Marker For Adverse Pregnancy Outcomes Research Articles

EP03.12: Early identification of fetal hydrothorax: investigating causes and potential significance as a new sonographic marker for adverse pregnancy outcomes

EP03.12: Early identification of fetal hydrothorax: investigating causes and potential significance as a new sonographic marker for adverse pregnancy outcomes

Pregnancy-Associated Plasma Protein-A: Its Significance as a Single Biomarker for Adverse Obstetric Outcomes

OBJECTIVES: Low levels of pregnancy-associated plasma protein-A in pregnant women linked to unhealthy placentation and a spectrum of maternal and fetal complications. Its assessment as a single biomarker has the potential to identify high-risk pregnancies. This prospective observational study was conducted to find a correlation between low pregnancy-associated plasma protein-A levels in the first trimester of pregnancy with various obstetric outcomes to establish if it can be used as a single biomarker for counseling couples. STUDY DESIGN: The study was conducted at Base Hospital, Delhi Cantt. Maternal serum pregnancy-associated plasma protein-A levels were assessed at 11 to 13+6 weeks of gestation, converted in multiples of the median and patients were followed till delivery. Maternal outcomes were recorded in terms of abortions, development of gestational hypertension, gestational diabetes, preeclampsia, placental abruption, fetal growth restriction, fetal demise, neonatal intensive care unit admission, etc., and analyzed to find an association with levels first trimester of pregnancy-associated plasma protein-A. RESULTS: Low pregnancy-associated plasma protein-A levels showed a statistically significant association with gestational hypertension, preeclampsia, abortion, fetal demise, and also for adverse neonatal outcomes like APGAR <5 at 1 min, fetal growth restriction, neonatal intensive care unit admission, and perinatal deaths. No significant association was observed for preterm delivery, gestational diabetes, and placental abruption. CONCLUSION: Serum pregnancy-associated plasma protein-A levels in the first trimester of pregnancy have the potential of being utilized as a validated marker for adverse pregnancy outcomes. Early identification of such pregnancies can help in optimizing feto-maternal outcomes through closer surveillance, timely intervention, and referral to tertiary care centers. Further research would help the fraternity in developing a prediction model.

Physical Activity and High-Sensitivity C-Reactive Protein in Pregnancy: Does It Matter during Leisure or Work?

Physical activity (PA), regardless of domain, is recommended for pregnant individuals in clinical guidelines, but limited evidence is available for work-related PA. This study aimed to examine the associations of occupational (OPA) and leisure-time PA (LTPA) with plasma high-sensitivity C-reactive protein (hs-CRP), a risk marker for adverse pregnancy outcomes, among pregnant individuals. This longitudinal study included 257 workers in the fetal growth cohort. OPA/LTPA and hs-CRP were measured in each trimester. OPA/LTPA was divided into high and low groups by the median level. Multivariable linear regressions were applied to estimate the adjusted geometric mean differences of hs-CRP (mg·L-1) comparing high versus low OPA/LTPA in each trimester and the changes in OPA/LTPA over pregnancy. OPA was positively associated with hs-CRP (high: 5.14 vs low: 3.59; P value: 0.001) in the first trimester, particularly for standing/walking or walking fast, regardless of carrying things. LTPA was negatively associated with hs-CRP in the second (high: 3.93 vs low: 5.08; 0.02) and third trimesters (high: 3.30 vs low: 4.40; 0.046). Compared with the low OPA + high LTPA group, hs-CRP was higher in both the high OPA + high LTPA and high OPA + low LTPA groups in the first trimester, and in the high OPA + low LTPA group only in the third trimester. The change in OPA during pregnancy was positively associated with hs-CRP, whereas the change in LTPA was negatively associated with hs-CRP from the second to the third trimester. In pregnant individuals, LTPA was negatively associated with hs-CRP, whereas OPA was positively associated with hs-CRP. More research on OPA's health impact among pregnant individuals is needed, and guidelines may consider the potential unfavorable influence of OPA on pregnant individuals.

Anti-β2 glycoprotein-I domain 1 antiphospholipid antibodies as a marker for adverse pregnancy outcomes

Anti-β2 glycoprotein-I domain 1 antiphospholipid antibodies as a marker for adverse pregnancy outcomes

Proteoglycans: Systems-Level Insight into Their Expression in Healthy and Diseased Placentas.

