Comparison of clinic and home blood pressure readings in higher risk pregnancies - Secondary analysis of the BUMP 1 trial.

OBJECTIVE: To compare clinic and home blood pressure readings in higher risk pregnancies in the antenatal period from 20 weeks gestation, and to evaluate differences between the two modalities. STUDY DESIGN: A cohort study comprising a secondary analysis of a large randomised controlled trial (BUMP 1). POPULATION: Normotensive women at higher risk of pregnancy hypertension randomised to self-monitoring of blood pressure. MAIN OUTCOME MEASURES: The primary outcome was the overall mean difference between clinic and home readings for systolic blood pressure (sBP) and diastolic blood pressure (dBP). Blood pressure readings were averaged across each gestational week for each participant and compared within the same gestational week. Calculations of the overall differences were based on the average difference for each week for each participant. RESULTS: The cohort comprised 925 participants. In total, 92 (10 %) developed a hypertensive disorder during the pregnancy. A significant difference in the overall mean sBP (clinic - home) of 1.1 mmHg (0.5-1.6 95 %CI) was noted, whereas no significant difference for the overall mean dBP was found (0.0 mmHg (-0.4-0.4 95 %CI)). No tendency of proportional bias was noted based on Bland-Altman plots. Increasing body mass index in general increased the difference (clinic - home) for both sBP and dBP in a multivariate analysis. CONCLUSIONS: No clinically significant difference was found between clinic and home blood pressure readings in normotensive higher risk pregnancies from gestational week 20+0 until 40+0. Clinic and home blood pressure readings might be considered equal during pregnancy in women who are normotensive at baseline.

Motivation towards first trimester screening for preeclampsia among pregnant women in Denmark: A cross-sectional questionnaire study.

INTRODUCTION: The aim of this cross-sectional questionnaire study was to investigate motivation to participate in a possible new screening for preeclampsia in the first trimester of pregnancy among Danish pregnant women through a questionnaire based on Theory of Planned Behavior developed for this specific purpose. The new screening combines maternal characteristics with mean arterial pressure, uterine artery pulsatility index and biochemical markers to predict the risk of preeclampsia, whereas the current Danish screening uses maternal characteristics alone. MATERIAL AND METHODS: Participation was offered to a proportion of women attending a first or a second trimester screening scan at two University Hospitals in Copenhagen. The questionnaire was set up in REDCap® and answers were entered directly into the database, which was accessed via a QR-code. RESULTS: We invited 772 pregnant women to participate in the questionnaire survey between November 2021 and April 2022 at Copenhagen University Hospital Rigshospitalet (study site one) (n = 238) and Copenhagen University Hospital Hvidovre (study site two) (n = 534). The response rate was 71.8% (171/238) at study site one and 33.9% (181/534) at study site two. A total of 352 women were included in the study (total participation rate 45.6%). Most women had a positive attitude towards preeclampsia screening in pregnancy, and 99.4% said they would participate in a risk assessment for preeclampsia if given the opportunity. A total of 97.4% answered "yes" to whether a first trimester preeclampsia screening should be offered to all pregnant women in Denmark. Positive motivation to participate in preeclampsia screening was correlated with having a network with a positive attitude towards preeclampsia screening. CONCLUSIONS: The results of this study indicate that Danish pregnant women have a positive attitude towards participation in a first trimester screening for preeclampsia. This observation might be useful in relation to possible future implementation in Denmark.

Risk of adverse pregnancy outcome in isolated single umbilical artery diagnosed at the mid-trimester anomaly scan: a large Danish retrospective cohort study.

