Phthalate and phthalate replacement concentrations in relationship to adiposity in a multi-racial cohort of children.

BACKGROUND/OBJECTIVE: Phthalates and phthalate replacements are used in multiple everyday products, making many of them bioavailable to children. Experimental studies suggest that phthalates and their replacements may be obesogenic, however, epidemiologic studies remain inconsistent. Therefore, our objective was to examine the association between phthalates, phthalate replacements and childhood adiposity/obesity markers in children. SUBJECTS/METHODS: A cross-sectional study was conducted in 630 racial/ethnically diverse children ages 4-8 years. Urinary oxidative metabolites of DINCH and DEHTP, three low molecular weight (LMW) phthalates, and eleven high molecular weight (HMW) phthalates were measured. Weight, height, waist circumference and % body fat were measured. Composite molar sum groups (nmol/ml) were natural log-transformed. Linear regression models adjusted for urine specific gravity, sex, age, race-ethnicity, birthweight, breastfeeding, reported activity level, mother's education and pre-pregnancy BMI. RESULTS: All children had LMW and HMW phthalate metabolites and 88% had DINCH levels above the limit of detection. One unit higher in the log of DINCH was associated with 0.106 units lower BMI z-score [ß = -0.106 (95% CI: -0.181, -0.031)], 0.119 units lower waist circumference z-score [ß = -0.119 (95% CI: -0.189, -0.050)], and 0.012 units lower percent body fat [ß = -0.012 (95% CI: -0.019, -0.005)]. LMW and HMW group values were not associated with adiposity/obesity. CONCLUSIONS: We report an inverse association between child urinary DINCH levels, a non-phthalate plasticizer that has replaced DEHP in several applications, and BMI z-score, waist circumference z-score and % body fat in children. Few prior studies of phthalates and their replacements in children have been conducted in diverse populations. Moreover, DINCH has not received a great deal of attention or regulation, but it is a common exposure. In summary, understanding the ubiquitous nature of these chemical exposures and ultimately their sources will contribute to our understanding of their relationship with obesity.

Mean Arterial Pressure and Neonatal Outcomes in Pregnancies Complicated by Mild Chronic Hypertension.

OBJECTIVE: To estimate the association between mean arterial pressure during pregnancy and neonatal outcomes in participants with chronic hypertension using data from the CHAP (Chronic Hypertension and Pregnancy) trial. METHODS: A secondary analysis of the CHAP trial, an open-label, multicenter randomized trial of antihypertensive treatment in pregnancy, was conducted. The CHAP trial enrolled participants with mild chronic hypertension (blood pressure [BP] 140-159/90-104 mm Hg) and singleton pregnancies less than 23 weeks of gestation, randomizing them to active treatment (maintained on antihypertensive therapy with a goal BP below 140/90 mm Hg) or standard treatment (control; antihypertensives withheld unless BP reached 160 mm Hg systolic BP or higher or 105 mm Hg diastolic BP or higher). We used logistic regression to measure the strength of association between mean arterial pressure (average and highest across study visits) and to select neonatal outcomes. Unadjusted and adjusted odds ratios (per 1-unit increase in millimeters of mercury) of the primary neonatal composite outcome (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage grade 3 or 4) and individual secondary outcomes (neonatal intensive care unit admission [NICU], low birth weight [LBW] below 2,500 g, and small for gestational age [SGA]) were calculated. RESULTS: A total of 2,284 participants were included: 1,155 active and 1,129 control. Adjusted models controlling for randomization group demonstrated that increasing average mean arterial pressure per millimeter of mercury was associated with an increase in each neonatal outcome examined except NEC, specifically neonatal composite (adjusted odds ratio [aOR] 1.12, 95% CI, 1.09-1.16), NICU admission (aOR 1.07, 95% CI, 1.06-1.08), LBW (aOR 1.12, 95% CI, 1.11-1.14), SGA below the fifth percentile (aOR 1.03, 95% CI, 1.01-1.06), and SGA below the 10th percentile (aOR 1.02, 95% CI, 1.01-1.04). Models using the highest mean arterial pressure as opposed to average mean arterial pressure also demonstrated consistent associations. CONCLUSION: Increasing mean arterial pressure was positively associated with most adverse neonatal outcomes except NEC. Given that the relationship between mean arterial pressure and adverse pregnancy outcomes may not be consistent at all mean arterial pressure levels, future work should attempt to further elucidate whether there is an absolute threshold or relative change in mean arterial pressure at which fetal benefits are optimized along with maternal benefits. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.

