Trimester Serum Markers Research Articles

Impact of inherited thrombophilias on first and second trimester maternal serum markers for aneuploidy

Objective: To evaluate first and second-trimester maternal serum markers in pregnancies complicated with inherited thrombophilias. Methods: A case-control study was conducted in 50 pregnancies complicated with hereditary thrombophilia and 100 control pregnancies. Results: Each woman with inherited thrombophilia received low molecular weight heparin (LMWH) throughout her pregnancy. Gravidity, parity, number of first-trimester and second-trimester abortions, and rate of adverse pregnancy outcomes (APO) were significantly higher in the thrombophilia group compared to the control group (P < 0.001 for all). Among the thrombophilia group median values of pregnancy associated placental protein-A (PAPP-A) (0.6 vs. 0.9; P < 0.001) and free β-human chorionic gonadotropin (β-hCG) (0.9 vs. 1.1; P = 0.001) in the first trimester; median values of α-fetoprotein (AFP) (0.7 vs. 1.1; P = 0.027), unconjugated estriol 3 (uE3) (0.9 vs. 1.1; P < 0.001), and hCG (0.7 vs. 1.2; P < 0.001) in the second trimester were significantly lower with respect to control pregnancies. Multivariate analysis revealed that low uE3 and hCG levels were independently associated with APO. Conclusion: Pregnant women with hereditary thrombophilias, all of whom were treated with LMWH, had decreased levels of all first and second trimester serum markers. In addition, levels of hCG and uE3 in the second trimester could independently predict placenta-related disorders and adverse outcomes in these patients.

722: Follow-up frequency of testing in patients at very low risk for Trisomy 21 on first trimester screening

low risk for Trisomy 21 on first trimester screening Alireza A. Shamshirsaz, Samadh Ravangard, Amirhoushang A. Shamshirsaz, James Egan, Winston A. Campbell, Peter Benn, Adam Borgida, Mary Beth Janicki, Anne-Marie Prabulos, Charles Ingardia, Debora Feldman, Gary Turner, Carolyn Zelop, Diane Timms, Padmalatha Gurram, Kisti Fuller, Yu Ming Victor Fang, Rachel Billstrom, Kevin Lenehan, Allison Sadowski University of Connecticut Health Center, Obstetrics and Gynecology, Farmington, CT, St. Francis Hospital, Obstetrics and Gynecology, Hartford, CT, University of Connecticut. Health Center, Department of Genetics and Developmental Biology, Farmington, CT, Hartford Hospital, Obstetrics and Gynecology, Hartford, CT, Beth Israel Deaconess Medical Center, Obstetrics and Gynecology, Boston, MA, Hartford Hospital, Maternal-Fetal Medicine, Hartford, CT OBJECTIVE: To determine the rate of utilization of second trimester serum [2nd TS] screening among women who are at very low risk after the first trimester [1stT] aneuploidy screen risk for trisomy 21 [T-21]. STUDY DESIGN: Records for all women with singleton pregnancies who received first trimester trisomy 21 screening (NT, PAPP-A, and hCG, the combined test) were retrospectively reviewed to determine which patients also received a sequential 2nd TS screening test (AFP, hCG, uE3, INH-A) and/or second trimester ultrasound exam (2nd US). Our screening policy was not to limit these follow-up tests to any particular sub-group of women. A very low trisomy 21 risk was defined as 1:270 in the second trimester. We excluded all the women with an increased trisomy 18 risk 1:100. RESULTS: A total of 12,218 women underwent 1stT screening, 9,332 (76.4%) were classified as very low risk for a trisomy 21 fetus. Of these 9, 332 women, 3,329 (35.6%, group A) had both 2nd TS markers and 2nd US, 1,825 (19.5%, group B) had only 2nd US, 2,343 (25.1%, group C) had only 2nd TS markers and 1,835 (19.8%, group D) had no more screening. Of the women who had 2nd TS markers (group A and C) (n 5,672, 60.7%), 56 women (1.0%) became screen-positive. The net number of women who had invasive testing (amnio) was 50 (0.5%) of which 14 women had invasive testing (amnio) after becoming screen positive in the 2nd TS markers. Within the 5,672women (group A and C) who had 2nd TS markers there was one case of trisomy 21 that remained at screen-negative after the 2nd TS markers. CONCLUSION: Women, who are at very low risk after the first trimester screening, are very unlikely to have a trisomy 21 affected pregnancy. The use of a full set of second trimester serum markers is not indicated for women who are at very low risk after first trimester screening and who have no other indications for further screening.

