Syphilis Treatment Among People Who Are Pregnant in Six U.S. States, 2018-2021.

OBJECTIVE: To describe syphilis treatment status and prenatal care among people with syphilis during pregnancy to identify missed opportunities for preventing congenital syphilis. METHODS: Six jurisdictions that participated in SET-NET (Surveillance for Emerging Threats to Pregnant People and Infants Network) conducted enhanced surveillance among people with syphilis during pregnancy based on case investigations, medical records, and linkage of laboratory data with vital records. Unadjusted risk ratios (RRs) were used to compare demographic and clinical characteristics by syphilis stage (primary, secondary, or early latent vs late latent or unknown) and treatment status during pregnancy (adequate per the Centers for Disease Control and Prevention's "Sexually Transmitted Infections Treatment Guidelines, 2021" vs inadequate or not treated) and by prenatal care (timely: at least 30 days before pregnancy outcome; nontimely: less than 30 days before pregnancy outcome; and no prenatal care). RESULTS: As of September 15, 2023, of 1,476 people with syphilis during pregnancy, 855 (57.9%) were adequately treated and 621 (42.1%) were inadequately treated or not treated. Eighty-two percent of the cohort received timely prenatal care. Although those with nontimely or no prenatal care were more likely to receive inadequate or no treatment (RR 2.50, 95% CI, 2.17-2.88 and RR 2.73, 95% CI, 2.47-3.02, respectively), 32.1% of those with timely prenatal care were inadequately or not treated. Those with reported substance use or a history of homelessness were nearly twice as likely to receive inadequate or no treatment (RR 2.04, 95% CI, 1.82-2.28 and RR 1.83, 95% CI, 1.58-2.13, respectively). CONCLUSION: In this surveillance cohort, people without timely prenatal care had the highest risk for syphilis treatment inadequacy; however, almost a third of people who received timely prenatal care were not adequately treated. These findings underscore gaps in syphilis screening and treatment for pregnant people, especially those experiencing substance use and homelessness, and the need for systems-based interventions, such as treatment outside of traditional prenatal care settings.

Candidate Gene and MicroRNA Expression in Fetal Membranes and Preterm Delivery Risk.

We investigated candidate gene and microRNA (miRNA) expression in amnion and chorion in relation to risk of preterm delivery (PTD). Amnion and chorion were separated from placenta and collected at delivery from participants who delivered at term (N = 10) and from participants who delivered preterm following spontaneous labor (sPTL-PTD; N = 10), premature rupture of membranes (PPROM-PTD; N = 10), and preeclampsia (PE-PTD; N = 10). Expression of genes (metalloproteinase [MMP] 2, MMP-9, and tissue inhibitors of MMP-1) and miRNAs (miR-199a*, -202*, -210, -214, -223, and -338) was profiled using quantitative real-time polymerase chain reaction approaches. Adjusted multinomial logistic regression models were used to calculate relative risk ratios (RRR), 95% confidence intervals, and P values. Among controls, the expression of miR-199a*, -202*, and -214 was lower in the amnion compared with their expression in the chorion, whereas the expression of miR-210 was higher in the amnion compared with its expression in the chorion (all P values < .05). In the amnion, MMP-9 expression was associated with PTD risk (overall P value = .0092), and MMP-9 expression was positively associated with the risk of PPROM-PTD (RRR: 31.10) and inversely associated with the risk of PE-PTD (RRR:6.55e-6), although individual associations were not statistically significant. In addition, in the amnion, the expression of miR-210 (RRR: 0.45; overall P value = .0039) was inversely associated with the risk of PE-PTD, and miR-223 was inversely associated with all subtypes of PTD (overall P value = .0400). The amnion and chorion differ in their miRNA expression. The expression of MMP-9, miR-210, and -223 in the amnion is associated with PTD risk.

Early Pregnancy Maternal Hepatocyte Growth Factor and Risk of Gestational Diabetes.