Prenatal medication use in a prospective pregnancy cohort by pre-pregnancy obesity status.

BACKGROUND: The association between obesity (body mass index (BMI) ≥ 30 kg/m2) and pattern of medication use during pregnancy in the United States is not well-studied. Higher pre-pregnancy BMI may be associated with increases or decreases in medication use across pregnancy as symptoms (e.g. reflux) or comorbidities (e.g. gestational diabetes) requiring treatment that may be associated with higher BMI could also change with advancing gestation. OBJECTIVES: To determine whether prenatal medication use, by the number and types of medications, varies by pre-pregnancy obesity status. METHODS: In a secondary data analysis of a racially/ethnically diverse prospective cohort of pregnant women with low risk for fetal abnormalities enrolled in the first trimester of pregnancy and followed to delivery (singleton, 12 United States clinical sites), free text medication data were obtained at enrollment and up to five follow-up visits and abstracted from medical records at delivery. RESULTS: In 436 women with obesity and 1750 women without obesity (pre-pregnancy BMI, 19-29.9 kg/m2), more than 70% of pregnant women (77% of women with and 73% of women without obesity) reported taking at least one medication during pregnancy, respectively (adjusted risk ratio (aRR)=1.10, 95% confidence interval (CI)=1.01, 1.20), with 81% reporting two and 69% reporting three or more. A total of 17 classes of medications were identified. Among medication classes consumed by at least 5% of all women, the only class that differed between women with and without obesity was hormones and synthetic substitutes (including steroids, progesterone, diabetes, and thyroid medications) in which women with obesity took more medications (11 vs. 5%, aRR = 1.9, 95% CI = 1.38, 2.61) compared to women without obesity. Within this class, a higher percentage of women with obesity took diabetes medications (2.3 vs. 0.7%) and progesterone (3.4 vs. 1.3%) than their non-obese counterparts. Similar percentages of women with and without obesity reported consuming medications in the remaining medication classes including central nervous system agents (50 and 46%), gastrointestinal drugs (43 and 40%), anti-infective agents (23 and 21%), antihistamines (20 and 17%), autonomic drugs (10 and 9%), and respiratory tract agents (7 and 6%), respectively (p > 0.05 for all adjusted comparisons). There were no differences in medication use by obesity status across gestation. Since the study exclusion criteria limited the non-obese group to women without thyroid disease, in a sensitivity analysis we excluded all women who reported thyroid medication intake and still a higher proportion of women with obesity took the hormones and synthetic substitutes class compared to women without obesity. CONCLUSION: Our findings suggest that pre-pregnancy obesity in otherwise healthy women is associated with a higher use of only selected medications (such as diabetes medications and progesterone) during pregnancy, while the intake of other more common medication types such as analgesics, antibiotics, and antacids does not vary by pre-pregnancy obesity status. As medication safety information for prenatal consumption is insufficient for many medications, these findings highlight the need for a more in-depth examination of factors associated with prenatal medication use.

Placental Location in Maternal-Fetal Surgery for Myelomeningocele.

