantly associated with early onset (before 34 weeks of gestation) compared with late onset or no preeclampsia (odds ratio [OR] 6.9, 95% CI 2.3-20.9; sensitivity 78%, 95% CI 52-94; specificity 66%, 95% CI 64-68). The presence of a notch or resistance index multiple of the median at or above the 75th percentile increased the odds of developing severe compared with mild or no preeclampsia (OR 2.2, 95% CI 1.4-3.7; sensitivity 53%, 95% CI 40-65; specificity 66%, 95% CI 64-68). CONCLUSION: Our data show poor sensitivity of second-trimester Doppler ultrasound measurements for prediction of preeclampsia overall in a well-characterized, low-risk, nulliparous population. The technique has utility in identifying poor trophoblast invasion of spiral arteries of a magnitude that severely compromises uteroplacental blood flow and gives early-onset disease. LEVEL OF EVIDENCE: II.

First-trimester prediction of preeclampsia in nulliparous women at low risk.

OBJECTIVE: To identify clinical characteristics and biochemical markers in first-trimester samples that would possibly predict the subsequent development of preeclampsia. METHODS: We conducted a multicenter observational study in 2,434 nulliparous women at low risk to identify biomarkers that possibly predict preeclampsia. Clinical history, complete blood count, and biochemical markers were assessed in the first trimester. The trophoblast and angiogenesis markers ADAM-12, pregnancy-associated plasma protein-A, placental protein 13, placental growth factor, soluble fms-like tyrosine kinase-1, and endoglin were measured in a case-control subset of 174 women with preeclampsia and 509 women in the control group. RESULTS: Univariable analysis revealed maternal age, race, marital status, years of education, source of medical payment, prenatal caregiver, body mass index (BMI, calculated as weight (kg)/[height (m)]), and systolic blood pressure at enrollment were significantly associated with preeclampsia. Mean platelet volume was greater at enrollment in women who later had development of preeclampsia (median 9.4 compared with 9.0 femtoliter (fl); P=.02). First-trimester concentrations (multiples of the median) of ADAM-12 (1.14 compared with 1.04; P=.003), pregnancy-associated plasma protein-A (0.94 compared with 0.98; P=.04), and placental growth factor (0.83 compared with 1.04; P<.001) were significantly different in women who had development of preeclampsia compared with women in the control group. The optimal multivariable model included African American race, systolic blood pressure, BMI, education level, ADAM-12, pregnancy-associated plasma protein-A, and placental growth factor, and yielded an area under the curve of 0.73 (95% confidence interval 0.69-0.77) and a sensitivity of 46.1% (95% confidence interval 38.3-54.0) for 80% specificity. CONCLUSION: A multivariable analysis of clinical data and biochemical markers in the first trimester did not identify a model that had clinical utility for predicting preeclampsia in a nulliparous population at low risk. LEVEL OF EVIDENCE: II.

Glycemic characteristics and neonatal outcomes of women treated for mild gestational diabetes.

OBJECTIVE: To estimate the association between fasting and 2-hour postprandial blood glucose levels and neonatal outcomes in women treated for mild gestational diabetes. METHODS: In this secondary analysis of a multicenter randomized treatment trial of mild gestational diabetes, the median fasting and 2-hour postprandial glucose levels were analyzed in 2-week intervals and change over time (slope) was calculated for women with gestational diabetes (abnormal oral glucose tolerance test) and a fasting glucose less than 95 mg/dL who received nutritional management with self blood glucose monitoring and insulin as needed. Regression analyses were performed to estimate the relationship between median fasting and postprandial glucose and neonatal fat mass, cord blood C-peptide, birth weight, large-for-gestational-age neonates, macrosomia (greater than 4,000 g), and neonatal hypoglycemia. RESULTS: Among 460 women with gestational diabetes, median fasting (P<.001), postprandial breakfast (P<.001), and postprandial lunch (P<.001) glucose values declined over the treatment period, whereas postprandial dinner values remained stable (P=.83). Higher median fasting glucose during the first 2 weeks of treatment was significantly associated with increased odds ratios for neonatal fat mass (1.35; 95% CI 1.09-1.66; P=.006) and elevated C-peptide (1.29; CI 1.09-1.52; P=.003). Higher median fasting glucose during the last 2 weeks before delivery was associated with higher rates of large-for-gestational-age neonates (1.27; CI 1.05-1.53; P=.01), macrosomia (1.32; CI 1.04-1.65; P = .02), and elevated C-peptide (1.19; CI 1.03-1.38; P=.02). CONCLUSION: In women treated for mild gestational diabetes, higher fasting glucose during initiation of diet therapy was associated with increased neonatal fat mass and elevated C-peptide and during the last 2 weeks before delivery with macrosomia, large-for-gestational age, and elevated C-peptide. LEVEL OF EVIDENCE: II.