Factors influencing uptake of the COVID-19 vaccination among pregnant women in Australia: A cross-sectional survey.

BACKGROUND: Mounting evidence shows the risk of COVID-19 on perinatal outcomes, as well as the safety and efficacy of vaccination during pregnancy. However, little is known about vaccine uptake among pregnant women in Australia, including women who are culturally and linguistically diverse (CALD), and about sources of information pregnant women use when making decisions about vaccines. We aimed to determine the proportion of pregnant women who had been vaccinated and to identify factors associated with vaccine uptake or decline during pregnancy. METHOD: A cross-sectional, anonymous, online survey was conducted from October 2021 to January 2022 in two metropolitan hospitals in New South Wales, Australia. RESULTS: Of 914 pregnant women, 406 (44%) did not speak English at home. Overall, 101 (11%) received a vaccine prepregnancy and 699 (76%) during pregnancy. In the nonvaccinated cohort, 87 (76%) declined vaccination during pregnancy. The uptake was more than 87% among women during pregnancy who received information from government or health professional websites but 37% when received from personal blogs. The main reasons for vaccine uptake were (1) hearing that COVID-19 affects pregnant women, (2) being concerned about the COVID-19 outbreak, and (3) receiving vaccine recommendation from a general practitioner. In a multivariable logistic regression, three main factors associated with declining or feeling unsure about vaccination were (1) concerns about the safety of the COVID-19 vaccine, (2) lack of trust and being unsatisfied with the information received about COVID-19 vaccination during pregnancy, and (3) doubting the importance of COVID-19 vaccine. CONCLUSION: Clinicians play a critical role in counseling women to alleviate vaccine fear, support vaccine acceptance, and direct women to use reliable information sources, such as government and professional healthcare organizations, for information about vaccines.

Increased prenatal detection of 22q11.2 deletion and 22q11.2 duplication after introduction of nationwide prenatal screening for trisomy 21, trisomy 13, and trisomy 18.

OBJECTIVE: To evaluate time of diagnosis of 22q11.2 deletion and 22q11.2 duplication as well as trisomies 21, 13, and 18 before and after introduction of a prenatal screening program including combined first-trimester screening (cFTS) for the trisomies in Denmark in 2004. METHOD: Cross-sectional, population-based register study employing The Danish Cytogenetic Central Register. Proportions of cases diagnosed 1998-2004 and 2005-2017 were compared before 14+0 and 22+0 weeks and birth (prenatal cases) or up to 1 or 10 years of age (postnatal cases). RESULTS: In total, 4562 cases were included. From 1998-2004 to 2005-2017, the proportion of 22q11.2 deletion cases identified prenatally increased from 4.3% (95% CI: 0.9-12.0%) to 27.3% (21.2-34.0%), while for 22q11.2 duplication an increase from 0/6 to 26/87 (prenatal cases/all cases) was observed. Similarly, proportions of trisomies 21, 13, and 18 detected before birth increased. A greater proportion of the studied conditions was identified earlier in pregnancy, but not generally earlier in the postnatal course. CONCLUSION: Proportions of 22q11.2 deletion and 22q11.2 duplication identified prenatally increased after introduction of a prenatal screening program not aimed specifically to identify these conditions,. A greater proportion of all cases were detected earlier in pregnancy, but not earlier postnatally, following introduction of screening.

New Australian birthweight centiles.

OBJECTIVES: To prepare more accurate population-based Australian birthweight centile charts by using the most recent population data available and by excluding pre-term deliveries by obstetric intervention of small for gestational age babies. DESIGN: Population-based retrospective observational study. SETTING: Australian Institute of Health and Welfare National Perinatal Data Collection. PARTICIPANTS: All singleton births in Australia of 23-42 completed weeks' gestation and with spontaneous onset of labour, 2004-2013. Births initiated by obstetric intervention were excluded to minimise the influence of decisions to deliver small for gestational age babies before term. MAIN OUTCOME MEASURES: Birthweight centile curves, by gestational age and sex. RESULTS: Gestational age, birthweight, sex, and labour onset data were available for 2 807 051 singleton live births; onset of labour was spontaneous for 1 582 137 births (56.4%). At pre-term gestational ages, the 10th centile was higher than the corresponding centile in previous Australian birthweight charts based upon all births. CONCLUSION: Current birthweight centile charts probably underestimate the incidence of intra-uterine growth restriction because obstetric interventions for delivering pre-term small for gestational age babies depress the curves at earlier gestational ages. Our curves circumvent this problem by excluding intervention-initiated births; they also incorporate more recent population data. These updated centile curves could facilitate more accurate diagnosis of small for gestational age babies in Australia.

