First trimester prediction of ischemic placental disease

Ischemic placental disease is characterized by one or more of the clinical manifestations of preeclampsia, fetal growth restriction, and/or placental abruption, resulting in indicated preterm delivery. Since over half of the indicated preterm deliveries are due to ischemic placental disease, accurate early prediction of the disease is of paramount importance in developing prevention strategies. This review article focuses on studies that have used the first trimester aneuploidy screening timing window to predict those patients who later develop ischemic placental disease. Emphasis was given to studies originating from the Fetal Medicine Foundation because of their uniformity in definitions and expertise of the personnel who performed the ultrasound screening exams.     

First trimester termination of pregnancy

First trimester termination of pregnancy (TOP) is a safe and effective procedure. The complete abortion rates of surgical and medical abortion are approximately 97% and 95%, respectively. Vacuum aspiration (VA) either by electrical suction or manual aspiration is the method of choice for surgical TOP. Risk of significant bleeding is ≤ 5% in VA, while major complications occur in <1%. The risk of infection after VA can be reduced significantly by using prophylactic antibiotics or by the screen-and-treat strategy. Pre-operative administration of misoprostol can also reduce the risk of complications. The combination of 200 mg mifepristone followed by 800 μg misoprostol 24–48 h later is recommended for first trimester medical TOP. If mifepristone is not available, misoprostol can also be used alone, but repeated doses may be required and the complete abortion rate may be lower. Due to the reduced efficacy in more advanced gestation, repeated doses of misoprostol may be required for medical TOP over 9 weeks of gestation. The complete abortion rate with this regimen is 95% or more. Gastrointestinal upsets can occur in up to 50% of women, but major complications are rare. There was no lower limit of gestational week for TOP, although extra precaution is required for the confirmation of completion of procedures and exclusion of ectopic pregnancy.     

First trimester screening of serum soluble fms-like tyrosine kinase-1 and placental growth factor predicting hypertensive disorders of pregnancy

ObjectiveTo assess the accuracy of first trimester soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in predicting pregnancy hypertension and pre-eclampsia; and compare with the accuracy of routinely collected maternal and clinical risk factors.Study designIn this population-based cohort study, serum sFlt-1 and PlGF levels were measured in first trimester in 2,681 women with singleton pregnancies in New South Wales, Australia.Main outcome measuresPrediction of pregnancy hypertension and pre-eclampsia.ResultsThere were 213 (7.9%) women with pregnancy hypertension, including 68 (2.5%) with pre-eclampsia. The area under the curve (AUC) for both sFlt-1 and PlGF was not different from chance, but combined was 0.55 (P = 0.005). Parity and previous diagnosed hypertension had better predictive accuracy than serum biomarkers (AUC = 0.64, P < 0.001) and the predictive accuracy for all maternal and clinical information was fair (AUC = 0.70, P < 0.001 for pregnancy hypertension and AUC = 0.74, P < 0.001 for pre-eclampsia). Adding sFlt-1 and PlGF to maternal risk factors did not improve the ability of the models to predict pregnancy hypertension or pre-eclampsia.ConclusionsMaternal first trimester serum concentrations of sFlt-1 and PlGF do not predict hypertensive disorders in pregnancy any better than routinely collected clinical and maternal risk factor information. Screening for sFlt-1 and PlGF levels in early pregnancy would not identify those pregnancies at-risk.     

Evaluation of agreement of placental growth factor (PlGF) tests and the soluble FMS-like tyrosine kinase 1 (sFlt-1)/PlGF ratio,comparison of predictive accuracy for pre-eclampsia,and relation to uterine artery Doppler and response to aspirin

Objectives: The objective of this study is to evaluate agreement between PlGF and sFlt-1/PlGF ratio tests and compare their predictive accuracy for pre-eclampsia in high-risk women. Also, to examine for associations of abnormal PlGF or sFlt-1/PlGF ratio with abnormal uterine artery Doppler and platelet response to aspirin.

Methods: Prospective cohort study, 150 pregnant women at high risk of pre-eclampsia prescribed 75?mg aspirin daily. Uterine artery Dopplers were assessed at 20⁺⁰–23⁺⁶ weeks. At 33⁺⁰–35⁺⁶ weeks platelet function aspirin metabolites, PlGF and the sFlt-1/PlGF ratio were measured.

