First-trimester Maternal Plasma Research Articles

Paternal pre-conceptional smoking and semen quality in the adult son.

Growing evidence suggests intergenerational effects of paternal pre-conceptional smoking through the germ line, but its specific impact on offspring semen quality remains uncertain because of challenges in isolating paternal exposure from maternal passive smoking or underreporting. We reran previous analyses estimating differences in semen parameters and testicular size according to paternal smoking in 867 young adult men, adding first-trimester maternal plasma cotinine to the original adjustment for maternal self-reported smoking. We also estimated differences in sperm DNA fragmentation. Paternal smoking was reported by the pregnant women around gestational week 16. Analyses were additionally adjusted for household occupational status, parental ages at birth, maternal pre-pregnancy body mass index and alcohol consumption, and abstinence time, and accounted for spillage, minutes from ejaculation to analysis, and son's own smoking. We found no association between paternal preconceptional smoking and any of the semen parameters or testicular size. Adjustment for son's own smoking did not change results. While maternal plasma cotinine offers an objective measure of tobacco exposure and allows for a more thorough adjustment of maternal smoking, the high correlation between paternal pre-conceptional smoking and maternal cotinine exposure may, have resulted in overadjustment removing some paternal effect. Inability to distinguish between paternal never smokers and former smokers, may have led to misclassification of paternal pre-conceptional smoking and underestimation of associations. We found no support for an independent association between paternal pre-conceptional smoking and semen quality in young adult sons, but studies with more detailed paternal smoking history are needed before firm conclusions can be drawn.

Maternal One-Carbon Metabolism during the Periconceptional Period and Human Foetal Brain Growth: A Systematic Review.

The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term risk of embryonic neural tube-related defects and (ii) long-term childhood behaviour, cognition, and autism spectrum disorders. Here we investigate the association between maternal one-carbon metabolism and foetal and neonatal brain growth and development. Database searching resulted in 26 articles eligible for inclusion. Maternal vitamin B6, vitamin B12, homocysteine, and choline were not associated with foetal and/or neonatal head growth. First-trimester maternal plasma folate within the normal range (>17 nmol/L) associated with increased foetal head size and head growth, and high erythrocyte folate (1538–1813 nmol/L) with increased cerebellar growth, whereas folate deficiency (<7 nmol/L) associated with a reduced foetal brain volume. Preconceptional folic acid supplement use and specific dietary patterns (associated with increased B vitamins and low homocysteine) increased foetal head size. Although early pregnancy maternal folate appears to be the most independent predictor of foetal brain growth, there is insufficient data to confirm the link between maternal folate and offspring risks for neurodevelopmental diseases.

Fetal fraction of cell free DNA in screening for hypertensive disorders at 11–13 weeks

Objective To investigate whether first-trimester maternal plasma fetal fraction is altered in women that subsequently develop preeclampsia (PE) or gestational hypertension (GH) and to examine its potential value in improving the performance of screening for PE and GH by maternal factors and maternal serum pregnancy associated plasma protein-A (PAPP-A), mean arterial pressure (MAP) and uterine artery pulsatility index (UtA-PI). Methods The study population of 10,131 pregnancies undergoing cell free fetal DNA testing at 11–13 weeks’ gestation included 91 (0.9%) cases with preterm-PE, 222 (2.2%) cases with term-PE, 360 (3.6%) with GH and 9,458 (93.4%) cases unaffected by hypertensive disorders. Maternal plasma fetal fraction levels were expressed as multiples of the median (MoM) after adjustment for maternal factors and crown-rump length. The performance of screening for preterm-PE, term PE and GH by maternal factors and MoM values of fetal fraction, PAPP-A, UtA-PI and MAP was evaluated by receiver operating characteristic (ROC) curves. Results The median fetal fraction MoM was significantly lower in the preterm-PE (0.825; IQR 0.689–1.115 MoM, p < .001), term-PE (0.946; IQR 0.728–1.211 MoM, p = .028) and GH (0.928; IQR 0.711–1.182 MoM, p < .001) groups than in the unaffected group (1.002; IQR 0.785–1.251 MoM). However, the performance of screening for PE or GH by maternal factors alone or by maternal factors and PAPP-A, UtA-PI and MAP was not significantly improved by the addition of fetal fraction. Conclusions First trimester maternal plasma fetal fraction is not useful in screening for hypertensive disorders of pregnancy.

