Multiple Gestation as a Risk Factor for SARS-CoV-2-Associated Adverse Maternal Outcome: Data From the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

Introduction: Studies have shown that pregnant women with COVID-19 have a higher risk of intensive care unit admission and invasive mechanical ventilation support than non-pregnant women. Pregnancy-associated physiological changes in respiratory function may contribute to the elevated risk. Alteration in lung volumes and capacities are attributed to the mechanical impediment caused by the growing fetus. Multiple pregnancies may therefore compromise functional lung capacity earlier than singleton pregnancies and contribute to severe respiratory symptoms of COVID-19. Materials and Methods: A total of 5514 women with a symptomatic SARS-CoV-2 infection during pregnancy registered in the COVID-19 Related Obstetric and Neonatal Outcome Study were included. The COVID-19-related adverse maternal outcomes were compared in 165 multiple versus 5349 singleton pregnancies. Combined adverse maternal outcome was defined as presence of COVID-19-related hospitalization and/or pneumonia and/or oxygen administration and/or transfer to ICU and/or death. Multivariate logistic regression was used to estimate the odds ratios and 95% confidence intervals were calculated. Results: The frequency of dyspnea, likelihood of developing dyspnea in a defined pregnancy week and duration of the symptomatic phase of the COVID-19 infection did not differ between the two groups. On average, COVID-19-related combined adverse outcome occurred earlier during pregnancy in women expecting more than one child than in singleton pregnancies. The overall incidence of singular and combined COVID-19-associated adverse maternal outcomes was not significantly different between groups. However, regression analysis revealed that multiple gestation, preconceptional BMI > 30 kg/m 2 and gestational age correlated significantly with an increased risk of combined adverse maternal outcome. Conversely, maternal age and medically assisted reproduction were not significant risk factors for combined adverse maternal outcome. Conclusion: Our data show that multiple gestation alone is a risk factor for COVID-19-associated combined adverse maternal outcome. Moreover, severe courses of COVID-19 in women expecting more than one child are observed earlier in pregnancy than in singleton pregnancies.

Correction: Multiple Gestation as a Risk Factor for SARS-CoV-2-Associated Adverse Maternal Outcome: Data From the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

[This corrects the article DOI: 10.1055/a-2196-6224.].

The adipokine preadipocyte factor-1 is downregulated in preeclampsia and expressed in placenta.

BACKGROUND: Adipokines contribute to the development of preeclampsia (PE), a severe pregnancy complication which increases the future risk for cardiovascular and metabolic disease in both mother and newborn. Pre-adipocyte factor-1 (Pref-1) was recently introduced as a novel antiangiogenic and antiadipogenic adipokine. MATERIAL AND METHODS: Pref-1 was quantified in patients with PE (n=51) and healthy pregnant controls (n=51) during pregnancy, as well as 6 months after delivery (study population 1). Furthermore, Pref-1 was investigated in the immediate peripartal period and the placenta in 40 healthy pregnant women undergoing elective cesarean section (study population 2). RESULTS: In study population 1, median Pref-1 serum concentrations during pregnancy were significantly lower in women with PE (0.5 µg/l) as compared to healthy pregnant controls (0.7 µg/l) (p<0.001). Furthermore, Pref-1 serum concentrations were independently predicted by PE, leptin levels, and gestational age in this population. In both study populations, Pref-1 serum levels significantly decreased after delivery as compared to prepartal levels. Moreover, significant expression of Pref-1 was detected in placental tissue. CONCLUSION: Maternal Pref-1 serum concentrations are significantly decreased in PE. The pathophysiological significance of this regulation needs to be studied in more detail in future experiments.

Serum levels of sclerostin in cardiometabolic disorders during pregnancy.