Effects of sample processing and storage on the integrity of cell-free miRNAs in maternal plasma.

BACKGROUND: Cell-free fetal miRNAs have been identified as potential biomarkers for fetal abnormalities and/or placental function. Factors affecting the stability of cell-free fetal miRNA samples (type of collection tube and time interval between sampling and analysis) have not previously been reported. METHODS: Blood from pregnant women (n = 12, 18 ± 4 weeks' gestation) was collected into two types of tube (EDTA and RNA BCT) and was stored at different temperatures for up to 72 h. Expression of seven apparently placental specific miRNAs was then measured to compare the effects of sampling and storage. These miRNAs were also assessed in non-pregnant women (n = 9). RESULTS: The quantity of miRNA extracted was not affected by time or tube. Three miRNAs (miR-518b, miR-525 and miR-526a*) were measureable only in pregnant women, but miR-518b was not always present. Detailed study of the two pregnancy specific miRNAs showed no effect of tube type at 4 h. However, variability in miRNA level was observed with increased time and was significant for one miRNA in the BCT tube at >48 h (p < 0.005). CONCLUSION: Some cffmiRNAs are placental specific, and these samples are stable when analyzed within 48 h of collection in either tube type. © 2017 John Wiley & Sons, Ltd.

The impact of non-invasive prenatal testing on anxiety in women considered at high or low risk for aneuploidy after combined first trimester screening.

OBJECTIVE: The aim of this study was to (1) examine the psychological impact of non-invasive prenatal testing (NIPT) in women with a high-risk (≥1 : 300) and low-risk (≤1 : 301) result on combined first trimester screening (cFTS) and (2) to examine factors influencing anxiety and decision-making in both risk populations. METHOD: Questionnaires and structured interviews were administered to low (n = 50) and high (n = 63) risk women at the time of NIPT blood draw (point A) and again at least 1 week after receiving their NIPT result (point B). Anxiety levels were measured at these two time points using the State-Trait Anxiety Inventory. RESULTS: Both high-risk and low-risk cFTS groups demonstrated similar intrinsic (trait) anxiety levels (36 ± 10 vs 35 ± 10; p = 0.70). High-risk women had significantly higher levels of state anxiety at point A than low-risk women (42 ± 11 vs 36 ± 11; p < 0.01). Both groups had a statistically significant reduction (p < 0.01), to similar final levels of state anxiety at point B (30 ± 11 vs 29 ± 8; p = 0.61). CONCLUSION: Women receiving a high-risk result on cFTS have higher levels of state anxiety than their low-risk counterparts. Following a low-risk NIPT result, the anxiety levels in both populations are reduced to similar levels. © 2017 John Wiley & Sons, Ltd.

Noninvasive fetal RHD genotyping of RhD negative pregnant women for targeted anti-D therapy in Australia: A cost-effectiveness analysis.

OBJECTIVE: To undertake a cost-effectiveness analysis of noninvasive fetal RHD genotyping to target pregnant women for antenatal anti-D prophylaxis therapy. METHOD: A decision-analytic model was constructed to compare RHD testing and targeted anti-D prophylaxis, with current universal anti-D prophylaxis among pregnant women with RhD negative blood type. Model estimates were derived from national perinatal statistics, published literature, donor program records, and national cost sources. One-way sensitivity analyses addressed the uncertainty of variables on the main findings. RESULTS: The unit cost for RHD genotyping was estimated at AU$45.48 (US$31.84). The "mean cost per healthy baby" was AU$7495 (US$5247) for universal prophylaxis and AU$7471 (US$5230) for targeted prophylaxis. The findings were sensitive to the unit costs of anti-D 625 IU (AU$59-AU$88) (US$41-US$62), the genetic test (AU$36-AU$55) (US$25-US$39), and packaging/transport costs of the samples for testing (AU$15-AU$40, US$11-US$28 per sample). With RHD genotyping, 13 938 women would avoid antenatal anti-D prophylaxis at a total cost savings to the National Blood Authority of AU$2.1 million (US$1.5 million) per year. To the health system, net cost savings of AU$159 701 (US$111 791) per year (0.05%) were predicted for total health care costs. CONCLUSIONS: Given the vulnerable supply of donor plasma and other health concerns, RHD genotyping is an economically sound option for Australia.

