Impact of COVID-19 disease on placental histopathology. PLAXAVID study.

BACKGROUND: The impact of COVID-19 on pregnancy has been analyzed suggesting an increased risk of placental lesions that might lead to maternal and neonatal complications. However, the current published evidence is not conclusive because contradictory results. METHODS: PLAXAVID is an observational, retrospective, histopathological, single-center study that aimed to evaluate the prevalence of vascular and inflammatory lesions in placental and umbilical cord samples of one hundred women infected by SARS-CoV-2 during pregnancy. RESULTS: The histopathological analysis showed that in most of the placentas (77.8%) there were signs of maternal vascular malperfusion (MVM; primary endpoint). The most common MVM features were an accelerated villous maturation (37.4%), central villous infarcts (33.3%), and villous agglutination (46.5%). Fetal vascular malperfusion (FVM) was identified in 57.6% of samples, and the most frequent features were hyalinized avascular villi (38.4%), fetal vascular thrombi (20.2%) and umbilical cord at risk of partial obstruction (14.1%). Acute and chronic inflammatory pathology were noticed in 22.2% and 49.5% of placentas, respectively. No significant correlations were found between MVM presence and the time, duration, and severity of infection, nor with the duration of pregnancy. However, in critically ill patients, the pregnancy duration (p=0.008), newborn weight (p=0.003), and APGAR test scores (p<0.001) were significantly lower. The same trend was observed considering the presence of infection at the time of delivery and in preterm births. CONCLUSION: A very high percentage of placentas with vascular and/or inflammatory lesions was found in the analyzed cohort. Therefore, PLAXAVID study results supported that COVID-19 should be considered a risk factor during gestation and requires close monitoring of pregnancy.

Timing of umbilical cord occlusion, delayed vs early, in preterm babies: A randomized controlled trial (CODE-P Trial).

INTRODUCTION: Our hypothesis was that delayed cord clamping (DCC) (not earlier than 30 s; at 30-60 s) in premature neonates (born between 26.0 and 32.6 weeks of gestation), as compared with the usual early cord clamping (ECC), significantly reduces the need for blood transfusions and incidence of intraventricular haemorrhage (IVH) without an increased rate of maternal postpartum haemorrhage. MATERIAL AND METHODS: A prospective, open-label, randomized, controlled trial was conducted at Vall d'Hebron Hospital from July 2014 to December 2018. All pregnant women at risk of impending preterm birth (≥26.0-<33.0 weeks of gestation) who were admitted to the obstetrics emergency department were evaluated for eligibility. If they met the eligibility criteria, they were invited to participate in the study and, if they agreed, they signed an informed consent. Patients were randomly assigned to one of two groups: ECC group and DCC group. RESULTS: Our study included a total of 57 patients: 30 in the ECC group and 27 in the DCC group. Due to a lack of funding and low recruitment rates, the study was discontinued in 2018. Maternal characteristics and obstetric outcomes were similar between both groups. The intention-to-treat analysis did not reveal any differences between groups for neonatal red blood cell transfusions, neonatal IVH or maternal postpartum haemorrhage. There were no differences for secondary outcomes. Similarly, no differences were observed in the as-treated analysis. CONCLUSION: The primary and secondary outcomes of our study were not achieved. Therefore, more meta-analysis and trials are needed to evaluate the appropriate timing of cord clamping in preterm birth.

Presurgery motor level assessment for prediction of motor level at birth in fetuses undergoing prenatal repair of open spina bifida: time to abandon anatomical level in counseling.

