Effect of nitric oxide donor and plasma volume expansion on pregnancies with early onset fetal growth restriction: a randomized controlled trial

Guideline No. 442: Fetal Growth Restriction: Screening, Diagnosis, and Management in Singleton Pregnancies

Fetal growth restriction (FGR) is defined as the failure of the fetus to meet its growth potential due to a pathological factor, most commonly placental dysfunction. Worldwide, FGR is a leading cause of stillbirth, neonatal mortality, and short- and long-term morbidity. Ongoing advances in clinical care, especially in definitions, diagnosis, and management of FGR, require efforts to effectively translate these changes to the wide range of obstetric care providers. This article highlights agreements based on current research in the diagnosis and management of FGR, and the areas that need more research to provide further clarification of recommendations. The purpose of this article is to provide a comprehensive summary of available evidence along with practical recommendations concerning the care of pregnancies at risk of or complicated by FGR, with the overall goal to decrease the risk of stillbirth and neonatal mortality and morbidity associated with this condition. To achieve these goals, FIGO (the International Federation of Gynecology and Obstetrics) brought together international experts to review and summarize current knowledge of FGR. This summary is directed at multiple stakeholders, including healthcare providers, healthcare delivery organizations and providers, FIGO member societies, and professional organizations. Recognizing the variation in the resources and expertise available for the management of FGR in different countries or regions, this article attempts to take into consideration the unique aspects of antenatal care in low-resource settings (labelled “LRS” in the recommendations). This was achieved by collaboration with authors and FIGO member societies from low-resource settings such as India, Sub-Saharan Africa, the Middle East, and Latin America.

Diagnosis and management of fetal growth restriction: the ISUOG guideline and comparison with the SMFM guideline.

Maternal cardiovascular profile is altered in the preclinical phase of normotensive early and late intrauterine growth restriction

Introduction: Pregnancies complicated by fetal growth restriction (FGR) are known to be associated with a reduced expansion of maternal intravascular space and a lower cardiac output. Therapy with nitric oxide (NO) donors, in addition to plasma volume expansion (PVE) could improve maternal haemodynamic indices and pregnancy outcome.Methods: To evaluate maternal cardiovascular effects of NO donors. We enrolled 52 women with the diagnosis of FGR. Patients were divided into those treated with transdermal patches of NO donors and PVE or a control group. We obtained haemodynamic indices using an USCOM system.Results: At enrolment, the two groups were similar in terms of maternal, fetal and haemodynamic characteristics. In the group treated with NO donors and PVE, we found a significant increase in cardiac output, stroke volume and a decrease of systemic vascular resistance after therapy (see table). At birth the treated group also gave birth to babies with higher birth weight centile.Conclusions: The combined therapeutic approach of NO donor administration and PVE in FGR significantly improves maternal hemodynamic indices. Despite the observation nature of the data, there is suggestion that the use of NO donors together with PVE may also improve pregnancy outcome by increasing the fetal growth.

Contrast-induced nephropathy (CIN) is associated with increased mortality and morbidity in patients undergoing coronary angiography (CAG) and percutaneous coronary intervention (PCI). We aimed to assess the latest evidence on the preventive effects of nitric oxide (NO) donors in CIN patients undergoing CAG/PCI. We conducted a comprehensive systematic review and meta-analysis of RCTs from PubMed, Web of Science, Scopus, Embase, and Cochrane searches until May 5th, 2024. Dichotomous data were pooled using risk ratio (RR), and continuous data were pooled using mean difference (MD), both with a 95% confidence interval (CI), using (R version 4.3). Our analysis included 13 RCTs encompassing 3,550 patients. NO donors were significantly associated with a decreased incidence of CIN compared to placebo either as an oral administration (RR: 0.33 with 95% CI [0.26, 0.42], P < 0.01) or IV infusions (RR: 0.56 with 95% CI [0.40, 0.78], P < 0.01). Moreover, NO donors were significantly associated with decreased serum creatinine levels compared to placebo either as an oral administration (MD: - 0.07 with 95% CI [- 0.10, - 0.04], P < 0.01) or IV infusions (MD: - 0.07 with 95% CI [- 0.09, - 0.04], P < 0.01). In terms of safety, NO donors were significantly associated with a decreased incidence of major adverse cardiac events (MACE) compared to placebo as an oral administration (RR: 0.64 with 95% CI [0.45, 0.89], P < 0.01). However, there was no significant difference between NO donors as IV infusions and placebo in MACE (RR: 0.68 with 95% CI [0.38, 1.21], P = 0.18). Finally, NO donors were significantly associated with a decreased incidence of all-cause mortality compared to placebo as an oral administration (RR: 0.58 with 95% CI [0.36, 0.94], P = 0.03). Nevertheless, there was no statistically significant difference in all-cause mortality between IV infusions of NO donors and placebo (RR: 1.84 with 95% CI [0.40, 8.52], P = 0.44). NO donors as adjunct therapy are associated with reduced incidence of CIN and decreased serum creatinine levels, either as an oral or IV administration. They were also associated with reduced incidence of MACE, all-cause mortality, and recurrent myocardial infarction as an oral administration, which makes this simple, low-cost intervention an important therapeutic option in patients undergoing CAG/PCI.

