Assessment of feto-placental oxygenation and perfusion in a rat model of placental insufficiency using T2* mapping and 3D dynamic contrast-enhanced MRI.

INTRODUCTION: Placental insufficiency may lead to preeclampsia and fetal growth restriction. There is no cure for placental insufficiency, emphasizing the need for monitoring fetal and placenta health. Current monitoring methods are limited, underscoring the necessity for imaging techniques to evaluate fetal-placental perfusion and oxygenation. This study aims to use MRI to evaluate placental oxygenation and perfusion in the reduced uterine perfusion pressure (RUPP) model of placental insufficiency. METHODS: Pregnant rats were randomized to RUPP (n = 11) or sham surgery (n = 8) on gestational day 14. On gestational day 19, rats imaged using a 7T MRI scanner to assess oxygenation and perfusion using T2* mapping and 3D-DCE MRI sequences, respectively. The effect of the RUPP on the feto-placental units were analyzed from the MRI images. RESULTS: RUPP surgery led to reduced oxygenation in the labyrinth (24.7 ± 1.8 ms vs. 28.0 ± 2.1 ms, P = 0.002) and junctional zone (7.0 ± 0.9 ms vs. 8.1 ± 1.1 ms, P = 0.04) of the placenta, as indicated by decreased T2* values. However, here were no significant differences in fetal organ oxygenation or placental perfusion between RUPP and sham animals. DISCUSSION: The reduced placental oxygenation without a corresponding decrease in perfusion suggests an adaptive response to placental ischemia. While acute reduction in placental perfusion may cause placental hypoxia, persistence of this condition could indicate chronic placental insufficiency after ischemic reperfusion injury. Thus, placental oxygenation may be a more reliable biomarker for assessing fetal condition than perfusion in hypertensive disorders of pregnancies including preeclampsia and FGR.

The effect of pregnancy on renal angiomyolipoma; a world of knowledge to gain, specifically in women with TSC.

BACKGROUND: Women are counseled preconceptionally about the potential risks of rAML progression and chance of complications during and due to pregnancy. However, a systematic search investigating the evidence on which this advice is based does not exist. The aim of this systematic review is to determine the effect of pregnancy on renal angiomyolipoma (rAML) size and risk of haemorrhage in patients with tuberous sclerosis complex (TSC). METHODS: We searched PubMed, EMBASE, Medline and ClinicalTrials.gov using terms for "renal angiomyolipoma" and "pregnancy". English-language articles published between January 1st 2000, and December 31st 2020 of which full-text was available were included. The initial search resulted in 176 articles. After the screening process we included 45 case reports and 1 retrospective study. For the retrospective study we assessed the risk of bias using the Newcastle-Ottawa Scale. We included articles about renal AML and pregnancy with and without an established diagnosis of TSC. From these articles we recorded the rAML sizes and rAML complications. RESULTS: Seven case reports, from a total of 45 case reports, provided follow-up data on renal AML size (these were all cases of renal AML without a known diagnosis of TSC). Of these cases, renal AML size decreased in one patient, was stable in one patient, increased in three patients and fluctuated in two others. Renal AML size of women who suffered a haemorrhage were significantly larger (12.1 ± 4.6 cm) than rAMLs of women who did not suffer a haemorrhage (8.3 ± 3.2 cm). Data from the retrospective study showed no difference in renal complications between the women with and without a history of pregnancy. Haemorrhage occurred in 30% of the women with a history of pregnancy (n = 20) and in 11% in the patients without a history of pregnancy (n = 2), however this retrospective study had methodological limitations. CONCLUSION: The effect of pregnancy on renal AML size and complications in patients with TSC is unclear. More research is needed to determine the risk of pregnancy on TSC-associated kidney disease in TSC patient.

Practice variation in timing of antenatal corticosteroid administration in early-onset fetal growth restriction: A secondary analysis of the Dutch STRIDER study.

