[show abstract][hide abstract] ABSTRACT: Given the unique role of the corticotrophin-releasing hormone (CRH) system in human fetal development, the aim of our study was to estimate the association of birth weight with DNA sequence variation in three maternal genes involved in regulating CRH production, bioavailability and action: CRH, CRH-Binding Protein (CRH-BP), and CRH type 1 receptor (CRH-R1), respectively, in three racial groups (African-Americans, Hispanics, and non-Hispanic Whites).
Our study was carried out on a population-based sample of 575 mother-child dyads. We resequenced the three genes in mouse-human hybrid somatic cell lines and selected SNPs for genotyping.
A significant association was observed in each race between birth weight and maternal CRH-BP SNP genotypes. Estimates of linkage disequilibrium and haplotypes established three common haplotypes marked by the rs1053989 SNP in all three races. This SNP predicted significant birth weight variation after adjustment for gestational age, maternal BMI, parity, and smoking. African American and Hispanic mothers carrying the A allele had infants whose birth weight was on average 254 and 302 grams, respectively, less than infants having C/C mothers. Non-Hispanic White mothers homozygous for the A allele had infants who were on average 148 grams less than those infants having A/C and C/C mothers.
The magnitudes of the estimates of the birth weight effects are comparable to the combined effects of multiple SNPs reported in a recent meta-analysis of 6 GWAS studies and is quantitatively larger than that associated with maternal cigarette smoking. This effect was persistent across subpopulations that vary with respect to ancestry and environment.
PLoS ONE 01/2012; 7(9):e43931. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: To estimate and compare the risk of morbid perinatal outcomes in pregnancies identified as small for gestational age (SGA) with customized compared with conventional standards of fetal growth.
Ultrasound-derived estimates of fetal weight were used to generate a fetal growth trajectory (N=7,510). The gestational age at delivery and pathologic and physiologic variables from 5,072 pregnancies were used to calculate a customized threshold for SGA. In a separate analysis of 32,070 pregnancies, rates of morbid outcomes were compared in participants classified as SGA according to a population-based birth weight standard only (SGApop only), a customized standard only (SGAcust only), and both methods (SGAboth).
Eight-hundred seventy-five (2.7%) participants were SGApop only, 1,970 (6.1%) participants were SGAboth, and 609 (1.9%) participants were SGAcust only. The odds ratios of neonatal death in SGApop only and SGAcust only pregnancies were 1.78 (95% confidence interval [CI] 0.2-13.1) and 54.6 (95% CI 29.0-102.8), respectively. Rates of prematurity in the SGApop only and SGAcust only cohorts were 4.8% and 64.5%, respectively. After adjustment for the effect of prematurity, odds ratios of neonatal death in the SGApop only and SGAcust only cohorts were 4.8 (95% CI 0.6-37.0) and 2.9 (95% CI 1.4-6.1), respectively.
After adjustment for confounding stemming from premature delivery, there is little difference in the risk of adverse outcomes between SGAcust only and SGApop only participants. Adoption of customized fetal growth standards into clinical practice may not improve the ability to identify pregnancies with increased risk of perinatal morbidity.
Obstetrics and Gynecology 01/2012; 119(1):21-7. · 4.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: Decidual cells are central to innate immunity at the maternal/fetal interface. We sought to characterize the response of decidual cells to stimulation and then removal of lipopolysaccharide (LPS) using a whole genome approach. Decidual cells were isolated from term unlabored cesarean sections. Cells were stimulated with LPS and RNA isolated both pre-stimulation and 2 and 24 h post-stimulation. Media were changed and RNA extracted 48 h later. Gene expression was measured using Agilent 44K whole genome microarrays. Data were visualized and interpreted using Ingenuity Pathway Analysis (IPA) software and selected (n=5) target gene expression was verified with quantitative real-time PCR. Genes related to immune function were up-regulated at 2 and 24 h after LPS exposure and then generally returned to baseline or were at least substantially reduced after LPS removal. Pathway analysis also revealed that genes involved in lipid metabolism (specifically cholesterol and steroid biosynthesis), iron metabolism, and the plasminogen system were coordinately altered following exposure to LPS. Our novel, preliminary findings provide insight into possible mechanisms via which the host inflammatory response could contribute to preterm birth and warrant further investigation in preterm samples.
