Harris Birthright Research Centre for Fetal Medicine

BACKGROUND: Previous randomized trials have shown that progesterone administration in women who previously delivered prematurely reduces the risk of recurrent premature delivery. Asymptomatic women found at midgestation to have a short cervix are at greatly increased risk for spontaneous early preterm delivery, and it is unknown whether progesterone reduces this risk in such women. METHODS: Cervical length was measured by transvaginal ultrasonography at a median of 22 weeks of gestation (range, 20 to 25) in 24,620 pregnant women seen for routine prenatal care. Cervical length was 15 mm or less in 413 of the women (1.7%), and 250 (60.5%) of these 413 women were randomly assigned to receive vaginal progesterone (200 mg each night) or placebo from 24 to 34 weeks of gestation. The primary outcome was spontaneous delivery before 34 weeks. RESULTS: Spontaneous delivery before 34 weeks of gestation was less frequent in the progesterone group than in the placebo group (19.2% vs. 34.4%; relative risk, 0.56; 95% confidence interval [CI], 0.36 to 0.86). Progesterone was associated with a nonsignificant reduction in neonatal morbidity (8.1% vs. 13.8%; relative risk, 0.59; 95% CI, 0.26 to 1.25; P=0.17). There were no serious adverse events associated with the use of progesterone. CONCLUSIONS: In women with a short cervix, treatment with progesterone reduces the rate of spontaneous early preterm delivery. (ClinicalTrials.gov number, NCT00422526 [ClinicalTrials.gov].).

OBJECTIVE: To examine the significance of fetal nuchal translucency at 10-14 weeks' gestation in the prediction of abnormal fetal karyotype. DESIGN: Prospective screening study. SETTING: The Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London. SUBJECTS: 827 fetuses undergoing first trimester karyotyping by amniocentesis or chorionic villus sampling. MAIN OUTCOME MEASURE: Incidence of chromosomal defects. RESULTS: The incidence of chromosomal defects was 3% (28 of 827 cases). In the 51 (6%) fetuses with nuchal translucency 3-8 mm thick the incidence of chromosomal defects was 35% (18 cases). In contrast, only 10 of the remaining 776 (1%) fetuses were chromosomally abnormal. CONCLUSION: Fetal nuchal translucency > or = 3 mm is a useful first trimester marker for fetal chromosomal abnormalities.

OBJECTIVES: To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies (SCA). METHODS: Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 31 December 2016. The inclusion criteria were peer-reviewed study reporting on clinical validation or implementation of maternal cfDNA testing in screening for aneuploidies, in which data on pregnancy outcome were provided for more than 85% of the study population. We excluded case-control studies, proof-of-principle articles and studies in which the laboratory scientists carrying out the tests were aware of fetal karyotype or pregnancy outcome. Pooled detection rates (DRs) and false-positive rates (FPRs) were calculated using bivariate random-effects regression models. RESULTS: In total, 35 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. In the combined total of 1963 cases of trisomy 21 and 223 932 non-trisomy 21 singleton pregnancies, the weighted pooled DR and FPR were 99.7% (95% CI, 99.1-99.9%) and 0.04% (95% CI, 0.02-0.07%), respectively. In a total of 563 cases of trisomy 18 and 222 013 non-trisomy 18 singleton pregnancies, the weighted pooled DR and FPR were 97.9% (95% CI, 94.9-99.1%) and 0.04% (95% CI, 0.03-0.07%), respectively. In a total of 119 cases of trisomy 13 and 212 883 non-trisomy 13 singleton pregnancies, the weighted pooled DR and FPR were 99.0% (95% CI, 65.8-100%) and 0.04% (95% CI, 0.02-0.07%), respectively. In a total of 36 cases of monosomy X and 7676 unaffected singleton pregnancies, the weighted pooled DR and FPR were 95.8% (95% CI, 70.3-99.5%) and 0.14% (95% CI, 0.05-0.38%), respectively. In a combined total of 17 cases of SCA other than monosomy X and 5400 unaffected singleton pregnancies, the weighted pooled DR and FPR were 100% (95% CI, 83.6-100%) and 0.004% (95% CI, 0.0-0.08%), respectively. For twin pregnancies, in a total of 24 cases of trisomy 21 and 1111 non-trisomy 21 cases, the DR was 100% (95% CI, 95.2-100%) and FPR was 0.0% (95% CI, 0.0-0.003%), respectively. CONCLUSIONS: Screening by analysis of cfDNA in maternal blood in singleton pregnancies could detect > 99% of fetuses with trisomy 21, 98% of trisomy 18 and 99% of trisomy 13 at a combined FPR of 0.13%. The number of reported cases of SCA is too small for accurate assessment of performance of screening. In twin pregnancies, performance of screening for trisomy 21 is encouraging but the number of cases reported is small. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVES: To validate the clinical efficacy and practical feasibility of massively parallel maternal plasma DNA sequencing to screen for fetal trisomy 21 among high risk pregnancies clinically indicated for amniocentesis or chorionic villus sampling. DESIGN: Diagnostic accuracy validated against full karyotyping, using prospectively collected or archived maternal plasma samples. SETTING: Prenatal diagnostic units in Hong Kong, United Kingdom, and the Netherlands. PARTICIPANTS: 753 pregnant women at high risk for fetal trisomy 21 who underwent definitive diagnosis by full karyotyping, of whom 86 had a fetus with trisomy 21. Intervention Multiplexed massively parallel sequencing of DNA molecules in maternal plasma according to two protocols with different levels of sample throughput: 2-plex and 8-plex sequencing. MAIN OUTCOME MEASURES: Proportion of DNA molecules that originated from chromosome 21. A trisomy 21 fetus was diagnosed when the z score for the proportion of chromosome 21 DNA molecules was >3. Diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were calculated for trisomy 21 detection. RESULTS: Results were available from 753 pregnancies with the 8-plex sequencing protocol and from 314 pregnancies with the 2-plex protocol. The performance of the 2-plex protocol was superior to that of the 8-plex protocol. With the 2-plex protocol, trisomy 21 fetuses were detected at 100% sensitivity and 97.9% specificity, which resulted in a positive predictive value of 96.6% and negative predictive value of 100%. The 8-plex protocol detected 79.1% of the trisomy 21 fetuses and 98.9% specificity, giving a positive predictive value of 91.9% and negative predictive value of 96.9%. CONCLUSION: Multiplexed maternal plasma DNA sequencing analysis could be used to rule out fetal trisomy 21 among high risk pregnancies. If referrals for amniocentesis or chorionic villus sampling were based on the sequencing test results, about 98% of the invasive diagnostic procedures could be avoided.