AIMS: We investigated associations of serum hepatocyte growth factor (HGF) with risk of gestational diabetes mellitus (GDM). We also examined whether pre-pregnancy overweight/obesity status or leisure-time physical activity (LTPA) modify these associations. METHODS: In a nested case-control study (173 GDM cases and 187 controls) among participants of a pregnancy cohort, early pregnancy (16 weeks of gestation, on average) serum HGF was measured using enzyme-linked immunoassay. GDM was diagnosed using American Diabetes Association guidelines. Logistic regression was used to calculate odd ratios (ORs) and 95% confidence intervals (CI). Effect modifications by pre-pregnancy overweight/obesity status or LTPA during pregnancy were examined using stratified analyses and interaction terms. RESULTS: Overall, we did not find significant associations of serum HGF with GDM risk (p-value> 0.05). However, compared with women who had low serum HGF concentrations (<2.29 ng/ml), women with high serum HGF concentrations (≥ 2.29 ng/ml) had 3.8-fold (95%CI: 1.30-10.98) and 4.5-fold (95%CI: 1.28-15.80) higher GDM risk among women who were overweight/obese, pre-pregnancy (body mass index≥25 kg/m2), or did not report LTPA, respectively. These associations were not present among women who were not overweight/obese (interaction p=0.05) or reported LTPA (interaction p=0.05). CONCLUSION: Overweight/obesity status and LTPA may modify associations of early pregnancy serum HGF with subsequent GDM risk.

Mitochondrial DNA copy number and oxidative DNA damage in placental tissues from gestational diabetes and control pregnancies: a pilot study.

BACKGROUND: Available evidence supports the role of reactive oxygen species in the pathogenesis of placental insufficiency, gestational diabetes mellitus (GDM), and other pregnancy complications. Abnormal placental mitochondrial function resulting from reactive oxygen species may also be an important precedent of adverse perinatal outcomes. METHODS: We investigated the association of placental oxidative stress with placental mitochondrial DNA (mtDNA) copy number, an indicator of placental mitochondrial density and possible mitochondrial dysfunction, using samples collected from GDM cases and controls. 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, was measured in placentas of 19 GDM cases and 21 controls using a competitive immunoassay. Placental mtDNA copy number was determined using real-time quantitative PCR. Bivariate and multivariable linear regression procedures were used to evaluate associations of these two biomarkers. RESULTS: Placental DNA oxidation was positively associated with mtDNA copy number in both GDM and control placentas. After adjusting for maternal age, pre-pregnancy body mass index and gestational age at delivery, mtDNA copy number increased (beta = 67.0; 95% CI 27.8 - 106.2, p = 0.001) for every 0.1 ng/microg increase of placental 8-OHdG among GDM cases and controls. CONCLUSIONS: These cross sectional data suggest an association of placental mtDNA copy number with oxidative stress. The consequences of placental oxidative stress and mitochondrial dysfunction on the course and outcomes of pregnancy remain to be elucidated in larger prospective studies.

Association of retinol binding protein 4 with risk of gestational diabetes.

AIM: We investigated association of maternal retinol binding protein 4 (RBP4) with risk of gestational diabetes (GDM). METHODS: GDM cases (N=173) and controls (N=187) were selected from among participants of a cohort study of risk factors of pregnancy complications. Early pregnancy (16 weeks on average) serum RBP4 concentration was measured using an ELISA-based immunoassay. Logistic regression was used to estimate unadjusted and adjusted odds ratios (ORs/aORs) and 95% confidence intervals (95%CI). RESULTS: Mean serum RBP4 was significantly higher among GDM cases compared with controls (47.1 vs. 41.1 µg/ml, respectively; p-value <0.05). Participants in the highest quartile for serum RBP4 had a 1.89-fold higher risk of GDM compared with participants in the lowest quartile (95%CI: 1.05-3.43). However, this relationship did not reach statistical significance after adjustment for confounders (aOR: 1.54; 95%CI: 0.82-2.90). Women who were ≥35 years old and who had high RBP4 (≥38.3 µg/ml, the median) had a 2.31-fold higher risk of GDM compared with women who were <35 years old and had low RBP4 (<38.3 µg/ml) (aOR: 2.31; 95%CI: 1.26-4.23; p-value for interaction=0.021). CONCLUSION: Overall, there is modest evidence of a positive association of early pregnancy elevated RBP4 concentration with increased GDM risk, particularly among women with advanced age.