OBJECTIVE: Sclerostin has recently been introduced as a novel osteocyte-secreted factor which is associated with an adverse metabolic profile. However, regulation of circulating sclerostin in cardiometabolic disorders during pregnancy including gestational diabetes mellitus (GDM) and preeclampsia (PE) has not been comprehensively assessed, so far. METHODS: Serum levels of sclerostin were quantified in 72 women with GDM and in 72 healthy, pregnant, gestational age-matched controls (study population 1). Furthermore, circulating sclerostin was assessed in 51 women with PE as compared to 51 pregnant controls in a second cohort (study population 2). RESULTS: In the first study population (GDM), median [interquartile range] sclerostin levels were not significantly different in women with GDM as compared to controls (GDM: 19.2 [8.1]pmol/l; controls: 18.6 [7.1]pmol/l; p=0.906). Interestingly, C reactive protein was a negative and independent predictor of circulating sclerostin in the GDM cohort in multivariate analysis. In study population 2 (PE), serum levels of sclerostin were not different between women with PE and controls (PE: 18.8 [9.2]pmol/l; controls: 19.3 [8.8]pmol/l; p=0.504). Furthermore, the osteocyte-secreted factor was not related to any metabolic and gestational parameter in this cohort. CONCLUSIONS: Sclerostin serum levels are not associated with an adverse metabolic profile during pregnancy in women with GDM and PE. The physiological significance of different associations of circulating sclerostin between pregnancy and non-pregnant status needs to be determined in future experiments.

Serum levels of irisin in gestational diabetes mellitus during pregnancy and after delivery.

OBJECTIVE: Irisin has recently been introduced as a novel an exercise-inducible myokine which improves glucose metabolism in mice. However, regulation of circulating irisin in gestational diabetes mellitus (GDM) and in the peripartal period has not been assessed so far. METHODS: Circulating irisin was quantified in 74 GDM patients and in 74 healthy, pregnant, gestational age-matched controls. In a subset of these patients (44 GDM, 41 controls), postpartum follow-up data were also available. In a second study population of 40 healthy women with singleton pregnancies undergoing elective Cesarean section, irisin was assessed in maternal serum before and within 24h after delivery, as well as in umbilical cord blood and in placental tissue. RESULTS: In the first study population, median [interquartile range] irisin levels were significantly higher in GDM patients as compared to controls after delivery (previous GDM: 446.3 [146.9]µg/l; controls: 378.0 [111.4]µg/l) but not during pregnancy (GDM: 482.1 [132.1]µg/l; controls: 466.6 [178.0]µg/l). Interestingly, fasting insulin (FI) was independently and positively associated with serum irisin in multivariate analysis during pregnancy. In agreement with these findings, relative changes (ratio) of FI independently and positively predicted relative changes of irisin (ratio) in the second study population. CONCLUSIONS: The myokine irisin is independently associated with FI in pregnancy. The physiological significance of these findings needs to be assessed in future experiments.

Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a serious cardiovascular complication in pregnancy, which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Fibroblast growth factor (FGF)-21 was recently introduced as a novel adipokine improving glucose metabolism in vitro and in vivo. MATERIAL AND METHODS: We investigated serum FGF-21 levels in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of FGF-21 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was elucidated in all individuals. RESULTS: Median maternal FGF-21 serum concentrations adjusted for body mass index and gestational age at blood sampling were significantly, almost 3-fold increased in PE patients (309.6 ng/l) as compared to healthy, age-matched pregnant women (105.2 ng/l) (p<0.001). Furthermore, FGF-21 concentrations were independently and positively correlated with triglycerides whereas an independent and negative association was observed with glomerular filtration rate and low density lipoprotein (LDL) cholesterol in pregnant women. Moreover, FGF-21 serum levels significantly decreased in former PE patients 6 months after pregnancy approaching levels found in control patients. CONCLUSIONS: Maternal FGF-21 serum concentrations are significantly increased in PE during pregnancy. Furthermore, triglycerides, glomerular filtration rate, and LDL cholesterol are independent predictors of circulating FGF-21 in pregnant women.

Vascular limb occlusion in twin-twin transfusion syndrome (TTTS): case series and literature review.