OBJECTIVES: To estimate procedure-related risks of miscarriage following amniocentesis and chorionic villus sampling (CVS) based on a systematic review of the literature and a meta-analysis. METHODS: A search of MEDLINE, EMBASE, CINHAL and The Cochrane Library (2000-2014) was performed to review relevant citations reporting procedure-related complications of amniocentesis and CVS. Only studies reporting data on more than 1000 procedures were included in this review to minimize the effect of bias from smaller studies. Heterogeneity between studies was estimated using Cochran's Q, the I(2) statistic and Egger bias. Meta-analysis of proportions was used to derive weighted pooled estimates for the risk of miscarriage before 24 weeks' gestation. Incidence-rate difference meta-analysis was used to estimate pooled procedure-related risks. RESULTS: The weighted pooled risks of miscarriage following invasive procedures were estimated from analysis of controlled studies including 324 losses in 42 716 women who underwent amniocentesis and 207 losses in 8899 women who underwent CVS. The risk of miscarriage prior to 24 weeks in women who underwent amniocentesis and CVS was 0.81% (95% CI, 0.58-1.08%) and 2.18% (95% CI, 1.61-2.82%), respectively. The background rates of miscarriage in women from the control group that did not undergo any procedures were 0.67% (95% CI, 0.46-0.91%) for amniocentesis and 1.79% (95% CI, 0.61-3.58%) for CVS. The weighted pooled procedure-related risks of miscarriage for amniocentesis and CVS were 0.11% (95% CI, -0.04 to 0.26%) and 0.22% (95% CI, -0.71 to 1.16%), respectively. CONCLUSION: The procedure-related risks of miscarriage following amniocentesis and CVS are much lower than are currently quoted.

OBJECTIVE: To evaluate the effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome by performing a systematic review of available published literature on pregnancies affected by COVID-19. METHODS: We performed a systematic review to evaluate the effect of COVID-19 on pregnancy, perinatal and neonatal outcome. We conducted a comprehensive literature search using PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure Database and Wan Fang Data up to and including 20 April 2020 (studies were identified through PubMed alert after that date). For the search strategy, combinations of the following keywords and medical subject heading (MeSH) terms were used: 'SARS-CoV-2', 'COVID-19', 'coronavirus disease 2019', 'pregnancy', 'gestation', 'maternal', 'mother', 'vertical transmission', 'maternal-fetal transmission', 'intrauterine transmission', 'neonate', 'infant' and 'delivery'. Eligibility criteria included laboratory-confirmed and/or clinically diagnosed COVID-19, patient being pregnant on admission and availability of clinical characteristics, including at least one maternal, perinatal or neonatal outcome. Exclusion criteria were non-peer-reviewed or unpublished reports, unspecified date and location of the study, suspicion of duplicate reporting and unreported maternal or perinatal outcomes. No language restrictions were applied. RESULTS: We identified a high number of relevant case reports and case series, but only 24 studies, including a total of 324 pregnant women with COVID-19, met the eligibility criteria and were included in the systematic review. These comprised nine case series (eight consecutive) and 15 case reports. A total of 20 pregnant patients with laboratory-confirmed COVID-19 were included in the case reports. In the combined data from the eight consecutive case series, including 211 (71.5%) cases of laboratory-confirmed and 84 (28.5%) of clinically diagnosed COVID-19, the maternal age ranged from 20 to 44 years and the gestational age on admission ranged from 5 to 41 weeks. The most common symptoms at presentation were fever, cough, dyspnea/shortness of breath, fatigue and myalgia. The rate of severe pneumonia reported amongst the case series ranged from 0% to 14%, with the majority of the cases requiring admission to the intensive care unit. Almost all cases from the case series had positive computed tomography chest findings. All six and 22 cases that had nucleic-acid testing in vaginal mucus and breast milk samples, respectively, were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Only four cases of spontaneous miscarriage or termination were reported. In the consecutive case series, 219/295 women had delivered at the time of reporting and 78% of them had Cesarean section. The gestational age at delivery ranged from 28 to 41 weeks. Apgar scores at both 1 and 5 min ranged from 7 to 10. Only eight neonates had birth weight < 2500 g and nearly one-third of neonates were transferred to the neonatal intensive care unit. There was one case of neonatal asphyxia and death. In 155 neonates that had nucleic-acid testing in throat swab, all, except three cases, were negative for SARS-CoV-2. There were no cases of maternal death in the eight consecutive case series. Seven maternal deaths, four intrauterine fetal deaths (one with twin pregnancy) and two neonatal deaths (twin pregnancy) were reported in a non-consecutive case series of nine cases with severe COVID-19. In the case reports, two maternal deaths, one neonatal death and two cases of neonatal SARS-CoV-2 infection were reported. CONCLUSIONS: Despite the increasing number of published studies on COVID-19 in pregnancy, there are insufficient good-quality data to draw unbiased conclusions with regard to the severity of the disease or specific complications of COVID-19 in pregnant women, as well as vertical transmission, perinatal and neonatal complications. In order to answer specific questions in relation to the impact of COVID-19 on pregnant women and their fetuses, through meaningful good-quality research, we urge researchers and investigators to present complete outcome data and reference previously published cases in their publications, and to record such reporting when the data of a case are entered into one or several registries. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

In an ultrasound screening study at 10 to 14 weeks of gestation for measurement of fetal nuchal translucency thickness there were 102 monochorionic and 365 dichorionic twin pregnancies. In the monochorionic compared with the dichorionic pregnancies there was a higher rate of fetal loss before 24 weeks of gestation (12.2% versus 1.8%), perinatal mortality (2.8% versus 1.6%), prevalence of delivery before 32 weeks (9.2% versus 5.5%), and prevalence of birthweight below the 5th centile in both twins (7.5% versus 1.7%). However, the proportion of pregnancies with a birthweight discordancy of more than 25% was similar in the two groups (11.3% versus 12.1%).