Prenatal perfluoroalkyl substance exposure and neuropsychological development throughout childhood: The INMA Project

BackgroundPerfluoroalkyl substances (PFASs) have been related to neurodevelopmental toxicity in animals. However, human studies are inconclusive. ObjectivesTo evaluate the association between prenatal PFAS exposure and neuropsychological development during childhood. Methods1240 mother–child pairs from the Spanish INMA Project were analyzed. Perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA) were measured in first-trimester maternal plasma. Neuropsychological development was assessed at 14 months, 4–5 and 7 years covering four domains: general cognitive, general motor, attention, and working memory. Associations were studied by means of multivariable regression analyses. ResultsPFHxS, PFOA, PFOS, and PFNA medians were: 0.6, 2.4, 6.1, and 0.7 ng/mL. Higher PFAS prenatal exposure was associated with worse motor development at 14 months, especially in the case of PFHxS (β[95%CI]: −1.49[−2.73, −0.24]) and to a lesser extent PFOS (−1.25[−2.62, 0.12]). There was also a marginal positive association between general cognitive development at 4–5 years and PFOS (1.17[−0.10, 2.43]) and PFNA (0.99[−0.13, 2.12]). No clear associations for other neuropsychological outcomes or any sex differences were found. DiscussionThis study shows no clear-cut evidence of an association between prenatal PFAS exposure and adverse neuropsychological development in children up to the age of 7 years.

Proteome profiling of gestational diabetes mellitus at 16-18 weeks revealed by LC-MS/MS.

BackgroundThe practices used to diagnose gestational diabetes mellitus (GDM) could only be carried out around the time of detectable symptoms, and predictive capacity is little.MethodsLC‐MS/MS was conducted to explore overview proteomics for GDM complicated pregnant woman at 16‐18 gestation weeks, while normal pregnant for control. Enzyme‐linked immunosorbent assay was further applied in an independent cohort of 15 GDM cases and 15 controls for verification.ResultsThe results indicated that 24 protein expression levels were significantly changed in GDM group samples, and inflammation, oxidative stress, insulin resistance, blood coagulation, and lipid homeostasis were associated with GDM. The abnormal expression of CRP and IGFBP2 was verified in the first‐trimester maternal plasma in women who subsequently developed GDM.ConclusionsThis study not only identified 24 potential predictive biomarkers for GDM also provided a global overview of protein rearrangements induced by GDM.

First-trimester maternal concentrations of polyfluoroalkyl substances and fetal growth throughout pregnancy

BackgroundSeveral studies have investigated the possible association between prenatal exposure to perfluoroalkyl substances (PFASs) and birth anthropometry. However, none has assessed fetal size longitudinally. We studied the possible association between PFASs and fetal biometry. MethodsIn 1230 mother–child pairs of three cohorts from the Spanish INMA-Project, we analyzed perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in first-trimester maternal plasma (collection: 2003–2008). We measured abdominal circumference (AC), femur length (FL), biparietal diameter (BPD), and estimated fetal weight (EFW) by ultrasounds at 12, 20, and 34 gestational weeks. We conducted multivariable linear regression analyses between log2-transformed (PFASs) and SD-scores of fetal parameters in each cohort and subsequent meta-analysis. We also assessed effect modification by sex and maternal smoking. ResultsPFHxS, PFOA, PFOS, and PFNA medians were: 0.58, 2.35, 6.05, and 0.65 ng/mL, respectively. There were no associations for the whole population in any trimester of pregnancy. However, we found an indication that maternal smoking modified the effect in different directions depending on the PFAS. Among smokers (31%), we found negative associations between both PFOA and PFNA and FL or EFW at week 20 (% change ranging between −6.8% and −5.7% per twofold PFAS increase) and positive associations between PFHxS or PFOS and BPD at week 34 (6.8% and 6.3%, respectively). ConclusionsResults did not suggest an overall association between prenatal PFASs and fetal growth. The results among smokers should be taken with caution and further studies are warranted to elucidate the possible role of smoking in this association.

IUGR Is Associated With Marked Hyperphosphorylation of Decidual and Maternal Plasma IGFBP-1.