Maternal plasma advanced glycation end products concentrations in response to oral 50-gram glucose load in mid-pregnancy: a pilot study.

BACKGROUND: Accumulating evidence documents the initiation of diverse physiologic and biochemical responses subsequent to an oral glucose load. OBJECTIVES: We sought to evaluate the extent to which acute hyperglycemia, resulting from a 50-gram glucose load, contributes to changes in maternal plasma concentrations of advanced glycation end products (AGEs), a heterogeneous group of molecules formed from the non-enzymatic reaction of reducing sugars with free amino groups of proteins, lipids, and nucleic acids. METHODS: Blood specimens were collected from each participant in mid-pregnancy using standard procedures before and after a 50-gram oral glucose load. Maternal plasma methylglyoxal (MG), pentosidine and N(epsilon)-(carboxymethyl)lysine (CML) (free and bound) were measured by HPLC-MS/MS method. Non-parametric methods were employed for statistical analysis. RESULTS AND CONCLUSIONS: Median plasma MG increased 1.27 fold as a result of acute hyperglycemia. Median bound CML concentrations were elevated 21% in post-load plasma samples as compared with pre-load samples, while median free pentosidine concentrations were 51% lower (both p-values < 0.05). Future studies of larger populations and longer periods of follow-up are warranted to investigate the consequences of acute and chronic hyperglycemia on placental function and fetal development.

Differential Expression of HrtA1 and ADAM12 in Placentas from Preeclamptic and Normotensive Pregnancies.

BACKGROUND: High temperature requirement factor A 1 (HtrA1) and a disintegrin and metalloproteinase 12 (ADAM12), which play roles in placental implantation and placental growth, have been implicated in the pathogenesis of preeclampsia. METHODS: We investigated relative mRNA expression of both genes in placental tissues from women with preeclampsia (N=18) (average gestational age 36 weeks) and an equal number of women with normotensive pregnancies (average gestational age 39 weeks). Real-time polymerase chain reaction was used to measure mRNA extracted from term placental biopsies. Differential gene expression was evaluated using Student's T-test and fold change analyses. RESULTS: Statistically significant increases in placental HtRA1 (1.69-fold, p=0.030) and ADAM12 (1.48-fold, p=0.010) mRNA expression were observed among preeclamptic cases as compared with normotensive controls. HtrA1 expression was correlated with maternal age (p-value <0.01) among preeclampsia cases. CONCLUSION: Increases in HtRA1 and ADAM12 placental gene expression in placentas from preeclamptic pregnancies are consistent with some earlier reports of altered serum protein concentrations in preeclamptic pregnancies. This adds to the literature suggesting that defects in placentation (e.g. involving trophoblast invasion) are of etiologic importance in preeclampsia.

Maternal plasma protein profiles in response to oral 50-gram glucose load in mid-pregnancy: a pilot study.

Accumulating evidence documents the initiation of diverse physiologic and biochemical response subsequent to an oral glucose load. However, significant gaps in knowledge exist in the understanding of consequences of glucose load during pregnancy, a state of insulin resistance. Using high dimensional protein arrays, we conducted a pilot proof-of-concept and feasibility study to investigate profiles of 120 plasma proteins in pre- and post- 50-gram oral glucose challenge samples. Participants (N = 10) were selected from among women enrolled in a pregnancy cohort. Differences in plasma protein concentrations between pre- and post-glucose load challenge samples were evaluated using Student's T-test (paired) and mean fold change comparisons. Multiple testing adjusted p-values (i.e., false discovery rate q values) were computed using Benjamini-Hochberg (BH) corrections. Plasma haptoglobulin, epidermal growth factor, hemoglobin, thrombospondin-1, and S100 protein concentrations were two to five fold higher in post-glucose load compared with pre-glucose load samples (all q-values <0.05). Among women aged >31 years (above median), post-load S100 protein was elevated 9.92-fold above pre-load concentrations, while it was elevated 4.10-fold among women aged <31 years (below median). Similarly, among women with post-load glucose concentrations <101mg/dl (below median), S100 was elevated 8.26-fold while it was elevated 3.28 fold among women with post-load glucose concentrations >101mg/dl (above median). Our study findings suggest that post-glucose load changes in plasma biomarkers represent a diverse set of cellular responses including receptor for advanced glycation end products (RAGE), inflammation, oxidative stress and adipogenesis, during mid-pregnancy. Future studies of larger populations and longer periods of follow-up are warranted.