OBJECTIVE: The purpose of this study was to evaluate the phenomenon of vascular ischemic limb necrosis in twin-twin transfusion syndrome (TTTS). STUDY DESIGN: This was a multicenter retrospective review of ischemic limb necrosis in patients with TTTS. RESULTS: Twenty cases of fetal ischemic limb necrosis in association with TTTS were identified from 10 fetal medicine centers. The recipient was affected in 19 cases, and the lower limb was affected in 17 cases. The extent of the damage correlated with TTTS severity. Eighty percent of limb defects (16/20) clearly were unrelated to laser treatment (3 cases untreated, 7 cases after amnioreduction, 6 cases present at time of laser). The recipient was relatively polycythemic in 5 of 7 cases in which neonatal or fetal hemoglobin/hematocrit levels were available. CONCLUSION: Ischemic limb necrosis is a rare complication of TTTS. The lesion is unrelated to therapy and may be the result of polycythemia, hypertension, and vasoconstriction.

Preliminary report: circulating levels of the adipokine vaspin in gestational diabetes mellitus and preeclampsia.

The objective of the study was to investigate serum levels of the insulin-sensitizing adipokine vaspin in patients with gestational diabetes mellitus (GDM) and preeclampsia (PE) as compared with healthy controls of similar gestational age. Vaspin serum levels were quantified by enzyme-linked immunosorbent assay in control (n = 102), GDM (n = 40), and PE (n = 22) subjects. Median maternal vaspin concentrations were not significantly different in GDM, PE, and control subjects. Furthermore, vaspin did not significantly correlate to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. Circulating vaspin levels are not significantly different between GDM, PE, and control subjects and do not correlate with insulin sensitivity in pregnant subjects.

Preliminary report: Serum levels of retinol-binding protein 4 in preeclampsia.

The objective of the study was to investigate serum levels of the adipokine retinol-binding protein 4 (RBP4) in patients with preeclampsia (PE) as compared with healthy controls of similar gestational age. Retinol-binding protein 4 serum levels were quantified by enzyme-linked immunosorbent assay in control (n = 20) and PE (n = 16) patients. Mean maternal RBP4 concentrations were not significantly different in PE (24.5 mg/L) as compared with controls (22.3 mg/L). Furthermore, RBP4 did not correlate to clinical and biochemical measures of pregnancy outcome, renal function, glucose, and lipid metabolism, as well as inflammation. Our results do not support a role of RBP4 in the pathogenesis of PE.

Serum levels of angiopoietin-related growth factor are increased in preeclampsia.

BACKGROUND: Preeclampsia is a serious complication in pregnancy with an increased future cardiovascular and metabolic risk for both mother and newborn. Recently, angiopoietin-related growth factor (AGF) was introduced as a novel liver-derived protein with proangiogenic and insulin-sensitizing effects. In the current study, we hypothesized that serum levels of AGF would be lower in preeclamptic patients as compared to healthy controls. METHODS: AGF was quantified by enzyme-linked immunosorbent assay (ELISA) in control and preeclamptic patients during pregnancy ( CONTROL: n =22, Preeclampsia: n =22) and 6 months after delivery ( CONTROL: n =20, Preeclampsia: n =20). Furthermore, circulating AGF was correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. RESULTS: During pregnancy, median maternal AGF concentrations were significantly higher in preeclampsia (191.6 microg/l) as compared to control subjects (136.3 microg/l) (P = 0.004). Furthermore, preeclampsia and systolic blood pressure (SBP) were associated with AGF levels in multivariate analyses independent of maternal age. However, higher circulating AGF concentrations in preeclampsia did not persist 6 months after delivery. CONCLUSIONS: Maternal AGF serum levels are significantly and paradoxically higher in preeclampsia during pregnancy. However, median postpartum circulating AGF levels are similar in preeclampsia and normal pregnancies.

Endogenous soluble receptor for advanced glycation endproducts is increased in preeclampsia.