Outcome: Measures were all pre-eclampsia and pre-eclampsia requiring delivery prior to 37 weeks.

Results: Overall percent agreement was 89.3% for PlGF tests but 74.7–78% for PlGF tests and the sFlt-1/PlGF ratio. AUCs were 0.70–0.75 for prediction of any pre-eclampsia and 0.92–0.99 for preterm pre-eclampsia. We found a significant association between abnormal PlGF or sFlt-1/PlGF ratio and abnormal uterine artery Doppler (χ² 5.47, p?=?.019), but no association with platelet response to aspirin (χ² 0.12, p?=?.913). There were no associations between suboptimal aspirin adherence and either abnormal angiogenic markers or uterine artery Dopplers (χ² 0.144, 0.038, p?=?.704, .846, respectively).

Conclusions: There was good agreement between PlGF tests and limited agreement between PlGF tests and the sFlt-1/PlGF ratio. All tests have heightened predictive accuracy for preterm pre-eclampsia. Abnormal PlGF or sFlt-1/PlGF ratio relates to abnormal uterine artery Doppler but not platelet response to aspirin.     

First trimester thyroid stimulating hormone as an independent risk factor for adverse pregnancy outcome

Purpose: Maternal thyroid gland dysfunction may adversely affect pregnancy outcome. We aimed to examine the association between subclinical thyroid dysfunction, both hypothyroidism and hyperthyroidism, to adverse pregnancy outcome.

Materials and methods: Retrospective cohort study of all women with an available first trimester thyroid function testing and known pregnancy outcome, categorized to subclinical hypothyroidism, or hyperthyroidism and evaluated for complication during gestation and delivery.

Results: Four thousand five hundred and four women were included in the final analysis – 3231 were euthyroid, 73 (1.6%) were categorized as subclinical hyperthyroidism and 1200 (26.6%) had subclinical hypothyroidism. Low thyroid-stimulating hormone (TSH) levels, i.e. subclinical hyperthyroidism, correlates with higher rates of placental abruption and extremely low birth weight, below 1500?g. Also, the risk for preterm delivery prior to 34 gestational weeks is higher among women with subclinical hypothyroidism, with greater risk among those with a higher TSH level. (OR 1.81, 95% CI 1.0–3.28 for TSH 2.5–4.0 mIU/L and OR 2.33, 95% CI 1.11–4.42 for those with TSH?>?4 4.0 mIU/L).

Conclusions: Subclinical hypothyroidism is associated with an increased risk for preterm delivery prior to 34 gestational weeks. Additionally, subclinical hyperthyroidism may also have a role in adverse pregnancy outcome – low birth weight and placental abruption – although this needs to be further explored.     

Pulse wave analysis: a preliminary study of a novel technique for the prediction of pre-eclampsia

Objective  To investigate whether first-trimester arterial pulse wave analysis (PWA) can predict pre-eclampsia.
Design  This was a prospective screening study.
Setting  The Homerton University Hospital, a London teaching hospital.
Population  Two hundred and ten low-risk women with a singleton pregnancy were analysed.
Methods  Radial artery pulse waveforms were measured between the 11⁺⁰ and 13⁺⁶ weeks of gestation and the aortic waveform derived by applying a generalised transfer function. Augmentation pressure (AP) and augmentation index at heart rate of 75 beats per minute (AIx-75), measures of arterial stiffness, were calculated. The multiple of the gestation-specific median in controls for AP and AIx-75 were calculated. Logistic regression models were developed and their predictive ability assessed using the area under the receiver operator curve.
Main outcome measures  Prediction of pre-eclampsia by AIx-75.
Results  Fourteen (6.7%) women developed pre-eclampsia, and 196 remained normotensive. Eight of the 14 women developed pre-eclampsia before 34 weeks of gestation (early-onset pre-eclampsia). For a false-positive rate of 11%, AIx-75 had a detection rate of 79% for all cases of pre-eclampsia and 88% for early-onset pre-eclampsia.
Conclusion  First-trimester arterial PWA can play a significant role in understanding the pathophysiology of pre-eclampsia and may play a role in early screening.     

