Renal dysfunction and podocyturia in pre-eclampsia may be explained by increased urinary VEGF.

BACKGROUND: Pre-eclampsia has a major impact on renal function as shown by the development of proteinuria and podocyturia. How the systemic, soluble Fms-like tyrosine kinase-1 (sFlt-1)-driven inhibition of vascular endothelial growth factor (VEGF) activity detected in pre-eclampsia directly affects renal function remains unknown. The aim of the study was to clarify whether a non-canonical, renal-centred escape from VEGF inhibition in the case of pre-eclamptic pregnancy might have a direct impact on renal function. METHODS: We evaluated plasma and urinary VEGF and placental growth factor (PlGF), plasma sFlt-1 and carbonic anhydrase IX (CAIX), albuminuria and podocyturia in 18 women with uncomplicated pregnancy, 21 with pre-eclampsia and 18 non-pregnant. The three groups were matched for age and the pregnant groups also for gestational age at enrolment. RESULTS: Plasma VEGF was reduced in uncomplicated (P = 0.001) and pre-eclamptic (P = 0.0003) pregnancies when compared with controls. In uncomplicated pregnancy, the dysfunction was balanced by an increase (P = 0.009) of plasma PlGF. Increased (P = 0.0001) plasma CAIX in pre-eclampsia was in line with hypoxia. Pre-eclampsia resulted in a paradoxical increase (P = 0.0004) of urinary excretion of VEGF. Urinary concentrations of VEGF and podocytes were correlated to each other (r2 = 0.48, P < 0.0005) but also to plasma sFlt-1 (r2 = 0.56, P < 0.0001 and r2 = 0.23, P = 0.03, respectively). CONCLUSIONS: In the case of pre-eclampsia, the systemic VEGF inhibition leads the kidney, possibly the podocyte, to increase the VEGF synthesis. The mechanisms leading to local VEGF overproduction or the overproduced VEGF itself are reasonably involved in the pathogenesis of podocyturia and, as a consequence, renal dysfunction in pre-eclampsia.

IVF/ICSI treatment and the risk of iatrogenic preterm birth in singleton pregnancies: systematic review and meta-analysis of cohort studies.

OBJECTIVES: Preterm birth (PTB) is more frequent among in vitro fertilization (IVF) as compared to natural conception and recent research in this group describes an increase of its spontaneous etiology. However, clear description and quantification of iatrogenic preterm birth (IPTB) was not determined in IVF/ICSI (intra-cytoplasmic sperm injection) conceptions. This study quantifies the risk of IPTB in singleton pregnancies resulting from IVF/ICSI as compared to spontaneous conceptions (SCs). METHODS: Web-based databases search (PubMed/Medline, Scopus, Web of Science) from inception up to January 2019 looking for cohort studies comparing the risk of IPTB in singleton pregnancies obtained with IVF/ICSI (intervention group) or SC (control group). Only studies with clear distinction of spontaneous and indicated PTB were included. Primary outcome was IPTB before 37 weeks of gestation, defined as indicated delivery for any medical recommendation. All pertinent secondary outcomes were also included: IPTB <34/32/28 weeks, abnormal cardiotocography (CTG), abruptio, placenta previa, pre-eclampsia, fetal growth restriction, any other available indication to IPTB. A meta-analysis calculated the pooled odds ratio (OR) for IPTB in IVF/ICSI and SC, using random effects model. Sensitivity analysis for study quality, methodology of case counting, use of cryotransfer, and secondary analyses for available indications of IPTB were also performed. Prospero RN: CRD42019117672. RESULTS: Pooled crude analysis showed a sample size of 9590 births with significant increase in IPTB <37 weeks in IVF/ICSI pregnancies (nine studies, pooled proportion IPTB IVF/ICSI 4.73% vs. SC 1.81%; OR = 2.47; 95% CI: 1.46-4.18; I2 = 67%). Pooled analysis was impossible for most secondary outcomes due to lack of available data and failed to show statistical significance for abnormal CTG. The risk for IPTB due to abruptio placentae or placenta previa was significantly increased in IVF/ICSI pregnancies (two studies, 561 pregnancies; pooled proportion IPTB IVF/ICSI 2.12% vs. SC 1.06%; OR = 5.41; 95% CI: 1.26-23.25; I2: 0%). CONCLUSION: The risk of IPTB <37 weeks in singleton pregnancies achieved after IVF/ICSI is significantly greater than that occurring in SC. This is likely due to a multifactorial etiology, in which placental diseases are included. Full etiologic understanding of this association needs further clarification. SUMMARY: The risk of IPTB below 37 weeks in singleton pregnancies achieved after IVF/ICSI is more than double than that occurring in natural conception.

Greater fetal crown-rump length growth with the use of in vitro fertilization or intracytoplasmic sperm injection conceptions after thawed versus fresh blastocyst transfers: secondary analysis of a prospective cohort study.