OBJECTIVE: Preeclampsia is a serious complication in pregnancy with an increased future cardiovascular risk for both mother and newborn. Recently, low levels of endogenous soluble receptor for advanced glycation endproducts (esRAGE) have been associated with increased cardiovascular risk. In the current study, we investigated esRAGE serum levels in patients with preeclampsia as compared to healthy gestational age-matched controls. METHODS: esRAGE was quantified by enzyme-linked immunosorbent assay in controls and patients with preeclampsia during pregnancy (control: n = 20, preeclampsia: n = 16) and 6 months after delivery (control: n = 19, preeclampsia: n = 15). Furthermore, esRAGE was correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation. RESULTS: During pregnancy, median maternal serum esRAGE concentrations were more than three-fold higher in patients with preeclampsia (200 ng/l) than in controls (63 ng/l) (P < 0.01). Furthermore, esRAGE levels positively correlated with age, blood pressure, creatinine, adiponectin, and C-reactive protein, whereas a negative correlation existed with fasting insulin and the homeostasis model assessment of insulin resistance index. In multivariate analyses, homeostasis model assessment of insulin resistance and C-reactive protein independently predicted esRAGE serum levels and explained 44% of the variation in esRAGE concentrations. Surprisingly, median esRAGE concentrations 6 months after delivery were significantly lower in former patients with preeclampsia (270 ng/l) than in controls (342 ng/l) in contrast to the results obtained during pregnancy. CONCLUSION: We showed that maternal esRAGE concentrations are significantly increased in patients with preeclampsia during pregnancy. Here, insulin sensitivity and inflammatory status independently predict serum esRAGE levels.

Serum levels of the adipokine adipocyte fatty acid-binding protein are increased in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a serious complication of pregnancy which is associated with an increased future metabolic and cardiovascular risk for both mother and newborn. Recently, adipocyte fatty acid-binding protein (AFABP) was introduced as a novel adipokine, serum levels of which independently correlate with the development of the metabolic syndrome and cardiovascular disease in humans. In this study, we investigated serum concentrations of the adipokine AFABP in patients with PE as compared to healthy controls of similar gestational age. METHODS: AFABP serum levels were quantified by enzyme-linked immunosorbent assay (ELISA) in control (n = 20) and PE (n = 16) patients. Furthermore, AFABP was correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. RESULTS: Mean maternal AFABP concentrations were significantly elevated in PE (24.5 +/- 9.7 microg/l) as compared to controls (14.8 +/- 7.1 microg/l). Furthermore, AFABP serum levels correlated positively with age, body mass index (BMI), blood pressure, serum creatinine, free fatty acids (FFAs), leptin, and C-reactive protein (CRP). In multivariate analyses, BMI and serum creatinine remained independently associated with AFABP concentrations and explained 58% of the variation in AFABP levels. CONCLUSION: We demonstrate that maternal AFABP serum concentrations are significantly increased in PE. Furthermore, BMI and serum creatinine are independent predictors of circulating AFABP.

Circulating high-molecular-weight adiponectin is upregulated in preeclampsia and is related to insulin sensitivity and renal function.

OBJECTIVE: Preeclampsia (PE) is a serious cardiovascular complication in pregnancy which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, a paradoxical upregulation of the insulin-sensitizing and anti-atherogenic adipokine adiponectin has been shown in PE. Furthermore, high-molecular-weight (HMW) adiponectin has been suggested as the biologically active form of this adipokine. DESIGN AND METHODS: HMW adiponectin and total adiponectin serum concentrations were quantified by ELISA in PE (n=16) patients and pregnant control women without PE (n=20). Furthermore, HMW adiponectin and total adiponectin were correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. RESULTS: Median maternal HMW adiponectin and total adiponectin levels were significantly and independently upregulated almost twofold in PE when compared with controls. HMW adiponectin and total adiponectin correlated positively with creatinine and negatively with fasting insulin in univariate and multivariate analyses. CONCLUSIONS: We show that maternal HMW adiponectin and total adiponectin serum concentrations are significantly increased in PE and are positively associated with markers of insulin sensitivity and renal dysfunction. Adiponectin might be part of a physiological feedback mechanism improving insulin sensitivity and cardiovascular health in PE.

Serum levels of the adipokine visfatin are increased in pre-eclampsia.