First trimester serum and ultrasound marker distribution in singleton pregnancy conceived with assisted reproductive technology

First trimester serum and ultrasound marker distribution in singleton pregnancy conceived with assisted reproductive technology

First trimester serum markers stability during sample transportation from the obstetrical site to the screening laboratory

Objective: To investigate the effect of temperature on first trimester free β-hCG and PAPP-A in serum during transportation. Methods: Maternal blood was collected from 30 East Asian women attending for Down syndrome screening at the primary obstetrical site. The extracted serum was split into two equal aliquots, placed in identical thermally insulated pouches with a temperature data logger and shipped to the screening laboratory. An 800 g frozen ice pack was placed in one of the pouches. Free β-hCG and PAPP-A levels were determined in the ‘Cooled’ and ‘Uncooled’ serum samples using a DELFIA® Xpress analyzer. The proportion of ‘Uncooled’ samples not within 5% of the ‘Cooled’ sample marker level was assessed. Results: The median age of subjects was 36 years, half were nulliparous and all were non-smokers. The assay stability ranged from 2.38% to 4.41%. The median total transport time from the obstetrical site to the laboratory was 17.37 h. Median recorded temperatures within the ‘Cooled’ pouch were significantly lower throughout the transportation of the samples (p < 0.0001). The median percentage change of free β-hCG and PAPP-A concentrations in ‘Uncooled’ samples relative to ‘Cooled’ samples were 2.72% (range 0.27–7.64%) and 1.10% (range 0.03%–4.29%), respectively. Free β-hCG concentrations differed by greater than 5% in eleven (37%) subjects. Conclusions: Insulated packaging, cooling media and temperature monitoring devices may be needed as additional measures to determine, minimize and exclude effects of ambient temperature on serum marker levels especially when travelling times are long or ambient temperatures are high.

Prenatal screening for trisomy 21: recent advances and guidelines

The performance of prenatal screening tests for the identification of trisomy 21 (Down syndrome) has markedly improved since the 1970s and early 1980s when maternal age was the sole mode of screening the general pregnant population. With the discovery of second trimester serum markers in the 1980s and 1990s and implementation of double, triple, and quad marker testing; the discovery of first trimester serum and ultrasound markers in the 1990s and implementation of the combined test; and the development of the integrated test and sequential screening strategies over the past decade, the performance of screening has improved to a detection rate of 90%–95% at a false positive rate of 2%–5%. In this review, I will describe the advances in prenatal screening for trisomy 21, present current screening strategies, and discuss guidelines published by professional societies and regulatory bodies, with a focus on current prenatal screening practice in the USA.

Impact of type 1 diabetes and glycemic control on fetal aneuploidy biochemical markers

To determine the influence of type 1 diabetes mellitus (T1DM) on the first trimester serum markers of fetal aneuploidy; pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (free β-hCG) and to evaluate the influence of glycemic control on these parameters in the pregnant diabetic women. Retrospective study. Data were extracted from electronic obstetric and laboratory databases at two Danish University Hospitals. Based on 36 415 pregnancies without T1DM (non-T1DM) and 331 pregnancies with T1DM; β-hCG and PAPP-A were obtained at 8+0 to 14+2 gestational weeks. Medians for PAPP-A and free β-hCG were generated and multiple of the normal gestation-specific median (MoM) values were calculated for each separate pregnancy. After adjustment for maternal weight, ethnicity and smoking status, MoM values were compared across the T1DM and non-T1DM groups, respectively. Additionally, the relationship between PAPP-A MoM and HgbA1C was examined in 348 T1DM pregnancies by Spearman's rank correlation. MAIN OUTCOME MEASURES. Difference in biochemical marker levels between T1DM and non-T1DM. PAPP-A was 0.86 MoM in T1DM pregnancies and 1.01 MoM in non-T1DM pregnancies, p < 0.0001. Conversely, free β-hCG was not altered in T1DM pregnancies (T1DM 0.99 MoM, non-T1DM 0.98 MoM; p=0.14). There was a significant inverse correlation between HgbA1C and PAPP-A (rho=-0.12, p=0.02). In T1DM pregnancies, PAPP-A MoM values were lower than in non-T1DM pregnancies. This suggests that correction should be considered in first trimester biochemical screening for fetal aneuploidy in T1DM women.

