Multiples Of The Median Levels Research Articles

First‐trimester pre‐eclampsia biomarker profiles in Asian population: multicenter cohort study

To (i) evaluate the applicability of the European-derived biomarker multiples of the median (MoM) formulae for risk assessment of preterm pre-eclampsia (PE) in seven Asian populations, spanning the east, southeast and south regions of the continent, (ii) perform quality-assurance (QA) assessment of the biomarker measurements and (iii) establish criteria for prospective ongoing QA assessment of biomarker measurements. This was a prospective, non-intervention, multicenter study in 4023 singleton pregnancies, at 11 to 13 + 6 weeks' gestation, in 11 recruiting centers in China, Hong Kong, India, Japan, Singapore, Taiwan and Thailand. Women were screened for preterm PE between December 2016 and June 2018 and gave written informed consent to participate in the study. Maternal and pregnancy characteristics were recorded and mean arterial pressure (MAP), mean uterine artery pulsatility index (UtA-PI) and maternal serum placental growth factor (PlGF) were measured in accordance with The Fetal Medicine Foundation (FMF) standardized measurement protocols. MAP, UtA-PI and PlGF were transformed into MoMs using the published FMF formulae, derived from a largely Caucasian population in Europe, which adjust for gestational age and covariates that affect directly the biomarker levels. Variations in biomarker MoM values and their dispersion (SD) and cumulative sum tests over time were evaluated in order to identify systematic deviations in biomarker measurements from the expected distributions. In the total screened population, the median (95% CI) MoM values of MAP, UtA-PI and PlGF were 0.961 (0.956-0.965), 1.018 (0.996-1.030) and 0.891 (0.861-0.909), respectively. Women in this largely Asian cohort had approximately 4% and 11% lower MAP and PlGF MoM levels, respectively, compared with those expected from normal median formulae, based on a largely Caucasian population, whilst UtA-PI MoM values were similar. UtA-PI and PlGF MoMs were beyond the 0.4 to 2.5 MoM range (truncation limits) in 16 (0.4%) and 256 (6.4%) pregnancies, respectively. QA assessment tools indicated that women in all centers had consistently lower MAP MoM values than expected, but were within 10% of the expected value. UtA-PI MoM values were within 10% of the expected value at all sites except one. Most PlGF MoM values were systematically 10% lower than the expected value, except for those derived from a South Asian population, which were 37% higher. Owing to the anthropometric differences in Asian compared with Caucasian women, significant differences in biomarker MoM values for PE screening, particularly MAP and PlGF MoMs, were noted in Asian populations compared with the expected values based on European-derived formulae. If reliable and consistent patient-specific risks for preterm PE are to be reported, adjustment for additional factors or development of Asian-specific formulae for the calculation of biomarker MoMs is required. We have also demonstrated the importance and need for regular quality assessment of biomarker values. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Factors affecting cord blood leptin levels in a consecutive birth cohort

Introduction The fetus that fails to meet its ideal growth trajectory has increased risks of poor health outcomes throughout life. “Gold standard” methods of anthropometric assessment such as measurement of percentage body fat can be difficult to apply across populations and other biomarkers such as serum concentration of umbilical cord blood leptin may be more effective for screening. This study reports cord blood leptin levels in a large prospective consecutive birth cohort and assesses the relationship between leptin and neonatal and maternal factors. Methods Venous umbilical cord blood samples were collected from a prospective consecutive cohort of pregnancies at the time of delivery. Maternal and neonatal characteristics and details of delivery were collated. Serum leptin levels were measured, associations with demographic features were identified, and a normal range was established. The association between cord leptin level and neonatal outcome was tested. Results Umbilical cord leptin and maternal and neonatal characteristics were collected at 1275 births. The median leptin value was 10.8 ng/ml (IQR: 6.4, 17.8 ng/ml). Log10 leptin was significantly associated with gestation at delivery, birthweight (BWt), infant sex, plurality, and maternal body mass index (BMI) (p < .001). Observed leptin values were expressed as multiples of the median (MoM). The mean leptin MoM was significantly lower in infants admitted to NICU following delivery (0.85; 95% confidence interval [CI]: 0.78–0.91 versus 1.05; 95% CI: 1.03–1.06 (controls), p < .001). There was no significant association between leptin MoM values and 5-min Apgar scores. Conclusions Neonatal cord leptin levels are influenced by a number of maternal and fetal characteristics. Absolute levels can be adjusted to account for normal population variation. Infants requiring admission to NICU have lower mean leptin MoM levels. Further studies are needed to see whether the identification of fetuses with polarized leptin levels (<5th or >95th centile) will benefit from further surveillance or intervention in infancy.

