Treatment of preeclampsia at extremely preterm gestation with therapeutic plasma exchange.

AIMS: Different forms of apheresis have been proposed as potential therapeutic approaches to remove soluble Fms-like tyrosine kinase-1 (sFlt-1) and allow safe pregnancy prolongation in cases of extremely preterm preeclampsia. This is a follow-up study presenting our experiences with therapeutic plasma exchange (TPE) in 5 women with preeclampsia at < 28 weeks of gestational age. MATERIALS AND METHODS: All women received standard treatment for preeclampsia and 2 - 3 TPE treatments per week. Blood samples for sFlt-1 and placental growth factor (PlGF) measurements were collected before and after each TPE. RESULTS: Seventeen TPE procedures were performed, 2 - 5 per patient. TPE significantly reduced sFlt-1 (by 35 ± 6%), sFlt-1/PlGF ratio (by 24 ± 13%), and to a lesser degree also PlGF (by 12 ± 16%), with a rebound observed on day 1 post procedure. TPE procedures were well tolerated by pregnant women and fetuses. Stabilization of sFlt-1 allowed pregnancy prolongation for a median of 8 (range 2 - 14) days from first TPE and for a median of 10 (range 4 - 17) days from hospital admission. There were no signs of increased risks of adverse neonatal outcome associated with TPE. One neonate died due to extreme prematurity 3 days after delivery, 2 had bronchopulmonary dysplasia, and 1 had retinopathy of prematurity. CONCLUSION: This study provides new evidence of effective reduction in sFlt-1 and sFlt-1/PlGF ratio with TPE treatment, which seems to allow a clinically meaningful prolongation of pregnancy. Controlled studies are necessary to convincingly show the potential benefit of apheresis treatment in preeclampsia at extremely preterm gestation.

Therapeutic plasma exchange and dextran-sulfate plasma adsorption as extracorporeal treatments of extremely preterm preeclampsia with fetal growth restriction.

AIM: To evaluate effectiveness and safety of therapeutic plasma exchange (TPE) and dextran-sulfate plasma adsorption (DSA) for extracorporeal removal of soluble Fms-like tyrosine kinase-1 (sFlt-1) as part of expectant management of preeclampsia at extremely preterm gestational age. METHODS: Retrospective case series of six patients with preeclampsia at <28 weeks of gestation, treated with DSA or TPE. Laboratory results, clinical characteristics and neonatal outcomes were collected from charts and National Perinatal Information System. RESULTS: Fetal growth restriction (FGR) was diagnosed in all cases. Pregnancy was prolonged for a median of 14 (range 5-74) days from admission and 10 (3-73) days from first apheresis. A mixed effects model showed a decrease in sFlt-1 and sFlt-1/PlGF ratio during DSA/TPE (significant effect of time [before/after]), which was comparable between DSA and TPE (no effect of procedure type). Median absolute reduction in sFlt-1 was 42% (inter-quartile range [IQR] 13%-57%) during DSA and 34% (16%-40%) during TPE; for sFlt-1/PlGF ratio it was 29% (22%-36%) and 38% (29%-42%), respectively. All procedures were well tolerated by fetuses. Anaphylactoid reaction, often with angioedema, occurred in 4/6 patients undergoing DSA and was attributed to bradykinin activation. One patient developed wound hematoma after cesarean section, possibly attributed to depletion coagulopathy. CONCLUSIONS: As potential novel treatment of early preeclampsia, a non-selective and widely available TPE was comparable to DSA regarding sFlt-1 reduction but was associated with fewer side-effects. Both seem to allow maternal stabilization and pregnancy prolongation even when early preeclampsia is complicated by FGR.

Usefulness of COVID-19 screen-and-test approach in pregnant women: an experience from a country with low COVID-19 burden.

OBJECTIVES: Information on the usefulness of screen-and-test strategies of pregnant women for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is lacking. METHODS: We retrospectively reviewed the Ljubljana Maternity Hospital database and searched for pregnant women, who were admitted to the hospital between March 15 and May 16, 2020, for a planned procedure or hospitalization. Their medical records were examined and SARS-CoV-2 test results were retrieved. RESULTS: During the two-month period analyzed, there were a total of 265 scheduled admissions of pregnant women to our hospital. Two hundred two (76.2%) were tested for SARS-CoV-2 1 day prior to admission. All tested negative for SARS-CoV-2 RNA, regardless of having coronavirus disease 2019 (COVID-19)-compatible signs or symptoms (n=28) or not (n=174). CONCLUSIONS: In a population with a low SARS-CoV-2 burden, usefulness of universal testing of pregnant women before admission to the hospital is limited. We recommend that obstetric units in regions with low SARS-CoV-2 burden enforce rational use of personal protective equipment and diligent screening protocols using targeted questionnaires, whereas SARS-CoV-2 laboratory testing should be performed only in screen-positives: those with high clinical suspicion of COVID-19 and/or suspected epidemiological history.

Establishing a Differential Marker Profile for Pregnancy Complications Near Delivery.