Background: Contrast-induced nephropathy (CIN) is associated with increased mortality and morbidity in patients undergoing coronary angiography (CAG) and percutaneous coronary intervention (PCI). We aimed to assess the latest evidence on the preventive effects of nitric oxide (NO) donors in CIN in patients undergoing CAG/PCI. Methods: We conducted a systematic review and meta-analysis of RCTs from PubMed, Web of Science, Scopus, Embase, and Cochrane searches until May 5th, 2024. Dichotomous data were pooled using risk ratio (RR), and continuous data were pooled using mean difference (MD), both with a 95% confidence interval (CI), using (R version 4.3). Results: Our analysis included 13 RCTs encompassing 3,550 patients. NO donors were significantly associated with a decreased incidence of CIN compared to placebo either as an oral administration (RR: 0.33 with 95% CI [0.26, 0.42], P&lt; 0.01) or IV infusions (RR: 0.56 with 95% CI [0.40, 0.78], P&lt; 0.01). Moreover, NO donors were significantly associated with decreased serum creatinine levels compared to placebo either as an oral administration (MD: -0.07 with 95% CI [-0.10, -0.04], P&lt; 0.01) or IV infusions (MD: -0.07 with 95% CI [-0.09, -0.04], P&lt; 0.01). In terms of safety, NO donors were significantly associated with a decreased incidence of MACE compared to placebo as an oral administration (RR: 0.64 with 95% CI [0.45, 0.89], P&lt; 0.01). However, there was no significant difference between NO donors as IV infusions and placebo in MACE (RR: 0.68 with 95% CI [0.38, 1.21], P= 0.18). Finally, NO donors were significantly associated with a decreased incidence of all-cause mortality compared to placebo as an oral administration (RR: 0.58 with 95% CI [0.36, 0.94], P= 0.03). However, there was no significant difference between NO donors as IV infusions and placebo in all-cause mortality (RR: 1.84 with 95% CI [0.40, 8.52], P= 0.44). Conclusion: NO donors as an adjunct therapy are associated with reduced incidence of CIN, and decreased serum creatinine levels either as an oral or IV administration. Also, it was associated with decreased incidence of MACE and all-cause mortality as an oral administration which make this simple low-cost intervention an important therapeutic option in patients undergoing CAG/PCI.

Objective: Our aim is to evaluate the role of the ratio of first-trimester CRL (crown rump length) measurement to NT (nuchal translucency) measurements in predicting early-onset fetal growth restriction (FGR) and to contribute to the existing literature. Methods: In the present case-control study, fetuses with early-onset FGR were compared to a frequency matched low risk control group. This study was conducted in the perinatology clinic of Ankara Bilkent City Hospital between 2020 and 2023. Maternal age, gravidity, parity, crown-rump length (CRL), and nuchal translucency (NT) measurements were compared between pregnant women with early onset FGR (n=39) and pregnant women without FGR (n=50). Results: The mean age of pregnant women with FGR who participated in the study was 27.1±0.8, and the mean age of pregnant women without FGR was 26.3±0.6, and no statistically significant difference was found between the two groups (p=0.4)). Mean CRL was 54.98±1.08 mm in the group with FGR and 56.99±1.11 mm in the group without FGR; there was no significant difference between the two groups (p=0.2). The NT value was 1.11 ± 0.04 mm in the FGR group and 1.13 ± 0.02 mm in the without FGR group, there was no significant difference between the two groups (p=0.73). The mean CRL/NT ratio was 52.00±2.33 in the group with early onset FGR and 51.46±1.48 in the group without FGR and there was no statistically significant difference between the two groups (p=0.83). When the early developing FGR group is evaluated within itself, the mean age at diagnosis was 31.7±0.3 weeks. EFW mean percentile at diagnosis was 4.5±0.6 and ac percentile was 2.9±0.4. The mean umbilical artery systole/diastole ratio (UA-SD) was 2.9±0.16 and the mean umbilical artery pulsatility index (UA-PI) was 1.02±0.05. Conclusion: Crown-rump length to nuchal translucency ratio is not clinically useful to predict early-onset FGR.