The mechanisms underpinning intrauterine growth restriction (IUGR), as a result of placental insufficiency, remain poorly understood, no specific treatment is available, and clinically useful biomarkers for early detection are lacking. We hypothesized that human IUGR is associated with inhibition of mechanistic target of rapamycin (mTOR) and activation of amino acid response (AAR) signaling, increased protein kinase casein kinase-2 (CK2) activity, and increased insulin-like growth factor-binding protein 1 (IGFBP-1) expression and phosphorylation in decidua and that maternal plasma IGFBP-1 hyperphosphorylation in the first trimester predicts later development of IUGR. Decidua [n = 16 appropriate-for-gestational age (AGA); n = 16 IUGR] and maternal plasma (n = 13 AGA; n = 13 IUGR) were collected at delivery from two different cohorts. In addition, maternal plasma was obtained in the late first trimester from a third cohort of women (n = 7) who later delivered an AGA or IUGR infant. Total IGFBP-1 expression and phosphorylation (Ser101/Ser119/Ser169), mTOR, AAR, and CK2 activity in decidua and IGFBP-1 concentration and phosphorylation in maternal plasma. We show that decidual IGFBP-1 expression and phosphorylation are increased, mTOR is markedly inhibited, and AAR and CK2 are activated in IUGR. Moreover, IGFBP-1 hyperphosphorylation in first-trimester maternal plasma is associated with the development of IUGR. These data are consistent with the possibility that the decidua functions as a nutrient sensor linking limited oxygen and nutrient availability to increased IGFBP-1 phosphorylation, possibly mediated by mTOR and AAR signaling. IGFBP-1 hyperphosphorylation in first-trimester maternal plasma may serve as a predictive IUGR biomarker, allowing early intervention.

Maternal Concentrations of Perfluoroalkyl Substances and Fetal Markers of Metabolic Function and Birth Weight.

Perfluoroalkyl substances (PFAS) are ubiquitous, persistent chemicals that have been widely used in the production of common household and consumer goods for their nonflammable, lipophobic, and hydrophobic properties. Inverse associations between maternal or umbilical cord blood concentrations of perfluorooctanoic acid and perfluorooctanesulfonate and birth weight have been identified. This literature has primarily examined each PFAS individually without consideration of the potential influence of correlated exposures. Further, the association between PFAS exposures and indicators of metabolic function (i.e., leptin and adiponectin) has received limited attention. We examined associations between first-trimester maternal plasma PFAS concentrations and birth weight and cord blood concentrations of leptin and adiponectin using data on 1,705 mother-infant pairs from the Maternal Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada birth cohort study that recruited women between 2008 and 2011. Bayesian hierarchical models were used to quantify associations and calculate credible intervals. Maternal perfluorooctanoic acid concentrations were inversely associated with birth weight z score, though the null value was included in all credible intervals (log10 β = −0.10, 95% credible interval: −0.34, 0.13). All associations between maternal PFAS concentrations and cord blood adipocytokine concentrations were of small magnitude and centered around the null value. Follow-up in a cohort of children is required to determine how the observed associations manifest in childhood.

Novel Epigenetic Markers on Chromosome 21 for Noninvasive Prenatal Testing of Fetal Trisomy 21

Until now, fetal placenta-specific epigenetic markers for noninvasive prenatal testing of fetal trisomy 21 (T21) have been identified based only on differences in tissue-specific epigenetic characteristics between placenta and maternal blood, but these characteristics have not been validated in T21 placenta. We aimed to discover novel epigenetic markers on chromosome 21 that show a hypermethylated pattern in fetal placenta compared with blood, regardless of the presence of T21. We performed a high-resolution tiling array analysis of chromosome 21 using the methylated-CpG binding domain protein-based method. We identified 93 epigenetic regions that showed fetal placenta-specific differential methylation patterns; among these, three regions showed fetal placenta-specific methylation patterns in T21 placenta samples. The methylation patterns of these three regions in the array were confirmed by bisulfite direct sequencing. The three regions were detectable in first-trimester maternal plasma. Moreover, a combination of their methylation ratio achieved high diagnostic accuracy for noninvasive prenatal testing of fetal T21 by further statistical analysis. These three novel regions with fetal placenta-specific differential methylation patterns on chromosome 21 were identified irrespective of the presence of T21. Our findings suggest that epigenetic characteristics of markers according to the presence or absence of T21 should be considered in the development of noninvasive prenatal testing of fetal T21 using fetal placenta-specific epigenetic markers.