Aneuploidy screening: a position statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, January 2011

Aneuploidy screening: a position statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, January 2011

Association between uterine leiomyomas and the biochemical screening test results in the first and second trimester of pregnancy: a pilot study

Objectives. The presence of the uterine leiomyomas may change the concentrations of the screening serum markers and so after the risk calculation of the fetal chromosomal abnormalities.Purpose. To estimate the influence of the uterine leiomyomas on the first and second trimester serum markers concentrations.Material and methods. The studied group consisted of 127 women between 11 and 20 weeks of normal singleton pregnancy. In each patient, the uterine leiomyomas were diagnosed – over 20 mm in the diameter and located in the uterine wall. Seventy-seven patients had undergone the first trimester screening, 50 patients the second trimester screening. The control group consisted of 1020 women between 11 and 20 weeks of normal singleton pregnancy without uterine leiomyomas.Results. In the first trimester group, the pregnancy-associated plasma protein A serum concentrations were not different from the controls. The median concentrations of free beta-human chorionic gonadotrophin (β-hCG) were significantly higher (1.43 MoM). In the second trimester group, no significant differences in AFP and estriol median concentrations were observed, while the median value for free β-hCG was significantly higher (2.01 MoM) than in control group.Conclusions. The presence of the uterine leiomyomas may increase maternal serum concentration of the β-hCG and so after the rate of the false positive results of the prenatal screening tests.

Role of second trimester maternal serum markers as predictor of preeclampsia

Objectives To evaluate the variations and potential clinical use of second trimester serum markers as predictor of preeclampsia.

OP09.01: An association between uterine leiomyomas and the biochemical screening test results in the first and second trimester of pregnancy: a pilot study

Objectives. The presence of the uterine leiomyomas may change the concentrations of the screening serum markers and so after the risk calculation of the fetal chromosomal abnormalities. Purpose. To estimate the influence of the uterine leiomyomas on the first and second trimester serum markers concentrations. Material and methods. The studied group consisted of 127 women between 11 and 20 weeks of normal singleton pregnancy. In each patient, the uterine leiomyomas were diagnosed ‐ over 20 mm in the diameter and located in the uterine wall. Seventy-seven patients had undergone the first trimester screening, 50 patients the second trimester screening. The control group consisted of 1020 women between 11 and 20 weeks of normal singleton pregnancy without uterine leiomyomas. Results. In the first trimester group, the pregnancy-associated plasma protein A serum concentrations were not different from the controls. The median concentrations of free beta-human chorionic gonadotrophin (b-hCG) were significantly higher (1.43 MoM). In the second trimester group, no significant differences in AFP and estriol median concentrations were observed, while the median value for free b-hCG was significantly higher (2.01 MoM) than in control group. Conclusions. The presence of the uterine leiomyomas may increase maternal serum concentration of the b-hCG and so after the rate of the false positive results of the prenatal screening tests.

Prediction of adverse pregnancy outcomes by combinations of first and second trimester biochemistry markers used in the routine prenatal screening of Down syndrome

To investigate the associations between four defined adverse pregnancy outcomes and levels of first and second trimester maternal serum markers focusing in particular on how well combinations of markers predict these adverse outcomes. This was a retrospective review of associations between first and second trimester serum markers and adverse pregnancy outcomes among 141 698 women who underwent prenatal screening for Down syndrome in Ontario, Canada. Detection rates (DR), false positive rates (FPR), and odds ratios were estimated using both single and combinations of markers for the adverse outcomes defined. Women with decreased second trimester unconjugated oestriol (uE3), deceased first trimester maternal serum pregnancy-associated plasma protein A (PAPP-A), increased second trimester serum alpha fetoprotein (AFP), or increased second trimester total human chorionic gonadotrophin (hCG) were at greater risk of developing adverse pregnancy outcomes. At a 5% FPR, combinations of these markers predicted at best 33.3% of fetal loss and 31.5% of preterm births (PTB) before 32 weeks of gestation. There are significant associations between the levels of first and second trimester serum markers and adverse obstetric outcomes. However, even combinations of these markers can only predict adverse obstetric outcomes with modest accuracy.