Objective:To evaluate demographics and outcomes of maternal-fetal pairs in early onset fetal growth restriction (FGR) requiring delivery prior to 34 weeks’ gestation based on ultrasound indication leading to diagnosis.Study Design:This is a descriptive study of maternal-fetal pairs with early FGR diagnosed prior to 30 weeks’ gestation and delivering between 22w0d and 34w0d under the care of Wake Forest University Perinatology 01/2012–12/2016. Serial ultrasounds to assess fetal growth and umbilical artery flow Doppler velocimetry were evaluated. Pairs were dichotomized into those with maternal comorbidities leading to ultrasound diagnosis, and those with ultrasound indicated only by appreciation of uterine size less than dates on exam. Patient characteristics and outcomes were tracked. Univariate and multivariate analyses were performed as appropriate.Results:56 pregnancies were identified with FGR prior to 30 weeks and subsequent delivery prior to 34 weeks. Common comorbidities present in the group with maternal comorbidities included chronic hypertension (30.5%), hypertensive disorders of pregnancy (36.1%), preexisting diabetes (13.9%), gestational diabetes (5.6%). None of the women in the S<D group developed hypertensive disorders of pregnancy or GDM. Other background characteristics were similar. Pregnancies evaluated for size less than dates were diagnosed on average 3 weeks later in gestation, had higher incidence of reverse end diastolic flow on Doppler evaluation both at diagnosis (80% vs. 22.9%, p=0.01, OR 0.08 (<0.01,0.74) and were more likely to be delivered for an urgent indication. Both groups of babies had similar survival to discharge rates and length of stay in the NICU. A subanalysis evaluating only babies with abnormal Doppler studies showed a shorter diagnosis to delivery interval and continued to show increased risk of urgent delivery due to fetal status in those pregnancies diagnosed based on size<dates.Conclusion:Women measuring size less than dates in the mid-trimester should be evaluated by ultrasound without delays. Early FGR carries a high mortality rate in all cases and in our pilot data, women measuring small were diagnosed later with fetal growth restriction and may represent a severe phenotype with poor fetal-placental circulation. These pregnancies often met criteria for urgent delivery in a short time frame, especially if abnormal umbilical artery Doppler velocimetry was noted.

Pregnancies complicated by late-onset fetal growth restriction (FGR) are at increased risk of short- and long-term morbidities. Despite this, identification of cases at higher risk of adverse perinatal outcome, at the time of FGR diagnosis, is challenging. The aims of this study were to elucidate the strength of association between fetoplacental Doppler indices at the time of diagnosis of late-onset FGR and adverse perinatal outcome, and to determine their predictive accuracy. This was a prospective study of consecutive singleton pregnancies complicated by late-onset FGR. Late-onset FGR was defined as estimated fetal weight (EFW) or abdominal circumference (AC) < 3rd centile, or EFW or AC < 10th centile and umbilical artery (UA) pulsatility index (PI) > 95th centile or cerebroplacental ratio (CPR) < 5th centile, diagnosed after 32 weeks. EFW, uterine artery PI, UA-PI, fetal middle cerebral artery (MCA) PI, CPR and umbilical vein blood flow normalized for fetal abdominal circumference (UVBF/AC) were recorded at the time of the diagnosis of FGR. Doppler variables were expressed as Z-scores for gestational age. Composite adverse perinatal outcome was defined as the occurrence of at least one of emergency Cesarean section for fetal distress, 5-min Apgar score < 7, umbilical artery pH < 7.10 and neonatal admission to the special care unit. Logistic regression analysis was used to elucidate the strength of association between different ultrasound parameters and composite adverse perinatal outcome, and receiver-operating-characteristics (ROC)-curve analysis was used to determine their predictive accuracy. In total, 243 consecutive singleton pregnancies complicated by late-onset FGR were included. Composite adverse perinatal outcome occurred in 32.5% (95% CI, 26.7-38.8%) of cases. In pregnancies with composite adverse perinatal outcome, compared with those without, mean uterine artery PI Z-score (2.23 ± 1.34 vs 1.88 ± 0.89, P = 0.02) was higher, while Z-scores of UVBF/AC (-1.93 ± 0.88 vs -0.89 ± 0.94, P ≤ 0.0001), MCA-PI (-1.56 ± 0.93 vs -1.22 ± 0.84, P = 0.004) and CPR (-1.89 ± 1.12 vs -1.44 ± 1.02, P = 0.002) were lower. On multivariable logistic regression analysis, Z-scores of mean uterine artery PI (P = 0.04), CPR (P = 0.002) and UVBF/AC (P = 0.001) were associated independently with composite adverse perinatal outcome. UVBF/AC Z-score had an area under the ROC curve (AUC) of 0.723 (95% CI, 0.64-0.80) for composite adverse perinatal outcome, demonstrating better accuracy than that of mean uterine artery PI Z-score (AUC, 0.593; 95% CI, 0.50-0.69) and CPR Z-score (AUC, 0.615; 95% CI, 0.52-0.71). A multiparametric prediction model including Z-scores of MCA-PI, uterine artery PI and UVBF/AC had an AUC of 0.745 (95% CI, 0.66-0.83) for the prediction of composite adverse perinatal outcome. While CPR and uterine artery PI assessed at the time of diagnosis are associated independently with composite adverse perinatal outcome in pregnancies complicated by late-onset FGR, their diagnostic performance for composite adverse perinatal outcome is low. UVBF/AC showed better accuracy for prediction of composite adverse perinatal outcome, although its usefulness in clinical practice as a standalone predictor of adverse pregnancy outcome requires further research. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Early onset fetal growth restriction (FGR) is one of the main adverse pregnancy conditions, often associated with poor neonatal outcomes. Frequently, early onset FGR is associated with early onset hypertensive disorders of pregnancy (HDP), and in particular preeclampsia (PE). However, to date, it is still an open question whether pregnancies complicated by early FGR plus HDP (FGR-HDP) and those complicated by early onset FGR without HDP (normotensive-FGR (n-FGR)) show different prenatal and postnatal outcomes and, consequently, should benefit from different management and long-term follow-up. Recent data support the hypothesis that the presence of PE may have an additional impact on maternal hemodynamic impairment and placental lesions, increasing the risk of poor neonatal outcomes in pregnancy affected by early onset FGR-HDP compared to pregnancy affected by early onset n-FGR. This review aims to elucidate this poor studied topic, comparing the clinical characteristics, perinatal outcomes, and potential long-term sequelae of early onset FGR-HDP and early onset n-FGR.