Adjusting antimüllerian hormone levels for age and body mass index improves detection of polycystic ovary syndrome

To examine whether accounting for a woman's age and body mass index (BMI) would improve the ability of antimüllerian hormone (AMH) to distinguish between women with (cases) and without (controls) polycystic ovarian syndrome (PCOS). An opportunistic case-control dataset of reproductive age women having evaluations for PCOS as defined by National Institutes of Health criteria. Two medical centers in the United States enrolled women. Serum samples were analyzed for relevant analytes. Women were between 18 and 39 years of age when samples and clinical information were collected. Residual samples had been stored for 2-17 years. AMH was measured via immunoassay. None; this was an observational study. Detection and false-positive rates for PCOS were computed for AMH results expressed as multiples of the median (MoM) both before and after adjustment for the woman's age and BMI. Using unadjusted AMH MoM results, 168 cases (78%) cases were at or beyond the 90th centile of controls (2.47 MoM). After accounting for each woman's age and BMI, 188 (87%) of those women were beyond the 90th centile of controls (2.20 MoM), a significant increase (P = .015). The adjusted AMH MoM levels fitted logarithmic normal distributions well (mean, standard deviation for controls and cases of 0.0000, 0.2765 and 0.6884, 0.2874, respectively) and this allowed for computation of patient-specific PCOS risks. Accounting for the woman's age and BMI resulted in significantly higher AMH-based detection rates for PCOS at a 10% false-positive rate, and patient-specific PCOS risks could be computed.

Maternal serum placental growth factor and pregnancy-associated plasma protein A measured in the first trimester as parameters of subsequent pre-eclampsia and small-for-gestational-age infants: A prospective observational study.

ObjectiveTo examine the first-trimester maternal serum placental growth factor (PlGF) and pregnancy-associated plasma protein A (PAPP-A) levels in pregnancies associated with pre-eclampsia (PE) or small-for-gestational-age (SGA) infants, and determine the predictive accuracy of PlGF and of PAPP-A for either PE or SGA infants.MethodsThis prospective, observational study included 175 pregnant women, and of these women, due to participant withdrawal or loss to follow-up, delivery data were collected from the medical records of 155 women, including 4 who had twin pregnancies. The women's maternal history was recorded, and the PlGF and PAPP-A levels at 11 to 13 gestational weeks were measured. During the second trimester, the maternal uterine artery's systolic/diastolic ratio was measured. Multiples of the median (MoM) of PlGF and PAPP-A were determined, and the associations of these values with the risk factors of SGA and PE were evaluated. Logistic regression analysis was used to determine whether PlGF and PAPP-A are useful markers for predicting SGA infants.ResultsThe PAPP-A MoM level was significantly lower in women with advanced maternal age, multipara women, and women with gestational diabetes than in their counterparts. The PlGF and PAPP-A MoM levels were higher in women with a twin pregnancy than in those with a singleton pregnancy. There was a significant relationship between the maternal serum PAPP-A MoM level in the first trimester and the uterine artery systolic/diastolic ratio in the second trimester. Results of logistic regression analysis showed that low PlGF and PAPP-A MoM levels were predictors of SGA infants (odds ratio, 0.143; 95% confidence interval, 0.025 to 0.806; odds ratio, 0.191; 95% confidence interval, 0.051 to 0.718, respectively).ConclusionPlGF and PAPP-A are potentially useful as first-trimester markers for SGA infants and some hypertensive disorders of pregnancy.

First trimester PAPP-A2, PAPP-A and hCGβ in small-for-gestational-age pregnancies.