INTRODUCTION: In early-onset fetal growth restriction the fetus fails to thrive in utero due to unmet fetal metabolic demands. This condition is linked to perinatal mortality and severe neonatal morbidity. Maternal administration of corticosteroids in high-risk pregnancies for preterm birth at a gestational age between 24 and 34 weeks has been shown to reduce perinatal mortality and morbidity. Practice variation exists in the timing of the administration of corticosteroids based on umbilical artery monitoring findings in early-onset fetal growth restriction. The aim of this study was to examine differences in neonatal outcomes when comparing different corticosteroid timing strategies. MATERIAL AND METHODS: This was a post-hoc analysis of the Dutch STRIDER trial. We examined neonatal outcomes when comparing institutional strategies of early (umbilical artery pulsatility index >95th centile) and late (umbilical artery shows absent or reversed end-diastolic flow) administration of corticosteroids. The primary outcomes were neonatal mortality and a composite of neonatal mortality and neonatal morbidity, defined as bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis or retinopathy of prematurity. We also analyzed predictors for adverse neonatal outcomes, including gestational age at delivery, birthweight, maternal hypertensive disorders, and time interval between corticosteroids and birth. RESULTS: A total of 120 patients matched our inclusion criteria. In 69 (57.5%) the early strategy was applied and in 51 (42.5%) patients the late strategy. Median gestational age at delivery was 28 4/7 (± 3, 3/7) weeks. Median birthweight was 708 (± 304) g. Composite primary outcome was found in 57 (47.5%) neonates. No significant differences were observed in the primary outcome between the two strategies (neonatal mortality adjusted odds ratio [OR] 1.22, 95% CI 0.44-3.38; composite primary outcome adjusted OR 1.05, 95% CI 0.42-2.64). Only gestational age at delivery was a significant predictor for improved neonatal outcome (adjusted OR 0.91, 95% CI 0.86-0.96). CONCLUSIONS: No significant differences in neonatal outcomes were observed when comparing early and late strategy of antenatal corticosteroid administration on neonatal outcomes in pregnancies complicated by early-onset fetal growth restriction. We found no apparent risk contribution of interval between corticosteroid administration and delivery in multivariate analysis. Gestational age at delivery was found to be an important predictor of neonatal outcome.

From Molecules to Imaging: Assessment of Placental Hypoxia Biomarkers in Placental Insufficiency Syndromes.

Placental hypoxia poses significant risks to both the developing fetus and the mother during pregnancy, underscoring the importance of early detection and monitoring. Effectively identifying placental hypoxia and evaluating the deterioration in placental function requires reliable biomarkers. Molecular biomarkers in placental tissue can only be determined post-delivery and while maternal blood biomarkers can be measured over time, they can merely serve as proxies for placental function. Therefore, there is an increasing demand for non-invasive imaging techniques capable of directly assessing the placental condition over time. Recent advancements in imaging technologies, including photoacoustic and magnetic resonance imaging, offer promising tools for detecting and monitoring placental hypoxia. Integrating molecular and imaging biomarkers may revolutionize the detection and monitoring of placental hypoxia, improving pregnancy outcomes and reducing long-term health complications. This review describes current research on molecular and imaging biomarkers of placental hypoxia both in human and animal studies and aims to explore the benefits of an integrated approach throughout gestation.

Telemonitoring for COVID-19 positive pregnant women; feasibility and user experience of SAFE@home Corona: prospective pilot study.

BACKGROUND: COVID-19 has catalysed digital innovations enabling remote healthcare. Pregnant women are at increased risk for severe course of COVID-19 infection. Also, the pandemic has a negative emotional impact on pregnant women as they worry about their own health and the health of their unborn child. We developed a telemonitoring platform called SAFE@home-corona consisting of a pulse oximeter and an app with symptom checklist. The aim of this study was to examine the feasibility, defined by compliance to the platform and by monitoring the course of COVID-19, patient satisfaction and user experience of a telemonitoring platform in COVID-19 positive pregnant women in the Netherlands. METHODS: We conducted a prospective pilot study among Dutch-speaking COVID-19 symptomatic pregnant women. Women were asked to monitor their oxygen-saturation with a pulse oximeter and COVID-related complaints with an in-app questionnaire daily. Oxygen-saturation and complaints were monitored by the Medical Management Centre with triage protocol. COVID-19, pregnancy, and user experience data were collected. To assess feasibility, compliance of daily self-monitoring and compliance of all intended measurements were calculated. Severity of COVID-19 was assessed via the platform and medical record. Patient satisfaction and user experience were measured through a self-developed questionnaire. RESULTS: Twenty-eight women were eligible of which 27 (93.1%) completed the study. Compliance of daily measurement and all intended measurements was high with 98.9 and 93.9%, respectively. Six women were hospitalized, of whom one to the intensive care unit. Overall, women indicated high satisfaction scores, varying from 8 to 10/10. Women were more concerned for the health of their unborn child or family then for themselves (66.7%). They stated that the platform offered reassurance. Patients would highly recommend the platform to pregnant peers during COVID infection. CONCLUSIONS: This pilot study demonstrated feasibility of the SAFE@home-corona platform for self-monitoring COVID-19 course in pregnant women. Patients were satisfied, it offered reassurance, women would recommend use to peers. Upscaling the platform is needed to draw conclusions from the early signalling abilities and to keep evaluating patient satisfaction. The platform has great potential for self-monitoring of COVID-19 and possibly other pulmonary infections in pregnant women.

Comparison of pregnancy outcomes in Dutch kidney recipients with and without calcineurin inhibitor exposure: a retrospective study.

