Umbilical venous flow and maternal hemodynamics as predictors of impaired fetal growth in gestational diabetes: a prospective study

Clinical and ultrasound assessment

At the time of enrolment, maternal demographic and clinical data were collected, including maternal age, body mass index (BMI), parity, ethnicity, mode of conception, GDM treatment modality (diet vs. pharmacological), glycemic control assessed at last prenatal visit, and smoking status.

Glycemic control was assessed at the last prenatal visit. Good glycemic control was defined according to the targets recommended by national scientific societies [9]. Pharmacological treatment for GDM followed our center’s protocol: insulin was prescribed as first-line therapy for patients with glucose values above target despite dietary and lifestyle interventions. Metformin was added in selected cases with suboptimal response to insulin or in rare patients with poor insulin compliance [9].

All participants underwent a standardized ultrasound assessment between 28- and 32-weeks’ gestation, including:

1. Fetal biometry: EFW was calculated using Hadlock formula [10], and expressed as centiles based on the Intergrowth-21st Project reference curves [11].

2. Umbilical Vein (UV) Doppler: the UV was sampled at a free-floating loop of the umbilical cord in the absence of fetal movements and respiratory acts [12]. Image magnification was applied to ensure the vessel occupied at least 30 % of the screen. UV diameter was measured inner-wall to inner-wall at three consecutive sites; the mean of these values was recorded. Time-averaged maximum velocity (TAMXV) was measured on a steady venous flow profile by adjusting the transducer to align the insonation angle with the vessel axis, maintaining an angle between 0° and 30°, and applying angle correction. Mean TAMXV was derived from three recordings taken during fetal quiescence. UV-Q was calculated as:

   UV − Q = π × UV   diameter / 2 2 × TAMXV × 0.5 × 60 ,

   assuming a circular cross-sectional area derived from the mean diameter, with results expressed in mL/min. UV parameters centiles were determined using reference charts published by Flo et al. [13].

Maternal hemodynamics assessment

On the same day, all participants were studied using Ultra Sonic Cardiac Output Monitor (USCOM^®, USCOM Ltd, Coffs Harbor, Australia). The measurements were performed by a trained operator under standardized conditions as described in previous studies [14], 15]. Blood pressure was measured using an automated device with appropriately sized cuffs.

We selected eight primary hemodynamic variables: SVR, CO, stroke volume (SV), heart rate (HR), flow time corrected (FTc), oxygen delivery (DO₂), Smith-Madigan Inotropy Index (INO), potential to kinetic energy ratio (PKR).

INO and PKR are derived from the evaluation of maternal cardiovascular potential energy and kinetic energy. During systole, the left ventricle imparts two forms of energy to the circulating blood: potential energy, reflected by blood pressure, and kinetic energy, associated with blood flow. The INO index is calculated as the sum of these two energy components, normalized to body surface area. The PKR index expresses the ratio between potential and kinetic energy, providing an indication of the balance between vascular resistance (pressure) and blood flow [16].

DO₂ was calculated as:

where CaO₂ represents arterial oxygen content, Hb is hemoglobin concentration, and SaO₂ is arterial oxygen saturation [17]. SpO₂ was measured non-invasively using integrated or external pulse oximetry.

Delivery and neonatal outcomes

Patients were followed until delivery, and delivery outcomes were collected, including mode of delivery, induction of labor, gestational age at delivery, BW. BW was categorized using gestational-age-adjusted centiles [18]:

1. SGA: <10th centile,

2. Appropriate for gestational age (AGA): 10th–90th centile,

3. Large for gestational age (LGA): >90th centile.

Participants were stratified into two groups:

1. Group A (n=24): neonates with suspected impaired growth, including SGA and AGA with DROP ≥40 centiles, and

2. Group B (n=60): neonates with normal growth, including AGA with DROP <40 centiles and LGA.

Statistical analysis

Statistical analysis was performed using MedCalc (MedCalc Software, West-Vlaanderen, Belgium). Continuous variables were reported as median (interquartile range), while categorical variables were expressed as frequencies and percentages. Group comparisons were conducted using Student's t- or Mann-Whitney test (continuous variables) and Chi-square test or Fisher test (categorical variables). A p-value <0.05 was considered statistically significant.