Age at menarche, menstrual cycle characteristics and risk of gestational diabetes.

AIMS: We examined associations of age at menarche and menstrual cycle characteristics with gestational diabetes mellitus (GDM) risk. METHODS: Study participants (N=3490) recruited prior to 16 weeks of gestation were followed until delivery. Menstrual history data were collected using questionnaires. GDM was diagnosed using the American Diabetes Association 2003 guidelines. Logistic regression was used to estimate odds-ratios (OR) and 95% confidence intervals (CI). RESULTS: Age at menarche was not associated with GDM risk. Women who had long menstrual cycles (>36 days) had higher risk of GDM compared with women who had normal cycle length (25-30 days) (OR=1.6; 95%CI0.98-2.67). Women who had long menstrual cycles and were either overweight or gained >5kg in adulthood had 4-5-fold higher GDM risk compared with women who had normal cycle length and were non-obese or gained <5kg in adulthood, respectively (OR=4.03; 95%CI:2.08-7.81 and OR=4.62, 95%CI:2.65-8.07, respectively). CONCLUSION: Longer menstrual cycles are significantly associated with increased risk of GDM, particularly among women who were either overweight or obese pre-pregnancy, or had ≥5kg weight gain in adult hood. Menstrual history may help identify women with increased risk of GDM.

Oxidative DNA damage in early pregnancy and risk of gestational diabetes mellitus: A pilot study.

OBJECTIVES: To examine the association of maternal early pregnancy oxidative stress with risk of gestational diabetes mellitus (GDM). DESIGN AND METHODS: A pilot prospective, nested case-control study was conducted. Study participants were recruited before 20weeks gestation. Maternal urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of systemic oxidative DNA damage and repair, was measured using competitive immunoassays. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (95%CI). RESULTS: Elevations in early pregnancy urinary 8-OHdG concentrations were associated with increased GDM risk. After adjusting for confounders, the OR for extreme quartiles (≥8.01 vs. <4.23ng/mg creatinine) of 8-OHdG was 3.79 (95%CI 1.03-14.00). The risk for GDM was highest for overweight women with urine 8-OHdG concentrations ≥8.01ng/mg creatinine (OR=5.36, 95%CI 1.33-21.55) when compared with lean women who had 8-OHdG concentrations <8.01ng/mg creatinine. CONCLUSIONS: Elevated urine 8-OHdG concentrations in early pregnancy appear to be associated with increased GDM risk.

Placental microRNA expression in pregnancies complicated by preeclampsia.

OBJECTIVE: The role of posttranscription regulation in preeclampsia is largely unknown. We investigated preeclampsia-related placental microRNA (miRNA) expression using microarray and confirmatory quantitative real-time polymerase chain reaction experiments. STUDY DESIGN: Placental expressions of characterized and novel miRNAs (1295 probes) were measured in samples collected from 20 preeclampsia cases and 20 controls. Differential expression was evaluated using Student t test and fold change analyses. In pathway analysis, we examined functions/functional relationships of targets of differentially expressed miRNAs. RESULTS: Eight miRNAs were differentially expressed (1 up-regulated and 7 down-regulated) among preeclampsia cases compared with controls. These included previously identified candidates (miR-210, miR-1, and a miRNA in the 14q32.31 cluster region) and others that are novel (miR-584 and miR-34c-5p). These miRNAs target genes that participate in organ/system development (cardiovascular and reproductive system), immunologic dysfunction, cell adhesion, cell cycle, and signaling. CONCLUSION: Expression of miRNAs that target genes in diverse pathophysiological processes is altered in the setting of preeclampsia.

Age at menarche, menstrual characteristics, and risk of preeclampsia.