The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages sound clinical practice, and high-quality teaching and research related to diagnostic imaging in women's healthcare. The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements as educational recommendations that provide healthcare practitioners with a consensus-based approach, from experts, for diagnostic imaging. They are intended to reflect what is considered by ISUOG to be the best practice at the time at which they are issued. Although ISUOG has made every effort to ensure that Guidelines are accurate when issued, neither the Society nor any of its employees or members accepts any liability for the consequences of any inaccurate or misleading data, opinions or statements issued by the CSC. The ISUOG CSC documents are not intended to establish a legal standard of care because interpretation of the evidence that underpins the Guidelines may be influenced by individual circumstances, local protocol and available resources. Approved Guidelines can be distributed freely with the permission of ISUOG ([email protected]). The incidence of multiple pregnancy is rising, mainly due to delayed childbirth and advanced maternal age at conception and the resultant widespread use of assisted reproduction techniques1. The twin birth rate increased by just under 70% between 1980 (19 per 1000 live births) and 2006 (32 per 1000 live births)2. Twin pregnancy is associated with a high risk of perinatal mortality and morbidity3-6. In 2009, the associated stillbirth rate was 12 per 1000 twin births and 31 per 1000 triplet and higher-order multiple births, compared with five per 1000 singleton births7, 8. Preterm birth prior to 37 weeks' gestation occurs in up to 60% of multiple pregnancies, contributing to the increased risk of neonatal mortality (65% of neonatal deaths among multiple births are preterm, compared with 43% of neonatal deaths in singletons) and long-term morbidity9-12. Of course, such complications rise with a reduction in gestational age at birth. In addition, compared with singletons, twins are at increased risk of iatrogenic preterm delivery due to the greater incidence of maternal and fetal complications. The risk is significantly higher in monochorionic compared with dichorionic pregnancy3-6. Ultrasound assessment of fetal biometry, anatomy, Doppler velocimetry and amniotic fluid volume is used to identify and monitor twin pregnancies at risk of adverse outcomes such as twin-to-twin transfusion syndrome (TTTS) and fetal growth restriction (FGR). As in singletons, impaired fetal growth can be assessed in twins by comparing biometry and Doppler velocimetry parameters against standards for uncomplicated pregnancy. This guidance will address the role of ultrasound in the care of uncomplicated twin pregnancy and those complicated by TTTS, selective FGR (sFGR), twin anemia–polycythemia sequence (TAPS), twin reversed arterial perfusion (TRAP) sequence, conjoined twins and single intrauterine death (IUD). The document provides guidance on the methods used to determine gestational age and chorionicity, screening for chromosomal and structural abnormalities, and screening for TTTS, TAPS, growth abnormalities and preterm birth. The management of higher-order multiple pregnancy will be covered in a separate document. The Cochrane Library and Cochrane Register of Controlled Trials were searched for relevant randomized controlled trials, systematic reviews and meta-analyses and a search of MEDLINE from 1966 to 2014 was carried out. The date of the last search was 15 November 2014. In addition, relevant conference proceedings and abstracts were searched. Databases were searched using the relevant MeSH terms including all sub-headings. This was combined with a keyword search using ‘twin’, ‘multiple’, ‘pregnancy’, ‘ultrasound’, ‘twin-to-twin transfusion syndrome’, ‘fetal growth restriction’, ‘twin anemia polycythemia sequence’, ‘twin reversed arterial perfusion’, ‘acardiac twin’, ‘monochorionic monoamniotic’, ‘conjoined’, ‘demise’. The National Library for Health and the National Guidelines Clearing House were also searched for relevant guidelines and reviews. Gray (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections and clinical trial registries. The search was limited to the English language. When possible, recommendations are based on, and explicitly linked to, the evidence that supports them, while areas lacking evidence are annotated as ‘good practice points’. Details of the grades of recommendations and levels of evidence used in these Guidelines are given in Appendix 1. Other studies have recommended the use of the smaller CRL or the mean CRL, which takes into account both fetuses13-15. The disadvantage of using the smaller CRL is the potential of the operator believing that the larger twin is large-for-gestational age, and therefore being falsely reassured that the smaller twin is still growing appropriately. The most common practice is to use the larger CRL. If the woman presents after 14 weeks' gestation, the larger head circumference should be used1. Twin pregnancies conceived via in-vitro fertilization should be dated using the oocyte retrieval date or the embryonic age from fertilization (EVIDENCE LEVEL: 2+). Every attempt should be made to determine the chorionicity of a twin pregnancy. Chorionicity should be determined between 11 + 0 and 13 + 6 weeks of gestation using the membrane thickness at the site of insertion of the amniotic membrane into the placenta, identifying the T-sign or lambda sign (Figure 1), and the number of placental masses visualized using ultrasound1. It is important to examine the dividing membrane carefully; in dichorionic diamniotic twin pregnancy, the twins are separated by a thick layer of fused chorionic membranes with two thin amniotic layers, one on each side, giving the appearance of a ‘full lambda’, compared with only two thin amniotic layers separating the two fetuses in monochorionic diamniotic (MCDA) twin pregnancy (the T-sign). In women presenting for the first time after 14 weeks of gestation, chorionicity is best determined using the same ultrasound signs, in particular by counting the membrane layers, and noting discordant fetal sex. The reliability of the number of placental masses is questionable, as dichorionic placentae are commonly adjacent to each other, appearing as a single mass, and 3% of monochorionic twin pregnancies have two placental masses on ultrasound, the presence of which does not preclude the presence of vascular anastomoses16. It is likely that using a combination of ultrasound features, rather than a single one, would be more accurate1. If it is not possible to determine chorionicity by transabdominal ultrasound imaging, this should be attempted using transvaginal sonography. If it is still not possible to determine chorionicity, a second opinion should be sought from a tertiary referral center. If the center is uncertain about the chorionicity, it is safer to classify the pregnancy as monochorionic1 (EVIDENCE LEVEL: 3). At the time at which chorionicity is determined, amnionicity (i.e. whether or not the twins share the same amniotic sac) should be determined and documented. In case of doubt, absence of the intertwin membrane is best confirmed by transvaginal scan. Another useful finding is demonstration of cord entanglement, which is almost universal in MCMA twin pregnancy, using color and pulsed-wave Doppler ultrasound. Using pulsed-wave Doppler, two distinct arterial waveform patterns with different heart rates are seen within the same sampling gate (EVIDENCE LEVEL: 4). All MCMA twin pregnancies should be referred to a tertiary center with expertise in their management1. It is recommended that an ultrasound image demonstrating the chorionicity is stored electronically and that a hard copy is added to the medical records. As determination of chorionicity is most accurate at 11–14 weeks' gestation when the amnion and chorion have not yet fused, the first-trimester scan in twin pregnancy is paramount (EVIDENCE LEVEL: 4). It is important to follow a reliable, consistent strategy for antenatal twin labeling. Options include: labeling according to their site, either left and right, or upper and lower; or mapping in the first trimester according to the insertion of their cords relative to the placental edges and membrane insertion. In some healthcare settings, Twin A is the fetus on the right side, while Twin B is