Intravoxel incoherent motion MRI to assess feto-placental diffusion and perfusion properties in small fetuses.

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.

Functional magnetic resonance imaging (MRI) can assess oxygenation and perfusion status in the placenta. We aimed to explore the differences in functional parameters between pregnancies complicated by fetal growth restriction (FGR) and small-for-gestational-age (SGA). This was a prospective study. A pregnancy complicated by SGA was defined by prenatal ultrasonic estimated fetal weight (EFW) and a final birthweight < the 10th percentile. A pregnancy complicated by FGR was defined as a more severe subtype (ultrasonic EFW < the 3rd percentile or abnormal Doppler results). All pregnant women underwent T2* and intravoxel incoherent motion (IVIM) scans using a 3.0-T MRI scanner. Functional parameters in the control, SGA, and FGR groups, namely, the T2* Z score, apparent diffusion coefficient (ADC), diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f), were calculated and compared. In total, 30 pregnancies complicated by SGA, 24 pregnancies complicated by FGR, and 28 control pregnancies were included in the final analysis. Oxygenation status, as assessed by the T2* Z score, was significantly lower in pregnancies complicated by FGR than in pregnancies complicated by SGA (p < 0.001). However, diffusion and perfusion parameters, including the ADC, D, D*, and f, were similar between pregnancies complicated by SGA and FGR (p > 0.05 for all). Compared to the control pregnancies, all the parameters were significantly decreased in the SGA and FGR groups, except for the D* value. The T2* Z score, ADC, and D values were negatively correlated with birthweight. Although both pregnancies complicated by SGA and FGR were associated with significantly lower oxygenation and perfusion than normal control pregnancies, placental hypoxia seemed to be more predominant in pregnancies complicated by FGR than in pregnancies complicated by SGA. • Pregnancy complicated by FGR was associated with a more severe type of hypoxia than pregnancy complicated by SGA. • The diffusion and perfusion parameters of pregnancies complicated by SGA and FGR were similar. • SGA may represent another growth disorder that is not entirely healthy.

Persistent short stature, other potential outcomes, and the effect of growth hormone treatment in children who are born small for gestational age.

Criteria for diagnosing fetal growth restriction (FGR) vary globally. The Japanese criterion is estimated fetal weight (EFW) below - 1.5 standard deviations, without distinctions based on gestational age or severity. However, some international diagnostic criteria classify FGR using gestational age, Doppler assessments, and growth. While the Japanese criterion is simple and easy to apply, including EFW, gestational age at diagnosis, growth, and Doppler findings can provide a more comprehensive assessment of fetoplacental function. The aims of this study were: [1] to reclassify small fetuses on the Japanese criterion into early FGR, late FGR, or small for gestational age (SGA) groups by applying Doppler-inclusive diagnostic criteria, and [2] compare the perinatal outcomes. In this retrospective study, FGR diagnosed based on the Japanese criterion between 2017 and 2021 at our hospital were reclassified into early FGR, late FGR, or SGA by applying Doppler-inclusive criteria. Cases not classified as early or late FGR were categorized as SGA. Perinatal, maternal, and neonatal outcomes were analyzed across all groups. Overall, 184 growth-restricted fetuses based on the Japanese criterion-160 cases (42 early FGR, 51 late FGR, and 67 SGA)-were enrolled after excluding 24 cases of fetal malformation. Gestational age at delivery, mode of delivery, and maternal and neonatal complications differed significantly among the groups. The early FGR group showed a significantly higher incidence of preterm birth, emergent Cesarean section, and severe maternal or neonatal complications. FGR with Doppler-inclusive criteria can be better for practical use providing high relevance to perinatal outcome.