INTRODUCTION: Uterine incision based on the placental location in open maternal-fetal surgery (OMFS) has never been evaluated in regard to maternal or fetal outcomes. OBJECTIVE: The aim of this study was to investigate whether an anterior placenta was associated with increased rates of intraoperative, perioperative, antepartum, obstetric, or neonatal complications in mothers and babies who underwent OMFS for fetal myelomeningocele (fMMC) closure. METHODS: Data from the international multicenter prospective registry of patients who underwent OMFS for fMMC closure (fMMC Consortium Registry, December 15, 2010-June 31, 2019) was used to compare fetal and maternal outcomes between anterior and posterior placental locations. RESULTS: The placental location for 623 patients was evenly distributed between anterior (51%) and posterior (49%) locations. Intraoperative fetal bradycardia (8.3% vs. 3.0%, p = 0.005) and performance of fetal resuscitation (3.6% vs. 1.0%, p = 0.034) occurred more frequently in cases with an anterior placenta when compared to those with a posterior placenta. Obstetric outcomes including membrane separation, placental abruption, and spontaneous rupture of membranes were not different among the 2 groups. However, thinning of the hysterotomy site (27.7% vs. 17.7%, p = 0.008) occurred more frequently in cases of an anterior placenta. Gestational age (GA) at delivery (p = 0.583) and length of stay in the neonatal intensive care unit (p = 0.655) were similar between the 2 groups. Fetal incision dehiscence and wound revision were not significantly different between groups. Critical clinical outcomes including fetal demise, perinatal death, and neonatal death were all infrequent occurrences and not associated with the placental location. CONCLUSIONS: An anterior placental location is associated with increased risk of intraoperative fetal resuscitation and increased thinning at the hysterotomy closure site. Individual institutional experiences may have varied, but the aggregate data from the fMMC Consortium did not show a significant impact on the GA at delivery or maternal or fetal clinical outcomes.

Association between gestational PFAS exposure and Children's adiposity in a diverse population.

Perfluoroalkyl substances (PFAS) are widely distributed suspected obesogens that cross the placenta. However, few data are available to assess potential fetal effects of PFAS exposure on children's adiposity in diverse populations. To address the data gap, we estimated associations between gestational PFAS concentrations and childhood adiposity in a diverse mother-child cohort. We considered 6 PFAS in first trimester blood plasma, measured using ultra-high-performance liquid chromatography with tandem mass spectrometry, collected from non-smoking women with low-risk singleton pregnancies (n = 803). Body mass index (BMI), waist circumference (WC), fat mass, fat-free mass, and % body fat were ascertained in 4-8 year old children as measures of adiposity. We estimated associations of individual gestational PFAS with children's adiposity and overweight/obesity, adjusted for confounders. There were more non-Hispanic Black (31.7 %) and Hispanic (42.6 %) children with overweight/obesity, than non-Hispanic white (18.2 %) and Asian/Pacific Islander (16.4 %) children (p < 0.0001). Perfluorooctane sulfonate (PFOS; 5.3 ng/mL) and perfluorooctanoic acid (2.0 ng/mL) had the highest median concentrations in maternal blood. Among women without obesity (n = 667), greater perfluoroundecanoic acid (PFUnDA) was associated with their children having higher WC z-score (ß = 0.08, 95%CI: 0.01, 0.14; p = 0.02), fat mass (ß = 0.55 kg, 95%CI: 0.21, 0.90; p = 0.002), and % body fat (ß = 0.01 %; 95%CI: 0.003, 0.01; p = 0.004), although the association of PFUnDA with fat mass attenuated at the highest concentrations. Among women without obesity, the associations of PFAS and their children's adiposity varied significantly by self-reported race-ethnicity, although the direction of the associations was inconsistent. In contrast, among the children of women with obesity, greater, PFOS, perfluorononanoic acid, and perfluorodecanoic acid concentrations were associated with less adiposity (n = 136). Our results suggest that specific PFAS may be developmental obesogens, and that maternal race-ethnicity may be an important modifier of the associations among women without obesity.

Subsequent pregnancy outcomes after open maternal-fetal surgery for myelomeningocele.

BACKGROUND: Open maternal-fetal surgery for fetal myelomeningocele results in reduction in neonatal morbidity related to spina bifida but may be associated with fetal, neonatal, and maternal complications in subsequent pregnancies. OBJECTIVE: The objective of this study was to ascertain obstetric risk in subsequent pregnancies after open maternal-fetal surgery for fetal myelomeningocele closure. STUDY DESIGN: An international multicenter prospective observational registry created to track and report maternal, obstetric, fetal/neonatal, and subsequent pregnancy outcomes following open maternal-fetal surgery for fetal myelomeningocele was evaluated for subsequent pregnancy outcome variables. Institutional Review Board approval was obtained for the registry. RESULTS: From 693 cases of open maternal-fetal surgery for fetal myelomeningocele closure entered into the registry, 77 subsequent pregnancies in 60 women were identified. The overall live birth rate was 96.2%, with 52 pregnancies delivering beyond 20 weeks gestational age and median gestational age at delivery of 37 (36.3-37.1) weeks. The uterine rupture rate was 9.6% (n = 5), resulting in 2 fetal deaths. Maternal transfusion was required in 4 patients (7.7%). CONCLUSION: The risk of uterine rupture or dehiscence in subsequent pregnancies with associated fetal morbidity after open maternal-fetal surgery is significant, but is similar to that reported for subsequent pregnancies after classical cesarean deliveries. Future pregnancy considerations should be included in initial counseling for women contemplating open maternal-fetal surgery.

