FIRST TRIMESTER SCREENING FOR HYPERTENSIVE DISORDER OF PLACENTAL AND MATERNOGENIC ORIGIN

FIRST TRIMESTER SCREENING OF HYPERTENSIVE DISORDERS OF PLACENTAL AND MATERNOGENIC ORIGIN Background: Hypertensive disorders (HD) constitute a heterogeneous group of conditions. They complicate around 10% of pregnancies, and are a major cause of maternal and perinatal morbidity and mortality. The most used classification is based on temporal criteria: diagnosis (or delivery) before/after 34 weeks’ of gestation. Early-onset HD (before 34 weeks) is commonly associated with abnormal uterine artery Doppler, fetal growth restriction, evidence of ischemic lesions on placental examination and adverse maternal and neonatal outcomes. In contrast, late-onset HD (after 34 weeks) is mostly associated with normal or slightly increased uterine resistance index, a low rate of fetal involvement, and more favourable perinatal outcomes. Nevertheless, the phenotypes of HD do not fit entirely into the temporal classification. Thus, it has been hypothesized that phenotypes of HD, rather than temporal classification, reflect the underlying aetiology of HD: 1) HD of placental origin, when the defect in placentation causes an altered remodelling of the spiral arteries leading to reduced placental flow, activation of coagulation cascade, organ damage and intrauterine fetal growth restriction (IUGR); and 2) HD of maternogenic origin, associated with normal feto-placental perfusion and normal fetal growth, probably related to chronic inflammation and insuline resistance, typical aspects of metabolic syndrome. The early identification of pregnancies at risk of HD is a major challenge. Extensive research has identified a series of 1st trimester biophysical and biochemical markers of impaired placentation. The combination of these markers and maternal history have been used by clinicians as a 1st trimester screening for the recognition of pregnancies at risk of early/late onset HD. The aim of the study is to evaluate a new classification of hypertensive disease based on physiopathology, and not on temporary factors and to evaluate the effectiveness of 1st trimester screening for HD of placental and maternal origin by Doppler velocimetry of uterine arteries (UtA). Material and Methods: This is a prospective longitudinal cohort study of pregnant women followed in two hospital: prenatal diagnosis and gynaecologic Unit of the Institute for Maternal and Child Health – IRCCS “Burlo Garofolo” in Trieste and Obstetrics and Gynecologic Unit of Children’s Hospital – ICP “Vittore Buzzi” in Milan, Italy. This study was offered to pregnant women at the time of first trimester ultrasound aneuploidy screening. All women were recruited consecutively from October 2007 to April 2009 in Triest and from October 2009 to December 2012 in Milan. We enrolled singleton pregnancies between 11+0 and 13+6 weeks of gestation. The inclusion criteria were: single pregnancy, gestational age between 11+0 and 13+6 weeks confirmed by scan measurements, and signed informed consent. Multiple pregnancies or pregnancies complicated by fetal malformation or aneuploidy, spontaneous abortion, intrauterine fetal death, maternal neurodevelopment delay or psychiatric disorders were excluded. The following data were collected at the time of the scan: maternal history, previous disease, age, body mass index (BMI), parity, mode of conception (spontaneous or IVF), and gestational age. Doppler velocimetry of both UtA was added to routine ultrasound measurements. Doppler study was performed trans-abdominally, after identifying with the Color Doppler each uterine artery along the side of the cervix and uterus at the level of the internal os. Pulsed wave Doppler was used with the sampling gate set at 2 mm to cover the whole vessel ensuring the angle of insonation <30°. When three similar consecutive waveforms were obtained the pulsatility index (PI) was measured, and the mean PI of the left and right arteries was calculated. The measurements were performed by sonographers qualified by Fetal Medicine Foundation. Once the ultrasound examination was performed and the gestational age confirmed, a blood sample (around 5 cc) was taken from each woman. Maternal serum PAPP-A and B-hCG were measured and converted in multiple of the median (MoM). Definitions: Placental HD was defined as gestational hypertension, with or without proteinuria, associated to IUGR (defined as the AC <5th centile or reduction in AC >40 centiles). Maternal HD was defined as gestational hypertension, with or without proteinuria, associated to appropriate for gestational age fetal growth. Chronic hypertension was defined as history of known hypertension or blood pressure ≥140/90 mmHg in