Pregnancy-associated plasma protein-A2 (PAPP-A2) is a recently discovered protease that cleaves a subset of insulin-like growth factor binding proteins (IGFBP). The molecular function suggests its involvement in the IGF system that is vital for fetal growth and development. Our objectives were to establish first trimester median curves of PAPP-A2, PAPP-A and hCGβ for singleton normal pregnancies and to investigate whether an altered level of one or more of the biomarkers is associated with small-for-gestational-age (SGA) neonates before and after stratification according to maternal hypertension and/or proteinuria. This was a case-control study based on 985 pregnant women delivering normal-weighted neonates and 170 pregnant women delivering SGA neonates. PAPP-A2 was measured by ELISA. PAPP-A and hCGβ were measured by an automatic analyzer. Median curves from 8+1 to 14+0 were established and all concentration values were converted to multiples of the median (MoM) values. Before stratification the SGA cases had unaffected PAPP-A2 MoM and hCGβ MoM levels but lower PAPP-A MoM compared with normal controls. After stratification the SGA normotensive subgroup had lower PAPP-A2 MoM and PAPP-A MoM levels than the normal normotensive subgroup. Severe preeclamptic women delivering SGA neonates had higher PAPP-A2 MoM compared to the normotensive women delivering SGA neonates. Pregnant women delivering SGA neonates did not have altered levels of PAPP-A2 or hCGβ but had lower PAPP-A level in the first trimester compared with pregnant women delivering normal-weighted neonates. Pregnancies complicated with severe preeclampsia and SGA may be associated with high PAPP-A2 level.

Obstructive sleep apnea is associated with alterations in markers of fetoplacental wellbeing

Background: Obstructive sleep apnea (OSA) has been associated with adverse fetal outcomes in some studies. Second trimester Down syndrome screening markers reflect fetal and fetoplacental wellbeing. We aimed to compare markers of fetal and feto-placental wellbeing in women with OSA and low risk controls.Methods: A retrospective case-control study of pregnant women with OSA and available second trimester markers was performed. Controls were screened for sleep disordered breathing (SDB) at the time of delivery using a questionnaire. Women at low risk for OSA were selected. Marker levels were adjusted for gestational age and race and reported as multiples of median and later adjusted for body mass index (BMI).Results: Twenty-four OSA cases and 166 controls were identified. Women with OSA had a higher mean BMI when compared to controls (37.1 ± 12.7 versus 24.1 ± 5.1, p = 0.03). Estriol (uE3) multiples of the median (MoM) levels were lower in women with OSA compared to controls, even after adjusting for BMI, 0.74 (interquartile range (IQR) 0.45) versus 1.06 (IQR 0.38), respectively, p = 0.026. Once adjusted for BMI, alpha feto-protein (AFP) MoM levels were no longer significantly different in women with OSA compared to controls.Conclusion: OSA is associated with reduced serum uE3 levels, independently of BMI, possibly indicating fetal distress.

Feasibility of Using Plasma Rather Than Serum in First and Second Trimester Multiple Marker Down's Syndrome Screening

To compare maternal plasma with serum for measuring markers currently used in first and second trimester screening for Down's syndrome. A laboratory-based investigation of two sample types in assays used in prenatal screening for Down's syndrome. A paired data-set included both plasma and serum from 101 pregnant women. A nested case/control data-set included only plasma samples from 34 first and 23 second trimester Down's syndrome pregnancies, each matched with six euploid controls. Analyte levels were measured and converted to multiples of the median (MoM). In the paired data-set, each of the five analytes (alphafetoprotein, unconjugated estriol, human chorionic gonadotropin, inhibin-A and pregnancy-associated plasma protein A) in serum and plasma was highly correlated (r > 0.970) and after conversion to MoM, the resulting distributions were equivalent (P > 0.7). In the matched data-set, plasma-based median MoM levels in cases were consistent with the published serum counterparts for all markers. This study provides strong evidence that current serum-based prenatal screening can be performed equally well using plasma samples. This may prove useful, especially if secondary screening using a DNA-based test requires maternal plasma.