OBJECTIVE: The aim of this work was to define a differential marker profile for pregnancy complications near delivery. METHODS: We enrolled pregnant women who were referred to the outpatient pregnancy clinic of the University Medical Center, Ljubljana, Slovenia, due to symptoms of pregnancy complications and women with a history of pregnancy complications attending the high-risk hospital clinic for close surveillance. They were evaluated for prior risk and were tested for biophysical and biochemical markers at the time of enrolment. Biochemical markers included the pro- and anti-angiogenic markers, along with additional previously reported markers of potential value, all tested by various formats of immuno-diagnostics. Biophysical markers included blood pressure, sonographic markers, and EndoPAT. Statistical differences were determined with Kruskal-Wallis and Mann-Whitney tests for continuous parameters, and Pearson χ2 for categorical values. p < 0.05 was considered significant. RESULTS: The cohort included 125 pregnant patients, 31 developed preeclampsia (PE) alone (13 were <34 weeks' gestation), 16 had intrauterine growth restriction (IUGR) alone (12 were <34 weeks), 42 had both IUGR and PE (22 were <34 weeks), and 15 had an iatrogenic preterm delivery (PTD; 6 were <34 weeks). Twenty-one were unaffected and delivered a healthy baby at term. Mean arterial blood pressure and proteinuria were significantly higher in PE and PE+IUGR but not in pure IUGR or PTD. In PE, IUGR, and PE+IUGR, the levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) were significantly higher, while placental growth factor (PlGF) was very low compared to unaffected controls and PTD. PE, IUGR, and PE+IUGR also had a high anti-angiogenic ratio (sFlt-1/PlGF) and a low proangiogenic ratio of PlGF/(sFlt-1+Eng). Levels of inhibin A were significantly higher in pure PE across subgroups but had many extreme values, which made it a poor differentiator. Higher uterine artery Doppler pulsatility indexes were detected in PE, IUGR, and PE+IUGR, with similar resistance indexes and peaks of systolic velocity. A significantly different marker level between PE and IUGR was found using arterial stiffness that was 10 times higher in PE; concurrently with an increase of the reactive hyperemia index, both were accompanied by a slight increase in placental protein 13. Higher tumor necrosis factor alpha (TNFα) differentially identified iatrogenic very early PTD (<34 weeks). CONCLUSION: Arterial stiffness can serve as a major marker to differentiate PE (with/without IUGR) from pure IUGR near delivery. TNFα can differentiate iatrogenic early PTD from other complications of pregnancy and term IUGR.

Zika Virus Associated with Microcephaly.

A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.

Total gestational weight gain and the risk of preeclampsia by pre-pregnancy body mass index categories: a population-based cohort study from 2013 to 2017.

Background Identifying the risk factors for preeclampsia (PE) is essential for the implementation of preventive actions. In the present study, we aimed at exploring the association between total gestational weight gain (GWG) and PE. Methods We performed a population-based cohort survey of 98,820 women with singleton pregnancies who delivered in Slovenia from 2013 to 2017. Aggregated data were obtained from the National Perinatal Information System (NPIS). The main outcome measure was the incidence of PE. The main exposure variable was total GWG standardized for the gestational duration by calculating the z-scores. The associations between total GWG and PE stratified by pre-pregnancy body mass index (BMI) categories adjusted for a variety of covariates were determined using multivariable logistic regression. We calculated the crude odds ratio (OR) and adjusted odds ratio (aOR) with a 95% confidence interval using a two-way test. Results Excessive GWG was associated with increased odds of PE in all pre-pregnancy BMI categories. The increase in the odds of PE by 445% was the highest in underweight women and by 122% was the lowest in obese women. Low GWG was associated with decreased odds of PE in all pre-pregnancy BMI categories except in normal-weight women with a GWG below -2 standard deviation (SD) and underweight women. The decrease in the odds of PE by 67% was the highest in obese women and by 41% was the lowest in normal-weight women. Conclusion Excessive GWG is a significant risk factor for PE, especially in underweight women, while low GWG is an important protective factor against PE, especially in obese women.

A dose-response relation exists between different classes of pre-gravid obesity and selected perinatal outcomes.

OBJECTIVE: To examine if a "dose-response" relation exists between different classes of pre-gravid obesity and selected perinatal outcomes. METHODS: We evaluated 16,566 obese mothers, including 12,064 (72.8%), 3410 (20.6%), and 1092 (6.6%) with obesity class I, II, and III, respectively. We compared maternal age, primiparity, gestational age at birth, birth weight, GDM, hypertensive disorders, and the incidence of cesarean sections. RESULTS: There was a significantly increased incidence (from class I to class III) for GDM (8.5-14.4%), chronic hypertension (2.8-9.0%), gestational hypertension (6.7-14.2%), and for preeclampsia (5.3-9.3%). No such relationship existed for birth weight and gestational duration. CONCLUSION: Classes of obesity during pregnancy exhibit a "dose-response" relationship with maternal morbidity, but no such relationship was found with pregnancy duration and birth weight.

Correlation between uterine artery Doppler and the sFlt-1/PlGF ratio in different phenotypes of placental dysfunction.