Proteoglycan macromolecules play key roles in several physiological processes (e.g., adhesion, proliferation, migration, invasion, angiogenesis, and apoptosis), all of which are important for placentation and healthy pregnancy. However, their precise roles in human reproduction have not been clarified. To fill this gap, herein, we provide an overview of the proteoglycans’ expression and role in the placenta, in trophoblast development, and in pregnancy complications (pre-eclampsia, fetal growth restriction), highlighting one of the most important members of this family, syndecan-1 (SDC1). Microarray data analysis showed that of 34 placentally expressed proteoglycans, SDC1 production is markedly the highest in the placenta and that SDC1 is the most upregulated gene during trophoblast differentiation into the syncytiotrophoblast. Furthermore, placental transcriptomic data identified dysregulated proteoglycan genes in pre-eclampsia and in fetal growth restriction, including SDC1, which is supported by the lower concentration of syndecan-1 in maternal blood in these syndromes. Overall, our clinical and in vitro studies, data analyses, and literature search pointed out that proteoglycans, as important components of the placenta, may regulate various stages of placental development and participate in the maintenance of a healthy pregnancy. Moreover, syndecan-1 may serve as a useful marker of syncytialization and a prognostic marker of adverse pregnancy outcomes. Further studies are warranted to explore the role of proteoglycans in healthy and complicated pregnancies, which may help in diagnostic or therapeutic developments.

Menstrual cycle length and adverse pregnancy outcomes among women in Project Viva.

Retrospective studies suggest that menstrual cycle length may be a risk marker of adverse pregnancy outcomes, but this evidence is susceptible to recall bias. To evaluate the prospective association between menstrual cycle length and the risk of adverse pregnancy outcomes. Secondary analysis of 2046 women enrolled in Project Viva at ~10weeks of gestation and followed through delivery. The exposure was menstrual cycle length. The outcomes included gestational glucose tolerance (gestational diabetes/impaired glucose tolerance [GDM/IGT] and isolated hyperglycaemia), hypertensive disorders of pregnancy (gestational hypertension/preeclampsia), gestational weight gain, birthweight-for-gestational age z-scores (BWZ) categorised in tertiles, preterm birth and birth outcome (live birth and pregnancy loss). We used modified Poisson and multinomial logistic regression adjusted for age, race/ethnicity, parity, age at menarche and pre-pregnancy body mass index. Mean (SD) age at enrolment was 32.1 (4.9) years. Most women (74.3%) had a cycle length of 26-34days (reference group), 16.2% reported short cycles (≤25days), and 9.5% reported long/irregular cycles (≥35days/too irregular to estimate). Compared with the reference group, women with short cycles had lower odds of GDM/IGT (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.28, 0.89), whereas women with long/irregular cycles had higher odds (OR 1.72, 95% CI 1.04, 2.83). Additionally, women with short cycles had higher odds of having a newborn in the lowest tertile of BWZ (OR 1.45, 95% CI 1.06, 1.98). There was a U-shaped relation between cycle length and preterm birth with both short (relative risk [RR] 1.49, 95% CI 0.98, 2.27) and long/irregular (RR 2.04, 95% CI 1.30, 3.20) cycles, associated with a higher risk. Variation in menstrual cycle length may be a risk marker of GDM/IGT, lower birth size and preterm birth and flag women who may benefit from targeted monitoring and care before and during pregnancy.

Non-Lactobacillus-Dominated Vaginal Microbiota Is Associated With a Tubal Pregnancy in Symptomatic Chinese Women in the Early Stage of Pregnancy: A Nested Case-Control Study.

The features of the vaginal microbiota (VM) community can reflect health status, and they could become new biomarkers for disease diagnosis. During pregnancy, domination of bacteria of the genus Lactobacillus in the VM community is regarded as a keystone because they stabilize the VM by producing antimicrobial compounds and competing adhesion. An altered VM composition provides a marker for adverse pregnancy outcomes. This nested case–control study aimed to characterize the VM in women with a tubal pregnancy (TP) presenting with pain and/or uterine bleeding in early pregnancy. Chinese women with a symptomatic early pregnancy of unknown location were the study cohort. 16S rDNA gene-sequencing of V3–V4 variable regions was done to assess the diversity, structures, taxonomic biomarkers, and classification of the VM community. The primary outcome was the location of the early pregnancy. The VM community in women with a TP showed higher diversity (PD-whole-tree, median: 8.26 vs. 7.08, P = 0.047; Shannon Diversity Index, median: 1.43 vs 0.99, P = 0.03) and showed different structures to those in women with an intrauterine pregnancy (IUP) (R = 0.23, P < 0.01). Bacteria of the genus Lactobacillus were significantly enriched in the IUP group, whereas bacteria of the genera Gardnerella and Prevotella were significantly enriched in the TP group. Lactobacillus abundance could be used to classify the pregnancy location (AUC = 0.81). Non-Lactobacillus-dominated microbiota (≤ 0.85% Lactobacillus) was significantly associated with a TP (adjusted odds ratio: 4.42, 95% confidence interval: 1.33 to 14.71, P = 0.02). In conclusion, among women with a symptomatic early pregnancy, a higher diversity and lower abundance of Lactobacillus in the VM is associated with a TP.