two or more occasions with a distance at least of 4 hours before 20 weeks of gestation. The HD were also distinguished into early-onset, diagnosed <34 weeks’ gestation, and late-onset, with diagnosis ≥ 34 weeks. Intra-uterine growth restriction (IUGR) was defined as ultrasound abdominal circumference below the 10th percentile according to standards references based on gestational age. Other causes of IUGR such as infection, anomalies and abnormal chromosomes were excluded in all cases. Pregnancy outcome data were collected as follows: fetal and maternal outcomes were obtained either directly from the clinical record if the delivery occurred in “Vittore Buzzi” Hospital or in “Burlo Garofolo” hospital or by a telephone questionnaires to the women after delivery. Statistical analysis: The distribution of data was evaluated with Kruskall-Wallis test. In case of non-uniformely distributed data a log transformation was applied. The results are represented as mean value and standard deviation (SD). Logistic regression models were computed to evaluate the significance of the variables considered. The following variables were included: UtA mean PI, BMI, parity, gestational age at time of recruitment and fetal sex. The receiver operating curves (ROC) constructed on regression models were computed and area under the ROC (AUC) calculated to evaluate the performance of the model. We evaluated the 1st trimester model to identify: firstly, women at risk of developing placental or maternogenic HD, and, secondly, the early and late-onset HD. Each disease was evaluated against the whole cohort. The analysis was performed with the program Stata/IC 11.2 for Windows (Stata Corp LP, College Station, USA). Results: 4218 women were enrolled in the study. 712 patients were lost to follow up or excluded because incomplete data acquisition. Overall 34 women were excluded because of: spontaneous abortion, aneuploidies or fetal malformations, and intrauterine fetal death. Among 3472 pregnancies included in the study, 122 women (3,5%) developed some hypertensive gestational disease, 56 fetuses were IUGR (1,6%), 10 women had chronic hypertension (0.3%) and 3284 women were unaffected (94.6%). If we considered classification based on the aetiology, 16 women (0.5%) developed placental HD, 106 (3.0%) presented maternal HD. If we considered classification based on time of delivery, 11 women (0.3%) developed early-HD, 111 women (3.2%) presented late-HD. The mean uterine artery PI was significantly higher in placental HD (2.36 p<0.01) when compared with the unaffected group (1.60). If we consider the early-late group, the mean uterine artery PI was significantly higher in early HD group (2.30, p<0.01) respect control group and in late HD group (1.71, p< 0.05). PAPP-A was significant lower in maternal-HD, late-HD and IUGR group (p< 0.01) and in CH group (p<0.05). There was no significant difference in BhCG levels through study group. Concerning prediction of the logistic regression, the validity of the uterine arteries Doppler velocimetry has been confirmed for early identification of women at risk of developing a hypertensive disease, especially of placental origin. In effect the area under the ROC curve for placental hypertensive diseases was 0.879, whereas for early diseases was 0.858. Conclusions: The main findings of the study are: 1) the UtA mean PI is altered in placental HD, while there were no differences in maternogenic HD; 2) the UtA mean PI is altered in early-onset HD and late-onset HD; 3) the predictive value of UtA mean PI is higher for placental HD than for early-onset HD; and 4) the performance of the model based on UtA PI in the 1st trimester performs best in the prediction of the placental HD compared to all other groups. Our study has some limitations: we acknowledge that the number of cases in the study is too small (the prevalence of HD in our cohort is low) to draw firm conclusions, and confirmation from larger studies will be required. Smoking habit was not considered. Diagnosis of early and late preeclampsia is based on time at delivery and not at time of diagnosis. Despite these limitations, the study shows that the classification based on phenotypes of HD is more appropriate than that based on temporal criteria. Indeed, our findings underline the importance of the “etiology” based classification in order to use, in the most appropriate way, the biophysical or biochemical marker screening tools. Thus, the usefulness of Doppler velocimetry of the uterine arteries to identify HD not associated with IUGR or simply based on temporal criteria appears to be of limited value. This finding is important when evaluating the performance of the screening programs or preventive policies.