OBJECTIVE: To compare first-trimester fetal crown-rump length (CRL) measurements in pregnancies obtained after thawed blastocyst transfer versus fresh blastocyst transfer after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN: Prospective longitudinal cohort study of CRL Z scores with adjustment for major confounders. SETTING: University-affiliated obstetrics, fetal medicine, and fertility units. PATIENT(S): Singleton gestations conceived via IVF/ICSI and fresh or thawed blastocyst transfer with ultrasound performed at 6-14 weeks of gestational age. INTEVENTION: None. MAIN OUTCOME MEASURE(S): CRL Z scores. RESULT(S): A total of 365 IVF/ICSI pregnancies were recruited (fresh: 161; thawed: 204). The mean CRL Z score at 6-14 weeks was significantly greater in thawed versus fresh transfers. Different growth trajectories between thawed and fresh transfers were detected: Mean CRL Z score was 0 at 65 days in fresh versus 80 days in frozen. Comparisons of both fresh and thawed transfers with reference values from the general population confirmed significantly lower CRL Z scores in both IVF/ICSI groups (P<.001). The risks of CRL <5th percentile in fresh versus thawed were, respectively 68% vs. 40% at 6 weeks and 2% vs. 1% at 14 weeks. A significant positive correlation between CRL Z scores and birth weight Z scores was found only for fresh transfers, not for thawed. CONCLUSION(S): At 6-14 weeks, thawed blastocyst transfers after IVF/ICSI conceptions present greater CRLs compared with fresh, and both IVF/ICSI groups show smaller CRLs than the general population. This effect is particularly evident before 9 weeks and it may favor birth weight difference of thawed versus fresh BT pregnancies.

Prevalence of Congenital Heart Defects in Pregnancies Conceived by Assisted Reproductive Technology: A Cohort Study.

BACKGROUND AND AIM OF THE STUDY: Pregnancies obtained by assisted reproductive technology (ART) are associated with an increased risk of complications and congenital anomalies, particularly congenital heart defects (CHDs). Therefore, our aim is to evaluate, retrospectively, the prevalence of CHD in ART pregnancies in our two centers and analyze their characteristics and outcomes. METHODS: Observational study including fetuses conceived by ART referred between June 2011 and September 2020 and undergoing a fetal cardiac ultrasound scan. Cases with genetic, chromosomal abnormalities or extracardiac malformations were excluded. Population included 1511 pregnancies, which consisted of 269 twins and 1242 singletons, 547 IVF (in vitro fertilization), 773 ICSI (intracytoplasmic sperm injection) and 191 oocyte donations (OD). RESULTS: CHDs were found in 29 fetuses, with an overall prevalence of 1.92% (29/1511), 1.85% (23/1242) in singletons and 2.23% in twins (6/269). Thirteen were IVF, eight ICSI and eight OD cases, with a greater risk of CHD after IVF and OD (IVF: 13/29 (44.8%)-one twin; ICSI: 8/29 (27.6%)-three twins); 22 had major and 7 minor defects. Two pregnancies with a hypoplastic left heart were terminated; the majority of live-born cases needed surgery. Three babies died (two post-surgery, one had a late death). CONCLUSIONS: Our data show an increased prevalence of CHD after ART with a heterogeneous spectrum of diagnoses, mainly major defects.

Low Birth Weight Is Associated with a Decreased Overall Adult Health Status and Reproductive Capability - Results of a Cross-Sectional Study in Primary Infertile Patients.

Individuals born with low birth weight (LBW) risk cardiometabolic complications later in life. However the impact of LBW on general health status and male reproductive function has been scantly analysed. We investigated the clinical and seminal impact of different birth weights (BW) in white-European men presenting for primary couple's infertility. Demographic, clinical, and laboratory data from 827 primary infertile men were compared with those of 373 consecutive fertile men. Patients with BW ≤2500, 2500-4200, and ≥4200gr were classified as having LBW, normal (NBW), and high BW (HBW), respectively. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Testicular volume was assessed with a Prader orchidometer. Semen analysis values were assessed based on 2010 WHO reference criteria. Descriptive statistics and regression models tested associations between semen parameters, clinical characteristics and BW categories. LBW, NBW and HBW were found in 71 (8.6%), 651 (78.7%) and 105 (12.7%) infertile men, respectively. LBW was more frequent in infertile patients than fertile men (p = 0.002). Infertile patients with LBW had a higher rate of comorbidities (p = 0.003), lower mean testicular volume (p = 0.007), higher FSH (p = 0.02) and lower tT levels (p = 0.04) compared to other BW groups. Higher rates of asthenozoospermia (p = 0.02) and teratozoospermia (p = 0.03) were also found in LBW men. At logistic regression models, LBW was univariably associated with pathologic progressive motility (p≤0.02) and pathologic sperm morphology (p<0.005). At multivariable logistic regression analysis, LBW achieved independent predictor status for both lower sperm motility and pathologic sperm morphology (all p≤0.04). Only LBW independently predicted higher CCI values (p<0.001). In conclusion, we found that LBW was more frequent in infertile than in fertile men. Infertile individuals with LBW showed a higher rate of comorbidities and significantly worse clinical, endocrine and semen parameters compared to other BW groups.