Serum levels of GDF15 are reduced in preeclampsia and the reduction is more profound in late-onset than early-onset cases.

BACKGROUND: Preeclampsia is a pregnancy specific disorder affecting 3-5% of pregnancies worldwide. It is clinically divided into early-onset and late-onset subtypes. Placental factors are involved in the pathogenesis of preeclampsia. Growth differentiation factor 15 (GDF15), a protein of the transforming growth factor beta superfamily, is highly expressed in the placenta. However, it is unclear whether the circulating levels of GDF15 are altered in preeclampsia at the time of or prior to disease presentation. METHODS: Serum samples across three trimesters from 29 healthy pregnancies, third trimester sera from 34 women presenting with preeclampsia (early-onset n=16, late-onset n=18) and 66 gestation-age-matched controls, and sera at 11-13weeks of pregnancy from women who later did (n=36) or did not (n=33) develop late-onset preeclampsia, were examined for GDF15 by ELISA. RESULTS: Serum GDF15 levels increased significantly with gestation in normal pregnancy. Serum GDF15 was significantly reduced in the third trimester in women presenting with preeclampsia compared to their gestation-age-matched controls. This reduction was apparent in both early-onset and late-onset subtypes, but it was more profound in late-onset cases. At 11-13weeks of gestation, however, serum levels of GDF15 were similar between women who subsequently did and did not develop late-onset preeclampsia. CONCLUSION: Serum GDF15 increased with gestation age, reaching the highest level in the third trimester. Serum GDF15 was significantly reduced in the third trimester in women presenting with preeclampsia, especially in late-onset cases. However, serum GDF15 was not altered in the first trimester in women destined to develop late-onset preeclampsia.

Pre-Implantation Genetic Screening Techniques: Implications for Clinical Prenatal Diagnosis.

Chromosomal aneuploidy is responsible for a significant proportion of pregnancy failures, whether conceived naturally or through in vitro fertilization (IVF). In an effort to improve the success rate of IVF, screening embryos for aneuploidy - or pre-implantation genetic screening (PGS) - has been proposed as a means of ensuring only euploid embryos are selected for transfer. Early PGS approaches were based on fluorescence in situ hybridization testing, and have been shown not to improve live birth rates. Recent developments in genetic testing technologies - such as next-generation sequencing and quantitative polymerase chain reaction, coupled with embryo biopsy at the blastocyst stage - have shown promise in improving IVF outcomes, but they remain to be validated in adequately powered, prospective randomized trials. The extent to which IVF with PGS lowers the a priori risk of aneuploidy in ongoing pregnancies so conceived has been poorly described, rendering it difficult to incorporate the potential benefit of PGS into existing prenatal aneuploidy screening regimens such as cell-free DNA testing or conventional combined nuchal translucency and maternal biochemistry assessment. Further data on the sensitivity and specificity of various forms of molecular PGS testing would improve our understanding of the effectiveness and accuracy of these technologies. This, in addition to further research into methods of risk combination and assessment, would allow us to help our patients make better- informed decisions about whether or not to proceed with invasive diagnostic tests.

Strategy for managing maternal variant RHD alleles in Rhesus D negative obstetric populations during fetal RHD genotyping.