the one on the left. This information should be documented clearly in the woman's notes in order to ensure consistent labeling during follow-up scans17. It is advisable to describe each twin using as many features as possible so as to enable others to identify them accurately; e.g. ‘Twin A (female) is on the maternal right with a posterior placenta and marginal cord insertion’. For pregnancies with discordance, the labeling should be accompanied by a description such as ‘Twin A, potential recipient’. It is important to acknowledge that labeling is less accurate in MCMA twin pregnancy, particularly in the first trimester. It should be borne in mind that the twins labeled as ‘Twin A’ and ‘Twin B’ during antenatal ultrasound scans may not necessarily be delivered in that order, in particular if the mode of delivery is Cesarean section18. It is important to alert parents and healthcare professionals attending the delivery to this fact, particularly in pregnancies in which the twins are discordant for structural abnormalities that are not obvious by external examination, e.g. congenital diaphragmatic hernia or cardiac defects. In such cases, an ultrasound scan should be performed just prior to delivery and also before instigating any specific neonatal intervention. In uncomplicated dichorionic twin pregnancy, ultrasound imaging should be performed in the first trimester, again at around 20 weeks' gestation (second-trimester anomaly scan), and every 4 weeks thereafter (unless a complication is detected which might require more frequent scans) (Figure 2)1. In uncomplicated monochorionic twins, an ultrasound scan should be performed in the first trimester. There should then be scans every 2 weeks from 16 weeks onwards, as timely detection of TTTS and TAPS has been shown to improve perinatal outcome (Figure 3)19, 20 (EVIDENCE LEVEL: 4). At each ultrasound assessment, the following should be assessed: fetal biometry, amniotic fluid volume and umbilical artery Doppler (from 20 weeks' gestation) for both twins. Discordance in estimated fetal weight (EFW) should be calculated and documented at each scan from 20 weeks. In monochorionic twin pregnancy, middle cerebral artery (MCA) peak systolic velocity (PSV) should be recorded from 20 weeks, in order to screen for TAPS. In MCDA twins, the amniotic fluid volume (deepest vertical pocket) should be assessed and documented at each ultrasound scan to screen for TTTS. Cervical length assessment is performed ideally at the same visit as the anomaly scan in the second trimester, in order to identify women at risk of extreme preterm birth (EVIDENCE LEVEL: 2+, 2++). In twin pregnancy, screening for trisomy 21 can be performed in the first trimester using the combined test, which includes maternal age, NT measurement and serum β-hCG and PAPP-A levels. An alternative is the combination of maternal age and the NT recorded between 11 + 0 and 13 + 6 weeks of gestation1. In case of a vanished twin, if there is still a measurable fetal pole, β-hCG and PAPP-A measurements are biased and NT alone should be used for risk estimation. The risk of trisomy 21 in monochorionic twin pregnancy is calculated per pregnancy based on the average risk of both fetuses (because the twins share the same karyotype), whereas in dichorionic twin pregnancy the risk is calculated per fetus (as around 90% are dizygotic so have different karyotypes). The DR for Down syndrome may be lower in twin compared with singleton pregnancy1. However, a recent meta-analysis reported similar performance (89% for singletons, 86% for dichorionic twins and 87% for monochorionic twins, at a false-positive rate (FPR) of 5%)22 (EVIDENCE LEVEL: 2++). The likelihood of being offered invasive testing on the basis of a combined screening result is greater in twin compared with singleton pregnancy1. Moreover, invasive testing carries greater risks in twins23-25. A meta-analysis showed that the overall pregnancy loss rate following chorionic villus sampling (CVS) in twin pregnancy was 3.8%, and following amniocentesis was 3.1%23. Other research has reported lower loss rates: 2% following CVS and 1.5–2% following amniocentesis26. The risk was found to be similar for transabdominal and transcervical approaches, use of a single-needle or double-needle system, and single or double uterine entry23 (EVIDENCE LEVEL: 2++). Screening and diagnostic testing for trisomy is more complex in twin compared with singleton pregnancy. It is important, therefore, that counseling prior to testing is provided by healthcare professionals with expertise in this area1. It is important to inform women and their partners in advance of the potentially complex decisions that they will need to make on the basis of the results of combined screening, bearing in mind the increased risk of invasive testing in twins, the possible discordance between dichorionic twins for fetal aneuploidy, and the risks of selective fetal reduction1 (EVIDENCE LEVEL: 2+). Cell-free DNA (cfDNA) analysis of maternal blood for risk assessment for fetal trisomy 21 is used increasingly in clinical practice. It has the potential to overcome many of these complex issues, because it has a much higher DR and lower FPR than does the combined test27. In a recent meta-analysis, the weighted pooled DR for trisomy 21 in singleton pregnancy was 99% for a FPR of 0.1%28. The corresponding values in twin pregnancy were 94.4% and 0%. However, so far, the reported number of trisomy-21 cases in twin pregnancy diagnosed using cfDNA testing is far smaller than that in singleton pregnancy (EVIDENCE LEVEL: 2++). Invasive testing for chromosomal or genetic analysis of twins should be carried out by a fetal medicine expert. CVS is preferred in dichorionic twin pregnancy because it can be performed earlier than can amniocentesis. Earlier diagnosis of any aneuploidy is particularly important in twin pregnancy, given the lower risk of selective termination in the first compared with the second trimester (7% risk of loss of the entire pregnancy, and 14% risk of delivery before 32 weeks)29. It is important to map carefully the position of the twins within the uterus. During amniocentesis in monochorionic twins, if monochorionicity has been confirmed before 14 weeks' gestation and the fetuses appear concordant for growth and anatomy, it is acceptable to sample only one amniotic sac. Otherwise, both amniotic sacs should be sampled because of the possibility of rare discordant chromosomal anomalies in monochorionic pregnancy. CVS in monochorionic pregnancy will sample only the single placenta so will miss these rare discordant chromosomal anomalies. Discordance for most of the common human aneuploidies (trisomies 13, 18 and 21, Turner syndrome and triploidy) has been reported in monochorionic twin pairs30. In the event of heterokaryotypic monochorionic pregnancy, selective reduction by umbilical cord occlusion can be offered from 16 weeks onwards, with a survival rate of more than 80% for the healthy twin31, 32. When monochorionic twins are discordant for an abnormality, prior to invasive testing a discussion should take place regarding the complexity of selective termination, should it become necessary32 (EVIDENCE LEVEL: 3). Although some studies have reported an association between first-trimester intertwin discordance in NT or CRL, or reversed a-wave in the ductus venosus (DV), and the development of TTTS, their predictive value is poor17, 33-35. NT discordance of ≥ 20% had a sensitivity of 52–64% and a specificity of 78–80%, a positive predictive value of 50% and a negative predictive value of 86% for the development of TTTS36, 37. Discordance in NT of ≥ 20% is found in around 25% of monochorionic twins and the risk of early IUD or development of severe TTTS in this group is more than 30%37. The risk of complications is less than 10% if the NT discordance is < 20%37. An abnormal DV will pick up only 38% of all pregnancies that subsequently develop TTTS, and, of those predicted to be at high risk, only 30% will ultimately develop TTTS35. Similarly, although intertwin discordance in CRL at 11–13 weeks' gestation is significantly associated with the risk of pregnancy loss (area under the receiver–operating characteristics curve (AUC), 0.5), birth-weight discordance (AUC, 0.6), sFGR (AUC, 0.6) and preterm delivery prior to 34 weeks' gestation (AUC, 0.5), again the predictive value is poor (pooled predictive risk of 52%)38, 39. Nevertheless, the management of