OBJECTIVES: First, to investigate the correlation between prenatal presurgery anatomical and motor levels of the lesion with motor level at birth in cases undergoing prenatal repair of open spina bifida and, second, to identify factors leading to a loss of two or more motor levels between the presurgery and postnatal assessments. METHODS: This was an observational study of singleton pregnancies undergoing prenatal repair of open spina bifida, conducted between March 2011 and May 2022. All fetuses underwent an ultrasound assessment at 20-24 weeks of gestation to determine the motor and anatomical levels of the lesion before surgery. The anatomical level of the lesion was defined as the highest open posterior vertebral arch. The motor level was determined by systematic observation of the lower limb movements and was defined as the most distal active muscle present. Prenatal repair was performed at 23-26 weeks. At birth, motor level was assessed by a rehabilitation specialist by physical examination. Cases of intrauterine death or termination of pregnancy and those delivered at other sites were excluded from the neonatal assessment. The agreement between presurgery motor level and motor level at birth, and between presurgery anatomical level and motor level at birth, was assessed using the weighted kappa index (wκ). Logistic regression analysis was used to assess factors leading to a loss of two or more motor levels between the presurgery and postnatal assessments. RESULTS: Presurgery motor and anatomical levels were assessed in 61 fetuses at a median gestational age of 22.7 (interquartile range (IQR), 21.6-24.4) weeks. Prenatal repair was performed at a median gestational age of 24.6 (IQR, 23.7-25.7) weeks. Motor level at birth was assessed in 52 neonates after exclusion of nine fetuses due to loss to follow-up or fetal loss. There was moderate agreement between presurgery motor level and motor level at birth (wκ = 0.42; 95% CI, 0.21-0.63), with a median difference of 0 (IQR, -2 to 9) levels. Factors leading to a loss of two or more motor levels between the presurgery ultrasound assessment and postnatal examination were higher presurgery anatomical level (odds ratio (OR), 0.59 (95% CI, 0.35-0.98); P = 0.04) and larger difference between the anatomical and motor levels before surgery (OR, 1.85 (95% CI, 1.12-3.06); P = 0.017). None of the other ultrasound, surgery-related or neonatal variables assessed was associated significantly with a loss of two or more motor levels. There was slight agreement between the presurgery anatomical level of the lesion and motor level at birth (wκ = 0.07; 95% CI, -0.02 to 0.15). CONCLUSIONS: There is moderate agreement between fetal motor level of the lesion before prenatal repair of open spina bifida and motor level at birth, as opposed to only slight agreement between presurgery anatomical level and motor level at birth. A loss of two or more motor levels between the presurgery and postnatal assessments is associated with a higher presurgery anatomical level and with a larger difference between the presurgery anatomical and motor levels. Consequently, motor level, rather than the anatomical level, should be used for prenatal counseling. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Fetal heart rate monitoring during fetoscopic repair of open spinal neural tube defects: a single-centre observational cohort study.

BACKGROUND: During fetal surgery, the haemodynamic stability of the fetus depends on the haemodynamic stability of the mother. The primary objective of this study was to assess changes in fetal heart rate (FHR) throughout the different stages of surgery. The secondary objective was to assess potential changes in maternal physiological parameters and their association with FHR. METHODS: This was a single-center observational cohort study conducted between 2015 and 2019 in 26 women undergoing intra-uterine fetoscopic repair of open spina bifida. The primary outcome was FHR. Maternal physiologic parameters were measured at the beginning, during and after surgery. The linear mixed-effects model fitted by maximum likelihood was used to assess changes in each variable at specific times throughout the surgery, and the repeated measures correlation coefficient was used to study the association between FHR and maternal physiological parameters. RESULTS: One (3.8%) case of fetal bradycardia (FHR <110 beats per minute) required the administration of intramuscular atropine. No other significant FHR changes were observed during surgery. Maternal oesophageal temperature (P <0.001), lactate levels (P=0.002), and mean arterial pressure (P=0.016) changed significantly during surgery, although none of these changes was clinically relevant. The FHR showed a significant association with maternal carbon dioxide tension (r=0.285, 95% CI 0.001 to 0.526) and maternal heart rate (r=0.302, 95% CI 0.025 to 0.535). CONCLUSION: The FHR remained stable during intra-uterine fetoscopic repair of open spina bifida. Maternal carbon dioxide tension and heart rate may have a mild influence on FHR.

Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study.

OBJECTIVES: To investigate the incidence of clinical, ultrasonographic and biochemical findings related to pre-eclampsia (PE) in pregnancies with COVID-19, and to assess their accuracy to differentiate between PE and the PE-like features associated with COVID-19. DESIGN: A prospective, observational study. SETTING: Tertiary referral hospital. PARTICIPANTS: Singleton pregnancies with COVID-19 at >20+0  weeks. METHODS: Forty-two consecutive pregnancies were recruited and classified into two groups: severe and non-severe COVID-19, according to the occurrence of severe pneumonia. Uterine artery pulsatility index (UtAPI) and angiogenic factors (soluble fms-like tyrosine kinase-1/placental growth factor [sFlt-1/PlGF]) were assessed in women with suspected PE. MAIN OUTCOME MEASURES: Incidence of signs and symptoms related to PE, such as hypertension, proteinuria, thrombocytopenia, elevated liver enzymes, abnormal UtAPI and increased sFlt-1/PlGF. RESULTS: Thirty-four cases were classified as non-severe and 8 as severe COVID-19. Five (11.9%) women presented signs and symptoms of PE, all five being among the severe COVID-19 cases (62.5%). However, abnormal sFlt-1/PlGF and UtAPI could only be demonstrated in one case. One case remained pregnant after recovery from severe pneumonia and had a spontaneous resolution of the PE-like syndrome. CONCLUSIONS: Pregnant women with severe COVID-19 can develop a PE-like syndrome that might be distinguished from actual PE by sFlt-1/PlGF, LDH and UtAPI assessment. Healthcare providers should be aware of its existence and monitor pregnancies with suspected pre-eclampsia with caution. TWEETABLE ABSTRACT: This study shows that a pre-eclampsia-like syndrome could be present in some pregnancies with severe COVID-19.