Non-invasive prenatal determination of fetal gender using QF-PCR analysis of cell-free fetal DNA in maternal plasma

BackgroundDetection of cell-free fetal DNA (cffDNA) in maternal plasma has given rise to the possibility of new non-invasive approaches for early prenatal diagnoses. We evaluated the feasibility and accuracy of non-invasive fetal gender determination using quantitative fluorescent-polymerase chain reaction (QF-PCR) analysis of circulating cffDNA in the first-trimester maternal plasma. MethodsPlasma samples were prospectively collected from 202 singleton pregnancies at 4 to 13weeks of gestation. Fetal gender was determined by QF-PCR with the sex-determining region Y (SRY) and amelogenin X/Y (AMELX/Y) genes. The result was confirmed by fetal karyotyping or phenotype at birth. ResultsOf the 202 pregnancies, 162 had pregnancy outcomes available and could be included in our evaluation. The accuracies of AMELX/Y, SRY, and combined AMELX/Y+SRY analysis for fetal gender determination were 83.3%, 82.1%, and 97.5%, respectively, compared with those of the invasive approach and the fetal gender outcome at birth (82 males and 80 females). Combined AMELX/Y+SRY analysis had the highest sensitivity (98.8%) for fetal gender determination with a specificity of 96.3%. Moreover, fetal gender detection by the combined AMELX/Y+SRY analysis at 11 to 13weeks of gestation was 100% correct. ConclusionFetal gender determination could be accurately determined from maternal cffDNA in the first-trimester using QF-PCR analysis of combined AMELX/Y+SRY.

Effective detection of fetal sex using circulating fetal DNA in first‐trimester maternal plasma

The aim of this study was to develop a simple and effective method for noninvasively detecting fetal sex using circulating fetal DNA from first-trimester maternal plasma. A study was conducted with maternal plasma collected from 203 women between 5 and 12 wk of gestation. The presence of circulating fetal DNA was confirmed by a quantitative methylation-specific polymerase chain reaction of the unmethylated-PDE9A gene (U-PDE9A). Multiplex real-time PCR was used to simultaneously quantify the amount of DYS14 and GAPDH in maternal plasma. The results were confirmed by phenotype at birth. Pregnancy outcomes and U-PDE9A concentrations were obtained in all cases, including 99 male-bearing and 104 female-bearing participants. At equivalent specificity (100%), the false-negative rate was 9.1% for DYS14 quantification cycle, 7.1% for DYS14 concentration, and 0.0% for the concentration ratio of DYS14/GAPDH, respectively. In male-bearing participants, DYS14, U-PDE9A, and GAPDH concentrations were significantly lower in the false-negative case than in correct case (P<0.001 in all). Moreover, DYS14, U-PDE9A, and GAPDH concentrations showed significantly positive associations with each other (P≤0.001 in all). The ratio of DYS14/GAPDH in maternal plasma was an effective biomarker for noninvasive fetal sex detection during the first trimester, indicating that it could be useful for clinical application.

Hypomethylated DSCR4 is a placenta-derived epigenetic marker for trisomy 21

Trisomy 21 is the most common chromosomal aberration in live births. Some efforts have been made to develop noninvasive prenatal detection of trisomy 21 by using fetal DNA in maternal plasma. Due to the maternal DNA background, a distinguishable marker between maternal DNA and fetal DNA must be used, such as DNA methylation. The objective of this study was to search for fetal-specific methylation markers on chromosome 21. We chose six genes highly or specifically expressed in placenta and screened the methylation status of these gene promoter regions by combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes assay (COMPARE-MS). We further determined the methylation status of each CpG site within selected gene fragments by bisulfite sequencing. At last, we detected the placenta-derived methylation marker in the first-trimester maternal plasma by real-time methylation-specific PCR (MSP). Down syndrome (DS) critical region gene 4 (DSCR4) promoter region was found to be hypomethylated in placental tissues and densely methylated in maternal blood cells. Unmethylated DSCR4 (Down syndrome) sequence can be detected in the first-trimester maternal plasma. DSCR4 promoter DNA is a candidate fetal epigenetic marker for noninvasive prenatal detection of trisomy 21.