OBJECTIVE: To examine the association of isolated single umbilical artery (iSUA) confirmed at the mid-trimester anomaly scan and adverse pregnancy outcome and congenital malformations with up to 10 years postnatal follow up. METHODS: This retrospective cohort study included 116,501 singleton pregnancies consecutively enrolled in first trimester screening for aneuploidies and mid-trimester anomaly scan at three University Hospitals in the Capital Region of Copenhagen, Denmark.Data from the Danish Fetal Medicine Database (2008-2017) were verified by manually scrutinizing pre- and postnatal records. The main outcomes of interest were intrauterine fetal demise (IUFD), small for gestational age (SGA), preterm delivery, cesarean section and unrecognized pre- and postnatal congenital malformations. RESULTS: In total, 775 pregnancies with iSUA were identified. Isolated SUA were associated with a significantly increased risk of IUFD (OR 4.16, 95% CI 2.06-8.44), SGA < 3rd centile (aOR 2.41, 95% 1.85-3.14) and SGA < 10th centile (aOR 1.84, 95% CI 1.53-2.21), but not with preterm delivery or cesarean section. The laterality of the missing artery was not associated with SGA. In total, 4.3% of pregnancies with iSUA had unrecognized congenital malformations. 1.5% with iSUA had congenital cardiovascular malformations, which were considered minor. CONCLUSION: Isolated SUA is associated with IUFD and SGA, supporting surveillance during third trimester. If, during the mid-trimester scan, the sonographer achieves thorough, extended cardiac views and finds no additional malformation other than SUA, fetal echocardiography seems not to be needed.

Cohort profile: The PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension (PEACH) Study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) remain a leading cause of maternal morbidity and mortality worldwide, with implications for maternal and neonatal well-being in the short term and for long-term maternal cardiovascular health. Although the mechanisms behind HDP remain incompletely understood, evidence suggests that preeclampsia in particular is a syndrome with more than one distinct subtype. OBJECTIVES: The PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction, Hypertension) Study was established to identify new HDP subtyping systems reflecting aetiology and prognosis and to find markers of later cardiovascular disease risk associated with preeclampsia. POPULATION: The PEACH Study recruited pregnant women referred to two Copenhagen-area hospitals with suspected preeclampsia (mean gestational age at enrolment: 36.7 weeks) and a group of frequency-matched pregnant women planning delivery at the same hospitals and healthy when enrolled mid-pregnancy. DESIGN: Prospective, longitudinal pregnancy cohort. METHODS: Participants underwent repeated third-trimester blood sample collection, longitudinal cardiac function assessments using the USCOM-1A during the third trimester and at 1 year postpartum and collection of placental samples immediately after delivery. Medical information was abstracted from medical records and hospital databases. PRELIMINARY RESULTS: During 2016-2018, we recruited 1149 pregnant women, of whom 1101 were followed to delivery. Among 691 women enrolled with suspected preeclampsia, 310 and 172 developed preeclampsia and gestational hypertension respectively. Among 410 women with healthy pregnancies when enrolled mid-pregnancy, 37 later developed hypertensive disorders of pregnancy. Of 1089 women still in the cohort 1 year postpartum, 578 (53.1%) participated in the follow-up assessment. CONCLUSIONS: The PEACH Study's rich data from women with and without HDP will enable us to identify new, clinically useful HDP subtypes to aid in decision-making regarding monitoring and treatment. Continued postpartum follow-up will help us develop algorithms to identify women at risk of persistent postpartum cardiac dysfunction and later cardiovascular disease after pregnancies complicated by HDP.

First-trimester biomarkers and the risk of cerebral palsy.

BACKGROUND: Cerebral palsy (CP) is the most common severe motor disability and a manifestation of early brain damage. AIMS: To analyze if abnormal levels of first-trimester biomarkers were associated with CP. Furthermore, to investigate their clinical applicability in early predicting of CP. STUDY DESIGN: Nationwide cohort study. SUBJECTS: We included 258.057 singleton live births, born during 2008-2013 with completed first-trimester assessments. OUTCOME MEASURES: Data on beta subunit of human chorionic gonadotropin (beta-hCG), pregnancy-associated plasma protein-A (PAPP-A), nuchal translucency thickness, and biparietal diameter (BPD) were converted to multiple of the medians (MoM). Associations were analyzed by comparing mean and extreme levels between pregnancies with and without CP. All CP diagnoses were validated by trained neuropediatricians. Logistic regression was used to create an early prediction model. RESULTS: The mean beta-hCG value was significantly lower in pregnancies with CP (0.96MoM [95% CI 0.91-1.02] vs 1.04MoM [1.04-1.04], p = 0.01) and the mean PAPP-A value tended to be lower (0.96MoM [0.91-1.01] vs 1.01MoM [1.00-1.01], p = 0.07). Moreover, fetuses that developed CP more likely had a BPD measurement below the fifth percentile (7.5% vs 5%, p = 0.045). The final prediction model had poor discrimination. CONCLUSIONS: Pregnancies with CP tend to have lower values of beta-hCG and PAPP-A in the first trimester, however, the associations are mediated differently. Nonetheless, abnormal levels of the most common first-trimester biomarkers only have weak associations with CP; resulting in inadequate predictive abilities when included in an early prediction model.