First trimester maternal serum ADAM12s levels in twin pregnancies

A disintegrin and metalloprotease 12s (ADAM12s) is a potential first trimester serum marker for fetal trisomy and adverse pregnancy outcome in singletons. In this study, ADAM12s levels in first trimester serum of uncomplicated and complicated twins were evaluated. ADAM12s was studied in maternal serum of 215 twin pregnancies, collected between 2004 and 2008. ADAM12s was measured 'blind to outcome' using AutoDelfia (PerkinElmer, Turku, Finland). As a reference, data from 2423 singletons were used. The median ADAM12s level was increased in euploid twins [1.61 multiples of the median (MoM); n = 209] compared with singletons. The median ADAM12s MoM was significantly lower in monochorionic (1.36 MoM; n = 41) compared with dichorionic twins (1.67 MoM; n = 168) (Mann-Whitney U test, p = 0.005). Trisomy 21 was identified in two pregnancies. Median ADAM12s MoM in twins complicated by hypertensive disorders (1.77 MoM, n = 35) or small for gestational age fetus (1.54 MoM; n = 24) was not significantly different from uncomplicated twins (1.64 MoM; n = 134). Median ADAM12s MoM in euploid twins was increased compared with singletons. Monochorionic had significantly lower median ADAM12s MoM than dichorionic twins. Median ADAM12s MoMs were not significantly different in twins complicated by hypertensive disorders or small for gestational age fetus compared with uncomplicated twins.

Early onset preeclampsia and second trimester serum markers

To examine serum markers measured in the second trimester to identify women who subsequently develop preeclampsia. Clinically defined preeclampsia was confirmed in 45 women who had provided a serum sample as part of Down syndrome screening. Preeclampsia was categorized as mild or severe, as well as early (<32 weeks) or late onset. Each case was matched with five controls based on gestational age and date of serum collection. Stored sera were retrieved and tested for inhibin A, soluble vascular endothelial growth factor receptor 1 (sVEGF R1), placental growth factor (PlGF), and endoglin. Results were converted to multiples of the median (MoM) and compared in case and control pregnancies. Univariate analysis was used to identify the strongest markers, which were then used in a multivariate model. Inhibin A, PlGF, and endoglin were consistently associated with preeclampsia, especially for early onset disease. A multivariate model using the three markers could identify 50% of the pregnancies with early onset preeclampsia with a 2% false positive rate. The levels of inhibin A, PlGF, and endoglin in the second trimester can be combined using a predictive model to provide individualized risk estimates for early onset preeclampsia.

P02.10: Stability of first trimester serum markers for assessment of risk for aneuploidy

P02.10: Stability of first trimester serum markers for assessment of risk for aneuploidy

The proform of eosinophil major basic protein: a new maternal serum marker for adverse pregnancy outcome

To establish the first trimester serum levels of the proform of eosinophil major basic protein (proMBP) in pregnancies with adverse outcome. Furthermore, to determine the screening performance using proMBP alone and in combination with other first trimester markers. A case-control study was conducted in a primary hospital setting. The proMBP concentration was measured in cases with small-for-gestational age (SGA) (n = 150), spontaneous preterm delivery (n = 88), preeclampsia (n = 40), gestational hypertension (n = 10) and in controls (n = 500). Concentrations were converted to multiples of the median (MoM) in controls and groups were compared using Mann-Whitney U-test. Logistic regression analysis was used to determine significant factors for predicting adverse pregnancy outcome. Screening performance was assessed using receiver operating characteristic curves. The proMBP median was significantly reduced in pregnancies with SGA (0.81 MoM), spontaneous preterm delivery (0.83 MoM), preeclampsia (0.88 MoM) and gestational hypertension (0.60 MoM). The best screening performance was found for preeclampsia including the covariates proMBP and nulliparity yielding an area under the curve equal to 0.737 (p < 0.0005) and a 75% detection rate for a 30% false positive rate. The proMBP is a novel first trimester serum marker for adverse pregnancy outcome.

Beckwith–Wiedemann syndrome in association with posterior hypoplasia of the cerebellar vermis

We present the case of a 28-year-old woman with an unremarkable medical and obstetrical history. Both parents are Caucasian; the couple is not consanguineous and have already had a healthy child after a normal pregnancy. The first ultrasound scan at 13 weeks was considered normal. Second trimester serum markers suggested a chromosomal abnormality risk of 1/108, leading to another diagnostic ultrasound at 18 weeks, which identified an omphalocele. Karyotype analysis of the fluid sampled by amniocentesis was normal, 46, XX. The 22-week ultrasound confirmed the omphalocele. The latter contained only the small bowel, and its collar measured 20 mm. The liver was in a normal position. In addition, the fourth ventricle was open, communicating with the cisterna magna through a large canal, with hypoplasia of the posterior vermis (Figure 1). No facial anomaly was noticed. A multidisciplinary group of staff explained the poor prognosis of these morphological abnormalities to the couple, whose request that the pregnancy be terminated was approved in accordance with French law. At 25 weeks, a 1040-g female fetus (95th percentile for term) was delivered. The subsequent pathology examination confirmed the features we had observed and also showed craniofacial dysmorphy involving macroglossia, large ears with indentation of the left lobe, and a marked under-eye crease, together with organomegaly. The placenta was hypertrophic and dysmature, with heterogeneous villi. Microscopic analysis highlighted cytomegaly of the extravillous placental trophoblast cells and the fetal adrenal cortex. The association of these anomalies led to a diagnosis of Beckwith–Wiedemann syndrome (BWS). Subsequent