OBJECTIVES: Fetal RHD screening programs that aim to reduce unnecessary antenatal anti-D prophylaxis are being introduced into clinical practice. Strategies to manage women serologically typed as Rhesus D negative who have maternal RHD variants are needed. This study describes maternal RHD allelic variants detected in nonselected and alloimmunised Rhesus D negative obstetric populations and explores a mathematical approach to identify these variants. METHODS: Fetal RHD status was defined by testing cell-free fetal DNA in maternal plasma. Women at risk of an RHD variant were identified by selection for C and E haplotypes or by recognition of low polymerase chain reaction cycle threshold on fetal RHD typing. Maternal RHD alleles were defined by SNP profiling or sequencing. RESULTS: The prevalence of RHD variants in nonselected and alloimmunised groups was 1% (6/603) and 5.5% (6/110), respectively (p < 0.001). An inverse association between RHD cycle threshold values and gestational age was described by a linear model (p < 0.001). Standard residual values with a Z score threshold of -3.00 would have detected all maternal variants with one (1/713) false positive. CONCLUSIONS: The prevalence of maternal RHD variants was significantly higher in alloimmunised cases. The causative mechanism for this needs further investigation. Mathematical modeling simplifies the detection of maternal RHD variants.

Anti-D in pregnant women with the RHD(IVS3+1G>A)-associated DEL phenotype.

BACKGROUND: Pregnant women with the DEL phenotype appear to be D- by routine serology. Women with DEL phenotypes that show a partial D-like epitope loss may develop anti-D. It has been proposed that this alloantibody could have a deleterious effect with respect to hemolytic disease in the fetus and newborn. CASE REPORTS: Two pregnant women, one in Australia and one in Germany, were serotyped as D- and were sensitized to the D antigen. Noninvasive fetal RHD genotyping was performed to plan pregnancy management. RESULTS: In both cases the fetal RHD status could not be assigned due to the presence of a maternal DEL allele. This was suspected through detection of high RHD amplicon levels during quantitative polymerase chain reaction. For both cases extended molecular typing of the maternal genomic DNA revealed a RHD(IVS3+1G>A) allele. For case one, the D+ infant developed a mild hemolytic disease requiring phototherapy. In the second case a D- (or DEL) newborn was unaffected. CONCLUSION: Fetal genotyping from maternal plasma reveals RHD variants in pregnant women with anti-D. Fetuses and newborns of sensitized pregnant women carrying the RHD(IVS3+1G>A) allele are at risk of hemolytic disease.

Combining early (<11 weeks' gestation) ultrasound features and maternal factors to predict small-for-gestational age neonates.

OBJECTIVES: Placental related adverse pregnancy outcomes such as fetal growth restriction have significant short- and long-term implications for both mother and fetus. This study aimed to determine if conventional and novel early first trimester ultrasound measures are associated with small for gestational age (SGA) neonates. In addition, we aimed to assess whether a combination of ultrasound measures, maternal characteristics and biochemistry improved the prediction of this adverse pregnancy outcome. METHODS: This was a prospective cohort study including ultrasound measurements: trophoblast thickness (TT), trophoblast volume (TV), mean uterine artery pulsatility index, crown-rump length, fetal heart rate, mean sac diameter (MSD) and yolk sac diameter. Biochemical markers considered in the analysis were placental growth factor (PIGF), pregnancy - associated plasma protein A (PAPP-A), beta human chorionic gonadotropin and alpha fetoprotein. Regression models were fitted for ultrasound parameters using multiples of the median (MoM). All measures were compared with normal birthweight (BW) ≥10th centile and SGA (BW < 10th centile). Logistic regression analysis was used to create a clinical prediction model for SGA based on maternal characteristics, ultrasound measurements at <11 weeks gestational age and maternal biochemistry collected at 10-14 weeks. RESULTS: As compared to pregnancies delivered of babies with normal BW (n = 1068), MoM values for TT, TV, MSD, PAPP-A and PIGF were significantly reduced (P < 0.05) in pregnancies delivered of SGA babies (n = 73). The proposed logistic regression model includes maternal height, TV and PIGF resulting in an area under the receiver operator curve 0.70 (95% CI 0.63-0.76) for the prediction of SGA. CONCLUSION: A significantly decreased TV, measured <11 weeks gestation, is predictive of BW < 10th centile. With addition of maternal height and PIGF, this three-marker algorithm provided a reasonable predictive value for the development of SGA later in pregnancy.