Altered cerebro-placental ratio is an early marker of adverse pregnancy outcome–a prospective study

Background: Fetal growth restriction (FGR) is a complex and common obstetric problem. It is associated with perinatal morbidity and mortality which accounts for about 10-15%. The diagnosis of FGR is made by clinical evaluation and ultrasonography. Objectives: To investigate the role of the efficacy of the cerebroplacental ratio as a marker of reduced fetal growth rate. To establish a relationship between Cerebro placental ratio at term with reduced fetal growth velocity and adverse pregnancy outcome. Methods: A Prospective study, in which study participants were subjected for Ultrasonography at 20 to 25 weeks for Abdominal Circumference and Ultrasonography above 35 weeks period of gestation were subjected to fetal biometry and Doppler studies. All Doppler indices will be converted into multiples of the median (MoM), correcting for gestational age using reference ranges, umbilical & middle cerebral arteries and birthweight values are converted into centiles. Results: Among 80 % of participants low cerebroplacental ratio were associated with low abdominal circumference and low growth velocity. The low cerebroplacental ratio risk is associated with the need for operative delivery. Conclusion: Altered Cerebroplacental ratio is the earlier marker of adverse fetal outcome than the biophysical profile. Low Cerebro placental ratio(<1) is associated with impaired fetal growth velocity and adverse pregnancy outcomes.

Relationship Between Placental Calcification and Estimated Fetal Weight Percentile at 30-34 Weeks of Pregnancy

Objectives: The identification of at-risk fetus is considered as one of the most difficult challenges for clinicians and researchers although the clinical significance of placental calcifications (PCs) and its relation to adverse pregnancy outcome are controversial. Therefore, the present study aimed to evaluate the relationship between PC and estimated fetal weight (EFW) percentile at 30-34 weeks of pregnancy. Materials and Methods: This prospective cross-sectional study was carried out on all pregnant women except for multiple pregnancy subjects who were admitted to an outpatient perinatal center from October 2016 to September 2018. Several parameters were measured at 30-34 weeks of pregnancy, including EFW, umbilical artery pulsatility index (PI), middle cerebral artery PI, cerebroplacental ratio (CPR), right and left uterine artery PI, along with right and left uterine artery notch. Finally, the calcification of the placenta with any shape and degree was determined as well. Results: In this study, 739 pregnant women were evaluated for PC, including patients with PC (9.87%), small-for-gestational age (SGA, 3.65%), and those with at least one abnormal Doppler index (23.95%). Patients with PC and those with at least one abnormal Doppler index had significantly higher SGA (29.62% and 12.42%, respectively). In addition, there were 55.55% and 30.13% patients with SGA and PC in the group with at least one abnormality in terms of Doppler indices. Conclusions: In general, the findings showed that PC is more common in SGA. Based on the results, at least one abnormality in Doppler indices was more common in PC and SGA, and uterine artery Doppler abnormality was the most prevalent abnormal findings in the arterial Doppler. Thus, PC may be an important marker for adverse pregnancy outcomes.

