Amy M. Valent

Regulatory T Cells: New Keys for Further Unlocking the Enigma of Fetal Tolerance and Pregnancy Complications

The immunological alterations required for successful pregnancy in eutherian placental mammals have remained a scientific enigma since the discovery of MHC haplotype diversity and unique immune signatures among individuals. Within the past 10 years, accumulating data suggest that immune-suppressive regulatory T cells (Tregs) confer essential protective benefits in sustaining tolerance to the semiallogeneic fetus during pregnancy, along with their more established roles in maintaining tolerance to self and “extended self” commensal Ags that averts autoimmunity. Reciprocally, many human pregnancy complications stemming from inadequacies in fetal tolerance have been associated with defects in maternal Tregs. Thus, further elucidating the immunological shifts during pregnancy not only have direct translational implications for improving perinatal health, they have enormous potential for unveiling new clues about how Tregs work in other biological contexts. In this article, epidemiological data in human pregnancy and complementary animal studies implicating a pivotal protective role for maternal Tregs are summarized.

Adjunctive Therapies to Cerclage for the Prevention of Preterm Birth: A Systematic Review

The aim of this paper is to provide a thorough summary of published studies that have assessed the efficacy of adjunctive therapies used in addition to cervical cerclage as a preventive measure for preterm birth. We limited our paper to patients treated with cerclage plus an additional prophylactic therapy compared to a reference group of women with cerclage alone. The specific adjunctive therapies included in this systematic review are progesterone, reinforcing or second cerclage placement, tocolytics, antibiotics, bedrest, and pessary. We searched PubMed and Cochrane databases without date criteria with restriction to English language and human studies and performed additional bibliographic review of selected articles and identified 305 total studies for review. Of those, only 12 studies compared the use of an adjunctive therapy with cerclage to a reference group of cerclage alone. None of the 12 were prospective randomized clinical trials. No comparative studies were identified addressing the issues of antibiotics, bedrest, or pessary as adjunctive treatments to cerclage. None of the 12 studies included in this paper demonstrated a clear benefit of any adjunctive therapy used in addition to cerclage over and above cerclage used alone; however, few studies with small numbers limited the strength of the conclusions.

Cytotrophoblast, Not Syncytiotrophoblast, Dominates Glycolysis and Oxidative Phosphorylation in Human Term Placenta

The syncytiotrophoblast (SCT) at the maternal-fetal interface has been presumed to be the primary driver of placental metabolism, and the underlying progenitor cytotrophoblast cells (CTB) an insignificant contributor to placental metabolic activity. However, we now show that the metabolic rate of CTB is much greater than the SCT. The oxygen consumption and extracellular acidification rate, a measure of glycolysis, are both greater in CTB than in SCT in vitro (CTB: 96 ± 16 vs SCT: 46 ± 14 pmol O2 × min−1 × 100 ng DNA−1, p < 0.001) and (CTB: 43 ± 6.7 vs SCT 1.4 ± 1.0 ∆mpH × min−1 × 100 ng DNA−1, p < 0.0001). Mitochondrial activity, as determined by using the mitochondrial activity-dependent dye Mitotracker CM-H2TMRosa, is higher in CTB than in SCT in culture and living explants. These data cast doubt on the previous supposition that the metabolic rate of the placenta is dominated by the SCT contribution. Moreover, differentiation into SCT leads to metabolic suppression. The normal suppression of metabolic activity during CTB differentiation to SCT is prevented with a p38 MAPK signaling inhibitor and epidermal growth factor co-treatment. We conclude that the undifferentiated CTB, in contrast to the SCT, is highly metabolically active, has a high level of fuel flexibility, and contributes substantially to global metabolism in the late gestation human placenta.

Effect of Post–Cesarean Delivery Oral Cephalexin and Metronidazole on Surgical Site Infection Among Obese Women: A Randomized Clinical Trial