Serum markers for pre-eclampsia: An update on the analytes to be determined in the first, second, and third trimester

Summary Pre-eclampsia is a pregnancy-specific disorder which affects up to 10% of pregnancies and which contributes substantially to perinatal morbidity and mortality of both mother and newborn. Many molecules have been evaluated as potential serum markers for the presence and confirmation of the disease in the third trimester, and subsequently for its prediction in the second trimester. With the increasing sensitivities of the laboratory assays, these efforts are now focused to the first trimester. Impaired early trophoblast invasion is supposed to be at the origin of the events leading to pre-eclampsia, suggesting that it should be possible to detect abnormal levels of certain molecules or markers, in particular those related to trophoblastic activity, at the very early stages of pregnancy. The scope of this paper is to review, with data from the literature as well as from an in-house study, the usefulness of various maternal serum markers, with a special focus on those of placental origin, for the early prediction of pre-eclampsia occurring later during gestation. It remains difficult to predict late-onset pre-eclampsia in early pregnancy, and no “miracle” first trimester serum marker has so far been found to be specifically associated to this pathology. The use of formulae combining concentrations of a set of markers, which must be regulated independently from each other, may increase the detection rate. Elevated concentrations of Inhibin A, Activin A and soluble endoglin (sEng), or reduced levels of Placenta Growth Factor (PLGF), Pregnancy-associated Plasma Protein A (PAPP-A), or Placental Protein-13 (PP13) indicate, with high sensitivity but low specificity, an increased risk of a later occurring gestational pathology and should alert the clinician.

587: Assessment of risk for birth weight < 5th percentile for gestational age by maternal characteristics with nuchal translucency and maternal serum markers

To develop and evaluate a method of patient-specific risk estimation for birth weight at <5th percentile for gestational age combining maternal characteristics with nuchal translucency and first and second trimester serum markers.

Prenatal screening and diagnosis—An introduction

Prenatal screening and diagnosis—An introduction

Patient choice in first trimester screening for fetal down syndrome

DEVEREUX SALLER, LISA PASTORE, KAREN VENTURA, LOGAN KARNS, ERIKA WERNER, University of Virginia, Obstetrics & Gynecology, Charlottesville, Virginia OBJECTIVE: Options for Down syndrome (DS) screening in the first trimester include combined first trimester screening (FTS) (nuchal translucency (NT) & first trimester serum markers) & integrated screening (Integrated) (NT, first & second trimester serum markers). We investigated patient choice & motivation regarding these screening options, theorizing that the test chosen might be predictable based on demographic characteristics. STUDY DESIGN: Patients had genetic counseling & were offered FTS or Integrated. An attempt was made to objectively describe the advantages of each test. All patients were offered a survey prior to undergoing NT. Whether completed or not, the survey was sealed in an envelope & forwarded to the study epidemiologist. Medical providers were blinded as to participation. RESULTS: Of 100 patients, 78 non-selected patients and 41 partners completed the form. 47 (60%) & chose FTS & 31 (40%) chose Integrated. There were no differences between FTS and Integrated patients in Maternal Age, genetic counselor, indication (O35yo vs. screening), educational level, working outside the home, or proximity to our medical center (p range=0.090.98). The median age in both groups was 35, however there was a significant difference in a priori age-related DS risk (Median risk: FTS 1:190 vs. Integrated 1:300, p=0.02). FTS was chosen by some of the youngest & oldest patients, yielding the same median age, but a higher median age-related risk. Reasons for choosing the screening test differ by test chosen (p!0.001). Reasons stated most frequently were: ‘‘earliest reassurance’’ (79% FTS) vs. ‘‘most information’’ (80% Integrated) and ‘‘lowest chance of needing additional diagnostic testing’’ (55% Integrated). CONCLUSION: Given the choice and objective counseling, significant percentages of patients chose each screening test. Patient choice of FTS or Integrated screening is not predictable based on demographic characteristics. Following genetic counseling, the stated reasons for choosing a particular screening test were consistent with the characteristics of that test.