EP02.06: Umbilical artery Doppler study at 28–30 weeks of gestation as a predictive marker of adverse pregnancy outcomes

EP02.06: Umbilical artery Doppler study at 28–30 weeks of gestation as a predictive marker of adverse pregnancy outcomes

Urinary IgM excretion: a reliable marker for adverse pregnancy outcomes in women with chronic kidney disease

ObjectiveChronic kidney disease (CKD) pregnancies are at high risk of developing adverse outcomes. In non-pregnant subjects with CKD, higher urinary IgM levels are associated with poor renal survival and higher rates of cardiovascular deaths. In this study, we assessed whether urinary IgM levels are associated with an increased risk of adverse pregnancy outcomes (APO) in CKD pregnancies.MethodsWe performed a nested case–control study within a cohort of CKD patients with singleton pregnancies attended at a tertiary care hospital. The study included 90 CKD patients who eventually developed one or more APO and 77 CKD patients who did not. Urinary IgM excretion was determined from the 24-h urine samples at enrollment by an ultrasensitive enzyme immunoassay.ResultsThe risk for combined APO and for preeclampsia (PE) was higher among women with urinary IgM and proteinuria levels values in the highest quartile or with CKD stages 4–5 (odds ratios, OR ≥ 2.9), compared with the lowest quartile or with CKD stage 1. Urinary IgM levels were more closely associated with the risk of either combined or specific APO (PE, preterm birth, and for having a small-for-gestational-age infant; OR ≥ 5.9) than either the degree of total proteinuria or CKD stages. Among patients with CKD stage 1, the risk of combined APO, PE, and preterm birth was higher in women with urinary IgM levels values in the highest quartile (OR ≥ 4.8), compared with the three lower quartiles, independently of proteinuria.ConclusionIn CKD pregnancies, at the time of initial evaluation, proteinuria and CKD stage are associated with increased risk of combined APO. However, urinary IgM concentrations appear to be better predictors of an adverse outcome and may be useful for risk stratification in CKD pregnancies.

Повышенное образование тромбина – потенциальный маркер неблагоприятных исходов беременности

Повышенное образование тромбина – потенциальный маркер неблагоприятных исходов беременности

Maternal-foetal outcomes in pregnant women with glomerulonephritides. Are all glomerulonephritides alike in pregnancy?

In spite of the interest for chronic renal diseases (CKD) in pregnancy data on specific diseases is fragmentary; while recent studies analysed the most common glomerulonephritides (GN), none was addressed at GN as a group. The aim of our study was to analyse the main pregnancy-related outcomes in GN patients in a large multicentre cohort.Patients with a diagnosis of GN were selected from the TOCOS cohort (TOCOS: TOrino Cagliari Observational Study): out of 714 singleton deliveries GN was the diagnosis in 126; lupus GN and IgA nephropathy accounted for 37 and 33 cases; 1418 low-risk singleton deliveries followed-up in the same Centers served as controls (non diabetic, non nephropathic, non obese women, without any other known chronic illness; pregnancies after ovodonation or in vitro fertilisation were excluded, if declared). Multiple regression analysis considered: pre-term (<37 weeks), early preterm delivery (<34 weeks), small for gestational age baby (SGA) and the development of hypertension, proteinuria and preeclampsia (PE) limiting this outcome to the cases without hypertension and proteinuria at baseline.The population consisted mainly of early CKD stages (stage 1: 61.9%; hypertension 27.8%; proteinuria <0.5 g/day: 55.7%). Age and parity were not different in cases and low-risk controls (age: 31.20 ± 5.5 vs 31.24 ± 5.5 years, primiparous 56.3% vs 57.5%). The incidence of preterm and early preterm delivery was higher in GN versus controls and increased commensurately with CKD stage. In the multivariate analysis, CKD stage was significantly associated with early preterm delivery and development-doubling of proteinuria (odds ratio (OR) around 3 in both), while the OR for baseline hypertension did not reach statistical significance. While the risk pattern did not differ in lupus and non-lupus GN, a significantly higher OR of PE was observed in IgA nephropathy (OR 28.09 versus other GN); risk for pre-term delivery was not increased (OR 0.27 (0.06–1.11)), thereby suggesting “late-maternal” PE.In conclusion, within the limits of heterogeneity and small numbers, our analysis identifies proteinuria as the most reliable risk marker for adverse pregnancy outcomes and suggests a specific association between IgA nephropathy and late-maternal PE.

Acoustic radiation force impulse elastosonography of placenta in maternal red blood cell alloimmunization: a preliminary and descriptive study.