Adiponectin concentration in mid-trimester amniotic fluid varies with the α-amylase level and maternal and neonatal outcomes.

OBJECTIVE: Factors influencing intraamniotic adiponectin levels and their functional significance remain incompletely elucidated. We prospectively measured adiponectin in amniotic fluid and identified its associations with maternal parameters, mediators in amniotic fluid and pregnancy outcomes. STUDY DESIGN: Mid-trimester amniotic fluid from 571 women was tested for adiponectin, interleukin (IL)-6, IL-8 and α-amylase by enzyme-linked immunosorbant assay (ELISA), after which clinical data were obtained. Correlations between adiponectin and clinical or laboratory variables were analyzed by the Kruskal-Wallis, Mann-Whitney and Spearman rank correlation tests. RESULTS: As compared to median levels in 462 women with a term delivery (7.8 ng/mL), adiponectin was elevated in 14 women who subsequently developed preterm premature rupture of membranes (pPROM) (17.3 ng/mL) and 24 women with an iatrogenic preterm birth (IPTB) (13.9 ng/mL) (P=0.0003), but not in 30 women who subsequently had a spontaneous preterm birth with intact membranes (8.1 ng/mL) (P>0.05). Median adiponectin was also elevated in 13 women whose babies developed fetal growth restriction (FGR) (20.6 ng/mL) (P=0.0055) and in 22 women whose babies had respiratory distress syndrome (RDS) (23.0 ng/mL) (P<0.0001). The adiponectin concentration was positively correlated with amylase (P=0.0089) and inversely correlated with maternal body mass index (P=0.0045). CONCLUSION: Adiponectin is a component of mid-trimester amniotic fluid and its concentration varies with maternal body mass index and subsequent development of pPROM, IPTB, FGR and RDS.

The North American Fetal Therapy Network consensus statement: prenatal surveillance of uncomplicated monochorionic gestations.

Because they share a common placenta, monochorionic gestations are subject to unique pregnancy complications that can threaten the life and health of both fetuses and therefore impose a disproportionate disease burden on overall perinatal morbidity and mortality. Early detection of these unique disease processes may allow for prompt referral to a regional treatment center, comprehensive counseling, and better patient outcomes. The North American Fetal Therapy Network is a consortium of 30 medical institutions in the United States and Canada with established expertise in fetal surgery and other forms of multidisciplinary care for complex fetal disorders. The goal of this publication is to briefly describe complications of monochorionic gestations and to provide multidisciplinary, evidence-based, and consensus-driven recommendations for surveillance of uncomplicated monochorionic gestations.

Placental chorioangioma: literature review.

Placental chorioangioma is the most common benign non-trophoblastic tumor of the placenta. It is derived from primitive chorionic mesenchyme and is typically vascular. Placenta chorioangiomas occur in approximately 1% of pregnancies. Most placental chorioangiomas are small and are not clinically important. However, those measuring more than 4-5 cm in diameter may be associated with maternal and fetal complications. Early diagnosis, close prenatal surveillance and appropriate intervention may prevent severe complications and perinatal mortality caused by chorioangioma. Here we review the incidence, prenatal diagnosis, complications, the pathophysiological mechanisms of maternal and fetal complications, and the therapeutic possibilities in pregnancies complicated by placental chorioangiomas.

Laser ablation of placental anastomoses in twin-to-twin transfusion syndrome: preoperative predictors of death by recursive partitioning.