Journal of Reproductive Immunology 12/2011; 93(1):17-27. · 2.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: Serum fatty acid binding protein 4 (FABP4) is associated with components of the metabolic syndrome in nonpregnant individuals, including dyslipidemia and insulin resistance. Preeclampsia shares many features with the metabolic syndrome, but the relationship between early pregnancy serum FABP4 levels and the development of preeclampsia is unknown.
The aim of the study was to test the hypothesis that FABP4 is elevated in women who develop preeclampsia before the onset of disease.
This was a nested case-control study within a larger prospective cohort of healthy women with singleton gestations. Cases included 22 women who developed preeclampsia, and a random sample of 72 unmatched controls delivered without preeclampsia was identified. Maternal serum FABP4 was measured at less than 13 wk gestation and 24-28 wk gestation, which was before the onset of preeclampsia in all patients.
The main outcome measure was preeclampsia (new-onset gestational hypertension and proteinuria for the first time after 20 wk gestation).
Maternal serum FABP4 concentrations were higher in women who ultimately developed preeclampsia both at 8-13 wk (20.4±12.3 vs. 10.1±4.7 ng/ml; P<0.01) and at 24-28 wk (20.7±11.7 vs. 9.9±4.5 ng/ml; P<0.01). After controlling for first trimester body mass index, systolic blood pressure, and nulliparity, FABP4 was associated with the development of preeclampsia (adjusted odds ratio, 1.2; 95% confidence interval, 1.1-1.3; P<0.01).
Maternal serum FABP4 levels are elevated before the clinical onset of preeclampsia, and this increase occurs independently of maternal body mass index.
The Journal of clinical endocrinology and metabolism 12/2011; 97(3):E349-56. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: We hypothesized that change in cervical length (CL) on serial ultrasounds is associated with spontaneous preterm birth (SPTB) <36 weeks for women with a short cervix (CL <25 mm).
This was a secondary analysis of a multicenter prospective observational study designed to study predictors of preterm birth. Women from the general obstetric population had serial CL ultrasounds between 20-33 weeks' gestation and were followed up until delivery.
Two thousand six hundred ninety five women had sonographic CL measurements. Change in CL was associated with SPTB for women with CL <25 mm (odds ratio, 0.97; 95% confidence interval, 0.96-0.98). Among women with a short cervix, for every 1 mm of cervical shortening between ultrasounds, there was a 3% increase in odds of SPTB. The association between change in CL and SPTB remained significant after controlling for age, race, body mass index, tobacco use, and fetal fibronectin test status.
Among women with a sonographically short cervix, the rate of change in CL is associated with SPTB, independent of fetal fibronectin test and other important risk factors for SPTB.
American journal of obstetrics and gynecology 12/2011; 206(3):234.e1-5. · 3.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine if subjects experiencing acute vaginal bleeding in early pregnancy have increased plasma markers of thrombin generation compared to nonbleeding controls.
Subjects with clinically apparent acute (within 24 h of sample collection) vaginal bleeding between 6 and 20 weeks estimated gestational age and without known thrombophilias were enrolled, along with nonbleeding controls, and underwent collection of maternal plasma. Concentrations of thrombin-antithrombin (TAT) and fragment 1 + 2 (F1 + 2) were determined by enzyme-linked immunosorbent assay. Differences between bleeding and nonbleeding subjects were assessed through linear regression with adjustment for gestational age.
Twenty subjects with vaginal bleeding and 20 controls were included. Bleeding was significantly associated with increased concentrations of TAT (p = 0.007) and F1 + 2 (p = 0.044) when corrected for gestational age. Among bleeding subjects, there was no association between markers of thrombin generation and the subject's description of bleeding quantity, though higher concentrations were associated with a longer self-reported duration of bleeding.
Clinically apparent vaginal bleeding in early pregnancy is associated with increased circulating maternal markers of thrombin generation. Thus, these maternal markers may have a future role in risk stratification.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 11/2011; 25(8):1479-82. · 1.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: We sought to evaluate the contributions of vaginal bleeding and cervical length to the risk of preterm birth.
This was a secondary analysis of a cohort study designed to study predictors of preterm birth. The study included 2988 women with singleton gestations. Women underwent midtrimester transvaginal ultrasound assessment of cervical length and were queried regarding first- and second-trimester vaginal bleeding.