First trimester diagnosis of partial mole

Background Partial mole is one of the two distinctive subtypes of hydatidiform mole. It is usually paternally derived triploid conceptions in which embryonal development occurs in association with trophoblastic hyperplasia. The definite diagnosis is confirmed by pathological and cytogenetic studies. Ultrasound might be helpful to diagnose partial mole in the first trimester.Case A 25-year-old woman, gravida 2, para 0-0-1-0, was initially seen for antenatal care at 6 weeks pregnant. Ultrasound was undertaken at 13 weeks pregnancy due to her first fetal anomaly, which demonstrated partial mole and embryonic death. The serum hCG was 190,900 mIU/ml. Suction curettage was performed without complication. Histopathological study confirmed partial mole and cytogenetic study of the placenta revealed an uncommon karyotype, mosaicism of triploid (69,XXX/69,XXY). Serum hCG was declined and negative at 8 weeks. The patient was well and serum hCG remained normal throughout 6 months of follow-up.Conclusion Although the majority of partial mole pregnancies cannot be detected by routine first trimester ultrasound examination, first trimester ultrasound can be helpful in some cases, such as this one. If partial mole is sonographically suspected, it should be confirmed with histopathology and cytogenetic studies. The management is similar to complete mole including prompt evacuation and careful monitoring of hCG.     

A first trimester prediction model for gestational diabetes utilizing aneuploidy and pre-eclampsia screening markers

Objective: We examined whether first trimester aneuploidy and pre-eclampsia screening markers predict gestational diabetes mellitus (GDM) in a large multi-ethnic cohort and the influence of local population characteristics on markers.

Methods: Clinical and first trimester markers (mean arterial pressure (MAP), uterine artery pulsatility index (UtA PI), pregnancy associated plasma protein A (PAPP-A), free-β human chorionic gonadotropin (free-hCGβ)) were measured in a case-control study of 980 women (248 with GDM, 732 controls) at 11 to 13?+?6 weeks’ gestation. Clinical parameters, MAP-, UtA PI-, PAPP-A-, and free-hCGβ-multiples-of-the-median (MoM) were compared between GDM and controls; stratified by ethnicity, parity, and GDM diagnosis?<24 versus?≥24 weeks’ gestation. GDM model screening performance was evaluated using AUROC.

Results: PAPP-A- and UtA PI-MoM were significantly lower in GDM versus controls (median ((IQR) PAPP-A-MoM 0.81 (0.58–1.20) versus 1.00 (0.70–1.46); UtA PI-MoM 1.01 (0.82–1.21) versus 1.05 (0.84–1.29); p?p?Conclusions: Addition of aneuploidy and pre-eclampsia markers is cost-effective and enhances early GDM detection, accurately identifying early GDM, a high-risk cohort requiring early detection, and intervention. Ethnicity and parity modified marker association with GDM, suggesting differences in pathophysiology and vascular risk.     

First trimester diagnosis of sirenomelia: a case report and review of the literature

Sirenomelia sequence is a rare lethal pattern of congenital anomalies characterized by a number of hallmark skeletal anomalies, including fusion of the lower extremities or a single lower limb, bilateral renal agenesis or dysgenesis with absent or hypoplastic renal arteries, oligohydramnios, and the presence of aberrant vasculature. The etiology is still controversial. Prognosis is very poor, with the babies being stillborn or succumbing soon after birth. In the second trimester, oligohydramnios due to renal agenesis makes the diagnosis of sirenomelia difficult. Conversely, in the first trimester, the amniotic fluid volume is usually normal, unrelated to the fetal urine production. Therefore, a first-trimester or early second trimester anatomic survey of the fetus is proposed as preferable and more accurate for the diagnosis of this rare anomaly. In this article, we report a case of sirenomelia detected by two- and three-dimensional ultrasound in the 11th week of gestation and the associated literature is discussed.     

Cystatin C as an indicator of renal damage in pre-eclampsia

ABSTRACT

Objective

To assess the predictive abilities of serum and urinary cystatin C levels for glomerular lesions in pregnant women with pre-eclampsia.     