OBJECTIVE: Pre-eclampsia (PE) is a serious cardiovascular complication in pregnancy which shares risk factors with the metabolic syndrome including insulin resistance and obesity. Recently, visfatin was introduced as a novel insulin-mimetic adipokine which is up-regulated when weight is gained. In the current study, we investigated visfatin serum levels in pre-eclamptic patients as compared to healthy gestational age-matched controls. PATIENTS AND MEASUREMENTS: Visfatin was quantified by ELISA in control (n = 20) and PE (n = 15) patients. Furthermore, visfatin was correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation. RESULTS: Mean maternal visfatin serum levels adjusted for maternal age were about twofold up-regulated in PE (31.1 +/- 23.4 microg/l) as compared to controls (15.7 +/- 23.1 microg/l). Furthermore, visfatin concentrations correlated positively with age, blood pressure, creatinine, free fatty acids (FFA), IL-6 and C reactive protein (CRP), whereas a negative correlation was found with fasting insulin and the HOMA-insulin resistance index (HOMA-IR). In multivariate analyses, HOMA-IR and CRP remained independently associated with visfatin serum levels and explained 58% of the variation in visfatin concentrations. CONCLUSIONS: We show that maternal visfatin levels are significantly increased in PE patients. Furthermore, insulin sensitivity and inflammatory status independently predict serum visfatin levels.

Incidence of rhegmatogenous retinal detachment after vitrectomy in eyes of diabetic patients.

PURPOSE: To assess the incidence of rhegmatogenous retinal detachment (RRD) after pars plana vitrectomy (PPV) among diabetic patients with complications of proliferative diabetic retinopathy. METHODS: Ninety-three eyes of diabetic patients-who underwent PPV with or without intraocular gas tamponade for complications of proliferative diabetic retinopathy-were reviewed retrospectively. Indication for vitrectomy was vitreous hemorrhage in 80 patients (86.1%), tractional retinal detachment in 3 (3.2%), and vitreous hemorrhage associated with tractional retinal detachment in 10 (10.7%). RESULTS: Four (4.3%) of 93 eyes developed an RRD after vitrectomy. The primary reason for vitrectomy was recurrent or nonresolving vitreous hemorrhage. The retina was attached with one additional surgical procedure in two of these eyes; the other two had to undergo a third operation before attachment was achieved. CONCLUSION: RRD occurs in a small percentage of patients after PPV with or without gas tamponade for vitreous hemorrhage or tractional retinal detachment caused by proliferative diabetic retinopathy. Thorough postoperative follow-up is important to make early diagnosis and intervention possible.

Cataract surgery in patients with diabetic retinopathy: visual outcome, progression of diabetic retinopathy, and incidence of diabetic macular oedema.

BACKGROUND: Compared to non-diabetic patients, outcome after cataract surgery was reported to be worse in diabetic patients--especially in those with diabetic retinopathy. This prospective study was planned to evaluate visual outcome, progression of diabetic retinopathy, and incidence of clinically significant macular oedema (CSME) in a homogenous group of patients with non-proliferative diabetic retinopathy (NPDR) without CSME at baseline 1 year after cataract surgery. METHODS: Over a period of 18 months, all consecutive patients with mild-to-moderate diabetic retinopathy who had cataract surgery with phacoemulsification and posterior chamber lens implantation were prospectively followed up. Outcomes were assessed 1 year postoperatively and included visual acuity (VA), progression of retinopathy, and incidence of CSME. Progression of retinopathy and incidence of CSME were compared to the non-operated fellow eyes. RESULTS: Of 50 patients included, 42 completed the 1-year follow-up. VA improved in 85% of patients, and was better than 0,5 in 71%. Progression of retinopathy occurred in 12% of eyes after cataract surgery and in 10.8% of non-operated fellow eyes. No patient developed proliferative diabetic retinopathy in the operated eye. CSME occurred in 13 operated eyes (31%), five of them with retinal ischemia, and in five non-operated eyes (13.5%). Patients with ischemic macular oedema had the worst prognosis regarding VA. CONCLUSION: Modern cataract surgery seems to have no influence on the progression of diabetic retinopathy. A visual improvement is achieved in the majority of patients with NPDR, but poorer visual outcome is observed in patients developing macular oedema.