New approach for estimating risk of miscarriage after chorionic villus sampling.

OBJECTIVE: To estimate the risk of miscarriage associated with chorionic villus sampling (CVS). METHODS: This was a retrospective cohort study of women attending for routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation at one of eight fetal-medicine units in Spain, Belgium and Bulgaria, between July 2007 and June 2018. Two populations were included: (1) all singleton pregnancies undergoing first-trimester assessment at Hospital Clínico Universitario Virgen de la Arrixaca in Murcia, Spain, that did not have CVS (non-CVS group); and (2) all singleton pregnancies that underwent CVS following first-trimester assessment at one of the eight participating centers (CVS group). We excluded pregnancies diagnosed with genetic anomalies or major fetal defects before or after birth, those that resulted in termination and those that underwent amniocentesis later in pregnancy. We used propensity score (PS) matching analysis to estimate the association between CVS and miscarriage. We compared the risk of miscarriage of the CVS and non-CVS groups after PS matching (1:1 ratio). This procedure creates two comparable groups balancing the maternal and pregnancy characteristics that are associated with CVS, in a similar way to that in which randomization operates in a randomized clinical trial. RESULTS: The study population consisted of 22 250 pregnancies in the non-CVS group and 3613 in the CVS group. The incidence of miscarriage in the CVS group (2.1%; 77/3613) was significantly higher than that in the non-CVS group (0.9% (207/22 250); P < 0.0001). The PS algorithm matched 2122 CVS with 2122 non-CVS cases, of which 40 (1.9%) and 55 (2.6%) pregnancies in the CVS and non-CVS groups, respectively, resulted in a miscarriage (odds ratio (OR), 0.72 (95% CI, 0.48-1.10); P = 0.146). We found a significant interaction between the risk of miscarriage following CVS and the risk of aneuploidy, suggesting that the effect of CVS on the risk of miscarriage differs depending on background characteristics. Specifically, when the risk of aneuploidy is low, the risk of miscarriage after CVS increases (OR, 2.87 (95% CI, 1.13-7.30)) and when the aneuploidy risk is high, the risk of miscarriage after CVS is paradoxically reduced (OR, 0.47 (95% CI, 0.28-0.76)), presumably owing to prenatal diagnosis and termination of pregnancies with major aneuploidies that would otherwise have resulted in spontaneous miscarriage. For example, in a patient in whom the risk of aneuploidy is 1 in 1000 (0.1%), the risk of miscarriage after CVS will increase to 0.3% (0.2 percentage points higher). CONCLUSIONS: The risk of miscarriage in women undergoing CVS is about 1% higher than that in women who do not have CVS, although this excess risk is not solely attributed to the invasive procedure but, to some extent, to the demographic and pregnancy characteristics of the patients. After accounting for these risk factors and confining the analysis to low-risk pregnancies, CVS seems to increase the risk of miscarriage by about three times above the patient's background risk. Although this is a substantial increase in relative terms, in pregnancies without risk factors for miscarriage, the risk of miscarriage after CVS remains low and similar to, or slightly higher than, that in the general population. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Nuevo enfoque para estimar el riesgo de aborto después de una biopsia de vellosidades coriónicas OBJETIVO: Estimar el riesgo de aborto asociado con la biopsia de vellosidades coriónicas (BVC). MÉTODOS: Se trata de un estudio retrospectivo de cohorte de mujeres que acudieron a un examen ecográfico de rutina entre las 11+0 y las 13+6 semanas de gestación a una de entre un total de ocho centros de medicina fetal en España, Bélgica y Bulgaria, entre julio de 2007 y junio de 2018. En el estudio se incluyeron dos poblaciones: 1) todos los embarazos con feto único sometidos a evaluación del primer trimestre en el Hospital Clínico Universitario Virgen de la Arrixaca de Murcia (España), a las que no se les hizo una BVC (grupo no BVC); y 2) todos los embarazos con feto único sometidos a BVC tras la evaluación del primer trimestre en uno de los ocho centros participantes (grupo BVC). Se excluyeron los embarazos diagnosticados con anomalías genéticas o defectos fetales importantes antes o después del nacimiento, los que resultaron en una interrupción y los que más tarde se sometieron a amniocentesis durante el embarazo. Para estimar la relación entre la BVC y el aborto espontáneo se utilizó el pareamiento por puntaje de propensión (PPP). Se comparó el riesgo de aborto de los grupos BVC y no BVC después del pareamiento PPP (razón 1:1). Este procedimiento creó dos grupos comparables en los que las características de la madre y el embarazo que se asocian con la BVC estaban equilibradas, de manera similar a cómo funciona la aleatorización en un ensayo clínico aleatorizado. RESULTADOS: La población de estudio consistió en 22.250 embarazos en el grupo no BVC y 3.613 en el grupo BVC. La incidencia de abortos en el grupo BVC (2,1%; 77/3.613) fue significativamente mayor que en el grupo no BVC (0,9% (207/22.250); P<0,0001). El algoritmo del PPP emparejó 2.122 BVC con 2.122 casos no BVC, de los cuales 40 (1,9%) y 55 (2,6%) embarazos en los grupos BVC y no BVC, respectivamente, resultaron en un aborto espontáneo (razón de momios (RM), 0,72 (IC 95%, 0,48-1,10); P=0,146). Se encontró una interacción significativa entre el riesgo de aborto espontáneo después de una BVC y el riesgo de aneuploidía, lo que sugiere que el efecto de la BVC en el riesgo de aborto espontáneo difiere según las características del contexto. Concretamente, cuando el riesgo de aneuploidía es bajo, el riesgo de aborto después de una BVC aumenta (RM, 2,87 (IC 95%, 1,13-7,30)) y cuando el riesgo de aneuploidía es alto, paradójicamente el riesgo de aborto después de una BVC se reduce (RM, 0,47 (IC 95%, 0,28-0,76)), presumiblemente debido al diagnóstico prenatal y a la interrupción de embarazos con aneuploidías importantes que, de otro modo, hubieran provocado un aborto espontáneo. Por ejemplo, en una paciente para quien el riesgo de aneuploidía es de 1 entre 1000 (0,1%), el riesgo de aborto después de la BVC aumenta al 0,3% (0,2 puntos porcentuales más alto). CONCLUSIONES: El riesgo de aborto espontáneo en las mujeres que se someten a una BVC es aproximadamente un 1% mayor que el de las mujeres a las que no se les hace, aunque este exceso de riesgo no se atribuye únicamente al procedimiento agresivo sino, en cierta medida, a las características demográficas y del embarazo de cada paciente. Después de tener en cuenta estos factores de riesgo y limitar el análisis a los embarazos de bajo riesgo, la BVC parece triplicar aproximadamente el riesgo de aborto en comparación con el riesgo de fondo de la paciente. Aunque se trata de un aumento sustancial en términos relativos, en los embarazos sin factores de riesgo de aborto, después de una BVC el riesgo de aborto sigue siendo bajo y similar, o ligeramente superior, al de la población en general. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Pregnancy outcomes after maternal Zika virus infection in a non-endemic region: prospective cohort study.