Maternal red blood cell alloimmunization is an important cause of fetal morbidity and mortality in the perinatalperiod, despite well-organized prophylaxis programs. The objective of the study was to evaluate placental elasticity by usingAcoustic Radiation Force Impulse (ARFI) in Rhesus (Rh) alloimmunized pregnant women with hydropic and nonhydropicfetuses and to compare those with healthy pregnant women. This case-control and descriptive studycomprised twenty-eight healthy pregnant women, 14 Rh alloimmunized pregnant women with nonhydropic fetuses, and 16 Rhalloimmunized pregnant women with hydropic fetuses in the third trimester of pregnancy. Placental elasticity measurementswere performed by ARFI elastosonography at the day of delivery. The maternal characteristics and neonatal outcomes of thepatients were also noted. The highest mean placental ARFI scores were observed in Rh alloimmunized pregnantwomen with hydropic fetuses (1.13 m/s) (p=0.001). Healthy controls and Rh alloimmunized pregnant women with nonhydropicfetuses had similar mean placenta ARFI scores (0.84 m/s, 0.88 m/s, respectively) (p<0.05). Based onthe present findings, the placenta becomes stiffer in Rh alloimmunized pregnancies complicated with hydrops fetalis. Theincreased placental ARFI scores may be a supplemental marker for adverse pregnancy outcomes, additional to Doppler evaluationof middle cerebral artery. This data should be confirmed with a large sample size and prospective studies by using serialmeasurements of ARFI elastosonography in maternal red blood cell alloimmunization.

96: Quantification of cell free fetal DNA in maternal circulation as a marker of adverse pregnancy outcomes

96: Quantification of cell free fetal DNA in maternal circulation as a marker of adverse pregnancy outcomes

Maternal serum disintegrin and metalloprotease protein-12 in early pregnancy as a potential marker of adverse pregnancy outcomes.

ObjectivesThe aim of this study was to determine whether the concentration of disintegrin and metalloprotease protein12 (ADAM12) in first trimester maternal serum can be used as a marker for first-trimester complete spontaneous abortions, missed abortions, ectopic pregnancies and hydatidiform moles.MethodsThe maternal serum concentrations of ADAM12 were measured in the range of 5–9+6 weeks of gestation using an automated AutoDelfia immunoassay platform in 9 cases of complete spontaneous abortion, 27 cases of missed abortions, 56 cases of ectopic pregnancies, 12 cases of hydatidiform moles, and 100 controls. Logistic regression analysis was used to determine significant factors for predicting adverse pregnancy outcomes in early pregnancy. Screening performance was assessed using receiver operating characteristic curves.ResultsTwo hundred and four women were enrolled in the study. In the control group, the level of ADAM12 increased with gestational age. The median ADAM12 levels in the spontaneous abortion (0.430 MoM), ectopic pregnancy (0.460 MoM) and hydatidiform mole (0.037 MoM) groups were lower than that in the control group, while the median ADAM12 level in the missed abortion group (1.062 MoM) was not significant from the controls (1.002 MoM). Logistic regression analysis demonstrated that the level of ADAM12 in maternal serum facilitated the detection of ectopic pregnancies (OR = 0.909; 95% CI = 0.841∼0.982) and complete spontaneous abortion (OR = 0.863; 95% CI = 0.787∼0.946).ConclusionsIn complete spontaneous abortion and ectopic pregnancy, ADAM12 maintained at low levels in early pregnancies, and there were significant differences compared to normal pregnancies. ADAM12 is a promising marker for the diagnosis of complete spontaneous abortion and ectopic pregnancy in symptomatic women, and under certain conditions, ADAM12 can diagnose ectopic pregnancy and spontaneous abortion before an ultrasonographic detection of the conditions.

Profiling Lgals9 Splice Variant Expression at the Fetal-Maternal Interface: Implications in Normal and Pathological Human Pregnancy1

Disruption of fetal-maternal tolerance mechanisms can contribute to pregnancy complications, including spontaneous abortion. Galectin-9 (LGALS9), a tandem repeat lectin associated with immune modulation, is expressed in the endometrium during the mid and late secretory phases and in decidua during human early pregnancy. However, the role of LGALS9 during pregnancy remains poorly understood. We used real-time PCR and immunohistochemical staining to analyze the expression of Lgals9/LGALS9 during mouse gestation as well as in human tissues obtained from normal pregnancy and spontaneous abortions. In mice, three Lgals9 splice variants were detected, the expression of which was differentially regulated during gestation. Furthermore, decidual Lgals9 expression was deregulated in a mouse model of spontaneous abortion, whereas placental levels did not change. We further found that the LGALS9 D5 isoform suppresses interferon gamma production by decidual natural killer cells. In human patients, six Lgals9 splice variants were detected, and a decrease in Lgals9 D5/10 was associated with spontaneous abortion. Altogether, these results show a differential regulation of Lgals9 isoform expression during normal and pathological pregnancies and designate Lgals9 as a potential marker for adverse pregnancy outcomes.