Altered placental syncytin and its receptor ASCT2 expression in placental development and pre-eclampsia

OBJECTIVE: To investigate the alterations of syncytin, a fusogenic membrane protein involved in syncytiotrophoblastic layer formation, and its receptor ASCT2 expression in placental development and pre-eclampsia. DESIGN: Analyses of syncytin and ASCT2 expression in placentas from different stages of pregnancy and women with pre-eclampsia and in cytotrophoblasts cultured in normoxic and hypoxic conditions. SETTING: Placental samples were collected from a tertiary medical centre. POPULATION: Sixteen women with pre-eclampsia and 58 pregnant women presented as pregnancy (5-19 weeks of gestation) for elective termination, preterm birth, or normal term delivery. METHODS: The quantitative real-time polymerase chain reaction was used to study the syncytin and ASCT2 expression during placental development in 35 placentas from women without pre-eclampsia (ranged from 5 to 40 weeks of gestation) and the alterations of pre-eclamptic placentas (n=16) compared with gestational-age-matched controls (n=16). Western blot analysis was performed to study the protein level of syncytin in pre-eclamptic placentas and gestational-age-matched controls. The hypoxic effect on trophoblastic syncytin and ASCT2 expression was further studied in cytotrophoblasts cultured in 2% oxygen (n= 7). MAIN OUTCOME MEASURES: Syncytin and ASCT2 messenger RNA (mRNA) in placental tissue and cytotrophoblasts. RESULTS: The level of syncytin mRNA expression increased significantly since the first trimester of pregnancy until 37 weeks of gestation, when the level of syncytin expression was reduced. The ASCT2 mRNA expression was decreased significantly since the second trimester and was relatively stable since then to 40 weeks of gestation. Furthermore, a significant reduction in syncytin mRNA expression was observed in pre-eclamptic placentas and cytotrophoblasts cultured in hypoxia, but not a reduction in ASCT2 mRNA expression. Correlatively, the protein level of syncytin was decreased in pre-eclamptic placentas. CONCLUSIONS: A reduced placental expression of syncytin but not ASCT2 may contribute to altered cytotrophoblastic cell fusion processes and disturbed placental function in pre-eclampsia. Correspondingly, hypoxia decreases syncytin but not ASCT2 gene expression in cultured cytotrophoblasts.     

Analysis of the original causes of placental oxidative stress in normal pregnancy and pre-eclampsia: A hypothesis

Pre-eclampsia (PE) and eclampsia remain enigmatic despite intensive research. Growing evidence suggests that placental oxidative stress (OS) is involved in the etiopathogenesis of pre-eclampsia. Reduced perfusion as a result of abnormal placentation was proposed to be responsible for placental OS in PE. However, placental OS was also observed in normal pregnancy. The exact differences and correlation of placental OS in PE and normal pregnancy remain elusive. In this review, we attempted to link both normal pregnancy and PE on the causes of placental OS and proposed a hypothesis that placental OS in normal pregnancy, plus the exploration of other placental and/or maternal factors, could provide a novel explanation of that in PE. We concluded that pregnancy, placental abnormality and preexisting maternal constitutional conditions are three principle factors that could contribute to placental OS in PE. The specific causes in each clinical case could be heterogeneous, which requires individual analysis.     

Combination of uterine artery Doppler velocimetry and maternal serum placental growth factor estimation in predicting occurrence of pre-eclampsia in early second trimester pregnancy: a prospective cohort study

Objective

To determine the effectiveness of the combined use of uterine artery Doppler velocimetry (UADV) and estimation of maternal serum placental growth factor (PlGF) levels in early second trimester (20–22 weeks of gestation) in identifying pregnant women at risk of developing pre-eclampsia.

Study design

Prospective cohort study on 1104 pregnant women with singleton pregnancies between May 2009 and December 2010. UADV and maternal serum PlGF estimation were done at 20–22 weeks’ gestation. Association between the two variables and the occurrence of pre-eclampsia was analyzed by logistic regression analysis and odds ratio was computed. The results were considered significant when p was <0.05.

Results

Logistic regression analysis showed that both abnormal UADV (odds ratio (OR) 4.1; 95% CI 2.3–7.2; p = 0.000) and serum PlGF < 188 pg/ml (OR 3.6; 95% CI 1.95–6.5; p = 0.000) are independent variables in the occurrence of pre-eclampsia, and the difference between the association of these two variables with pre-eclampsia was statistically insignificant as 95% CI values overlap. Multivariate logistic regression analysis showed that a combination of abnormal UADV and serum PlGF < 188 pg/ml at 20–22 weeks had a very poor association (OR 1.1; 95% CI 0.3–3.8; p = 0.938) with the occurrence of pre-eclampsia, as the 95% CI values encompass 1 and p is >0.05.