OBJECTIVES: The aim was to describe pregnancy outcomes after Zika virus (ZIKV) infection in a non-endemic region. METHODS: According to the Spanish protocol issued after the ZIKV outbreak in Brazil in 2015, all pregnant women who had travelled to high-burden countries were screened for ZIKV. Serological and molecular tests were used to identify ZIKV-infected pregnant women. They were classified as confirmed ZIKV infection when reverse transcription (RT) PCR tested positive, or probable ZIKV infection when ZIKV immunoglobulin M and/or immunoglobulin G and ZIKV plaque reduction neutralization tests were positive. Women found positive using molecular or serological tests were prospectively followed-up with ultrasound scans and neurosonograms on a monthly basis until delivery; magnetic resonance imaging and amniotic fluid testing were performed after signed informed consent. Samples of placenta, and fetal and neonatal tissues were obtained. RESULTS: Seventy-two pregnant women tested positive for ZIKV infection: ten were confirmed by RT-PCR, and 62 were probable cases based on serological tests. The prevalence of adverse perinatal outcomes was 33.3% (three out of nine, 95% CI 12.1-64.6%): two cases of congenital ZIKV syndrome (CZS) and one miscarriage, all born to women infected in the first trimester of gestation. All ZIKV-confirmed women had persistent viraemias beyond 2 weeks (median 61.50 days; IQR 35.50-80.75). Amniotic fluid testing was only positive in the two fetuses with anomalies. CONCLUSION: The prevalence of perinatal adverse outcomes for women with ZIKV-confirmed infection was 33.3%. Amniocentesis for ZIKV RT-PCR is recommended when fetal abnormalities are found. Intensive prenatal and postnatal follow-up of ZIKV-infected pregnancies is advised in confirmed cases.