Prediction of Preeclampsia in Nulliparous Women according to First Trimester Maternal Factors and Serum Markers.

OBJECTIVE: To evaluate the performance of maternal risk factors (BMI and mean arterial pressure [MAP]) and first-trimester maternal serum markers in the early prediction of preeclampsia (PE) in nulliparous women. MATERIAL AND METHODS: This was a case-cohort study based on a cohort of 14,207 nulliparous women. A total of 213 cases with term PE (from 37 weeks + 0 days) and 55 cases with preterm PE (before 37 weeks + 0 days) were identified and validated. Randomly, 449 controls were selected. Serum samples previously collected for the double test (pregnancy-associated plasma protein A [PAPP-A] and free ß human chorionic gonadotrophin [hCGß]) as part of the first-trimester screening program were retrieved and analyzed for placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and neutrophil gelatinase-associated lipocalin (NGAL). Concentrations were transformed to multiples of the median (MoM). Multivariate regression analysis was used for prediction models. Receiver-operating characteristics (ROC) curves were used for evaluation of the screening performance. RESULTS: In preterm PE, the PlGF (0.79 MoM), sFlt-1 (0.86 MoM), NGAL (1.15 MoM), and PAPP-A (0.89 MoM) medians were significantly altered. In term PE, PlGF (0.90 MoM) and NT-proBNP (0.86 MoM) medians were significantly reduced. The combination of MAP and PlGF yielded a 39% detection rate of preterm PE for a 10% false-positive rate. The combination of MAP, BMI, and PlGF yielded a 33% detection rate of term PE with a 10% false-positive rate. CONCLUSION: First-trimester MAP, maternal serum PlGF, and NGAL are markers of preterm PE. Maternal serum sFlt-1 is a significant marker of preterm PE, but only early in the first trimester. First-trimester maternal serum NT-proBNP is not a predictor of PE. Screening performance for PE with these markers individually or in combination is modest.

Maternal serum laeverin (aminopeptidase Q) measured in the first trimester of pregnancy does not predict preeclampsia.

Objective: The aim of this study was to compare the laeverin level in maternal serum from first trimester (11-14 weeks) of pregnancy between normal pregnancies and pregnancies that later developed preeclampsia (PE). Material and methods: This was a case-cohort study. The laeverin concentration was measured in cases with preterm PE (n = 55), term PE (n = 95), and a reference group of randomly selected women with normal pregnancy outcome (n = 200) in stored serum samples collected from the double-test as part of the combined first trimester trisomy 21 screening program. The samples were thawed and analyzed for laeverin. The median gestational age at blood sampling was 77 days (range 57-96 days). Multiple regression analysis was performed to establish a normal median. Concentrations were converted to multiples of the median (MoM) and groups were compared using the Mann-Whitney U-test. Results: In the reference group, laeverin was significantly correlated with gestational age (r = 0.18, p = .01) and its concentration ranged from 41-393 µg/L. No significant differences in the median laeverin MoM were found between the reference group (1.01 MoM) and cases with preterm PE (0.98 MoM) or term PE (0.96 MoM). Conclusions: First trimester maternal serum laeverin level cannot be used to predict preeclampsia.

Spontaneous Septostomy in a Twin Pregnancy Causing Fatal Amniotic Band Syndrome.

Complications due to spontaneous septostomy of the dividing membrane in monochorionic diamniotic pregnancies are rarely described. Herein, we report the case of a preterm female neonate from a monochorionic diamniotic twin pregnancy delivered by caesarean section at 32 weeks of gestation. She was born with a broad band of a transparent membrane-like material firmly attached to her lower abdomen. Postnatally, she developed respiratory distress syndrome and persistent pulmonary hypertension, complicated by bilateral pneumothorax. She died due to respiratory failure when she was 1 day old. Her twin sister survived with no malformations. At postmortem examination, the neonate had severe lung hypoplasia, and the attached material was diagnosed as the dividing septum. We hypothesize that the lung hypoplasia was secondary to local oligohydramnios, which developed as a consequence of the twin being firmly stuck in the defect of the dividing membrane. To our best knowledge, spontaneous septostomy causing an ultimately fatal amniotic band syndrome has not previously been described.