There was a significant second-order relation between cervical length and preterm birth (P < .001, P = .005). Women with vaginal bleeding were at higher risk of preterm birth (odds ratio, 1.5; 95% confidence interval, 1.3-2.0). There was a significant interaction between cervical length and vaginal bleeding (P = .015). After accounting for cervical length and interaction, the adjusted odds ratio for vaginal bleeding and preterm birth was 4.8 (95% confidence interval, 1.89-12.4; P = .001).
The magnitude of risk of preterm birth associated with sonographic cervical length depends on a woman's history of first- and second-trimester vaginal bleeding.
American journal of obstetrics and gynecology 11/2011; 206(3):224.e1-4. · 3.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: To examine associations between rs9883204 in ADCY5 and rs900400 near LEKR1 and CCNL1 with birth weight in a preterm population. Both markers were associated with birth weight in a term population in a recent genome-wide association study of Freathy et al.
A meta-analysis of mother and infant samples was performed for associations of rs900400 and rs9883204 with birth weight in 393 families from the US, 265 families from Argentina, and 735 mother-infant pairs from Denmark. Z-scores adjusted for infant sex and gestational age were generated for each population separately and regressed on allele counts. Association evidence was combined across sites by inverse-variance weighted meta-analysis.
Each additional C allele of rs900400 (LEKR1/CCNL1) in infants was marginally associated with a 0.069 SD lower birth weight (95% CI, -0.159 to 0.022; P = .068). This result was slightly more pronounced after adjusting for smoking (P = .036). No significant associations were identified with rs9883204 or in maternal samples.
These results indicate the potential importance of this marker on birth weight regardless of gestational age.
The Journal of pediatrics 08/2011; 160(1):19-24.e4. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the association between cerebral palsy (CP) or infant death and putative cord blood biomarkers of neurologic injury, we performed a nested case-control secondary analysis of a multicenter randomized trial of magnesium sulfate (MgSO(4)) versus placebo to prevent CP or death among offspring of women with anticipated delivery from 24 to 31 weeks' gestation. Cases were infants who died by 1 year (n=25) or developed CP (n=16), and were matched 1:2 to a control group (n=82) that survived without developing CP. Umbilical cord sera concentrations of S100B, neuron-specific enolase (NSE) and the total soluble form of the receptor for advanced glycation end-products (sRAGE) were measured by ELISA in duplicates. Maternal characteristics were similar between the 2 groups. Cases were born at a lower gestational age (GA) and had lower birth weight compared with controls. There were no differences in concentrations of the three biomarkers and the composite outcome of CP or infant death. However, S100B was higher (median 847.3 vs. 495.7 pg/ml; P=0.03) in infants who had CP and total sRAGE was lower (median 1259.3 vs. 1813.1 pg/ml; P=0.02) in those who died compared with the control group. When corrected for delivery GA and treatment group, both differences lost statistical significance. In conclusion, cord blood S100B level may be associated with CP, but this association was not significant after controlling for GA and MgSO(4) treatment.
International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 06/2011; 29(8):917-22. · 2.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: The objective was to assess the impact of genetic variation on cervical cytokine concentrations of interleukin (IL)-1α, IL-1β, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α), and first, to determine if these variants interact with polymorphisms in Toll-like receptor 4 (TLR4) that were previously shown to associate with pro-inflammatory cervical cytokine concentrations, and second, to determine if findings are affected by bacterial vaginosis (BV). We examined 183 single nucleotide polymorphisms (SNPs) in 13 cytokine genes and receptors for associations with cervical cytokine levels in 188 African American and European American women. We tested for associations of gene-gene interactions between SNPs in TLR4 and cytokine gene and receptor polymorphisms with cervical pro-inflammatory cytokines. None of the single locus associations were significant after correction for multiple testing in either European Americans or African Americans. However, there were significant gene-gene interactions between IL-1R2 rs485127 and two SNPs in TLR4 (rs1554973 and rs7856729) with IL-1β after correction for multiple testing. Our study demonstrates that interactions between TLR4 and IL-1R2 are associated with cervical pro-inflammatory cytokine concentrations. These results provide important insights into the possible regulatory mechanisms of the inflammatory response in the presence and absence of microbial disorders such as BV. Additionally, the observed differences in allele frequencies between African Americans and those of European descent may partially explain population disparity in pregnancy-related phenotypes that are cytokine concentration-dependent.