Impact of bias in serum free beta‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A multiples of the median levels on first‐trimester screening for trisomy 21

To examine the effect of bias in median multiples of the median (MoM) levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (β-hCG) on first-trimester combined screening for trisomy 21. The effects of deviations in the MoM levels of free β-hCG and PAPP-A were investigated by simulating nuchal translucency (NT) at 12 weeks and MoM values for PAPP-A and free β-hCG for 500 000 euploid and 500 000 trisomy 21 pregnancies at 9 and at 12 weeks of gestation. Likelihoods were calculated using the mixture model for NT and the standard Gaussian model for log MoM PAPP-A and free β-hCG values. Deviations in MoM marker levels were simulated by applying percentage changes of 5% to 20% to MoM values. Detection and false-positive rates were calculated with and without adjustments of the maternal serum marker levels by taking the proportion of euploid and aneuploid cases above given thresholds for each maternal age and then taking a weighted average with respect to the maternal age distribution. With median MoM levels on target, the modeled detection and false-positive rates in combined screening for trisomy 21 at 12 weeks of gestation with a fixed risk cut-off of 1 in 100 were 85% and 2.5%, respectively. For median MoM levels of free β-hCG and PAPP-A between 0.8 and 1.2 MoM, detection rates ranged from 77% to 91%, with corresponding false-positive rates ranging from 1.0% to 6.1%. In first-trimester screening for trisomy 21, biases in the serum marker MoM levels of 10% can increase false-positive rates by over 50%, whilst biases of 20% can more than double false-positive rates.

Early first‐trimester maternal serum placental growth factor in trisomy 21 pregnancies

To measure maternal serum placental growth factor (PlGF) levels in trisomy 21 cases and controls in samples drawn before 11 weeks' gestation. Early first-trimester maternal serum samples, drawn between 8 + 0 and 10 + 6 weeks' gestation, for 37 trisomy 21 cases and 244 unaffected controls were retrieved from frozen storage, and PlGF was retrospectively measured using a DELFIA Xpress immunoassay platform. PlGF levels were converted to multiples of the median (MoM), and trisomy 21 and unaffected groups were compared. Raw PlGF and MoM levels were significantly higher in the maternal serum of trisomy 21 cases than in controls over the 3-week gestational window (unaffected 1.0 MoM compared with trisomy 21 1.3 MoM (P < 0.0001)). However at 8 completed weeks of gestation the increase was most significant and at 10 completed weeks there was no significant difference between trisomy 21 and unaffected PlGF levels. Early PlGF levels in maternal serum in trisomy 21 cases may be increased relative to unaffected controls, however, the relationship between PlGF levels and gestational age in trisomy 21 and unaffected pregnancies in the first two trimesters of pregnancy appears to be complex and requires further study.

Adjustment of maternal serum alpha‐fetoprotein levels in women with pregestational diabetes

Decreased second trimester levels of maternal serum alpha-fetoprotein (MSAFP) have been reported in women with pregestational diabetes leading some laboratories to use a correction factor. The aim of this study is to determine if MSAFP levels in pregnant women with diabetes managed on oral antidiabetic agents is lower than non-diabetic controls and require adjustment similar to those on insulin. We performed a nested case/control study of an existing dataset using women with pregestational diabetes who had routine MSAFP values available. Before adjusting the MSAFP value for weight, both the diabetic patients who used insulin (n = 68) and those who used oral antidiabetic agents (n = 37) showed a non-significant trend toward a lower multiples of the median (MoM) as compared with controls (n = 244). After converting the raw MSAFP values to race-adjusted MoM and adjusting for weight, the median MSAFP MoM for women taking insulin (1.01) versus those on oral antidiabetic agents (1.00) were essentially the same. Furthermore, both of the diabetic groups were virtually identical to non-diabetic controls. In our study, women with pregestational diabetes managed on either insulin or oral antidiabetic agents had weight-adjusted MSAFP MoM levels equivalent to those in control pregnancies and did not require a correction factor.