OBJECTIVE: The aim of this study was to develop a simple clinical algorithm for prediction of donor and recipient death using 'yes'or 'no' questions through the process of recursive partitioning for patients undergoing laser therapy for twin to twin transfusion syndrome (TTTS). The intent was to identify a subset of patients with very high specificity to whom clinical decisions would be simplified. METHOD: Secondary analysis of data retrospectively collected from laser procedures was performed for TTTS at NAFTNet centers from 2002 to 2009. Preoperative factors associated with donor and recipient death were identified by recursive partitioning regression analysis. Classification And Regression Trees (CARTs) were developed to refine specificity for prediction of death. RESULTS: There were 466 TTTS patients from eight centers. CARTs were obtained for prediction of donor death. Improved specificity was achieved through recursive partitioning as demonstrated in receiver operator characteristic curves for prediction of death of the donor. There was less than optimal predictive ability for prediction of death in the recipient, as demonstrated by lack of generation of CARTs. CONCLUSION: Recursive partitioning improves the specificity and refines the prediction of donor fetal and neonatal demise in TTTS treated with laser therapy. This has the potential to improve therapeutic choices and refine counseling regarding outcomes.

Fatty acid composition of mid-trimester amniotic fluid in women of different ethnicities.

OBJECTIVE: To determine whether the fatty acid composition of mid-trimester amniotic fluid differs by ethnicity and pregnancy outcome. METHODS: Fatty acid composition was analyzed by gas chromatography in 198 women undergoing amniocentesis at 15-19 weeks gestation. Cytokine levels were determined by ELISA in a subgroup of 52 subjects. RESULTS: The major fatty acids detected were palmitic acid (31.8%) and stearic acid (31.5%). The n-6 polyunsaturated fatty acids (PUFA), linoleic acid (LA, 18:2) and arachidonic acid (AA, 20:4), were 11.3%, while the n-3 PUFA fatty acids, α linolenic acid (ALA, 18:3) and docosahexaenoic acid (DHA, 22:6), were 3.8% of the total. Palmitic acid was a higher percentage in Asians (40.5%) and Whites (34.5%) than in Blacks (22.2%) and Hispanics (23.7%) (p ≤ 0.0012). Oleic acid (18:1 n-9) was a higher percentage in Blacks (12.2%) and Hispanics (12.1%) than in Whites (9.2%) or Asians (7.5%) (≤0.0002). LA and AA were higher in Blacks (9.0%, 5.4%) and Hispanics (8.6%, 4.1%) than in Whites (6.1%, 3.7%) and Asians (5.5%, 2.9%) (p ≤ 0.0002). DHA did not differ among the ethnic groups or according to pregnancy outcome. A reduced palmitic acid percentage was identified in the six women with preeclampsia (p = 0.0233). Tumor necrosis factor-α levels were inversely proportional to the palmitic acid percentage (p = 0.0275) and positively associated with the percentages of stearic (18:0) (p = 0.0132) and oleic (p = 0.0290) acids. CONCLUSIONS: Amniotic fluid fatty acid composition differed among the ethnic groups and may influence inflammatory mediator production and susceptibility to preeclampsia.

Influence of mid-trimester amniotic fluid on endogenous and lipopolysaccharide-mediated responses of mononuclear lymphoid cells.

PROBLEM We evaluated the influence of amniotic fluid (AF) on immune mediator production by mononuclear leukocytes. METHOD OF STUDY Thirty mid-gestation AFs were incubated with peripheral blood mononuclear cells (PBMCs) in the presence or absence of lipopolysaccharide (LPS). Supernatants were tested for interleukin (IL) - 6, 10, 12, 23, tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein (MCP)-1. RESULTS Endogenous mediator production was minimal or non-detectable. AF stimulated endogenous MCP-1, IL-6 and TNF-α release. In the presence of LPS, production of MCP-1 and IL-10 by PBMCs was enhanced eight- to ninefold by AF. Release of IL-6 and IL-23 was enhanced less than twofold by the addition of AF while TNF-α production was unchanged. AF-stimulated mediator production was similar irrespective of pregnancy outcome. CONCLUSION Selective AF stimulation of LPS-mediated MCP-1 and IL-10 release may be a mechanism to promote antibody production and the influx of phagocytic cells to engulf pathogens while downregulating the production of pro-inflammatory cytokines.

Twin-to-twin transfusion syndrome (TTTS).