Serum podocalyxin at 11-13 weeks of gestation in the prediction of small for gestational age neonates.

OBJECTIVE: To investigate a potential new marker for the prediction of small for gestational age (SGA) infants. STUDY DESIGN: Nested case-control study involving 280 uncomplicated pregnancies and 70 cases of SGA without pre-eclampsia. Serum podocalyxin was measured at 11-13 weeks of gestation and results were expressed in multiples of the median (MoM). The performance of screening by a combination of maternal history and podocalyxin levels was assessed with ROC curves. RESULTS: SGA was predicted by maternal age, height, South Asian ethnicity, and previous delivery without pre-eclampsia. Median podocalyxin levels were higher in affected than uncomplicated pregnancies (1.303 versus 0.994 MoM, p < 0.001). At a 10% false-positive rate, maternal history identified 40.0% of the cases (AUC = 0.74, 95%CI 0.671-0.809). The addition of podocalyxin increased the detection to 54.3% (AUC = 0.78, 95%CI 0.771-0.842, p = 0.027 for the difference in ROC curves). CONCLUSION: First-trimester podocalyxin may be useful in screening for SGA infants.

A survey of opinion and practice regarding prenatal diagnosis of vasa previa among obstetricians from Australia and New Zealand.

OBJECTIVES: To define current obstetric opinion and clinical practice regarding the prenatal diagnosis of vasa previa in Australia and New Zealand. METHODS: A population-based cross-sectional survey of Fellows of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists was conducted from April to May, 2016. Descriptive analysis was used to define factors influencing opinion and practice regarding definition of vasa previa, attributable risk factors, and the value of screening. RESULTS: Overall, 453 respondents were included in the study. Two-thirds (304/453; 67.1%) defined vasa previa as exposed fetal vessel(s) running over or within 2 cm of the internal os. A higher proportion of ultrasound specialists (30/65; 46.2%) preferred a broader definition as compared with generalists (115/388; 29.6%; P<0.001). Overall, Fellows were supportive (342/430; 79.5%) of both reporting ultrasound-based risk factors at the 20-week anomaly scan and targeted screening (298/430; 69.3%). Only 77/453 (17.0%) respondents recognized all five "known" risk factors for vasa previa. CONCLUSIONS: There was a lack of consensus regarding the definition and diagnosis process for vasa previa. There was also a knowledge gap in risk factors for vasa previa that would inform a targeted screening policy. Nevertheless, support for targeted screening was strong from obstetricians who responded.

The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: A pragmatic guide for first-trimester screening and prevention.