Maternal Homocysteine Level and Markers Used in First-Trimester Screening for Fetal Down Syndrome

This study examined possible relationships between homocysteine and markers used in first-trimester screening for Down syndrome. Pregnancies were categorized into 4 groups according to quartile ranking of maternal plasma homocysteine concentration. Of the 595 pregnancies, 147 were assigned to group 1 (homocysteine level 0.6-3.5 μmol/L), 156 to group 2 (homocysteine level 3.6-4.5 μmol/L), 142 to group 3 (homocysteine level 4.6-5.6 μmol/L), and 150 pregnancies to group 4 (homocysteine level 5.7-12.6 μmol/L). No significant difference in mean nuchal translucency and mean free β-human chorionic gonadotropin (free-βhCG) multiples of the median (MoM) levels were observed. However, the mean pregnancy-associated plasma protein A (PAPP-A) MoM levels were significantly decreased in inverse relationship with homocysteine level among all 4 groups (F = 31.127, P < .001). If homocysteine is assayed as part of the first-trimester maternal serum testing, it is important to adjust for homocysteine concentration when using PAPP-A serum level for calculating the risk of fetal aneuploidy.

Examination of the pregnancy-associated plasma protein-A assay on the Beckman Coulter Access® platform: suitability for use in first trimester Down's syndrome screening

To explore the clinical validity of the new Access(®) pregnancy-associated plasma protein-A (PAPP-A) assay for Down's syndrome screening. Academic hospital. Residual serum samples (n = 416) received for routine first trimester Down's syndrome screening (10-13 weeks) were retrieved from freezer storage and tested using two PAPP-A immunoassay methods. The new Access(®) assay was specifically compared, on a subset of these samples (n = 194), with an assay proven to give acceptable Down's syndrome screening performance, the PerkinElmer (PE) AutoDELFIA method. Access(®) PAPP-A levels were examined in relation to gestational age and maternal weight, and were compared with the PE method by regression and Bland-Altman analyses. Access(®) PAPP-A assay results were highly correlated with the PE AutoDELFIA method (r = 0.97). PAPP-A levels obtained using the Access(®) assay increased with advancing gestational age and were inversely related to maternal weight, as expected. The distribution of multiples of the median (MoM) values fit a log Gaussian distribution and the standard deviation of the log MoM (0.2331) matched published estimates. PAPP-A MoM levels in Down's syndrome pregnancies (n = 6, median 0.30) showed the expected reduction. Using an appropriate gestational age-specific median equation, the Access(®) PAPP-A assay is expected to perform acceptably in first trimester Down's syndrome screening.

Medians and correction factors for biochemical and ultrasound markers in Chinese women undergoing first‐trimester screening for trisomy 21

To establish normative values and distribution parameters of first-trimester maternal serum free beta-human chorionic gonadotropin (beta-hCG), pregnancy-associated plasma protein-A (PAPP-A) and fetal nuchal translucency (NT) thickness in Chinese women and to examine the effects of covariates on their levels. Maternal serum free beta-hCG, PAPP-A and fetal NT were measured in 9762 women presenting for first-trimester combined screening for Down syndrome at 11 to 14 weeks of gestation. Individuals' markers were converted to multiples of the median (MoM) using expected medians estimated by performing a weighted regression analysis. Multivariate regression analysis was performed to assess the influence of maternal weight, parity, ethnicity, chorionicity in twin pregnancies, smoking, insulin-dependent diabetes and mode of conception on individual marker MoM levels. Both free beta-hCG and PAPP-A median values demonstrated an exponential relationship with gestational age in days. Multivariate regression analysis indicated that free beta-hCG MoM was statistically significantly dependent on maternal weight (P < 0.0001) and chorionicity in twin pregnancy (both monochorionic and dichorionic P < 0.0001), that PAPP-A MoM was dependent on maternal weight (P < 0.0001), parity (P < 0.0001), chorionicity in twin pregnancy (both monochorionic and dichorionic P < 0.0001) and mode of conception (P = 0.002), and that fetal NT-MoM was dependent on maternal weight (P = 0.0006) and mode of conception (P = 0.012). Normative values have been generated to allow conversion of NT, free beta-hCG and PAPP-A to their MoM equivalents and correction factors have been determined to adjust for maternal and pregnancy characteristics for use in ethnic Chinese women undergoing first-trimester screening for aneuploidy.