twin pregnancy with CRL discordance ≥ 10% or NT discordance ≥ 20% should be discussed with a fetal medicine expert and in these pregnancies there should be detailed ultrasound assessment and testing for karyotype abnormalities. The risk of fetal abnormalities was found to be 25% in pregnancies with CRL discordance ≥ 10%, compared with 4% in pregnancies with CRL discordance < 10%40. However, CRL discordance at 7 + 0 to 9 + 6 weeks' gestation is a predictor of the risk of single fetal demise in the first trimester (DR of 74% for a FPR of 5%)41 (EVIDENCE LEVEL: 2++). At the first-trimester scan (between 11 + 0 and 13 + 6 weeks' gestation) the fetuses should be assessed for the presence of any major anomalies42. Routine second-trimester ultrasound screening for anomalies in twins should be performed by an experienced operator at around 20 (18–22) weeks' gestation1, 43. This scan may be more difficult than usual because of the presence of a second fetus, and it is important to allow adequate time (i.e. in the order of 45 min). The risk of fetal anomaly is greater in twin compared with singleton pregnancy44. The rate per fetus in dizygotic twins is probably the same as that in singletons, whereas it is two-to-three times higher in monozygotic twins. In around 1 in 25 dichorionic, 1 in 15 MCDA and 1 in 6 monoamniotic twin pregnancies, there is a major congenital anomaly that typically affects only one twin45, 46. screening for anomalies should be considered in monochorionic twin pregnancy, bearing in mind that and cardiac abnormalities might become more obvious in the trimester. associated with twins abnormalities, cardiac and anomalies. screening cardiac assessment should be performed according to ISUOG including and and It is important to make the woman of the of ultrasound screening, which according to the of The of screening for fetal anomaly in the second trimester giving parents the to for the birth of a with a potential them the of termination, to a center for the and, intrauterine (EVIDENCE LEVEL: 3). to two of twin pregnancies will have an anomaly only one fetus, to the between management and selective termination of the in monozygotic twins, for a structural anomaly is found in than 20% of pregnancies should be referred to a fetal medicine center for management1. In monochorionic twins discordant for a structural abnormality, discordant aneuploidy is rare not In these expert ultrasound assessment in a tertiary with invasive fetal chromosomal or genetic testing if and a discussion of the likely for both the and the twin, are For that are and a high risk of intrauterine management is preferred in dichorionic twins, whereas in monochorionic twin pregnancy this would to the healthy against the adverse of demise of the The of selective termination in twin pregnancy the risk of preterm birth. This is particularly relevant in twin pregnancies discordant for in which selective termination in the second trimester is associated with a higher risk of and preterm compared with that in the first trimester (7% risk of loss of the entire pregnancy, and 14% risk of delivery before 32 weeks)29. When the diagnosis is made in the second trimester, women might for a selective termination in the trimester, if the when the is associated with a risk of preterm birth rather than fetal loss of the The and of each should be considered loss of a fetal medicine to the in the event of preterm and risk of complications associated with the specific (EVIDENCE LEVEL: 2++). in dichorionic twin pregnancy is performed by or of or When selective termination of one twin of a monochorionic is the of is not an because of the risk to the healthy cord or of the twin is This to demise of the twin while the healthy twin against of its blood volume into the twin following its The survival rate of the is 80% and the risk of of the membranes and preterm birth prior to 32 weeks is The risk of adverse in the may also be increased compared with that in uncomplicated (EVIDENCE LEVEL: 2++). and iatrogenic preterm births are more common in twin than in singleton than of twins are before 37 weeks of gestation and of twin births before 37 and 32 weeks of gestation, these rates are and times the rates for singleton pregnancy, women found to have a at the second-trimester ultrasound scan are to be at increased risk of preterm However, the sensitivity of this finding is and the of the length used to increased risk of preterm birth is A length < 25 at weeks' gestation in twin pregnancy is a predictor of preterm birth before 34 weeks, not before 37 In a length 20 at weeks was the most accurate predictor of preterm birth before 32 and before 34 weeks (pooled and positive and negative likelihood were and and and and and A length 25 at weeks had a pooled positive likelihood of for the of preterm birth before The predictive of length for preterm birth was in (EVIDENCE LEVEL: 2++). Moreover, there is strategy to preterm birth in these or not the risk of preterm delivery in these However, might the risk of neonatal and research may management in this in due (EVIDENCE LEVEL: The assessment and management of FGR are among If both twins have an < the fetuses should be sFGR is a to twin pregnancies in which one fetus has an < and the intertwin discordance is The of and a of in the to discordant fetal A of for discordance in birth weight was found to adverse outcome not take into account the intertwin discordance use < in one the discordance most predictive of adverse outcome is likely to with gestational A discordance of 20% a for pregnancies at increased risk of adverse outcome of discordance is calculated by the following of larger twin weight of smaller of larger twin (EVIDENCE LEVEL: 2++). a diagnosis has been a should be This search should a detailed anomaly scan and screening for and may also be to chromosomal abnormalities as a of sFGR in monochorionic twin pregnancy occurs mainly due to of the placental and (EVIDENCE LEVEL: 3). using ultrasound is less accurate in twin than in singleton that a combination of and measurements best in both singleton and twin the used to monitor fetal growth in twin pregnancy are the same as those used for However, there is a reduction in fetal growth in twin compared with singleton pregnancy, particularly in the This is particularly in MCDA This that specific twin growth should be used for and growth in twin However, the use of specific twin growth is due to the that the growth in the trimester in most twin pregnancies might be by some of placental (EVIDENCE LEVEL: 2++). discordance between twins is significantly associated with the risk of perinatal The for the risk of perinatal loss in twins with an discordance ≥ 25% was found to be to the National for Health and discordance should be calculated and documented at every scan from 20 weeks If this discordance 25% or a referral should be made to a fetal medicine for assessment, increased fetal including fetal Doppler, and of delivery when (EVIDENCE LEVEL: 2++). The of sFGR on the of velocity in the umbilical artery (Figure In the umbilical artery Doppler waveform has positive In there is or reversed In there is a of The survival rate in sFGR is greater than 90% mortality rates of up to sFGR is associated with a high risk of IUD of the twin preterm delivery with associated risk of if the twin of either twin in up to and risk of in up to of cases prior to sFGR is associated with a risk of death of the fetus, which is in cases in which ultrasound features have been There is also a high to associated rate of in the larger (EVIDENCE LEVEL: 2++). In dichorionic twin pregnancy complicated by the of delivery should be determined based on a assessment and according to the of the by and neonatal As these twins have separate the pregnancy can be as in singleton pregnancy, for of umbilical and DV Doppler, and of pregnancies should be in with the relevant There is limited evidence to the management of monochorionic twins by Options include: management by early or cord occlusion of the twin order to the (EVIDENCE LEVEL: In monochorionic twin pregnancy complicated by fetal growth should be assessed at every 2 weeks, and fetal Doppler artery and at If the umbilical artery Doppler is assessment of the DV blood should be The in these pregnancies is to the pregnancy at is while at the same time single IUD with its associated consequences for the In dichorionic twin pregnancy complicated by follow-up be less as delivery is not recommended