Pre­eclampsia (PE) is a multisystem disorder that typically affects 2%­5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Globally, 76 000 women and 500 000 babies die each year from this disorder. Furthermore, women in low­resource countries are at a higher risk of developing PE compared with those in high­resource countries. Although a complete understanding of the pathogenesis of PE remains unclear, the current theory suggests a two­stage process. The first stage is caused by shallow invasion of the trophoblast, resulting in inadequate remodeling of the spiral arteries. This is presumed to lead to the second stage, which involves the maternal response to endothelial dysfunction and imbalance between angiogenic and antiangiogenic factors, resulting in the clinical features of the disorder. Accurate prediction and uniform prevention continue to elude us. The quest to effectively predict PE in the first trimester of pregnancy is fueled by the desire to identify women who are at high risk of developing PE, so that necessary measures can be initiated early enough to improve placentation and thus prevent or at least reduce the frequency of its occurrence. Furthermore, identification of an "at risk" group will allow tailored prenatal surveillance to anticipate and recognize the onset of the clinical syndrome and manage it promptly. PE has been previously defined as the onset of hypertension accompanied by significant proteinuria after 20 weeks of gestation. Recently, the definition of PE has been broadened. Now the internationally agreed definition of PE is the one proposed by the International Society for the Study of Hypertension in Pregnancy (ISSHP). According to the ISSHP, PE is defined as systolic blood pressure at ≥140 mm Hg and/or diastolic blood pressure at ≥90 mm Hg on at least two occasions measured 4 hours apart in previously normotensive women and is accompanied by one or more of the following new­onset conditions at or after 20 weeks of gestation: 1.Proteinuria (i.e. ≥30 mg/mol protein:creatinine ratio; ≥300 mg/24 hour; or ≥2 + dipstick); 2.Evidence of other maternal organ dysfunction, including: acute kidney injury (creatinine ≥90 µmol/L; 1 mg/dL); liver involvement (elevated transaminases, e.g. alanine aminotransferase or aspartate aminotransferase >40 IU/L) with or without right upper quadrant or epigastric abdominal pain; neurological complications (e.g. eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, and persistent visual scotomata); or hematological complications (thrombocytopenia­platelet count <150 000/µL, disseminated intravascular coagulation, hemolysis); or 3.Uteroplacental dysfunction (such as fetal growth restriction, abnormal umbilical artery Doppler waveform analysis, or stillbirth). It is well established that a number of maternal risk factors are associated with the development of PE: advanced maternal age; nulliparity; previous history of PE; short and long interpregnancy interval; use of assisted reproductive technologies; family history of PE; obesity; Afro­Caribbean and South Asian racial origin; co­morbid medical conditions including hyperglycemia in pregnancy; pre­existing chronic hypertension; renal disease; and autoimmune diseases, such as systemic lupus erythematosus and antiphospholipid syndrome. These risk factors have been described by various professional organizations for the identification of women at risk of PE; however, this approach to screening is inadequate for effective prediction of PE. PE can be subclassified into: 1.Early­onset PE (with delivery at <34+0 weeks of gestation); 2.Preterm PE (with delivery at <37+0 weeks of gestation); 3.Late­onset PE (with delivery at ≥34+0 weeks of gestation); 4.Term PE (with delivery at ≥37+0 weeks of gestation). These subclassifications are not mutually exclusive. Early­onset PE is associated with a much higher risk of short­ and long­term maternal and perinatal morbidity and mortality. Obstetricians managing women with preterm PE are faced with the challenge of balancing the need to achieve fetal maturation in utero with the risks to the mother and fetus of continuing the pregnancy longer. These risks include progression to eclampsia, development of placental abruption and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. On the other hand, preterm delivery is associated with higher infant mortality rates and increased morbidity resulting from small for gestational age (SGA), thrombocytopenia, bronchopulmonary dysplasia, cerebral palsy, and an increased risk of various chronic diseases in adult life, particularly type 2 diabetes, cardiovascular disease, and obesity. Women who have experienced PE may also face additional health problems in later life, as the condition is associated with an increased risk of death from future cardiovascular disease, hypertension, stroke, renal impairment, metabolic syndrome, and diabetes. The life expectancy of women who developed preterm PE is reduced on average by 10 years. There is also significant impact on the infants in the long term, such as increased risks of insulin resistance, diabetes mellitus, coronary artery disease, and hypertension in infants born to pre­eclamptic women. The International Federation of Gynecology and Obstetrics (FIGO) brought together international experts to discuss and evaluate current knowledge on PE and develop a document to frame the issues and suggest key actions to address the health burden posed by PE. FIGO's objectives, as outlined in this document, are: (1) To raise awareness of the links between PE and poor maternal and perinatal outcomes, as well as to the future health risks to mother and offspring, and demand a clearly defined global health agenda to tackle this issue; and (2) To create a consensus document that provides guidance for the first­trimester screening and prevention of preterm PE, and to disseminate and encourage its use. Based on high­quality evidence, the document outlines current global standards for the first­trimester screening and prevention of preterm PE, which is in line with FIGO good clinical practice advice on first trimester screening and prevention of pre­eclampsia in singleton pregnancy.1 It provides both the best and the most pragmatic recommendations according to the level of acceptability, feasibility, and ease of implementation that have the potential to produce the most significant impact in different resource settings. Suggestions are provided for a variety of different regional and resource settings based on their financial, human, and infrastructure resources, as well as for research priorities to bridge the current knowledge and evidence gap. To deal with the issue of PE, FIGO recommends the following: Public health focus: There should be greater international attention given to PE and to the links between maternal health and noncommunicable diseases (NCDs) on the Sustainable Developmental Goals agenda. Public health measures to increase awareness, access, affordability, and acceptance of preconception counselling, and prenatal and postnatal services for women of reproductive age should be prioritized. Greater efforts are required to raise awareness of the benefits of early prenatal visits targeted at reproductive­aged women, particularly in low­resource countries. Universal screening: All pregnant women should be screened for preterm PE during early pregnancy by the first­trimester combined test with maternal risk factors and biomarkers as a one­step procedure. The risk calculator is available free of charge at https://fetalmedicine.org/research/assess/preeclampsia. FIGO encourages all countries and its member associations to adopt and promote strategies to ensure this. The best combined test is one that includes maternal risk factors, measurements of mean arterial pressure (MAP), serum placental growth factor (PLGF), and uterine artery pulsatility index (UTPI). Where it is not possible to measure PLGF and/or UTPI, the baseline screening test should be a combination of maternal risk factors with MAP, and not maternal risk factors alone. If maternal serum pregnancy­associated plasma protein A (PAPP­A) is measured for routine first­trimester screening for fetal aneuploidies, the result can be included for PE risk assessment. Variations to the full combined test would lead to a reduction in the performance screening. A woman is considered high risk when the risk is 1 in 100 or more based on the first­trimester combined test with maternal risk factors, MAP, PLGF, and UTPI. Contingent screening: Where resources are limited, routine screening for preterm PE by maternal factors and MAP in all pregnancies and reserving measurements of PLGF and UTPI for a subgroup of the population (selected on the basis of the risk derived from screening by maternal factors and MAP) can be considered. Prophylactic measures: Following first­trimester screening for preterm PE, women identified at high risk should receive aspirin prophylaxis commencing at 11­14+6 weeks of gestation at a dose of ~150 mg to be taken every night until 36 weeks of gestation, when delivery occurs, or when PE is diagnosed. Low­dose aspirin should not be prescribed to all pregnant women. In women with low calcium intake (<800 mg/d), either calcium replacement (≤1 g elemental calcium/d) or calcium supplementation (1.5­2 g elemental calcium/d) may reduce the burden of both early­ and late­onset PE.