OBJECTIVE: To explore correlations between the sFlt-1/PlGF ratio and uterine arteries (UtA) Doppler indexes in placental dysfunction-related disorders (PDD). METHODS: We prospectively included women with a singleton pregnancy with preeclampsia (PE) only (n = 22), preeclampsia with fetal growth restriction (FGR) (n = 32), FGR only (n = 12), or normal pregnancy (n = 29). RESULTS: In PDDs, significantly positive correlations between the sFlt-1/PlGF ratio and the mean UtA pulsatility (mPI-UtA), as well as the resistance index (mRI-UtA) were found (p = 0.015, p = 0.019, respectively), but not in normal pregnancies. PDD with signs of impaired placentation, evidenced by the increased sFlt-1/PlGF ratio and mPI-UtA, was found in 50.0%, and, by the increased sFlt-1/PlGF ratio and mRI-UtA, in 65.2%. PDD without signs of impaired placentation, evidenced by the increased sFlt-1/PlGF ratio but normal mPI-UtA, was found in 24.2%, and, by the increased sFlt-1/PlGF ratio but normal mRI-UtA, in 7.6%. A substantial proportion of women with signs of impaired placentation were diagnosed with FGR with or without PE. CONCLUSION: In PDD, the sFlt-1/PlGF ratio and UtA Doppler indexes increase proportionally. Correlations between the sFlt-1/PlGF ratio and UtA Doppler indexes might help to distinguish between PDDs with and without impaired placentation. However, further studies are needed to explore the correlations in different phenotypes of PDD.

The impact of inter-pregnancy interval on subsequent risk of preterm birth.

OBJECTIVE: The aim of the study was to assess optimal time to conceive after previous delivery associated with smallest risk of preterm birth. METHODS: We selected all women (n = 2723) with their first and second singleton delivery between the years 2004 and 2012. Inter-pregnancy interval was defined as that between live birth and subsequent conception. We performed logistic regression analyses to assess the risk of preterm birth adjusted for maternal age and body mass index. RESULTS: Association between inter-pregnancy interval and the natural logarithm of the adjusted relative risk of preterm birth had a J-shaped curve with lowest risk at 15 months after last birth. CONCLUSION: The optimal time to conceive after a previous delivery is 15 months, as longer or shorter interval are associated with increased risk of preterm birth. Women with short or long inter-pregnancy intervals were 1.6 times more likely to experience preterm birth.

Peripheral arterial tonometry and angiogenic biomarkers in preeclampsia.

OBJECTIVE: To evaluate changes in vascular function and serum biomarkers in women with and without preeclampsia (PE) to create a model for the easier and more precise diagnosis of PE in the future. METHODS: Endothelial function and arterial stiffness were evaluated using peripheral arterial tonometry and concentrations of placental growth factor (PlGF), soluble fms like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) were determined by immunoassay. RESULTS: Arterial stiffness deteriorates and endothelial function is better in women with PE compared with a healthy pregnancy. Women who developed PE had a decreased PlGF and PlGF/(sFlt-1+ sEng) ratio and an increased sEng, and sFlt-1/PlGF ratio. CONCLUSION: Peripheral arterial analysis did provide additional information beyond serum biomarkers in the diagnosis of PE.

Hypertensive disorders during monozygotic and dizygotic twin gestations: A population-based study.

OBJECTIVE: To determine whether the incidence of hypertensive disorders is different in monozygotic compared to dizygotic twin pregnancies. METHODS: A registry-based survey of twin pregnancies delivered during 2003 to 2012. We used the best clinical estimate of zygosity based on the concept that all monochorionic twins are monozygotic and all unlike-sex pairs are dizygotic, thus excluding same-sex dichorionic twin gestations for which zygosity cannot be ascertained on clinical grounds. Study cohorts were twin pregnancies with or without preeclampsia and gestational hypertension. RESULTS: A total of 3419 twin gestations met the inclusion criteria, of which 442 (12.9%) were monochorionic and 1255 (36.7%) were unlike-sex twins, excluding 1722 same-sex dichorionic twin gestations (50.4%). There was no significant difference in the incidence of preeclampsia (OR: 0.9; 95% CI: 0.4-2.0 for monozygotic males and OR: 0.6; 95% CI: 0.3-1.4 for monozygotic females) and gestational hypertension (OR: 0.7; 95% CI: 0.2-2.5 for monozygotic males, and OR: 0.7; 95% CI: 0.2-2.3 for monozygotic females) between monochorionic and unlike-sex pairs. Maternal prepregnancy obesity and nulliparity were the only significant associated factors of preeclampsia (OR: 3.8; 95% CI: 2.0-7.0, and OR: 2.5; 95% CI: 1.4-4.4, respectively). Maternal prepregnancy obesity (OR: 5.5; 95% CI: 2.5-12.2), maternal age ≥36 years (OR: 2.5; 95% CI: 1.1-6.1), and family history of hypertension (OR: 2.6; 95% CI: 1.3-5.1) were significantly associated with gestational hypertension. CONCLUSION: Based on a large population-based dataset and on the best clinical estimate of twin zygosity, it appears that zygosity is not associated with hypertensive disorders in twin gestations.