Effective screening for major aneuploidies can be provided in the first trimester of pregnancy. Screening by a combination of fetal nuchal translucency and maternal serum free-β-human chorionic gonadotrophin and pregnancy-associated plasma protein-A can identify about 90% of fetuses with trisomy 21 and other major aneuploidies for a false-positive rate of 5%. Improvement in the performance of first-trimester screening can be achieved by firstly, inclusion in the ultrasound examination assessment of the nasal bone and flow in the ductus venosus, hepatic artery and across the tricuspid valve, and secondly, carrying out the biochemical test at 9 to 10 weeks and the ultrasound scan at 12 weeks.

OBJECTIVE: To develop models for prediction of preeclampsia (PE) based on maternal characteristics, biophysical and biochemical markers at 11-13 weeks' gestation in which the gestation at the time of delivery for PE is treated as a continuous variable. METHODS: This was a screening study of singleton pregnancies at 11-13 weeks including 1,426 (2.4%) that subsequently developed PE and 57,458 that were unaffected by PE. We developed a survival time model for the time of delivery for PE in which Bayes' theorem was used to combine the prior information from maternal characteristics with uterine artery pulsatility index (PI), mean arterial pressure (MAP), serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PLGF) multiple of the median (MoM) values. RESULTS: In pregnancies with PE, there was a linear correlation between MoM values of uterine artery PI, MAP, PAPP-A and PLGF with gestational age at delivery and therefore the deviation from normal was greater for early than late PE for all four biomarkers. Screening by maternal characteristics, biophysical and biochemical markers detected 96% of cases of PE requiring delivery before 34 weeks and 54% of all cases of PE at a fixed false-positive rate of 10%. CONCLUSIONS: A new model has been developed for effective first-trimester screening for PE.