HtrA3 Isoform-Specific ELISAs for Early Detection of Preeclampsia.

Preeclampsia is a serious disorder of human pregnancy occurring after 20 weeks of gestation. It can be divided into subtypes of early onset (<34 weeks of gestation) and late onset (>34 weeks). Presymptomatic detection to identify those at high risk is important for managing this disease. HtrA3, a serine protease with high expression in the developing placenta, exists in long (HtrA3-L) and short (HtrA3-S) isoforms. They are identical, except HtrA3-S lacks the C-terminal PDZ domain. We have previously shown by Western blot analysis that serum HtrA3 levels at the end of the first trimester are significantly higher in women who later develop preeclampsia than in controls. In this study, using highly specific HtrA3 monoclonal antibodies, we established and fully validated two enzyme-linked immunosorbent assays to detect both HtrA3 isoforms together (HtrA3-T) and HtrA3-L alone in the human serum. We then determined serum HtrA3 at 11 to 13 weeks of gestation in a cohort of singleton pregnancies that proceeded without complications or developed preeclampsia in the third trimester. Compared with controls, those who developed late-onset preeclampsia had significantly higher levels of HtrA3-L, whereas those who developed early-onset preeclampsia had significantly lower ratios of HtrA3-L/HtrA3-T. These data support a potential utility of these HtrA3 ELISAs for early detection of preeclampsia.

Serum podocalyxin for early detection of preeclampsia at 11-13 weeks of gestation.

Podocalyxin is expressed on endothelial surface throughout the body and is likely released into the circulation during pregnancy in association with vessel remodeling. We have recently reported that serum podocalyxin is significantly increased in preeclampsia at disease presentation. In this study we investigated whether serum podocalyxin is altered prior to clinical presentation of preeclampsia. At 11-13 weeks of gestation, serum podocalyxin was significantly elevated in women who subsequently developed preeclampsia. Multi-factorial analysis suggests that combination of serum podocalyxin with the long isoform of HtrA3 and mean arterial pressure, may provide effective detection of late-onset preeclampsia at 11-13 weeks of pregnancy.