According to the classification system used, 15-60% of stillbirths remain unexplained, despite undergoing recommended autopsy examination, with variable attribution of fetal growth restriction (FGR) as a cause of death. Distinguishing small-for-gestational age (SGA) from pathological FGR is a challenge at postmortem examination. This study uses data from a large, well-characterized series of intrauterine death autopsies to investigate the effects of secondary changes such as fetal maceration, intrauterine retention and postmortem interval on body weight. Autopsy findings from intrauterine death investigations (2005-2013 inclusive, from Great Ormond Street Hospital and St George's Hospital, London) were collated into a research database. Growth charts published by the World Health Organization were used to determine normal expected weight centiles for fetuses born ≥ 24 weeks' gestation, and the effects of intrauterine retention (maceration) and postmortem interval were calculated. There were 1064 intrauterine deaths, including 533 stillbirths ≥ 24 weeks' gestation with a recorded birth weight. Of these, 192 (36%) had an unadjusted birth weight below the 10th centile and were defined as SGA. The majority (86%) of stillborn SGA fetuses demonstrated some degree of maceration, indicating a significant period of intrauterine retention after death. A significantly greater proportion of macerated fetuses were present in the SGA population compared with the non-SGA population (P = 0.01). There was a significant relationship between increasing intrauterine retention interval and both more severe maceration and reduction in birth weight (P < 0.0001 for both), with an average artifactual reduction in birth weight of around -0.8 SD of expected weight. There was an average 12% reduction in fetal weight between delivery and autopsy and, as postmortem interval increased, fetal weight loss increased (P = 0.0001). Based on birth weight alone, 36% of stillbirths are classified as SGA. However, fetuses lose weight in utero with increasing intrauterine retention and continue to lose weight between delivery and autopsy, resulting in erroneous overestimation of FGR. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Objective To explore the predictive accuracy of two estimated fetal weight (EFW) standards (INTERGROWTH and Hadlock) and Doppler parameters for late-onset fetal growth restriction (FGR). Methods A prospective cohort of women with singleton pregnancies who attended research scans and had a livebirth at the obstetrics and gynecology hospital of Fudan University during 32-41 weeks of gestation was involved. The markers of ultrasound examinations (including growth measurements, umbilical artery and middle cerebral artery parameters) were obtained every two weeks. The INTERGROWTH-EFWc and Hadlock-EFWc data were obtained from the last ultrasonography (within 7 days before delivery) and were used to predict later-onset FGR in a single model or in combined models with other Doppler parameters by logistic regression analyses, respectively. According to delivery gestation of age and Chinese birth weight (BW) standards, all cases were divided into a control group (non-FGR, BW≥ 10th%) and a FGR group (Late-onset FGR, BW<10th%). ROC curve analyses were performed to compare the predictive accuracy for the late-onset FGR between the Hadlock-EFWc and INTERGROWTH-EFWc. Results A total of 820 eligible women were identified and 676 had finished the follow-up and were enrolled in this prospective cohort study. Among them, 116 neonates were assigned to the late-onset FGR group, and 560 as control group (non-FGR). The cut-off value of the INTERGROWTH-EFWc was percentile 27.5, at which had a sensitivity and specificity of 71.4% and 83.7%. The corresponding sensitivity and specificity were 87.3% and 82.8% at a cut-off value of percentile 22.6 of the Hadlock-EFWc. The Hadlock-EFWc had a higher predictive accuracy for the late-onset FGR than the INTERGROWTH-EFWc, their AUC were 0.930 (0.908-0.953) and 0.847 (0.807-0.888), respectively. The accuracy of Doppler single-parameter (umbilical artery and middle cerebral artery) for late-onset FGR were low (AUC<0.7), but the accuracy of combined model-Ⅰ and Ⅱ were high (AUC 0.865 and 0.936, respectively), similar to their corresponding EFWc models, respectively. Conclusions The INTERGROWTH-EFWc could predict effectively for late-onset FGR, however, its predictive accuracy is lower than that of the Hadlock-EFWc. The predictive accuracy of Doppler parameters for late-onset FGR are poor, routine monitoring of non-selected populations is not recommended. Key words: Ultrasonography; Fetal growth restriction; Small for gestational age; Estimated fetal weight; INTERGROWTH standard; Hadlock standard