OBJECTIVES: To examine the utility of measuring fetal nuchal translucency thickness in screening for major defects of the heart and great arteries at 10-14 weeks of gestation. DESIGN: Population based cohort study. SUBJECTS: 29 154 singleton pregnancies with chromosomally normal fetuses at 10-14 weeks of gestation. SETTING: Fetal medicine centre in London. MAIN OUTCOME MEASURE: Prevalence of major defects of the heart and great arteries. RESULTS: Of 50 cases with major defects of the heart and great arteries (prevalence 1.7 per 1000 pregnancies) 28 (56%, 95% confidence interval 42% to 70%) were in the subgroup of 1822 pregnancies with fetal nuchal translucency thicknesses above the 95th centile of the normal range. The positive and negative predictive values for this cut off point of nuchal translucency thickness were 1.5% and 99.9% respectively. CONCLUSIONS: Measurement of fetal nuchal translucency thickness-traditionally used to identify fetuses at high risk of aneuploidy-at 10-14 weeks of gestation can identify a large proportion of fetuses with major defects of the heart and great arteries.

OBJECTIVE: To examine the potential impact of combining maternal age with fetal nuchal translucency thickness and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in screening for trisomy 21 at 10-14 weeks of gestation. METHODS: Maternal serum free beta-hCG and PAPP-A were measured by Kryptor, a random access immunoassay analyzer using time-resolved amplified cryptate emission, in 210 singleton pregnancies with trisomy 21 and 946 chromosomally normal controls, matched for maternal age, gestation and sample storage time. In all cases the fetal crown-rump length and nuchal translucency thickness had been measured by ultrasonography at 10-14 weeks of gestation and maternal blood had been obtained at the time of the scan. The distributions (in multiples of the median; MoM) of free beta-hCG and PAPP-A (corrected for maternal weight) and fetal nuchal translucency (NT) were determined in the trisomy 21 group and the controls. Likelihood ratios for the various marker combinations were calculated and these were used together with the age-related risk for trisomy 21 in the first trimester to calculate the expected detection rate of affected pregnancies, at a fixed false-positive rate, in a population with the maternal age distribution of pregnancies in England and Wales. RESULTS: In a population with the maternal age distribution of pregnancies in England and Wales, it was estimated that, using the combination of maternal age, fetal nuchal translucency thickness and maternal serum free beta-hCG and PAPP-A, the detection of trisomy 21 pregnancies would be 89% at a fixed false-positive rate of 5%. Alternatively, at a fixed detection rate of 70%, the false-positive rate would be 1%. The inclusion of biochemical parameters added an additional 16% to the detection rate obtained using NT and maternal age alone. CONCLUSIONS: Rapid diagnostic technology like Kryptor, which can provide automated reproducible biochemical measurements within 30 min of obtaining a blood sample, will allow the development of interdisciplinary one-stop clinics for early fetal assessment. Such clinics will be able to deliver improved screening sensitivity, rapidly and more efficiently, leading to reduced patient anxiety and stress.

PROBLEM: We determined the evolution of the maternal-fetal transport of immunoglobulins during human pregnancy. METHOD: Paired blood samples were collected between 17-41 weeks of gestation (WG) by puncture of a peripheral maternal vein and by cordocentesis (17-36 WG, n = 91) or directly at delivery (37-41 WG n = 16) from the umbilical vein. Additional maternal samples were collected from the same individual (n = 16) at 10, 20, 30 WG, and at term. The concentration of IgG and its four subclasses and of IgA were determined in the sera using ELISA method. RESULTS: The mean level of IgG and IgA in maternal sera at 9-16 WG was 13.72 +/- 2.53 g/L and 3.95 +/- 1.23 g/L, respectively. Both, IgG and IgA throughout pregnancy decreased to a level of 60-70% (37-41 WG) of the initial concentration in early pregnancy. The ratio of IgG1:IgG2 in the maternal circulation was 2-3 and remained constant throughout pregnancy (17-41 WG). IgG3 and IgG4 levels remained constant and together were less than 10% of total IgG. In the fetal circulation a continuous rise in the level of both IgG and IgA was observed between 17 and 41 WG. Fetal level of IgG at 17-22 WG was only 5-10% of the maternal level and at term exceeded the maternal level reaching a value of 11.98 +/- 2.18 g/L. IgG1 at 17-22 WG was 0.93 +/- 0.42 g/L, which is approximately three times higher than IgG2. IgG1 showed an exponential rise and at 37-41 WG its concentration was seven times higher than IgG2. IgG3 and IgG4 also showed an exponential rise and at term reached a similar level as in the maternal circulation. Striking was the difference in results for IgG2 with a slow linear rise throughout gestation. The fetal IgG2 level at term remained significantly below the maternal concentration. The IgG subclasses when characterized according to the differences in transport capacity gave the following sequence: IgG1 > IgG4 > IgG3 > IgG2. Fetal IgA showed a slow linear rise with fetal levels at term remaining approximately 1,000 times lower than the concentration in the maternal circulation. CONCLUSIONS: Comparison of fetal and maternal levels of immunglobulines indicate that the human placenta during pregnancy develops a specific transport mechanism for IgG. There are differences for the four subclasses with preferential transfer of IgG1 while the slowest transfer is seen for IgG2.

OBJECTIVE: To determine the value of transvaginal color Doppler assessment of the uterine arteries at 23 weeks of gestation in predicting the subsequent development of pre-eclampsia and fetal growth restriction. PATIENTS AND METHODS: Women with singleton pregnancies attending for routine ultrasound examination at 23 weeks in any one of seven hospitals underwent Doppler assessment of the uterine arteries. The presence of an early diastolic notch in the waveform was noted, and the mean pulsatility index of the two arteries was calculated. Screening characteristics in the prediction of pre-eclampsia and the delivery of a low birth-weight infant were calculated. RESULTS: Doppler examination of the uterine arteries was attempted in 8335 consecutive singleton pregnancies, satisfactory waveforms were obtained from both vessels in 8202 (98.4%) cases and complete outcome data were available in 7851 (95.7%) of these. The mean gestational age was 23 (range, 22-24) weeks. The mean uterine artery pulsatility index did not change significantly with gestation (r = -0.0078; P = 0.483); the median value was 1.04 and the 95th centile was 1.63. In 9.3% of cases early diastolic notches in the waveform from both uterine arteries were present and in an additional 11.1% of cases there were notches unilaterally. Pre-eclampsia with fetal growth restriction occurred in 42 (0.5%) cases, pre-eclampsia without fetal growth restriction in 71 (0.9%) and fetal growth restriction without pre-eclampsia in 698 (8.9%). The sensitivity of increased pulsatility index above the 95th centile (1.63) for pre-eclampsia with fetal growth restriction was 69%, for pre-eclampsia without fetal growth restriction was 24%, for fetal growth restriction without pre-eclampsia was 13%, for pre-eclampsia irrespective of fetal growth restriction was 41% and for fetal growth restriction irrespective of pre-eclampsia was 16%. The sensitivity of fetal growth restriction defined by the 5th rather than the 10th centile was higher (19% vs. 16%). The sensitivity for both pre-eclampsia and fetal growth restriction was inversely related to the gestational age at delivery; when delivery occurred before 32 weeks, the sensitivity for all cases of pre-eclampsia with fetal growth restriction, pre-eclampsia without fetal growth restriction and fetal growth restriction without pre-eclampsia increased to 93%, 80% and 56%, respectively. The sensitivity of bilateral notches in predicting pre-eclampsia and/or fetal growth restriction was similar to that of increased pulsatility index but the screen-positive rate with notches (9.3%) was much higher than that with increased pulsatility index (5.1%). CONCLUSIONS: A one-stage color Doppler screening program at 23 weeks identifies most women who subsequently develop severe pre-eclampsia and/or fetal growth restriction.