Correlation analyses were performed between maternal hemodynamic parameters and fetal biometric/Doppler variables. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive performance of the different variables in identifying neonatal with impaired growth. Finally, multivariate logistic regression analysis was conducted to identify independent predictors of impaired fetal growth, with calculation of odds ratios (ORs) and 95 % confidence intervals (CIs).

Main findings

This study found that in pregnancies complicated by gestational diabetes, impaired fetal growth was associated with lower umbilical vein blood flow, higher maternal systemic vascular resistance, lower cardiac output, and reduced oxygen delivery measured between 28 and 32 weeks of gestation. Notably, UV-Q centile≤24, SVR>916 dyn s cm⁻⁵, and DO₂≤1,061.41 mL/min emerged as independent predictors of impaired growth, regardless of fetal estimated weight.

Interpretation

Our findings support the growing recognition that impaired fetal growth in GDM pregnancies may not only result from glycemic factors but also from placental insufficiency and subclinical maternal cardiovascular maladaptation [1]. Maternal diabetes can worsen placental perfusion and fetal hemodynamics, potentially increasing FGR severity [19].

Women with GDM often exhibit impaired maternal hemodynamic adaptation to pregnancy ;– likely due to hyperglycemia and reduced cardiovascular reserve – characterized by a hypodynamic, high-resistance cardiovascular profile compared to controls [20].

It has previously been demonstrated that a hypodynamic maternal hemodynamic profile in the third trimester, characterized by high SVR and low CO, is associated with intrauterine growth restriction [21]. Our results confirm that FGR in pregnancies affected by GDM is associated with the same maternal cardiovascular alterations observed in FGR nondiabetic patients [22].

In fact, patients with impaired fetal growth exhibited a hypodynamic hemodynamic profile, and the maternal cardiovascular system showed a reduced capacity for oxygen delivery to the placenta. SVR and DO₂ showed a significant correlation with BW and with drop in fetal growth and emerged as independent predictive factors.

UV-Q reflects the amount of oxygen and nutrients reaching the fetus, thereby serving as an indicator of placental vascular function. It has been reported a statistically significant reduction in UV-Q in fetuses showing a ≥20th centile drop in abdominal circumference, suggesting a potential role for these parameters in the early detection of fetal growth alterations, even in the absence of a fully developed FGR phenotype [23]. Previous studies demonstrated that UV-Q is an independent predictor of fetal growth velocity and adverse perinatal outcomes, highlighting its potential as a functional marker for early identification of fetuses at risk [7], 24]. In our study, UV-Q was lower in the group with impaired growth. We observed a significant negative correlation between UV-Q and BW, confirming its role as an independent predictor of BW.

This evidence supports the notion that the population with impaired growth exhibits impairment of the cardiac-fetal-placental unit like nondiabetic population [2], 25].

The use of a ≥40 centile decline between EFW at enrolment and BW centile (DROP) represents an attempt to identify clinically meaningful impairments in fetal growth trajectory that are not captured by the conventional SGA definition. Recent evidence supports the prognostic value of longitudinal growth deceleration in predicting adverse perinatal outcomes. It has been demonstrated that fetuses with a late gestational fall in EFW centile were at increased risk of stillbirth and neonatal complications, even when BW remained above the 10th centile [26]. Similarly, DROP may reflect fetal adaptive responses to chronic hypoxemia or reduced nutrient supply in a subset of pregnancies complicated by GDM, which are typically assumed to be at risk for overgrowth rather than restriction.

In our cohort, the inclusion of fetuses with a marked DROP allowed us to identify a clinically relevant group with abnormal maternal hemodynamics and impaired UV-Q, despite BW often falling within the AGA range. This underscores the potential utility of DROP as a tool for uncovering “hidden” growth restriction phenotypes in GDM pregnancies.