First-trimester maternal plasma cell-free fetal DNA and preeclampsia

The purpose of this study was to determine whether, in pregnancies that experience preeclampsia, plasma cell-free fetal DNA (cffDNA) at 11-13 weeks of gestation is increased and whether this increase is related to the uterine artery pulsatility index (PI). Plasma cffDNA and uterine artery PI were measured in 44 cases with preeclampsia, which included 11 cases that required delivery at <34 weeks of gestation and 176 normal control subjects. All fetuses were male, and cffDNA was assessed by amplification of the DYS14 gene. The association between cffDNA and uterine artery PI was assessed by regression analysis. Median cffDNA was higher in early preeclampsia (median, 95.5 genome equivalents/mL; interquartile range, 72.7-140.9 genome equivalents/mL), but not late preeclampsia (median, 50.8 genome equivalents/mL; interquartile range, 25.0-103.8 genome equivalents/mL), than control subjects (median, 51.5 genome equivalents/mL; interquartile range, 31.1-84.9 genome equivalents/mL). There was a significant association between cffDNA and uterine artery PI (P = .038) but not in the control subjects (P = .174). The increase in plasma cffDNA in pregnancies that experience preeclampsia is associated with the degree of impairment in placental perfusion.

First-Trimester Maternal Plasma Concentrations of C-Reactive Protein in Low-Risk Patients and the Subsequent Development of Chorioamnionitis

Baseline elevations of C-reactive protein (CRP) during pregnancy have been associated with adverse outcomes, including preterm delivery. Acute elevations have also been associated with intrauterine infections. The relationship between chronic, baseline elevations of CRP and histological chorioamnionitis, however, has not previously been explored. A nested case-control study was performed within a prospective observational cohort of low-risk patients seeking prenatal care. CRP was measured from maternal plasma collected before 13 weeks of estimated gestational age. Cases were defined by histological chorioamnionitis, and controls were selected randomly from patients without chorioamnionitis. We identified 36 cases of chorioamnionitis. There were no significant differences (p=0.64) in CRP concentrations between cases and controls. CRP concentrations remained nonsignificant in a logistic regression model that incorporated prepregnancy body mass index, placental weight, race, and gestational age at delivery (p=0.72). We concluded that the development of histological chorioamnionitis is not associated with elevations in maternal plasma CRP earlier in pregnancy.

Fetal lead exposure at each stage of pregnancy as a predictor of infant mental development.

BackgroundThe impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure.ObjectiveWe studied prenatal lead exposure’s impact on neurodevelopment using repeated measures of fetal dose as reflected by maternal whole blood and plasma lead levels.MethodsWe measured lead in maternal plasma and whole blood during each trimester in 146 pregnant women in Mexico City. We then measured umbilical cord blood lead at delivery and, when offspring were 12 and 24 months of age, measured blood lead and administered the Bayley Scales of Infant Development. We used multivariate regression, adjusting for covariates and 24-month blood lead, to compare the impacts of our pregnancy measures of fetal lead dose.ResultsMaternal lead levels were moderately high with a first-trimester blood lead mean (± SD) value of 7.1 ± 5.1 μg/dL and 14% of values ≥10 μg/dL. Both maternal plasma and whole blood lead during the first trimester (but not in the second or third trimester) were significant predictors (p < 0.05) of poorer Mental Development Index (MDI) scores. In models combining all three trimester measures and using standardized coefficients, the effect of first-trimester maternal plasma lead was somewhat greater than the effect of first-trimester maternal whole blood lead and substantially greater than the effects of second- or third-trimester plasma lead, and values averaged over all three trimesters. A 1-SD change in first-trimester plasma lead was associated with a reduction in MDI score of 3.5 points. Postnatal blood lead levels in the offspring were less strongly correlated with MDI scores.ConclusionsFetal lead exposure has an adverse effect on neurodevelopment, with an effect that may be most pronounced during the first trimester and best captured by measuring lead in either maternal plasma or whole blood.