Importance The rate of obesity among US women has been increasing, and obesity is associated with increased risk of surgical site infection (SSI) following cesarean delivery. The optimal perioperative antibiotic prophylactic regimen in this high-risk population undergoing cesarean delivery is unknown. Objective To determine rates of SSI among obese women who receive prophylactic oral cephalexin and metronidazole vs placebo for 48 hours following cesarean delivery. Design, Setting, and Participants Randomized, double-blind clinical trial comparing oral cephalexin and metronidazole vs placebo for 48 hours following cesarean delivery for the prevention of SSI in obese women (prepregnancy BMI ≥30) who had received standard intravenous preoperative cephalosporin prophylaxis. Randomization was stratified by intact vs rupture of membranes prior to delivery. The study was conducted at the University of Cincinnati Medical Center, Cincinnati, Ohio, an academic and urban setting, between October 2010 and December 2015, with final follow-up through February 2016. Interventions Participants were randomly assigned to receive oral cephalexin, 500 mg, and metronidazole, 500 mg (n = 202 participants), vs identical-appearing placebo (n = 201 participants) every 8 hours for a total of 48 hours following cesarean delivery. Main Outcomes and Measures The primary outcome was SSI, defined as any superficial incisional, deep incisional, or organ/space infections within 30 days after cesarean delivery. Results Among 403 randomized participants who were included (mean age, 28 [SD, 6] years; mean BMI, 39.7 [SD, 7.8]), 382 (94.6%) completed the trial. The overall rate of SSI was 10.9% (95% CI, 7.9%-14.0%). Surgical site infection was diagnosed in 13 women (6.4%) in the cephalexin-metronidazole group vs 31 women (15.4%) in the placebo group (difference, 9.0% [95% CI, 2.9%-15.0%]; relative risk, 0.41 [95% CI, 0.22-0.77]; P = .01). There were no serious adverse events, including allergic reaction, reported in either the antibiotic group or the placebo group. Conclusions and Relevance Among obese women undergoing cesarean delivery who received the standard preoperative cephalosporin prophylaxis, a postoperative 48-hour course of oral cephalexin and metronidazole, compared with placebo, reduced the rate of SSI within 30 days after delivery. For prevention of SSI among obese women after cesarean delivery, prophylactic oral cephalexin and metronidazole may be warranted. Trial Registration clinicaltrials.gov Identifier: NCT01194115

Biological features of placental programming

The placenta is a key organ in programming the fetus for later disease. This review outlines nine of many structural and physiological features of the placenta which are associated with adult onset chronic disease. 1) Placental efficiency relates the placental mass to the fetal mass. Ratios at the extremes are related to cardiovascular disease risk later in life. 2) Placental shape predicts a large number of disease outcomes in adults but the regulators of placental shape are not known. 3) Non-human primate studies suggest that at about mid-gestation, the placenta becomes less plastic and less able to compensate for pathological stresses. 4) Recent studies suggest that lipids have an important role in regulating placental metabolism and thus the future health of offspring. 5) Placental inflammation affects nutrient transport to the fetus and programs for later disease. 6) Placental insufficiency leads to inadequate fetal growth and elevated risks for later life disease. 7) Maternal height, fat and muscle mass are important in combination with placental size and shape in predicting adult disease. 8) The placenta makes a host of hormones that influence fetal growth and are related to offspring disease. Unfortunately, our knowledge of placental growth and function lags far behind that of other organs. An investment in understanding placental growth and function will yield enormous benefits to human health because it is a key player in the origins of the most expensive and deadly chronic diseases that humans face.

Accuracy of Sonographically Estimated Fetal Weight Near Delivery in Pregnancies Complicated With Diabetes Mellitus: Accuracy of Sonography in Diabetic Pregnancies

The purpose of this study was to evaluate the accuracy of sonographic estimations of fetal weight (FW) and signed percent error between pregnant patients with and without diabetes mellitus (DM).

A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes

Use of oral agents to treat gestational diabetes mellitus remains controversial. Recent recommendations from the Society for Maternal-Fetal Medicine assert that metformin may be a safe first-line alternative to insulin for gestational diabetes mellitus treatment and preferable to glyburide. However, several issues should give pause to the widespread adoption of metformin use during pregnancy. Fetal concentrations of metformin are equal to maternal, and metformin can inhibit growth, suppress mitochondrial respiration, have epigenetic modifications on gene expression, mimic fetal nutrient restriction, and alter postnatal gluconeogenic responses. Because both the placenta and fetus express metformin transporters and exhibit high mitochondrial activity, these properties raise important questions about developmental programming of metabolic disease in offspring. Animal studies have demonstrated that prenatal metformin exposure results in adverse long-term outcomes on body weight and metabolism. Two recent clinical randomized controlled trials in women with gestational diabetes mellitus or polycystic ovary syndrome provide evidence that metformin exposure in utero may produce a metabolic phenotype that increases childhood weight or obesity. These developmental programming effects challenge the conclusion that metformin is equivalent to insulin. Although the Society for Maternal-Fetal Medicine statement endorsed metformin over glyburide if oral agents are used, there are few studies directly comparing the 2 agents and it is not clear that metformin alone is superior to glyburide. Moreover, it should be noted that prior clinical studies have dosed glyburide in a manner inconsistent with its pharmacokinetic properties, resulting in poor glycemic control and high rates of maternal hypoglycemia. We concur with the American Diabetes Association and American Congress of Obstetricians and Gynecologists, which recommend insulin as the preferred agent, but we believe that it is premature to embrace metformin as equivalent to insulin or superior to glyburide. Due to the uncertainty of the long-term metabolic risks of either metformin or glyburide, we call for carefully controlled studies that optimize oral medication dosing according to their pharmacodynamic and pharmacokinetic properties in pregnancy, appropriately target medications based on individual patterns of hyperglycemia, and follow the offspring long-term for metabolic risk.