Twin pregnancies are at higher risk of stillbirth compared to singletons. Fetal growth restriction (FGR) is a major cause of perinatal mortality, but its impact on twins vs singletons remains unclear. The primary objective of this study was to investigate the association of FGR and small-for-gestational age (SGA) with stillbirth in twin compared with singleton pregnancies. A secondary objective was to assess these associations stratified by gestational age at delivery. Furthermore, we aimed to compare the associations of FGR and SGA with stillbirth in twin pregnancies using twin-specific vs singleton birth-weight charts, stratified by chorionicity. This was a retrospective cross-sectional study of pregnancies receiving obstetric care and giving birth between 1999 and 2022 at St George's Hospital, London, UK. The exclusion criteria included triplet and higher-order pregnancies, those resulting in miscarriage or live birth at ≤ 23 + 6 weeks, termination of pregnancy and missing data regarding birth weight or gestational age at birth. Birth-weight data were collected and FGR and SGA were defined as birth weight <5th and <10th centiles, respectively. While standard logistic regression was used for singleton pregnancies, the association of FGR and SGA with stillbirth in twin pregnancies was investigated using mixed-effects logistic regression models. For twin pregnancies, intercepts were allowed to vary for twin pairs to account for intertwin dependency. Analyses were stratified by gestational age at delivery and chorionicity. Statistical significance was set at P ≤ 0.001. The study included 95 342 singleton and 3576 twin pregnancies. There were 494 (0.52%) stillbirths in singleton and 41 (1.15%) stillbirths in twin pregnancies (17 dichorionic and 24 monochorionic). SGA and FGR were associated significantly with stillbirth in singleton pregnancies across all gestational ages at delivery: the odds ratios (ORs) for SGA and FGR were 2.36 ((95% CI, 1.78-3.13), P < 0.001) and 2.67 ((95% CI, 2.02-3.55), P < 0.001), respectively, for delivery before 32 weeks; 2.70 ((95% CI, 1.71-4.31), P < 0.001) and 2.82 ((95% CI, 1.78-4.47), P < 0.001), respectively, for delivery between 32 and 36 weeks; and 3.85 ((95% CI, 2.83-5.21), P < 0.001) and 4.43 ((95% CI, 3.16-6.12), P < 0.001), respectively, for delivery after 36 weeks. In twin pregnancies, when stratified by gestational age at delivery, both SGA and FGR determined by twin-specific birth-weight charts were associated with increased odds of stillbirth for those delivered before 32 weeks (SGA: OR, 3.87 (95% CI, 1.56-9.50), P = 0.003 and FGR: OR, 5.26 (95% CI, 2.11-13.01), P = 0.001), those delivered between 32 and 36 weeks (SGA: OR, 6.67 (95% CI, 2.11-20.41), P = 0.001 and FGR: OR, 9.54 (95% CI, 3.01-29.40), P < 0.001) and those delivered beyond 36 weeks (SGA: OR, 12.68 (95% CI, 2.47-58.15), P = 0.001 and FGR: OR, 23.84 (95% CI, 4.62-110.25), P < 0.001). However, the association of stillbirth with SGA and FGR in twin pregnancies was non-significant when diagnosis was based on singleton charts (before 32 weeks: SGA, P = 0.014 and FGR, P = 0.005; 32-36 weeks: SGA, P = 0.036 and FGR, P = 0.008; after 36 weeks: SGA, P = 0.080 and FGR, P = 0.063). Our study demonstrates that SGA and, especially, FGR are associated significantly with an increased risk of stillbirth across all gestational ages in singleton pregnancies, and in twin pregnancies when twin-specific birth-weight charts are used. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

1123 Midtrimester fetal growth restriction as predictor of small for gestational age and adverse obstetrical outcomes

Small-for-gestational-age (SGA) pregnancies, and in particular those with fetal growth restriction (FGR) are associated with an increased risk of adverse outcomes. Abnormal uterine artery (UtA) Doppler and other measures of maternal hemodynamics appear to be independently associated with adverse fetal outcome. The aim of this study was to describe the maternal hemodynamic differences in normotensive, SGA pregnancies with and without FGR. This was a prospective study of SGA and control pregnancies. Measurements of maternal hemodynamics, using a non-invasive device (USCOM-1A) were obtained. Variables that are affected by gestational age and maternal characteristics were corrected for using device-specific reference ranges. Pregnancies with evidence of FGR were compared to those with SGA only and normal pregnancies using descriptive statistics. Statistical analysis was performed using the Chi-squared test and Mann-Whitney test. A total of 102 FGR, 64 SGA and 401 control pregnancies at 28-41 weeks were included in the analysis. Compared to controls, the FGR group had significantly lower median heart rate (HR) (80bpm vs 85bpm, p = 0.001), lower cardiac output (CO) (0.91MoM vs 0.98MoM, p = 0.003), and higher systemic vascular resistance (SVR) (1.2MoM vs 1.0MoM, p < 0.001). There was no significant difference in stroke volume (SV) (1.0MoM vs 0.98MoM, p = 0.647) between the FGR and normal pregnancy groups. In contrast, there were no significant differences in maternal hemodynamics between the SGA and control groups. FGR pregnancies present with maternal cardiovascular dysfunction, as evidenced by lower HR and CO as well as higher mean arterial pressure (MAP), SVR and UtA resistance. SV is unchanged in FGR pregnancy suggesting that the observed drop in CO is a consequence of lower maternal HR. Pregnancies resulting in SGA neonate, without evidence of fetal hypoxemia or adverse outcome have normal cardiovascular adaptation. Maternal HR and other hemodynamic parameters may be of value in distinguishing SGA from FGR.

