Joseph Biggio

Ten Putative Contributors to the Obesity Epidemic

The obesity epidemic is a global issue and shows no signs of abating, while the cause of this epidemic remains unclear. Marketing practices of energy-dense foods and institutionally-driven declines in physical activity are the alleged perpetrators for the epidemic, despite a lack of solid evidence to demonstrate their causal role. While both may contribute to obesity, we call attention to their unquestioned dominance in program funding and public efforts to reduce obesity, and propose several alternative putative contributors that would benefit from equal consideration and attention. Evidence for microorganisms, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects as contributing factors to the obesity epidemic are reviewed herein. While the evidence is strong for some contributors such as pharmaceutical-induced weight gain, it is still emerging for other reviewed factors. Considering the role of such putative etiological factors of obesity may lead to comprehensive, cause specific, and effective strategies for prevention and treatment of this global epidemic.

Mild gestational diabetes mellitus and long-term child health

OBJECTIVE To evaluate whether treatment of mild gestational diabetes mellitus (GDM) confers sustained offspring health benefits, including a lower frequency of obesity. RESEARCH DESIGN AND METHODS Follow-up study of children (ages 5–10) of women enrolled in a multicenter trial of treatment versus no treatment of mild GDM. Height, weight, blood pressure, waist circumference, fasting glucose, fasting insulin, triglycerides, and HDL cholesterol were measured. RESULTS Five hundred of 905 eligible offspring (55%) were enrolled. Maternal baseline characteristics were similar between the follow-up treated and untreated groups. The frequencies of BMI ≥95th (20.8% and 22.9%) and 85th (32.6% and 38.6%) percentiles were not significantly different in treated versus untreated offspring (P = 0.69 and P = 0.26). No associations were observed for BMI z score, log waist circumference, log triglycerides, HDL cholesterol, blood pressure, or log HOMA-estimated insulin resistance (HOMA-IR). The effect of treatment was different by sex for fasting glucose and log HOMA-IR (P for interaction = 0.002 and 0.02, respectively) but not by age-group (5–6 and 7–10 years) for any outcomes. Female offspring of treated women had significantly lower fasting glucose levels. CONCLUSIONS Although treatment for mild GDM has been associated with neonatal benefits, no reduction in childhood obesity or metabolic dysfunction in the offspring of treated women was found. However, only female offspring of women treated for mild GDM had lower fasting glucose.

Congenital diaphragmatic hernia: Is 15q26.1-26.2 a candidate locus?

Congenital diaphragmatic hernia is a developmental abnormality due to failure of the normal formation of the diaphragm. While the majority of cases are idiopathic, chromosomal abnormalities have been implicated in approximately 15% of cases. Several recent series have suggested that 15q24‐26 is critical in normal development of the diaphragm. We present a patient with a karyotype of 46, XX, del (15)(q26.1) born with a diaphragmatic hernia, coarctation of the aorta, and dysmorphic features. This patient represents the smallest isolated chromosomal aberration on distal 15q reported to date. The DNA regulatory proteins, myocyte‐specific enhancer factor 2 proteins (MEF2), play a critical role in the control of muscle differentiation and development. One member of this gene family, MEF2A, maps to 15q26. We propose that this region is a candidate locus for diaphragmatic hernia and future investigations should examine the role of MEF2A in diaphragm formation.

Surgical Staples Compared With Subcuticular Suture for Skin Closure After Cesarean Delivery A Randomized Controlled Trial

OBJECTIVE: To compare the risk of cesarean wound disruption or infection after closure with surgical staples compared with subcuticular suture. METHODS: Women with viable pregnancies at 24 weeks of gestation or greater undergoing scheduled or unscheduled cesarean delivery were randomized to wound closure with surgical staples or absorbable suture. Staples were removed at postoperative days 3–4 for low transverse incisions and days 7–10 for vertical incisions. Standardized wound evaluations were performed at discharge (days 3–4) and 4–6 weeks postoperatively. The primary outcome was a composite of wound disruption or infection within 4–6 weeks. Secondary outcomes included operative time, highest pain score on analog scale, cosmesis score, and patient scar satisfaction score. Analyses were by intent to treat. RESULTS: Of 398 patients, 198 were randomized to staples and 200 to suture (but four received staples). Baseline characteristics including body mass index, prior cesarean delivery, labor, and type of skin incision were similar by group. The primary outcome incidence at hospital discharge was 7.1% for staples and 0.5% for suture (P<.001, relative risk 14.1, 95% confidence interval [CI] 1.9–106). Of 350 (87.9%) with follow-up at 4–6 weeks, the cumulative risk of the primary outcome at 4–6 weeks was 14.5% for staples and 5.9% for suture (P=.008, relative risk 2.5, 95% CI 1.2–5.0). Operative time was longer with suture closure (median time of 58 versus 48 minutes; P<.001). Pain scores at 72–96 hours and at 6 weeks, cosmesis score, and patient satisfaction score did not differ by group. CONCLUSION: Staples closure compared with suture is associated with significantly increased composite wound morbidity after cesarean delivery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01008449. LEVEL OF EVIDENCE: I