Journal of Reproductive Immunology 06/2011; 90(2):220-6. · 2.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: The authors tested whether the relation between gestational weight gain (GWG) and 5 adverse pregnancy outcomes (small-for-gestational-age (SGA) birth, large-for-gestational-age (LGA) birth, spontaneous preterm birth, indicated preterm birth, and unplanned cesarean delivery) differed according to maternal race/ethnicity, smoking, parity, age, and/or height. They also evaluated whether GWG guidelines should be modified for special populations by studying GWG and risk of at least 1 adverse outcome within different subgroups. Data came from a cohort of 23,362 normal-weight mothers who delivered singletons at Magee-Womens Hospital in Pittsburgh, Pennsylvania (2003-2008). Adequacy of GWG was defined as observed GWG divided by recommended GWG. The synergy analysis found that the combination of smoking, black race/ethnicity, primiparity, or short height with poor GWG was associated with an excess risk of SGA birth, while high GWG combined with each of these characteristics diminished risk of LGA birth in comparison with the same GWG among the women's counterparts. Nevertheless, there were no significant or meaningful differences in the risk of at least 1 adverse outcome between the GWG recommended by the Institute of Medicine in 2009 and the GWG that minimized risk of the composite outcome. These findings do not support the tailoring of GWG guidelines on the basis of a mother's smoking status, race/ethnicity, parity, age, or height among normal-weight women.
American journal of epidemiology 06/2011; 174(2):136-46. · 5.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: The inflammatory milieu of the cervix may play a role in preventing intrauterine infection and subsequent preterm birth. The objectives of this study were to use exploratory factor analysis to discover the underlying structure of cytokines in the lower genital tract immunological milieu, and evaluate the association between the cytokine factors and risk of preterm birth. Women (n=613) enrolled in a prospective pregnancy cohort study in Pittsburgh, Pennsylvania had cervical cytokine concentrations assayed at <16 weeks and were followed for data on pregnancy outcomes. Principal factor analysis identified two primary cytokine patterns at <16 weeks gestation: Factor 1 (pro-inflammatory/immunomodulatory factor), which loaded highly on interleukin (IL)-1β, IL-6, IL-8, monocyte chemotactic protein-1, and IL-10, and Factor 2 (anti-inflammatory factor), which loaded heavily on IL-4, IL-10, and IL-13. Women in the highest tertile of anti-inflammatory cytokine factor scores at <16 weeks had an increased risk of spontaneous preterm birth (confounder-adjusted odds ratio [95% confidence interval]: 2.4 [1.1, 5.7]). There was no association between pro-inflammatory cytokine factor scores and preterm birth risk. These data support the hypothesis that increased concentrations of anti-inflammatory cytokines may represent a cervical immune milieu that permits subsequent microbial invasion of the uterus during pregnancy, leading to subsequent spontaneous preterm birth.
Paediatric and Perinatal Epidemiology 05/2011; 25(3):277-82. · 2.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: We previously reported that elevated antiinflammatory cervical cytokines in early pregnancy were associated with spontaneous preterm birth. Our objective was to explore the relation between serum folate vitamers and the lower genital tract inflammatory milieu.
Pregnant women (n = 417) at <16 weeks' gestation had serum samples that were analyzed for folate species 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and cervical fluid that was assayed for cytokine concentrations. Patterns in proinflammatory cytokines (interleukin [IL]-1β, -6, -8, and -10; monocyte chemotactic protein-1) and antiinflammatory cytokines (IL-4, IL-10, IL-13) were identified with factor analysis.
After confounder adjustment, maternal serum 5-methyltetrahydrofolate concentrations had a strong negative association with elevated antiinflammatory scores; serum 5-formyltetrahydrofolate concentrations were associated positively with elevated antiinflammatory scores (both P < .05). Maternal folate was not associated with proinflammatory scores.
Maternal serum folate vitamers are associated with cervical cytokine concentrations, which suggests a possible mechanistic link between folate and preterm birth risk.