Fetoscopic two-layer closure of open neural tube defects.

OBJECTIVE: Fetoscopy for closure of open neural tube defects (NTD) remains controversial, as the use of patches or single-layer closure is not considered to meet the standards of good neurosurgical reconstruction. In this study, we describe a fetoscopic two-layer (myofascial and skin) closure technique for the treatment of NTD in five patients and report the preliminary anatomical outcome at birth. METHODS: From February to September 2017, five pregnant women with a fetus with a NTD, including three cases of myelomeningocele and two cases of myelocele, were operated on using a fetoscopic two-layer closure technique. In this technique, with the uterus exteriorized and using three 10-Fr ports, the placode is dissected from the surrounding tissue and detethered, removing the cystic tissue. The skin is undermined by blunt dissection and the defect is sutured to the midline in two layers (myofascial and skin) using a running 4/0 resorbable barbed suture. RESULTS: Median gestational age at the procedure was 24 + 3 (range, 23 + 5 to 27 + 3) weeks. Surgery was successful in all cases, without any intraoperative complications. Median time in surgery was 180 (range, 140-180) min and median time for fetoscopy was 105 (range, 65-120) min. In terms of obstetric complications, three cases of premature rupture of membranes and one case of chorioamnionitis were recorded. Median gestational age at delivery was 34 + 1 (range, 25 + 4 to 37 + 2) weeks and two patients delivered vaginally. The closed defect was watertight with good quality tissue in all cases. CONCLUSION: Fetoscopic two-layer closure of NTD may improve the quality of the tissue covering the defect, diminishing the need for postnatal surgical revision, and preserving the well-documented beneficial effects of prenatal closure on the neural tissue and hindbrain herniation. However, this technique may not be appropriate for those cases with wide diastasis of the myofascial layer or with a low quantity of available tissue. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal changes in maternal serum placental growth factor and soluble fms-like tyrosine kinase-1 in women at increased risk of pre-eclampsia.

OBJECTIVES: To investigate longitudinal changes in maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in pregnant women who develop pre-eclampsia (PE) or gestational hypertension (GH). METHODS: This was a prospective longitudinal study in women with singleton pregnancies identified by screening at 11 + 0 to 13 + 6 weeks' gestation as being at high-risk of PE. Blood samples were taken every 4 weeks until delivery. Values were compared in women who developed preterm PE (requiring delivery before 37 weeks' gestation), term PE or GH and those who remained normotensive. RESULTS: A total of 1069 samples were analyzed in 234 women, including 172 who remained normotensive, 18 who developed GH, 22 who developed preterm PE and 22 who developed term PE. In the preterm PE group, compared to the normotensive group, sFlt-1 levels were significantly higher from 15 weeks' gestation onward and the difference increased with gestational age (P < 0.001). In the preterm PE group, compared to the normotensive group, PlGF levels were significantly lower from 11 weeks' gestation onward and the difference increased significantly with gestational age (P < 0.001). Similarly, in the term PE and GH groups, PlGF levels were lower from 13 and 27 weeks onward, respectively, and the differences increased significantly with gestational age (P < 0.001 for both groups). In the preterm PE group, compared to the normotensive group, the sFlt-1/PlGF ratio was significantly higher from 11 weeks onward and the difference increased significantly with gestational age (P < 0.001). A random slope model provided a significantly better fit to the data than did a single-level model for sFlt-1 (likelihood ratio (LR) = 516; degrees of freedom (df) = 3; P < 0.001), PlGF (LR = 542; df = 3; P < 0.001) and the sFlt-1/PlGF ratio (LR = 468; df = 3; P < 0.001). CONCLUSION: Repeat measurements of the biochemical markers used in this study are likely to be better predictors of PE than are measurements at a single time point during pregnancy, as the differences between normotensive and hypertensive pregnancies increase with gestational age. In screening for preterm PE, maternal serum level of PlGF is a useful marker from the first trimester onward, while the level of sFlt-1 is likely to have a predictive value from the second trimester onward. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal changes in maternal corin and mid-regional proatrial natriuretic peptide in women at risk of pre-eclampsia.