Low Maternal Serum Levels of Pregnancy-associated Plasma Protein-A During the First Trimester are Associated with Subsequent Preterm Delivery with Preterm Premature Rupture of Membranes

To assess the relationship between the first-trimester maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels and pregnancies complicated by preterm delivery. The correlation between PAPP-A levels and gestational age at delivery was analyzed by linear regression. The probabilities of low PAPP-A multiples of the median (MoM) levels between preterm delivery and control population were analyzed by logit model. A positive correlation was noted between the first-trimester PAPP-A MoM levels and gestational age at delivery between 34-38 weeks (p < 0.001). Lower PAPP-A MoM level had a significantly higher likelihood of preterm delivery (p < 0.05). When preterm premature rupture of membranes (PPROM) and preterm labor (PTL) were analyzed separately, there was an increasing likelihood of PPROM with decreasing PAPP-A MoM levels (p < 0.05), but not for PTL with intact membranes. Low maternal serum PAPP-A levels during the first trimester may reflect a trophoblast invasion defect in the maternal-fetal interface, resulting in subsequent preterm delivery, particularly in those of PPROM.

Technical standards and guidelines: Prenatal screening for open neural tube defects: This new section on “Prenatal Screening for Open Neural Tube Defects,” together with the new section on “Prenatal Screening for Down Syndrome,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories

Technical standards and guidelines: Prenatal screening for open neural tube defects: This new section on “Prenatal Screening for Open Neural Tube Defects,” together with the new section on “Prenatal Screening for Down Syndrome,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories *

Association between second-trimester isolated high maternal serum maternal serum human chorionic gonadotropin levels and obstetric complications in singleton and twin pregnancies

Objective: The purpose of this study was to examine the clinical significance of high maternal serum human chorionic gonadotropin levels in the second trimester in singleton and twin pregnancies within the Ontario maternal serum screening program Study Design: The study group comprised 564 women with singleton pregnancies with total maternal serum human chorionic gonadotropin levels of ≥4.0 multiples of the median (MoM) and serum marker α-fetoprotein levels of <2.0 MoM. The cases were matched with 1692 control subjects who had both serum marker α-fetoprotein levels and maternal serum human chorionic gonadotropin levels of <2.0 MoM. The second part of the study comprised 93 twin pregnancies with maternal serum human chorionic gonadotropin levels of ≥5.0 MoM and serum marker α-fetoprotein levels of <4.0 MoM; the control group (n = 1496) had serum marker α-fetoprotein levels of <4.0 MoM and maternal serum human chorionic gonadotropin levels of <5.0 MoM. The final part of the study included 25 women with extremely high maternal serum human chorionic gonadotropin levels (≥ 14;10 MoM). Results: Of the singleton pregnancies with maternal serum human chorionic gonadotropin levels of ≥ 14;4.0 MoM, 22.5% had severe adverse obstetric outcomes, compared with only 10.9% of the matched control population (P =.001). Women with markedly elevated maternal serum human chorionic gonadotropin levels had significantly increased risks of having spontaneous miscarriage, small-for-gestational-age infants, pregnancy-associated hypertensive disorder, and preterm delivery. Of the women with twin pregnancies with high maternal serum human chorionic gonadotropin levels (≥5.0 MoM), 71% had at least one complication (such as miscarriage and preterm delivery) compared with 55.3% in the control group. Finally, 23 of 25 women with extremely high maternal serum human chorionic gonadotropin levels (≥ 14;10 MoM) had serious adverse outcomes (such as fetal abnormalities, pregnancy-associated hypertensive disorder, premature separation of placenta, intrauterine growth restriction, neonatal respiratory distress syndrome, and neonatal jaundice). Conclusion: Pregnancies with an elevated maternal serum human chorionic gonadotropin level are associated with adverse obstetric outcomes. Increased maternal and fetal surveillance is warranted in these pregnancies.