Twin-to-twin transfusion syndrome (TTTS) is a severe complication of monochorionic (MC) twin pregnancies, characterized by the development of unbalanced chronic blood transfer from one twin, defined as donor twin, to the other, defined as recipient, through placental anastomoses. If left untreated, TTTS is associated with very high perinatal mortality and morbidity rates, due to a combination of fetal and/or obstetric complications. The reported prevalence is 10-15% of all MC twins, or about 1 in 2000 pregnancies. This consensus document reviews available evidence and offers practical guidance to clinicians by providing recommendations on various aspects concerning diagnosis and management of TTTS.

Preoperative predictors of death in twin-to-twin transfusion syndrome treated with laser ablation of placental anastomoses.

OBJECTIVE: To determine preoperative predictive factors for donor and recipient death after laser ablation of placental vessels in twin-to-twin transfusion syndrome. STUDY DESIGN: Retrospective analysis of North American Fetal Therapy Network center laser procedures, 2002-2009. Factors associated with donor and recipient death were identified by regression analysis. RESULTS: There were 466 patients from 8 centers. Factors significantly associated with donor fetal death were low donor estimated fetal weight (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.55-0.87) and reversed end diastolic velocity in the umbilical artery (OR, 4.0; 95% CI, 1.54-10.2); for recipient fetal death-low recipient estimated fetal weight (OR, 0.65; 95% CI, 0.44-0.95), recipient reversed "a" wave in the ductus venosus (OR, 2.39; 95% CI, 1.27-4.51) and hydrops (OR, 3.7; 95% CI, 1.1-12.7); for recipient neonatal death-low donor estimated fetal weight (OR, 0.54; 95% CI, 0.30-0.95), high recipient estimated fetal weight (OR, 1.55; 95% CI, 1.06-2.26) and recipient reversed end diastolic velocity in the umbilical artery (OR, 7.8; 95% CI, 1.03-59.3). CONCLUSION: Preoperative findings predict fetal and neonatal demise in twin-to-twin transfusion syndrome treated with laser therapy.

A new obstetrical polyurethane versus stainless steel forceps: a comparison of forces generated to the base of the fetal skull during simulated deliveries.

BACKGROUND: Decreasing the maximum force applied during traction to the base of the fetal skull using a less rigid polyurethane forceps is the basis of this study. Our hypothesis was that less force would be generated with polyurethane forceps than with steel forceps. OBJECTIVE: To test a new soft polyurethane obstetrical forceps for maximal force generated to the base of the skull during simulated occiput anterior deliveries and to compare this to a similar shaped steel forceps. METHODS: After designing a prototype polyurethane forceps, we used a pelvic manikin model and a fetal manikin model. Force and load sensors were attached at the inner tips of the distal forceps blade. A Tekscan 201 (accurate for measuring 0-25 pounds of force) 0.0008 inches flexible printed circuit was used that measured contact forces. Forceps with an attached calibrated sensor were applied to the fetal head while inside the pelvic model. RESULTS: The median maximum traction force at the base of the fetal skull was 4.60 pounds (range 4.3-4.62) for polyurethane forceps vs. 9.52 pounds (range 9.22-9.52) for steel forceps (P=0.027). CONCLUSION: The polyurethane forceps applied 50% less overall mechanical force than the steel forceps at the tip of the forceps and base of the skull during simulated occiput anterior outlet deliveries.

An interleukin-23 binding protein in mid-trimester amniotic fluid.

PROBLEM: The binding of mid-trimester amniotic fluid to cytokines was evaluated. METHOD OF STUDY: Purified tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-10, IL-12, and IL-23 were incubated with amniotic fluid from 25 women undergoing a mid-trimester amniocentesis, or with bovine serum albumin or saline, and cytokine binding to monoclonal antibodies was quantitated by ELISA. Aliquots of amniotic fluid were heated to 95 degrees C for 15 min and then retested for IL-23 binding. The effect of amniotic fluid dilution on IL-23 quantitation was evaluated. RESULTS: All amniotic fluids had a negligible effect on TNF-alpha, IL-10, and IL-12 detection. In marked contrast, pre-incubation with amniotic fluid from each subject reduced the subsequent ability to detect IL-23 by >50%. The extent of inhibition was directly proportional to the amniotic fluid dilution and was markedly reduced following heating at 95 degrees C for 15 min. Amniotic fluids from White, Black, Asian, East Indian, and Hispanic women were equally effective. CONCLUSION: Interleukin-23 and IL-12 share a common p40 subunit and no inhibition of IL-12 was apparent. It appeared that a component of mid-trimester amniotic fluid specifically interacts with the p19 subunit unique to IL-23. Mid-trimester amniotic fluid reactivity with IL-23 may be a mechanism to limit intra-amniotic neutrophil-derived inflammation.