Pyelonephritis in Pregnancy: Prediction of Prolonged Hospitalization and Maternal Morbidity using Prognostic Scoring Systems

Objective This study aims to evaluate the usefulness of prognostic scoring systems to differentiate women admitted for pyelonephritis who develop maternal morbidity and require prolonged hospitalization. Study Design Multicenter retrospective cohort study to compare the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Modified Obstetric Early Warning System (MOEWS) to predict prolonged hospitalization (> 4 days) and composite maternal morbidity for all pregnant women admitted with pyelonephritis between 2012 to 2013. One‐way analysis of variance for continuous variables, Fishers exact test for categorical variables, and receiver operating characteristic curves were used. Results Among 123 pyelonephritis cases analyzed, 25 (20%) required prolonged hospitalization. Women with prolonged hospitalization had higher rates of composite maternal morbidity, required diagnostic imaging, and had delayed administration of intravenous antibiotics (292 ± 381 vs. 218 ± 233 min, p = 0.002). APACHE II and MOEWS scores calculated from data collected within the first 24 hours of admission had a modest ability to discriminate maternal morbidity (APACHE II: area under the curve [AUC], 0.72; 95% confidence interval [CI], 0.58‐0.86 and MOEWS: AUC, 0.71; 95% CI, 0.56‐0.85). Conclusion We observed that one in five pregnancies admitted for treatment of pyelonephritis requires hospitalization for over 4 days with significant maternal morbidities. Prognostic scoring systems may be useful clinical tools to assess these patients systematically and improve morbidity.

The influence of obesity on perinatal outcomes in pregnancies achieved with assisted reproductive technology: A population-based retrospective cohort study

Objective To determine the influence of obesity on neonatal outcomes of pregnancies resulting from assisted reproductive technology. Methods Population-based retrospective cohort study of all non-anomalous, live births in Ohio from 2007 to 2011, comparing differences in the frequency of adverse neonatal outcomes of women who conceived with assisted reproductive technology versus spontaneously conceived pregnancies and stratified by obesity status. Primary outcome was a composite of neonatal morbidities defined as ≥1 of the following: neonatal death, Apgar score of <7 at 5 min, assisted ventilation, neonatal intensive care unit admission, or transport to a tertiary care facility. Results Rates of adverse neonatal outcomes were significantly higher for assisted reproductive technology pregnancies than spontaneously conceived neonates; non-obese 25% versus 8% and obese 27% versus 10%, p < 0.001. Assisted reproductive technology was associated with a similar increased risk for adverse outcomes in both obese (adjusted odds ratio (aOR): 1.33, 95% confidence interval (CI): 1.11–1.59) and non-obese women (aOR: 1.34, 95% CI: 1.18–1.51) even after adjustment for coexisting risk factors. This increased risk was driven by higher preterm births in assisted reproductive technology pregnancies; obese (aOR: 1.06, 95% CI: 0.86–1.31) and non-obese (aOR: 1.15, 95% CI: 1.00–1.32). Discussion Assisted reproductive technology is associated with a higher risk of adverse neonatal outcomes. Obesity does not appear to adversely modify perinatal risks associated with assisted reproductive technology.

Gestational age-specific neonatal morbidity among pregnancies complicated by advanced maternal age: a population-based retrospective cohort study

Abstract Objective: Compare significant neonatal morbidity frequency differences in advanced maternal age (AMA) versus non-AMA pregnancies, assessing which gestational week is associated with the lowest morbidity risk. Methods: Population-based retrospective cohort study. Adverse neonatal outcome frequency differences were stratified by each week of gestation. Multivariate logistic regression estimated the relative risk (RR) of composite neonatal morbidity for women aged 35–39, 40–44, 45–49 and 50–55 versus 18–34 years, adjusted sequentially for relevant risk factors. Results: Neonatal morbidity decreased with each advancing week of term gestation, lowest at 39 weeks for all the groups. Adverse neonatal outcome risk for births to AMA women increased at 40 weeks: 35–39 years adjRR 1.12 [1.01–1.24] and ≥40 years 1.24 [1.01–1.52]. Each older maternal age category had increased risk for overall neonatal morbidity: 35–39 years adjRR 1.11 [95% CI 1.08–1.15], 40–44 years 1.21 [95% CI 1.14–1.29] and 45–49 years 1.34 [95% CI 1.05–1.69]. Conclusions: Lowest neonatal morbidity risk is at 39-week gestation with a significantly increased risk observed thereafter, especially in women ≥40 years.