Importantly, while current surveillance strategies in GDM focus primarily on detecting macrosomia, our findings suggest that attention should also be directed toward fetuses at risk of growth deceleration. The integration of DROP into routine fetal growth surveillance may offer a more precise risk stratification model, leading to closer monitoring or earlier delivery when combined with abnormal maternal-fetal hemodynamic markers.

Clinical implications

To date, several biomarkers and composite scoring systems have been proposed to predict FGR, particularly in high-risk pregnancies. Among the most widely studied are uterine artery Doppler velocimetry, maternal serum markers, and fetal biometry-based growth velocity charts. Uterine artery pulsatility index, especially when combined with maternal characteristics, has shown moderate predictive value for early-onset FGR, but its performance is significantly lower in late-onset forms or in GDM pregnancies, where uteroplacental resistance may remain within normal range despite placental dysfunction [27], 28]. Similarly, biomarkers of angiogenesis have demonstrated utility in preeclampsia prediction and early-onset FGR, but their role in normotensive GDM pregnancies remains uncertain [29]. In contrast, the hemodynamic markers used in our study provide a real-time, functional assessment of the maternal-fetal unit, and may capture dynamic alterations preceding overt clinical manifestations [30].

Compared to composite scores such as the Fetal Medicine Foundation (FMF) algorithm for FGR – which integrates maternal factors, biometry, and Doppler [31] – our model offers the advantage of including direct functional measurements of maternal cardiovascular adaptation. The moderate diagnostic performance of our multivariate models (AUC up to 0.78) is comparable to existing algorithms, suggesting that maternal hemodynamics and UV-Q may represent valuable adjuncts to standard assessment tools, particularly in GDM populations where growth impairment is often underestimated.

Strengths

This study has several notable strengths. First, by focusing on pregnancies complicated by GDM, it provides novel insights into early predictors of impaired fetal growth, employing innovative technologies for maternal and fetal assessment. Second, maternal hemodynamic assessment and UV-Q evaluation were performed using standardized protocols by an experienced operator, ensuring reliable and reproducible measurements. Finally, the prospective observational design allowed systematic collection of both maternal and fetal parameters, as well as neonatal outcomes.

Limitations

Several methodological limitations should be acknowledged. First, the sample size, although adequate for an exploratory analysis, was relatively small and cannot be considered representative of the broader population of women GDM. Consequently, chronic maternal conditions (e.g., thyroid disorders, celiac disease, inflammatory bowel disease) were few and heterogeneous, preventing adjustment for their potential impact on maternal hemodynamics and fetal growth; this could be addressed in future studies with larger cohorts.

Additionally, the proportion of cases classified as impaired fetal growth in our cohort (28.5 %) was relatively high, which may reflect the specific characteristics of our study population and further limits the generalizability of the findings.

Both the maternal hemodynamic evaluation using USCOM^® and the ultrasound assessment of fetal UV parameters are moderately operator-dependent techniques. Although all examinations were performed by the same expert following standardized protocols, and using modern ultrasound technology allows reliable measurements of the UV-Q and employing a rigorous methodology ensuring that this evaluation achieves moderate to good reproducibility.

Another limitation is the lack of detailed longitudinal data on the degree of glycemic control during pregnancy. While we reported the proportion of women achieving good glycemic control at the last prenatal visit (Table 1), subtle variations throughout gestation cannot be excluded. All women were managed according to standardized protocols, including close glucose monitoring and initiation of insulin or metformin as needed. Although different pharmacological approaches may theoretically influence maternal hemodynamics or fetal growth, the similar distribution of therapy between groups minimizes its potential impact.

Finally, although the ≥40 centiles DROP cutoff is clinically plausible, its choice remains arbitrary and not externally validated. In our cohort, the 10th centile of the observed DROP distribution corresponded to a DROP of 44.5 centiles, which provides some internal support for this threshold but should be interpreted with caution.