Formation of high-molecular-weight angiotensinogen during pregnancy is a result of competing redox reactions with the proform of eosinophil major basic protein.

The plasma concentration of the placentally derived proMBP (proform of eosinophil major basic protein) increases in pregnancy, and three different complexes containing proMBP have been isolated from pregnancy plasma and serum: a 2:2 complex with the metalloproteinase, PAPP-A (pregnancy-associated plasma protein-A), a 2:2 complex with AGT (angiotensinogen) and a 2:2:2 complex with AGT and complement C3dg. In the present study we show that during human pregnancy, all of the circulating proMBP exists in covalent complexes, bound to either PAPP-A or AGT. We also show that the proMBP-AGT complex constitutes the major fraction of circulating HMW (high-molecular weight) AGT in late pregnancy, and that this complex is able to further associate with complement C3 derivatives post-sampling. Clearance experiments in mice suggest that complement C3-based complexes are removed faster from the circulation compared to monomeric AGT and the proMBP-AGT complex. Furthermore, we have used recombinant proteins to analyse the formation of the proMBP-PAPP-A and the proMBP-AGT complexes, and we demonstrate that they are competing reactions, depending on the same cysteine residue of proMBP, but differentially on the redox potential, potentially important for the relative amounts of the complexes in vivo. These findings may be important physiologically, since the biochemical properties of the proteins change as a consequence of complex formation.

ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome.

BACKGROUND: ADAM12 has been shown to be an efficient maternal serum marker for Down syndrome (DS) in the first trimester; but recent studies, using a second generation assay, have not confirmed these findings. We examined the efficiency of a second generation assay for ADAM12. MATERIALS AND METHODS: ADAM12 concentrations were determined in 28 first trimester DS and 503 control pregnancies using a novel Research Delfia ADAM12 kit. Log10MoM distributions of ADAM12 and correlations with other markers were established. Population performance of screening was estimated by Monte Carlo simulation. RESULTS: ADAM12 was significantly reduced in the first trimester in DS pregnancies with a log10MoM of -0.1621 (equivalent to 0.68 MoM) (p < 0.001). The reduction decreased with advancing gestational age. ADAM12 used with PAPP-A + hCG beta + NT (CUB screening) increased the detection rate (DR) from 86% to 89% for a false positive rate (FPR) of 5%. When used for a fixed DR of 90%, the addition of ADAM12 resulted in a 25% reduction of the FPR. CONCLUSION: ADAM12 is a moderately effective DS marker. It is not a cost-effective addition to CUB screening, but may be used to reduce the FPR in selected high-risk cases.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: SP1 is a first trimester maternal serum marker of SGA and preterm delivery.

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

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

Leptin in first trimester pregnancy serum: no reduction associated with small-for-gestational-age infants.

Leptin is an adipocytokine that is also synthesized by the placenta. Leptin and its receptor, which is also expressed by the placenta, are believed to play an auto- and paracrine role in trophoblast invasion and placental development. The leptin concentration in first trimester maternal serum and its relation to fetal growth disturbances were examined in this study. The study is a case-control study with 36 small-for-gestational-age (SGA) (<5th percentile) pregnancies and 108 appropriate-for-gestational-age (AGA) (> or =5th percentile) pregnancies. The groups were matched by maternal age, gestational age and body mass index (BMI). All were non-smokers. Leptin was measured in maternal serum in weeks 8-13 and was normalized for BMI with concentrations expressed as multiples of the median for the actual BMI. It was found that maternal serum leptin increased strongly (r = 0.7, P < 10(-4))with maternal BMI. There was no significant difference in maternal serum leptin concentrations between SGA and AGA pregnancies. In conclusion, SGA pregnancies are not associated with a lower maternal serum leptin concentration in first trimester. The maternal serum leptin concentration is largely determined by maternal BMI. Variation in the leptin concentration in maternal serum in first trimester does not seem to be associated with impaired fetal growth.