OBJECTIVE: Corin, an atrial natriuretic peptide-converting enzyme, has been found to promote trophoblast invasion and spiral artery remodeling. Yet, elevated maternal plasma atrial natriuretic peptide (ANP) and corin levels have been reported in pregnancies complicated by pre-eclampsia (PE). The aim of this study was to investigate longitudinal changes in maternal plasma levels of corin and mid-regional proatrial natriuretic peptide (MR-PANP) in pregnancies that develop PE and gestational hypertension (GH). METHODS: This was a nested case-control study drawn from a larger prospective longitudinal study in singleton pregnancies identified as being at high risk for PE by screening at 11 + 0 to 13 + 6 weeks' gestation. Blood samples were taken every 4 weeks until delivery. Values were compared in pregnancies that developed preterm PE (requiring delivery before 37 weeks' gestation), term PE, GH and those that remained normotensive. RESULTS: A total of 471 samples were analyzed from 122 women, including 85 that remained normotensive, 12 that developed GH, 13 term PE and 12 preterm PE. In the normotensive group, log10 corin levels were associated with gestational age (P < 0.01), whereas log10 MR-PANP levels were not. In the preterm-PE group, compared with the normotensive group, corin was significantly lower until 20 weeks' gestation (P = 0.001). In the GH and term-PE groups, corin did not differ significantly from the normotensive group (P = 0.637 and P = 0.161, respectively). Compared with the normotensive group, MR-PANP levels were significantly higher in the pregnancies that developed preterm PE and GH (P = 0.046 and P = 0.019, respectively), but not term PE (P = 0.467). CONCLUSION: Maternal-plasma corin and MR-PANP could potentially be useful biomarkers for the prediction of preterm PE.

Longitudinal changes in maternal soluble endoglin and angiopoietin-2 in women at risk for pre-eclampsia.

OBJECTIVE: To investigate longitudinal changes in maternal plasma levels of soluble endoglin (sEng) and angiopoietin-2 (Ang-2) in pregnant women who develop pre-eclampsia (PE) and gestational hypertension (GH). METHODS: This was a nested case-control study drawn from a larger prospective longitudinal study in singleton pregnancies identified by screening at 11 + 0 to 13 + 6 weeks' gestation as being at high-risk for PE. Blood samples were taken every 4 weeks until delivery. Values were compared in women who developed preterm PE (requiring delivery before 37 weeks), term PE, GH and those who remained normotensive. RESULTS: A total of 471 samples were analyzed in 122 women, comprising 85 who remained normotensive, 12 who developed GH, 13 who developed term PE and 12 who developed preterm PE. In the normotensive group, there was an increase in log10 sEng levels with gestational age. In the preterm PE group, compared with the normotensive group, sEng was higher from 18 weeks onwards, and the difference increased significantly with gestational age (P < 0.001). In the GH and term PE groups, sEng did not differ significantly from that of the normotensive group (P = 0.583 and P = 0.890, respectively). The square root of Ang-2 decreased significantly with gestational age, but did not differ significantly among the different outcome groups (P = 0.571). CONCLUSION: Maternal plasma sEng, but not Ang-2, may be a useful mid- and late-gestation biomarker for the development of PE.

Longitudinal changes in maternal hemodynamics in a population at risk for pre-eclampsia.

OBJECTIVE: To investigate longitudinal changes in maternal hemodynamics from the first trimester onward in women who develop pre-eclampsia (PE) or gestational hypertension (GH). METHODS: This was a prospective longitudinal study of singleton pregnancies identified by screening at 11 + 0 to 13 + 6 weeks' gestation as being at high risk for PE. Measurements of augmentation index (AIx), pulsed wave velocity (PWV) and aortic systolic blood pressure (SBPao) were taken every 4 weeks until delivery. Values were compared between women who developed preterm PE requiring delivery before 37 weeks, term PE or GH, and those who remained normotensive. RESULTS: A total of 1198 observations were recorded in 245 women, including 181 who were normotensive, 22 with preterm PE, 22 with term PE and 20 with GH. In the normotensive group, there was a U-shaped relationship between AIx and gestational age with a trough at 25 weeks' gestation, whereas changes in levels of PWV or SBPao were minimal, with a mild increase from 25 and 30 weeks' gestation onward, respectively. In the GH and preterm PE groups, compared to the normotensive group, SBPao was higher and the difference did not change significantly with gestational age. In the term PE group, SBPao did not differ significantly from that in the normotensive group. In the preterm PE group compared to the normotensive group, PWV and AIx were significantly higher from 16-17 weeks' gestation onward and the difference increased with gestational age in both cases. In the term PE and GH groups, PWV and AIx did not differ significantly from normal. CONCLUSION: This study describes temporal changes in AIx, PWV and SBPao in normotensive pregnant women and in women who develop PE or GH.

Longitudinal changes in uterine artery Doppler and blood pressure and risk of pre-eclampsia.