American journal of obstetrics and gynecology 03/2011; 205(1):61.e1-7. · 3.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose of this study was to determine whether a customized standard of large-for-gestational age (LGA) identifies pregnancies with increased perinatal risk.
We evaluated 7510 estimates of fetal weight to generate a fetal growth curve. Next, we analyzed the gestational age at delivery, physiologic and pathological variables from 5072 pregnancies to predict birthweight, and calculated a customized ideal birthweight and cutoff for LGA. In a separate analysis of 32,271 pregnancies, rates of macrosomia-related adverse outcomes were compared in pregnancies that had been identified as LGA by a customized standard (LGA(cust)) and those pregnancies that had been identified as LGA or macrosomic by conventional standards.
LGA(cust) pregnancies carried increased risk of shoulder dystocia, third- or fourth-degree laceration, and cephalopelvic disproportion. LGA(cust) pregnancies that did not meet conventional criteria for LGA/macrosomia were at increased risk of all measured outcomes.
A customized standard of LGA identifies a previously unrecognized population that is at increased risk of perinatal morbidity.
American journal of obstetrics and gynecology 03/2011; 204(6):499.e1-10. · 3.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: We sought to determine if pyelonephritis and preterm delivery occur more frequently among pregnant women with polymicrobial growth from screening urine culture than among women with negative urine culture. A retrospective cohort study was performed. Three hundred eighty pregnant women with greater than 100,000 colony-forming units per milliliter of polymicrobial growth from urine culture performed at less than 20 weeks of pregnancy were compared with 375 women with negative urine culture. Admissions for pyelonephritis were identified from discharge records. Gestational age at delivery was determined from a research registry. Frequency of pyelonephritis and preterm delivery did not differ between the two groups. Frequencies of pyelonephritis were 0.3% and 0% in women with polymicrobial and negative urine culture, respectively ( P=0.32). Frequencies of preterm delivery were 16.8% and 16% ( P=0.76). Among those with repeat urine cultures, 4.6% in the polymicrobial group and 2.4% of those in the negative initial urine culture group had a positive culture later in the pregnancy ( P=0.21). There is no association between polymicrobial growth from screening urine culture and pyelonephritis or preterm delivery.
American Journal of Perinatology 03/2011; 28(7):537-42. · 1.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: The objectives were to determine whether single-nucleotide polymorphisms (SNPs) in KCNN3 (encodes the small conductance calcium-activated potassium channel subfamily N, member 3), associate with preterm birth (PTB). In all, 602 preterm families with at least 1 preterm (<37 weeks gestation) infant were studied: DNA from the infant and one or both parents were genotyped for 16 SNPs in KCNN3. A region of interest within KCNN3 was sequenced in 512 Caucasian non-Hispanic mothers (412 with preterm deliveries;100 who delivered at term). Family-based association testing was used for genotyping analysis; Fisher exact test was used for sequencing analysis. Six SNPs (rs1218585, rs4845396, rs12058931, rs1218568, rs6426985, and rs4845394) were associated with PTB (all Ps < .05). These variations were all located within the intronic region between exons 1 and 2. Maternal sequencing revealed an association of 3 SNPs with spontaneous PTB; rs1218585 (P = .007), rs1218584 (P = .05), and a novel SNP at chromosome1:153099353 (P = .02). Polymorphisms in KCNN3 are associated with PTB and investigation into the functional significance of these allelic changes is warranted.
[show abstract][hide abstract] ABSTRACT: Providers occasionally screen women thought to be at particularly increased risk of gestational diabetes mellitus (GDM) with a first- or second-trimester ("early") glucose tolerance test (GTT). We sought to describe how the frequency of abnormal early GTT varies by indication for testing. This is a retrospective cohort study of women receiving prenatal care in our clinic who underwent a 50-g GTT at less than 24 weeks between 2003 and 2006. Three hundred five women received an early GTT. The most common indications for early screening were obesity (53%), family history of diabetes (15%), prior history of GDM (10%), and multifetal gestation (5%). The frequency of abnormal testing in patients with multifetal gestations and a personal history of GDM was higher than in those undergoing early testing because of obesity. The frequency of abnormal early GTT varies by indication for testing. These data may be used in the allocation of health care resources.
American Journal of Perinatology 01/2011; 28(6):485-8. · 1.57 Impact Factor