Within pregnancies occurring between 1986 and 2017 in Dutch kidney transplant recipients (KTR), we retrospectively compared short-term maternal and foetal outcomes between patients on calcineurin inhibitor (CNI) based (CNI+) and CNI-free immunosuppression (CNI-). We identified 129 CNI+ and 125 CNI- pregnancies in 177 KTR. Demographics differed with CNI+ having higher body mass index (P = 0.045), shorter transplant-pregnancy interval (P < 0.01), later year of transplantation and -pregnancy (P < 0.01). Serum creatinine levels were numerically higher in CNI+ in all study phases, but only reached statistical significance in third trimester (127 vs. 105 µm; P < 0.01), where the percentual changes from preconceptional level also differed (+3.1% vs. -2.2% in CNI-; P = 0.05). Postpartum both groups showed 11-12% serum creatinine rise from preconceptional level. Incidence of low birth weight (LBW) tended to be higher in CNI+ (52% vs. 46%; P = 0.07). Both groups showed equal high rates of preterm delivery. Using CNIs during pregnancy lead to a rise in creatinine in the third trimester but does not negatively influence the course of graft function in the first year postpartum or direct foetal outcomes. High rates of preterm delivery and LBW in KTR, irrespective of CNI use, classify all pregnancies as high risk.

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction: A Randomized Clinical Trial.

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). Conclusions and Relevance: These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT02277132.

Longitudinal follow-up of kidney function in patients with a history of preeclampsia: From 11 to 18 years postpartum.

Formerly preeclamptic (fPE) women are reported to have an increased risk to develop end stage kidney disease. To gain more insight in the course of kidney function after preeclampsia we assessed blood pressure, eGFR and urinary protein loss in 75 fPE women at 11 and 18 years postpartum. We found that during follow-up blood pressure did not increase and no cases of CKD were identified. Only a small decrease in eGFR (6-7 mL/min) and a small increase in urinary protein loss were observed, which fall within the expected range of normal aging. In conclusion, our data suggests that progression to kidney disease might not be a major concern in women after preeclampsia within 18 years postpartum.

Association between parity and persistent weight gain at age 40-60 years: a longitudinal prospective cohort study.

OBJECTIVES: Physiological metabolic adaptations occur in the pregnant woman. These may persist postpartum and thereby contribute to an unfavourable cardiovascular disease (CVD) risk profile in parous women. The aim of the current study is to assess time-dependent changes of cardiometabolic health in parous women compared with nulliparous women. DESIGN AND SETTING: We studied data of 2459 women who participated in the Prevention of Renal and Vascular End-stage Disease study, a population-based prospective longitudinal cohort for assessment of CVD and renal disease in the general population. PARTICIPANTS: We selected women ≥40 years at the first visit, who reported no new pregnancies during the four follow-up visits. All women were categorised in parity groups, and stratified for age. OUTCOME MEASURES: We compared body mass index (BMI), high-density lipoprotein (HDL) cholesterol, blood pressure as continuous measurements and as clinical relevant CVD risk factors among parity groups over the course of 6 years using generalised estimating equation models adjusted for age. RESULTS: The BMI was significantly higher in women para 2 or more in all age categories: per child, the BMI was 0.6 kg/m2 higher. corresponding with 1.5-2.0 kg weight gain per child. HDL cholesterol was significantly lower in women para 2 or more aged 40-49 and 50-59 years: per child, the HDL cholesterol was up to 0.09 mmol/L lower. Blood pressure did not differ among parity groups in any of the age categories. CONCLUSIONS: Higher parity is associated with higher BMI, lower HDL cholesterol and a higher prevalence of cardiovascular risk factors, which is constant over time. These findings warrant for prospective research assessing determinants of cardiometabolic health at earlier age to understand the role of pregnancy in the development of CVD in women.

PP013. Single nucleotide polymorphisms of the maternal cystathionine-b-synthase gene are associated with preeclampsia (PE).

INTRODUCTION: Cystathionine-b-synthase (CBS) produces the vasodilatory and anti-inflammatory hydrogen sulfide (H2S) by conversion of homocysteine (Hcy). H2S is involved in placental vascular tone regulation. Previously, we showed that woman with PE have hyperhomocysteinemia and decreased placental CBS gene expression. OBJECTIVES: Aberrant CBS gene expression may play a role in hyperhomocysteinemia and decreased H2S and could be involved in pathogenesis of PE. We studied whether the presence of CBS single nucleotide polymorphisms (SNPs) is associated with the development of PE. METHODS: Six CBS SNPs (rs12329764, rs2851391, rs234713, rs234706, rs1789953, rs11203172) were genotyped in 99 controls, 60 severe, and 39 mild PE cases. Severe and mild PE cases were additionally subdivided into late- (>34 weeks) and early-onset (<34 weeks) PE. The association of the alleles with development PE was tested with logistic regression. RESULTS: Two of the six SNPs are associated with PE. The minor allele for rs11203172 reduces the risk for developing severe PE (OR[95% CI]=0.54[0.21-0.94], p=0.023). The minor allele for rs234706, which is associated with low Hcy, increased the risk to develop mild, late-onset PE (2.10[1.15-3.85], p=0.016). CONCLUSION: SNPs in the CBS gene are associated with risk of developing PE. Within the CBS gene, SNPs associated with both a decreased and an increased risk to develop PE were found. Altered effectiveness of CBS may affect PE through decreased H2S production or Hcy accumulation.