OBJECTIVE: To investigate longitudinal changes in the uterine artery mean pulsatility index (UtA-PI) and mean arterial pressure (MAP) in women who develop pre-eclampsia (PE) and gestational hypertension (GH). METHODS: This was a prospective longitudinal study of singleton pregnancies identified by screening at 11 + 0 to 13 + 6 weeks' gestation as being at high risk for PE. Measurements of UtA-PI and MAP were taken every 4 weeks until delivery and were compared in women who developed preterm PE, requiring delivery before 37 weeks, term PE and GH with those in women who remained normotensive. RESULTS: In the normal outcome group, UtA-PI decreased with gestational age and MAP decreased between 12 and 24 weeks and then increased. In the preterm PE group, as compared to the normal group, UtA-PI and MAP were higher from early pregnancy onward and the difference for both increased with gestational age. In the term PE group, UtA-PI was significantly increased only from 33 weeks onward and MAP was increased from 12 weeks onward but the difference from normal did not increase with gestation. In GH, UtA-PI did not differ significantly from normal but MAP was higher from 12 weeks onward. CONCLUSION: The study describes temporal changes in UtA-PI and MAP in normal pregnancies and in women who develop PE and GH.

Maternal age and adverse pregnancy outcome: a cohort study.

OBJECTIVE: To examine the association between maternal age and a wide range of adverse pregnancy outcomes after adjustment for confounding factors in obstetric history and maternal characteristics. METHODS: This was a retrospective study in women with singleton pregnancies attending the first routine hospital visit at 11 + 0 to 13 + 6 weeks' gestation. Data on maternal characteristics, and medical and obstetric history were collected and pregnancy outcomes ascertained. Maternal age was studied, both as a continuous and as a categorical variable. Regression analysis was performed to examine the association between maternal age and adverse pregnancy outcome including pre-eclampsia, gestational hypertension, gestational diabetes mellitus (GDM), preterm delivery, small-for-gestational age (SGA) neonate, large-for-gestational age (LGA) neonate, miscarriage, stillbirth and elective and emergency Cesarean section. RESULTS: The study population included 76 158 singleton pregnancies with a live fetus at 11 + 0 to 13 + 6 weeks. After adjusting for potential maternal and pregnancy confounding variables, advanced maternal age (defined as ≥ 40 years) was associated with increased risk of miscarriage (odds ratio (OR), 2.32 (95% CI, 1.83-2.93); P < 0.001), pre-eclampsia (OR, 1.49 (95% CI, 1.22-1.82); P < 0.001), GDM (OR, 1.88 (95% CI, 1.55-2.29); P < 0.001), SGA (OR, 1.46 (95% CI, 1.27-1.69); P < 0.001) and Cesarean section (OR, 1.95 (95% CI, 1.77-2.14); P < 0.001), but not with stillbirth, gestational hypertension, spontaneous preterm delivery or LGA. CONCLUSIONS: Maternal age should be combined with other maternal characteristics and obstetric history when calculating an individualized adjusted risk for adverse pregnancy complications. Advanced maternal age is a risk factor for miscarriage, pre-eclampsia, SGA, GDM and Cesarean section, but not for stillbirth, gestational hypertension, spontaneous preterm delivery or LGA.

Lateral ventricles in fetuses with aneuploidies at 11-13 weeks' gestation.

OBJECTIVE: To examine the possible association between aneuploidies and fetal lateral cerebral ventriculomegaly in the first trimester of pregnancy. METHODS: Three-dimensional brain volumes were acquired by transvaginal ultrasound examination at 11-13 weeks' gestation in 410 euploid fetuses and 63 fetuses with trisomy 21, 34 with trisomy 18 and seven with trisomy 13. Lateral ventricles were assessed in a transverse view, just above the roof of the third ventricle and measurements of the areas of the lateral ventricles and choroid plexuses were obtained. The ratio between choroid plexus and lateral ventricle areas (CLR) was calculated. Measurements in aneuploid fetuses were compared to those in euploid fetuses. RESULTS: In euploid fetuses the lateral ventricle and choroid plexus areas increased, whereas the CLR decreased with fetal biparietal diameter. In fetuses with trisomy 21, lateral ventricle and choroid plexus areas were smaller but CLR was not significantly different from that in euploid fetuses. In trisomy 18 and 13 fetuses, CLR was significantly smaller than in euploid fetuses. The CLR was below the 5(th) centile of normal range in 11 (32.4%) fetuses with trisomy 18 and in six (85.7%) with trisomy 13. CONCLUSION: There is evidence of ventriculomegaly at 11-13 weeks' gestation in most fetuses with trisomy 13 and one third of fetuses with trisomy 18.

Effect of temperature on free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A concentration.