Conclusion

UADV and maternal serum PlGF estimation at 20–22 weeks of gestation are strong predictors of the occurrence of pre-eclampsia when used individually but in combination their association with pre-eclampsia is not significant.     

First trimester screening for Down syndrome in multiple pregnancy

The incidence of twins, triplets, and high-order multiples has increased substantially in the last two decades secondary to fertility treatments and to delayed childbearing. Prenatal diagnosis in these patients is challenging. Options for screening tests are limited. First trimester screening for Down syndrome in patients with multiples appears promising. This paper will review the advantages of first trimester screening in this high-risk patient population.     

Therapeutic strategies for the prevention and treatment of pre-eclampsia and intrauterine growth restriction

Intrauterine growth restriction and pre-eclampsia are common pregnancy complications that contribute significantly to maternal and perinatal morbidity and mortality, and long term health outcomes. The underlying aetiology of these conditions involves placental underperfusion and placental ischaemia. Most prophylactic and treatment measures for these conditions are hypothesized to have effect through improved placental perfusion, or reduced oxidative stress and subsequent placental damage. However, while many therapies have biologic plausibility, there is a lack of high quality evidence that they substantially improve important outcomes such as birth weight, prematurity, mortality or serious morbidity. This review will describe and evaluate therapies currently available in clinical practice for the prevention and treatment of pre-eclampsia and intrauterine growth restriction, and outline some promising new therapies, which may change the way these conditions are managed in the future.     

First trimester serum inhibin A in normal pregnant women

Objectives To establish reference ranges for maternal serum inhibin A in normal first trimester pregnant women. Materials and methods This was a cross-sectional study. We measured maternal serum inhibin A in normal pregnant women gestation age between 6⁺⁰ and 14⁺⁶ weeks using the enzyme-linked immunosorbent assay (ELISA) method. Maternal serum inhibin A was analyzed according to gestational ages (GA). Results Serum of 300 pregnancies was analyzed and the outcome demonstrated the median of maternal serum inhibin A according to gestational age. The levels of maternal serum inhibin A during the 6⁰–6⁺⁶ week of gestations are lowest when compared with other gestational age. The levels of maternal serum inhibin A during 9⁰–9⁺⁶ week of gestations are maximal. Maternal serum inhibin A then declined until 14 weeks of gestation. Conclusion Serum inhibin A can be measured during the first trimester of pregnancy by using the recent ELISA technique. Our reference ranges might be useful for further studies, such as prediction of adverse pregnancy outcome in threatened abortion.     

Therapeutic strategies for the prevention and treatment of pre-eclampsia and fetal growth restriction

Fetal growth restriction and pre-eclampsia are common pregnancy complications that contribute significantly to maternal and perinatal morbidity and mortality, and long term health outcomes. The underlying aetiology of these conditions is placental under-perfusion and ischemia. Most prophylactic and treatment measures for these conditions are hypothesized to have effect through improved placental perfusion, or reduced oxidative stress, inflammation and subsequent placental damage. However, while many therapies have biologic plausibility, there is a lack of high quality evidence that they substantially improve important outcomes such as birth weight, prematurity, mortality or serious morbidity. This review will describe therapies currently available in clinical practice for the prevention and treatment of pre-eclampsia and intrauterine growth restriction, and outline some promising new therapies, which may change the way these conditions are managed in the future.     

Four-dimensional sonographic assessment of fetal movement in the late first trimester

Objective

To evaluate, using four-dimensional (4D) sonography, the frequency of fetal movements during the late first trimester of normal singleton pregnancies.

Methods

Singleton pregnancies were studied—using transvaginal 4D sonography—for 10 minutes at 10-11 and 12-13 weeks of gestation. The frequencies of 5 fetal movements (isolated arm, isolated leg, short trunk, long trunk, and jumping movements) were evaluated.

Results

In the 17 pregnancies studied, the most frequent fetal movements were isolated arm movement at 10-11 weeks and jumping movement at 12-13 weeks. There was a significant difference in the frequency of jumping movement between 10-11 and 12-13 weeks (P < 0.05).

Conclusion

The difference in frequency of 5 fetal movements at 10-11 and 12-13 weeks of gestation may be caused by early neuromuscular development and differentiation of the neuromuscular system.