We examined associations of age at menarche and menstrual characteristics with the risk of preeclampsia among participants (n = 3,365) of a pregnancy cohort study. Data were collected using in-person interviews and medical record abstraction. Logistic regression was used to estimate adjusted odds ratio (OR) and 95% confidence interval (95% CI). There was a significant inverse association between age at menarche and risk of preeclampsia (P value for trend < 0.05). Association of long cycle length (>36 days) with higher risk of preeclampsia was present only among women who had prepregnancy body mass index <25 kg/m(2) (interaction P value = 0.04). Early menarche is associated with higher risk of preeclampsia. Prepregnancy weight may modify associations of long menstrual cycles with risk of preeclampsia.

Glucose intolerance and gestational diabetes risk in relation to sleep duration and snoring during pregnancy: a pilot study.

BACKGROUND: Insufficient sleep and poor sleep quality, considered endemic in modern society, are associated with obesity, impaired glucose tolerance and diabetes. Little, however, is known about the consequences of insufficient sleep and poor sleep quality during pregnancy on glucose tolerance and gestational diabetes. METHODS: A cohort of 1,290 women was interviewed during early pregnancy. We collected information about sleep duration and snoring during early pregnancy. Results from screening and diagnostic testing for gestational diabetes mellitus (GDM) were abstracted from medical records. Generalized linear models were fitted to derive relative risk (RR) and 95% confidence intervals (95% CIs) of GDM associated with sleep duration and snoring, respectively. RESULTS: After adjusting for maternal age and race/ethnicity, GDM risk was increased among women sleeping < or = 4 hours compared with those sleeping 9 hours per night (RR = 5.56; 95% CI 1.31-23.69). The corresponding RR for lean women (<25 kg/m2) was 3.23 (95% CI 0.34-30.41) and 9.83 (95% CI 1.12-86.32) for overweight women (> or = 25 kg/m2). Overall, snoring was associated with a 1.86-fold increased risk of GDM (RR = 1.86; 95% CI 0.88-3.94). The risk of GDM was particularly elevated among overweight women who snored. Compared with lean women who did not snore, those who were overweight and snored had a 6.9-fold increased risk of GDM (95% CI 2.87-16.6). CONCLUSIONS: These preliminary findings suggest associations of short sleep duration and snoring with glucose intolerance and GDM. Though consistent with studies of men and non-pregnant women, larger studies that include objective measures of sleep duration, quality and apnea are needed to obtain more precise estimates of observed associations.

Adipocytokine expression in placentas from pre-eclamptic and chronic hypertensive patients.

OBJECTIVE: Growing evidence suggests that concentration of the adipocytokines leptin and adiponectin may be affected by risk of hypertension during pregnancy. Leptin and leptin receptor gene expression has been studied in placentas obtained from pre-eclamptic patients, but not in those with chronic high blood pressure (CHBP). Adiponectin receptors remain unstudied in placentas obtained from hypertensive patients. METHODS: Therefore, we investigated relative mRNA expression of selected adipocytokine genes (leptin, leptin receptors (LEPRA, LEPRB, LEPRC, LEPRD) and adiponectin receptors (ADIPOR1, ADIPOR2)) in placental tissues from women with pre-eclampsia (n = 6) or CHBP (n = 8). Placentas from 28 normotensive patients were analyzed as controls. mRNA extracted from biopsies taken from the maternal and fetal sides of the placenta was investigated using real-time polymerase chain reaction. RESULTS: Compared with controls, significant increases in leptin mRNA expression were seen in placentas from pre-eclamptic patients on the maternal (p = 0.01) and fetal (p = 0.02) sides, and in placentas from CHBP mothers on the fetal side (p = 0.001). Maternal-side tissue from CHBP patients was not significantly different from that of controls (p = 0.08), but this might be due to the small sample size. No significant differences were seen in mRNA expression for most of the adipocytokine receptors tested for hypertensive cases compared with controls. However, there was a decrease in LEPRC (pre-eclamptic, maternal side, p = 0.03) and LEPRD (pre-eclamptic, maternal side, p = 0.01; CHBP, fetal side, p = 0.009) in case-control analysis. CONCLUSIONS: This pilot study shows that increases seen in leptin expression in placentas from hypertensive mothers might be a consequence of defects in placentation associated with this disease, and motivates further region-specific adipocytokine gene expression analysis across this organ.