Endogenous adenosine down-modulates mid-trimester intraamniotic tumor necrosis factor-alpha production.

PROBLEM: To determine whether adenosine in amniotic fluid down-regulates pro-inflammatory cytokine production. METHOD OF STUDY: Mid-trimester amniotic fluid from 21 women was incubated ex vivo in the presence or absence of human adenosine deaminase, the enzyme that irreversibly degrades adenosine. After 24 hr, supernatants were assayed by ELISA for tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-10. Clinical parameters were obtained after completion of laboratory testing. RESULTS: Inclusion of adenosine deaminase resulted in a median increase in TNF-alpha production from 0.9 to 7.3 pg/mL (P = 0.0014). IL-6 production exhibited a non-significant median increase from <2.0 to 53.0 pg/mL (P = 0.0780). Median IL-10 production increased slightly from a median of <0.2 to 1.3 pg/mL. Adenosine deaminase-stimulated TNF-alpha production was proportional to parity and unrelated to gestational age, time of delivery, maternal age or indication for amniocentesis. CONCLUSION: Adenosine deaminase treatment increases TNF-alpha production by ex vivo-cultured amniotic fluid. Adenosine contributes to immune modulation in the amniotic cavity.

Hyaluronan modulates pro-inflammatory immune activity in the mid-trimester amniotic cavity.

Hyaluronan (HA), which comprises repeating disaccharides of D-glucuronic acid and N-acetyl-glucosamine, is a component of the extracellular matrix. In response to infection or tissue injury HA is released into the extracellular milieu where it modulates immune activity. We hypothesized that HA is present in mid-trimester amniotic fluid and contributes to immune regulation at that site. Amniotic fluid from 392 women undergoing a mid-trimester amniocentesis were tested for HA by ELISA. Amniotic fluids from 41 women were also cultured ex vivo in the presence or absence of lipopolysaccharide (LPS). Supernatants were collected after 24h and tested for tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-10 by ELISA. Clinical parameters were obtained after completion of laboratory testing. All amniotic fluids were positive for HA. The median (range) concentration was 3.2 (0.6-91.7) microg/mg amniotic fluid protein. Women with at least 2 prior pregnancies and a history of > or =2 spontaneous abortions had a higher median HA concentration than did previously pregnant women with 0-1 prior abortions. Women who conceived following in vitro fertilization also had an elevated median amniotic fluid HA compared to women with spontaneous conceptions. Both endogenous and LPS-induced TNFalpha production by ex vivo cultured amniotic fluid cells, but not IL-10 production, was inversely proportional to the amniotic fluid HA concentration. In conclusion, intraamniotic HA levels are elevated in pregnancies at risk for adverse outcome and HA may be a component of the fetal response to immune alterations that threaten gestation.

Gelsolin down-regulates lipopolysaccharide-induced intraamniotic tumor necrosis factor-alpha production in the midtrimester of pregnancy.

OBJECTIVE: The purpose of this study was to identify gelsolin in midtrimester amniotic fluid and evaluate its interaction with lipopolysaccharide (LPS). STUDY DESIGN: Supernatants from 40 midtrimester amniotic fluid samples were incubated with Escherichia coli LPS, and gelsolin binding was measured by enzyme-linked immunosorbent assay. Unfractionated aliquots of 25 of the fluids were cultured ex vivo for 24 hours in the presence of LPS and supernatants tested for tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 production, and the influence of antigelsolin antibody was evaluated. RESULTS: Each amniotic fluid was positive for gelsolin that bound to LPS. LPS-induced TNF-alpha production was inversely proportional to the amniotic fluid concentrations of LPS-bound gelsolin (r = -0.5047; P = .006). Preincubation with monoclonal antibody to gelsolin led to an increase in LPS-induced TNF-alpha production (P = .01). There was no relationship between gelsolin and IL-10 production. CONCLUSION: Gelsolin is present in midtrimester amniotic fluid, binds to LPS, and inhibits the induction of TNF-alpha.