Reverse end-diastolic flow in a fetus with a rare liver malformation: a case report

IntroductionWe describe a case of early and persistent reverse end-diastolic flow in the middle cerebral artery in a fetus with severe ascites. These features are associated with a rare liver malformation known as ductal plate malformation.Case presentationA 28-year-old Caucasian woman was referred to our high-risk obstetric unit at 24 weeks' gestation for fetal ascites detected during a routine ultrasound examination. During her hospitalization we performed medical investigations, including a fetal paracentesis, to detect the etiology of fetal ascites. The cause of fetal ascites (then considered non-immune or idiopathic) was not evident, but a subsequent ultrasound examination at 27 weeks' gestation showed a reverse end-diastolic flow in the middle cerebral artery without any other Doppler abnormalities. A cesarean section was performed at 28 weeks' gestation because of the compromised fetal condition. An autopsy revealed a rare malformation of intrahepatic bile ducts known as ductal plate malformation.ConclusionPersistent reverse flow in the middle cerebral artery should be considered a marker of adverse pregnancy outcome. We recommend careful ultrasound monitoring in the presence of this ultrasonographic sign to exclude any other cause of increased intracranial pressure. To better understand the nature of these ultrasonographic signs, additional reports are deemed necessary. In fact in our case, as confirmed by histopathological examination, the fetal condition was extremely compromised due to failure of the fetal liver. Ductal plate malformation altered the liver structures causing hypoproteinemia and probably portal hypertension. These two conditions therefore explain the severe hydrops that compromised the fetal situation.

First trimester maternal serum pregnancy‐specific beta‐1‐glycoprotein (SP1) as a marker of adverse pregnancy outcome

To establish the first trimester levels of pregnancy-specific beta-1-glycoprotein (SP1) in pregnancies with adverse outcome. Furthermore, to determine the screening performance for adverse outcome using SP1 alone and in combination with other first trimester markers including proMBP and PAPP-A. A case-control study was conducted in a primary hospital setting. The SP1 concentration was measured in first trimester maternal serum in pregnancies with small-for-gestational age fetuses (SGA) (n = 150), spontaneous preterm delivery (n = 88), preeclampsia (n = 40) 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 (ROC) curves. The SP1 MoM median was significantly reduced in cases with SGA (0.76 MoM, p < 0.0005) and spontaneous preterm delivery (0.77 MoM, p < 0.0005) whereas no alteration was found in cases with preeclampsia (0.94 MoM, p = 0.723). A significant correlation (r = 0.217) between log(10)(SP1 MoM) and the birth weight percentile was found in the SGA group. Screening performance was only slightly improved when SP1 was combined with PAPP-A or proMBP. SP1 is a first trimester maternal serum marker of SGA and preterm delivery.

Nuchal translucency measurement and pregnancy outcome in karyotypically normal fetuses.

The aim of the study was to evaluate the use of nuchal translucency measurement as a marker of adverse pregnancy outcome in karyotypically normal fetuses. During the years 1995-99, nuchal translucency (NT) measurement was routinely offered to all women who had their dating scan in our unit. From the data collected, we calculated the 95th and 99th centiles of the NT for a given crown-rump length using regression analysis. The NT measurements were analyzed in relation to pregnancy outcome, especially with regards to miscarriage, intrauterine death and diagnosis of fetal structural abnormalities, after excluding chromosomal abnormalities. The pregnancy outcome was available in 6650 (89%) of the 7500 pregnancies. In fetuses with an NT over the 99th centile, 17.8% (relative risk 12.2, 95% CI 7.2-20.8) had an adverse pregnancy outcome (miscarriage, intrauterine death, or termination for fetal abnormality) versus 1.5% for those with a normal measurement. The incidence of structural abnormalities, especially heart defects, was significantly increased in the high-NT groups. Three out of 11 fetuses with major cardiac abnormalities had an NT measurement over the 99th centile. The calculated relative risk for major heart defects in fetuses with increased NT was 33.5 (95% CI 9-123). In the setting of routine antenatal screening, an increased NT measurement is a marker of a high-risk pregnancy even in karyotypically normal fetuses. In addition, the increased incidence of structural abnormalities makes the close follow-up of these pregnancies imperative and should include specialized fetal echocardiography.