Considering evidence in the management of fetal growth restriction.

The purpose of the study was to evaluate the differences in individual histopathologic placental lesions in pregnancies complicated by early-onset (<32weeks at diagnosis) and late-onset (≥32weeks at diagnosis) fetal growth restriction (FGR). A cohort study of 440 singleton pregnancies complicated by FGR, diagnosed according to standard ultrasonographic criteria, followed up and delivered at the same institution between 2010 and 2016. Placental lesions were classified according to the Amsterdam Placental Workshop Consensus Criteria. Pathologic examination of placentas from 113 healthy singleton term pregnancies served as controls. Binary and multinomial logistic regression models were used to evaluate the independent association of placental lesions with the type of FGR. In our cohort the prevalences of early and late FGR were 37.3% (164/440) and 62.7% (276/440), respectively. The overall rates of preeclampsia (69/164 vs 59/276, P<0.01) and absent/reversed umbilical artery pulsatility indices (61/164 vs 14/276, P<0.001) were higher among early FGR than late FGR. Placental characteristics from early and late FGR pregnancies differed mainly in regard to maternal vascular malperfusion scores rather than fetal scores, with preeclampsia found to be a cofactor modulating the rates and severity of associated lesions. In the binary logistic analysis, recent infarcts (OR 2.44, 95% CI 1.2-5), distal villous hypoplasia (OR 1.8, 95% CI 1.0-3.2), atherosis (OR 2.71, 95% CI 1.35-5.47), persistent endovascular trophoblasts (OR 1.67, 95% CI 1.03-2.7), and a reduced fetal/placental weight score (OR 0.27, 95% CI 0.2-0.38) were independently associated with an increased likelihood of early FGR compared with late FGR. The sensitivity, specificity, and area under the curve of the model were 60% (95% CI 51.2-66.2), 89.1% (95% CI 84.9-92.3), and 0.81 (95% CI 0.77-0.85), respectively, suggesting a fair to good predictive value. Individual placental lesions suggestive of increased rates of ischemia, defective remodeling of spiral arteries, peripheral hypoxia interfering with villus development, and reduced placental efficiency were significantly more common in early FGR than late FGR.

Effect of nitric oxide donors on extracellular ATP, ADP, and AMP catabolism in rat hippocampal synaptosomes

Effects of nitric oxide donors on basal and K +-evoked release of [formula omitted]noradrenaline from rat cerebral cortex synaptosomes