OBJECTIVE: To examine the potential value of routine measurement of cervical length in singleton pregnancies at 23 weeks of gestation in the prediction of the risk for early spontaneous preterm delivery. METHODS: Cervical length was measured by sonography at 23 weeks in 2567 singleton pregnancies in women attending for routine antenatal care. In 43 women, the length was < or = 15 mm and 21 of these were managed expectantly, whereas in 22 cases a cervical cerclage was placed. In the pregnancies that were managed expectantly, the relation between cervical length and preterm delivery was examined and the risk of spontaneous delivery at < or = 32 weeks was estimated. RESULTS: Cervical length at 23 weeks was < or = 15 mm in 1.7% of cases; this group contained 86%, 58% and 20% of pregnancies that delivered spontaneously at < or = 28, < or = 32 and < or = 36 weeks, respectively. The risk for delivery at < or = 32 weeks decreased from 78% at a cervical length of 5 mm to 4% at 15 mm and 0.5% at 50 mm. CONCLUSIONS: Cervical length at 23 weeks is < or = 15 mm in < 2% of the population; this group contains about 90% and 60% of the women delivering at < or = 28 and < or = 32 weeks, respectively. Measurement of cervical length provides accurate prediction of risk for early preterm delivery.

Preeclampsia complicates 2 to 4% of all pregnancies and accounts for about 46,000 maternal deaths and 500,000 fetal or newborn deaths each year. Antihypertensive agents and magnesium sulfate can help control the systemic manifestations of preeclampsia, which is usually resolved by delivery of the placenta.

Abstract Normal ranges for a wide variety of biometrical parameters were established from cross‐sectional data on 1040 normal singleton pregnancies resulting in livebirth at term of normal, and appropriately grown infants. Patients were selected so that the birth weight distribution was similar to that reported by Yudkin and colleagues' and the ranges can, therefore, be used for any population that has a simular birth weight distribution. Copyright © 1994 International Society of Ultrasound in Obstetrics and Gynecology

OBJECTIVE: To examine the performance of the 11-13 weeks scan in detecting non-chromosomal abnormalities. METHODS: Prospective first-trimester screening study for aneuploidies, including basic examination of the fetal anatomy, in 45 191 pregnancies. Findings were compared to those at 20-23 weeks and postnatal examination. RESULTS: Aneuploidies (n = 332) were excluded from the analysis. Fetal abnormalities were observed in 488 (1.1%) of the remaining 44 859 cases; 213 (43.6%) of these were detected at 11-13 weeks. The early scan detected all cases of acrania, alobar holoprosencephaly, exomphalos, gastroschisis, megacystis and body stalk anomaly, 77% of absent hand or foot, 50% of diaphragmatic hernia, 50% of lethal skeletal dysplasias, 60% of polydactyly, 34% of major cardiac defects, 5% of facial clefts and 14% of open spina bifida, but none of agenesis of the corpus callosum, cerebellar or vermian hypoplasia, echogenic lung lesions, bowel obstruction, most renal defects or talipes. Nuchal translucency (NT) was above the 95th percentile in 34% of fetuses with major cardiac defects. CONCLUSION: At 11-13 weeks some abnormalities are always detectable, some can never be and others are potentially detectable depending on their association with increased NT, the phenotypic expression of the abnormality with gestation and the objectives set for such a scan.

Increased fetal nuchal translucency thickness at 10-14 weeks of gestation is a common phenotypic expression of fetal chromosomal defects, structural abnormalities and genetic syndromes. This study reports on the prevalence of structural abnormalities and genetic syndromes in 4116 chromosomally normal pregnancies with increased fetal nuchal translucency thickness and reviews the relevant literature. In fetuses with increased nuchal translucency thickness, the prevalence of major cardiac defects, diaphragmatic hernia, exomphalos, body stalk anomaly and fetal akinesia deformation sequence is substantially higher than expected in the general population. In addition, there may be an association between increased nuchal translucency thickness and a wide range of rare skeletal dysplasias and genetic syndromes that are usually found in less than one in 10,000 pregnancies; however, the number of affected cases, both in the present and in previous series of fetuses with increased nuchal translucency thickness, is too small for definite conclusions to be drawn. The rates of miscarriage and perinatal death increase, whereas the rate of survival and the prevalence of live births with no obvious abnormalities decrease with increasing nuchal translucency thickness.

This study aimed to establish a method of screening for pregnancy hypertension by a combination of maternal variables, including mean arterial pressure, uterine artery pulsatility index, pregnancy-associated plasma protein-A, and placental growth factor in early pregnancy. The base-cohort population constituted of 7797 singleton pregnancies, including 34 case subjects who developed preeclampsia (PE) requiring delivery before 34 weeks (early PE) and 123 with late PE, 136 with gestational hypertension, and 7504 cases subjects (96.3%) who were unaffected by PE or gestational hypertension. Maternal history, uterine artery pulsatility index, mean arterial pressure, and pregnancy-associated plasma protein-A were recorded in all of the cases in the base cohort, but placental growth factor was measured only in the case-control population of 209 cases who developed hypertensive disorders and 418 controls. In each case the measured mean arterial pressure, uterine artery pulsatility index, pregnancy-associated plasma protein-A, and placental growth factor were converted to a multiple of the expected median (MoM) after correction for maternal characteristics found to affect the measurements in the unaffected group. Early PE and late PE were associated with increased mean arterial pressure (1.15 MoM and 1.08 MoM) and uterine artery pulsatility index (1.53 MoM and 1.23 MoM) and decreased pregnancy-associated plasma protein-A (0.53 MoM and 0.93 MoM) and placental growth factor (0.61 MoM and 0.83 MoM). Logistic regression analysis was used to derive algorithms for the prediction of hypertensive disorders. It was estimated that, with the algorithm for early PE, 93.1%, 35.7%, and 18.3% of early PE, late PE, and gestational hypertension, respectively, could be detected with a 5% false-positive rate and that 1 in 5 pregnancies classified as being screen positive would develop pregnancy hypertension. This method of screening is far superior to the traditional approach, which relies entirely on maternal history.