Cervical conization and the risk of preterm delivery

The current body of literature concerning cervical conization and its effect on subsequent pregnancy outcome is conflicting. Depending on the type of conization procedure that is examined and the quality of the control group, the results and conclusions vary widely. Because treatment for cervical intraepithelial neoplasia is commonplace among women of reproductive age, it is imperative that practitioners have an understanding of the issues surrounding the treatment. Therefore, this review will summarize the published literature that addresses excisional procedures of the uterine cervix and the risk of preterm delivery in subsequent pregnancies and provide reasonable treatment recommendations for women with cervical abnormalities and a desire for future fertility.

A genome-wide association study of early spontaneous preterm delivery.

Preterm birth is the leading cause of infant morbidity and mortality. Despite extensive research, the genetic contributions to spontaneous preterm birth (SPTB) are not well understood. Term controls were matched with cases by race/ethnicity, maternal age, and parity prior to recruitment. Genotyping was performed using Affymetrix SNP Array 6.0 assays. Statistical analyses utilized PLINK to compare allele occurrence rates between case and control groups, and incorporated quality control and multiple‐testing adjustments. We analyzed DNA samples from mother–infant pairs from early SPTB cases (200/7–336/7 weeks, 959 women and 979 neonates) and term delivery controls (390/7–416/7 weeks, 960 women and 985 neonates). For validation purposes, we included an independent validation cohort consisting of early SPTB cases (293 mothers and 243 infants) and term controls (200 mothers and 149 infants). Clustering analysis revealed no population stratification. Multiple maternal SNPs were identified with association P‐values between 10 × 10–5 and 10 × 10–6. The most significant maternal SNP was rs17053026 on chromosome 3 with an odds ratio (OR) 0.44 with a P‐value of 1.0 × 10–6. Two neonatal SNPs reached the genome‐wide significance threshold, including rs17527054 on chromosome 6p22 with a P‐value of 2.7 × 10–12 and rs3777722 on chromosome 6q27 with a P‐value of 1.4 × 10–10. However, we could not replicate these findings after adjusting for multiple comparisons in a validation cohort. This is the first report of a genome‐wide case‐control study to identify single nucleotide polymorphisms (SNPs) that correlate with SPTB.

Fetal Anomalies in Obese Women: The Contribution of Diabetes

OBJECTIVE: To examine temporal changes in maternal weight and the association with major structural anomalies and other factors, such as diabetes, in our primary obstetric population. METHODS: We conducted a serial, cross-sectional study using a perinatal database to identify all women with singletons who delivered in our system from 1991 to 2004. Three 5-year time epochs were defined to compare patient cohorts. Maternal weight, body mass index (BMI), diabetes status, incidence of major anomalies, and demographic data were compared. Multiple logistic regression was performed to estimate factors contributing to anomaly rates. RESULTS: A total of 41,902 pregnancies were included. In each time epoch, there was an increase in the mean maternal weight, the mean BMI, the proportion of women weighing in excess of 200 lb, the proportion with a BMI higher than 29, the prevalence of pregestational diabetes, and the prevalence of major anomalies (all P<.001). There was no significant independent association between maternal obesity and the presence of a major anomaly. In a multivariable logistic model, the major factor contributing to the increasing rate of congenital anomalies was the prevalence of pregestational diabetes (odds ratio 3.8, 95% confidence interval 2.1–6.6). The population-attributable risk of anomalies related to obesity increased from essentially 0% in 1991–1994 to 6.1% in 2000–2004, whereas that related to diabetes increased from 3.3% to 9.2% during the same time periods. CONCLUSION: Although the prevalence of maternal obesity and anomaly have increased, maternal weight alone was not associated with an increase in congenital anomalies. Instead, diabetes was significantly associated with the increase in the rate of anomalies seen in our population. Identification of maternal weight as a risk factor in epidemiologic studies may be a surrogate for pregestational diabetes. LEVEL OF EVIDENCE: II

Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women

Significance Premature birth (PTB) is a major global public health burden. Previous studies have suggested an association between altered vaginal microbiota composition and PTB, although findings across studies have been inconsistent. To address these inconsistencies, improve upon our previous signature, and better understand the vaginal microbiota’s role in PTB, we conducted a case-control study in two cohorts of pregnant women: one predominantly Caucasian at low risk of PTB, the second predominantly African American at high risk. With the results, we were able to replicate our signature in the first cohort and refine our signature of PTB for both cohorts. Our findings elucidate the ecology of the vaginal microbiota and advance our ability to predict and understand the causes of PTB. Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. Previous studies have suggested that the maternal vaginal microbiota contributes to the pathophysiology of PTB, but conflicting results in recent years have raised doubts. We conducted a study of PTB compared with term birth in two cohorts of pregnant women: one predominantly Caucasian (n = 39) at low risk for PTB, the second predominantly African American and at high-risk (n = 96). We profiled the taxonomic composition of 2,179 vaginal swabs collected prospectively and weekly during gestation using 16S rRNA gene sequencing. Previously proposed associations between PTB and lower Lactobacillus and higher Gardnerella abundances replicated in the low-risk cohort, but not in the high-risk cohort. High-resolution bioinformatics enabled taxonomic assignment to the species and subspecies levels, revealing that Lactobacillus crispatus was associated with low risk of PTB in both cohorts, while Lactobacillus iners was not, and that a subspecies clade of Gardnerella vaginalis explained the genus association with PTB. Patterns of cooccurrence between L. crispatus and Gardnerella were highly exclusive, while Gardnerella and L. iners often coexisted at high frequencies. We argue that the vaginal microbiota is better represented by the quantitative frequencies of these key taxa than by classifying communities into five community state types. Our findings extend and corroborate the association between the vaginal microbiota and PTB, demonstrate the benefits of high-resolution statistical bioinformatics in clinical microbiome studies, and suggest that previous conflicting results may reflect the different risk profile of women of black race.

The institute of medicine guidelines for gestational weight gain after a diagnosis of gestational diabetes and pregnancy outcomes.

OBJECTIVE The objective of this study was to assess the impact of gestational weight gain outside the Institute of Medicine (IOM) recommendations after the diagnosis of gestational diabetes (GDM) on perinatal outcomes. MATERIALS AND METHODS This was a retrospective cohort study. Women were classified as gestational weight gain (GWG) within, less than, or greater than IOM recommendations for body mass index as calculated by gestational weight gain per week after a diagnosis of GDM. Outcomes assessed were preeclampsia, cesarean delivery, A2 GDM, birth weight, small for gestational age (SGA), large for gestational age (LGA), macrosomia, and preterm delivery. Groups were compared using analysis of variance and chi-square test for trend, as appropriate. Backward stepwise logistic regression was used to adjust for significant confounding factors. RESULTS Of 635 subjects, 92 gained within, 175 gained less than, and 368 gained more than IOM recommendations. The risk of cesarean delivery and A2 GDM was increased in those gaining above the IOM recommendations compared with within. For every 1-lb/week increase in weight gain after diagnosis of GDM, there was a 36 to 83% increase in the risk of preeclampsia, cesarean delivery, A2 GDM, macrosomia, and LGA, without decreases in SGA or preterm delivery. CONCLUSION Weight gain more than the IOM recommendations per week of gestation after a diagnosis of GDM is associated with adverse pregnancy outcomes.

Is midtrimester vitamin D status associated with spontaneous preterm birth and preeclampsia

OBJECTIVE The objective of this study is to evaluate whether midtrimester maternal vitamin D is associated with preeclampsia < 37 weeks or spontaneous preterm birth (SPTB) < 35 weeks. STUDY DESIGN Nested case-control comprising two case subsets: (1) 100 women with preeclampsia < 37 weeks and (2) 100 women with SPB < 35 weeks. Controls consisted of 200 women delivered between 39 and 40 weeks. Stored maternal serum obtained between 15 and 21 weeks was tested for total 25-hydroxy vitamin D (25-OH D) levels using liquid chromatography-tandem mass spectrometry. Mean 25-OH D levels and prevalence of vitamin D insufficiency (25-OH D < 30 ng/mL) and deficiency (25-OH D < 15 ng/mL) were compared. RESULTS In this study, 89 preeclampsia, 90 SPTB cases, and 177 controls had valid measurements. Mean midtrimester vitamin D was not significantly different between women with preeclampsia (27.4 ng/mL ± 14.4) and controls (28.6 ± 12.6) (p = 0.46), or SPTB (28.8 ± 13.2) and controls (p = 0.92). After adjusting for potential cofounders, neither vitamin D insufficiency (adjusted odds ratio [OR], 1.1; 95% confidence interval [CI], 0.6-2.0) nor deficiency (adjusted OR, 1.4; 95% CI, 0.7-3.0) was significantly associated with preeclampsia. Likewise, SPTB was not significantly associated with either vitamin D insufficiency or deficiency (adjusted OR, 0.8; 95% CI, 0.4-1.4, adjusted OR, 1.3 or 95% CI, 0.6-3.0, respectively). CONCLUSION Midtrimester maternal vitamin D was not significantly associated with preeclampsia < 37 weeks or SPTB < 35 weeks.