First trimester maternal serum PAPP-A, beta-hCG and ADAM12 in prediction of small-for-gestational-age fetuses.

OBJECTIVE: To examine the ability of predicting fetuses being small-for-gestational-age (SGA) at delivery with the maternal serum markers pregnancy-associated plasma protein A (PAPP-A), beta-human chorionic gonadotrophin (beta-hCG) and A disintegrin and metalloprotease 12 (ADAM12) in first trimester. METHODS: In all,36 cases being SGA (birth weight < 5th centile) and 108 controls being non-SGA were matched on ethnicity (only Caucasians), smoking status (only nonsmokers), body mass index (BMI), age and parity. Stored blood samples from PAPP-A and beta-hCG testing obtained at gestational age (GA) of 8 weeks to 13 weeks and 6 days were analyzed for ADAM12. Median MoM values were compared using Mann-Whitney test. Monte Carlo estimation and receiver-operator-characteristics curves were used to asses screening performance. RESULTS: Median MoM values of PAPP-A (0.64 vs 1.02, p < 0.001), beta-hCG (0.74 vs 1.04, p = 0.007) and ADAM12 (0.74 vs 0.97, p = 0.004) were significantly reduced in cases compared to controls. The combination of PAPP-A MoM and beta-hCG MoM yielded a detection rate (DR) for SGA of 26% for a 5% false-positive rate (FPR). Addition of ADAM12 only improved (28% DR for a 5% FPR) screening performance modestly. CONCLUSION: Early prediction of fetuses being SGA is feasible with the combination of first trimester PAPP-A, beta-hCG and ADAM12. Screening performance is approaching clinical relevance. The inclusion of further markers is an attractive option.

[Quality control of prenatal screening]. / Kvalitetskontrol af praenatal screening.

INTRODUCTION: In 2004 the Danish National Board of Health (DNBH) published new guidelines for the prenatal risk assessment and diagnostic service. The new guidelines are nationally implemented. DNBH has pointed out the importance of quality control, but has not given any specific guidelines concerning this. We demonstrate the feasibility of a quality assessment of a considerable part of the screening programme. MATERIALS AND METHODS: The quality assessment is conducted on a cohort from Holbaek Hospital during 12 months by merging data from one local hospital database to data from the Danish Cytogenetic Centralregistry and the Danish National Newborn Screening Registry. RESULTS: The study included 1796 singleton pregnancies and 47 twin pregnancies. 46 invasive procedures were carried out among the singleton pregnancies, which corresponds to an invasive rate of 2.6%. Two fetuses with Down's syndrome (DS) and one with trisomy 18 were found and the pregnancies were terminated. One fetus with Turners syndrome was diagnosed prenatally, but ended as a missed abortion. One child with DS was not diagnosed prenatally. The detection rate for DS was 2/3 (67%). CONCLUSION: We suggest that the outlined quality program is implemented as a national programme.

First-trimester combined screening for Down syndrome: prediction of low birth weight, small for gestational age and pre-term delivery in a cohort of non-selected women.

OBJECTIVE: To establish the relationship between the first-trimester screening markers [pregnancy-associated plasma protein A (PAPP-A), free human chorionic gonadotrophin-beta (beta-hCG), nuchal translucency (NT)], the Down syndrome (DS) risk estimate, and the adverse outcomes such as low birth weight, small for gestational age (SGA) and pre-term delivery. METHODS: A retrospective cohort study including 1,734 non-selected singleton pregnancies consecutively enrolled into the programme of first-trimester combined screening for DS in a 12-month period at a single centre. Data from the Prenatal Patient Registry in ASTRAIA were combined with the Danish National Newborn Screening Registry and Danish Birth Registry. RESULTS: There was a significant relation between low PAPP-A MoM, low beta-hCG MoM, increased risk estimate for DS and low birth weight and SGA. Low PAPP-A MoM and increased NT showed a significant relation to pre-term and spontaneous pre-term delivery. Low PAPP-A MoM showed a significant relation to early pre-term delivery. CONCLUSION: First-trimester screening markers exhibited a significant relation to low birth weight, SGA and to some extent, to pre-term and early pre-term delivery. The screening performance of individual markers was poor.