OBJECTIVE: To examine the effect of the duration of storage of serum and whole blood at different controlled temperatures on the concentrations of both serum free-beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in first-trimester screening for aneuploidies. METHODS: The concentrations of free beta-hCG and PAPP-A were measured in samples collected from 10 pregnant women and stored as whole blood or serum for 1-8 days at 4, 20 or 40 degrees C. The concentrations measured were adjusted to take day-to-day variations into account and were expressed as a percentage of the values on day 0. In a second study involving 10 pregnant women, free beta-hCG was measured at 10 min and at 2, 4, 8 and 12 h after collection and storage at 30 or 40 degrees C, either as separated serum or as whole blood. RESULTS: The change in the levels of PAPP-A in the separated serum at all three temperatures and in whole blood at 4 degrees C was always less than 10% throughout the 8 days of storage. In whole blood stored at 20 and 40 degrees C, the percentage variation was less than 10% only if the storage period was shorter than 4 days. The concentration of free beta-hCG was not altered by storage of either whole blood or separated serum at 4 degrees C throughout the 8 days of storage. At 20 degrees C, reliable results were obtained only if the maximum storage time was 2 days for separated serum and 1 day for whole blood. At 30 degrees C, reliable results were obtained only if the samples were analyzed within 2 h of collection, and at 40 degrees C the concentrations increased by more than 50% within 2 h and by about 500% after 1 day of storage. CONCLUSION: In first-trimester screening for aneuploidies, analysis of blood samples should be undertaken within a few minutes of collection, otherwise the samples should be refrigerated at 4 degrees C throughout the interval between collection and analysis.

Hypertensive disorders in pregnancy: screening by uterine artery Doppler at 11-13 weeks.

OBJECTIVES: To examine the performance of screening for hypertensive disorders in pregnancy by a combination of the maternal factor-derived a-priori risk with the uterine artery (UtA) pulsatility index (PI) and to determine whether it is best in such screening to use the mean PI of the two arteries, the highest PI or the lowest PI. METHODS: This was a prospective screening study for pre-eclampsia (PE) requiring delivery before 34 weeks (early PE), late PE and gestational hypertension (GH) in women attending their routine first hospital visit in pregnancy at 11 + 0 to 13 + 6 weeks of gestation. Maternal history was recorded and color flow Doppler imaging was used to measure the left and right UtA-PI. The performance of screening for PE and GH by a combination of the maternal factor-derived a-priori risks determined in a previous study and the UtA-PI was assessed. RESULTS: There were 8061 (96.4%) cases unaffected by PE or GH, 37 (0.4%) that developed early PE, 128 (1.5%) with late PE and 140 (1.7%) with GH. The lowest, mean and highest UtA-PI were significantly higher in early PE and late PE than in the controls (P < 0.0001) and in early PE than late PE (P < 0.0001). The lowest UtA-PI was higher in GH than in controls (P = 0.014). The best performance in screening was provided by the lowest PI. The detection rate of early PE at a 10% false-positive rate increased from 47% in screening by maternal factors alone to 81% in screening by maternal factors and the lowest UtA-PI. The respective detection rates for late PE increased from 41% to 45% and those for GH increased from 31% to 35%. CONCLUSIONS: The patient-specific risk for PE and GH can be derived by combining the disease-specific maternal factor-derived a-priori risk with the measurement of the lowest UtA-PI in a multivariate regression model.

Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.

OBJECTIVES: To investigate the performance of first-trimester screening for aneuploidies by including assessment of ductus venosus flow in the combined test of maternal age, fetal nuchal translucency thickness, fetal heart rate, and serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. METHODS: Screening by the combined test was performed in singleton pregnancies, including 19 614 with euploid fetuses, 122 with trisomy 21, 36 with trisomy 18, 20 with trisomy 13 and eight with Turner syndrome. In all cases the a-wave in the fetal ductus venosus flow was assessed. We examined the performance of two screening strategies: first, assessment of the a-wave in all patients and, second, first-stage screening using the combined test in all patients followed by second-stage assessment of the a-wave only in those with an intermediate risk of one in 51 to one in 1000 after the first stage RESULTS: Reversed a-wave was observed in 3.2% of the euploid fetuses, and in 66.4%, 58.3%, 55.0% and 75.0% of fetuses with trisomies 21, 18 and 13 and Turner syndrome, respectively. Inclusion of ductus venosus flow in all pregnancies would detect 96%, 92%, 100% and 100% of trisomies 21, 18 and 13 and Turner syndrome, respectively, at a false-positive rate of 3%. The same detection rates were achieved with the two-stage strategy at a false-positive rate of 2.6%, in which it was necessary to assess the ductus venosus in only 15% of the total population. CONCLUSIONS: Assessment of ductus venosus flow improves the performance of first-trimester screening for aneuploidies.