To perform a comprehensive assessment of the placental aging process in small term fetuses classified as being small-for-gestational age (SGA) or having fetal growth restriction (FGR) through analysis of senescence and apoptosis markers. This was a prospective nested case-control study of singleton pregnancies delivered at term, including 21 control pregnancies with normally grown fetuses and 36 with a small fetus classified as SGA (birth weight between the 3rd and 9th percentiles and normal fetoplacental Doppler; n = 18) or FGR (birth weight < 3rd percentile and/or abnormal cerebroplacental ratio and/or uterine artery Doppler; n = 18). Telomerase activity, telomere length (quantified by comparing the amount of amplification product for the telomere sequence (T) to that of a single copy of the gene 36B4 (S)) and RNA expression of senescence (Sirtuins 1, 3 and 6) and apoptosis (p53, p21, BAX and Caspases 3 and 9) markers (analyzed using the 2-ΔΔCt method) were determined in placental samples collected at birth and compared between the three groups. Compared to pregnancies with a normally grown fetus, both SGA and FGR pregnancies presented signs of accelerated placental aging, including lower telomerase activity (mean ± SD, 12.8 ± 6.6% in controls vs 7.98 ± 4.2% in SGA vs 7.79 ± 4.6% in FGR; P = 0.008), shorter telomeres (mean ± SD T/S ratio, 1.20 ± 0.6 in controls vs 1.08 ± 0.9 in SGA vs 0.66 ± 0.5 in FGR; P = 0.047) and reduced Sirtuin-1 RNA expression (mean ± SD 2-ΔΔCt , 1.55 ± 0.8 in controls vs 0.91 ± 0.8 in SGA vs 0.63 ± 0.5 in FGR; P = 0.001) together with increased p53 RNA expression (median (interquartile range) 2-ΔΔCt , 1.07 (0.3-3.3) in controls vs 5.39 (0.6-15) in SGA vs 3.75 (0.9-7.8) in FGR; P = 0.040). FGR cases presented signs of apoptosis, with increased Caspase-3 RNA levels (median (interquartile range) 2-ΔΔCt , 0.94 (0.7-1.7) in controls vs 3.98 (0.9-31) in FGR; P = 0.031) and Caspase-9 RNA levels (median (interquartile range) 2-ΔΔCt , 1.21 (0.6-4.0) in controls vs 3.87 (1.5-9.0) in FGR; P = 0.037) compared with controls. In addition, Sirtuin-1 RNA expression, telomerase activity, telomere length and Caspase-3 activity showed significant linear trends across groups as severity of the condition increased. Accelerated placental aging was observed in both clinical forms of late-onset fetal smallness (SGA and FGR), supporting a common pathophysiology and challenging the concept of SGA fetuses being constitutionally small. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Small for gestational age (SGA) and fetal growth restriction (FGR)

Objective: To assess the clinical features of fetal growth restriction (FGR) in women with hypertensive disorders of pregnancy in China. Methods: This is a retrospective cohort study. The clinical data of 4 451 women with hypertensive disorders of pregnancy were retrospectively collected from 11 tertiary hospitals across ten provinces in China during January 2015 to December 2015. The mean maternal age was (31.0 ± 5.4) years old. Participants were divided into FGR group (n = 670) and non-FGR group (n = 3 781). The incidence and clinical features of FGR, and its correlation with gestational age, previous FGR history, 24-hour urinary protein excretion, and hemolysis, elevated liver enzyme and low platelet count (HELLP) syndrome were analyzed. Student's t-test and Chi-square test were used when comparing clinical features between FGR and non-FGR groups. Results: The overall incidence of FGR was 15.1% (670/4 451). The FGR incidence was 22.4% (433/1 937) in women with severe preeclampsia and 18.6% (68/365) in women with chronic hypertension with superimposed preeclampsia, respectively. FGR was more prevalent in women who had preterm births than those who had term births (22.8% (432/1 898) vs. 9.3% (238/2 553), P &lt; 0.001). It was also more prevalent in women with early-onset preeclampsia than those with late-onset preeclampsia (18.4% (189/1 025) vs. 14.0% (481/3 426), P = 0.001). Women with a previous FGR history had a significantly higher FGR incidence than those without an FGR history (66.7% (4/6) vs. 15.7% (250/1 596), P = 0.007). The presence of abnormal results of the umbilical artery Doppler (13% (87/670) vs. 2.4% (89/3 781), P &lt; 0.001) and the middle cerebral artery Doppler (3.3% (22/670) vs. 0.4% (15/3 781), P &lt; 0.001) was higher in the FGR group compared with the non-FGR group, while the presence of increased uterine artery resistance was not statistically different (1.5% (10/670) vs. 0.8% (29/3 781), P = 0.072). The FGR group delivered earlier than the non-FGR group ((35.3 ± 3.0) weeks vs. (36.4 ± 4.3) weeks, P &lt; 0.001) with lower birth weight (1 731.0 ± 574.5) g vs. (2 753.9 ± 902.1) g, P &lt; 0.001, higher fetal or neonatal death (9.4% (63/670) vs. 4.2% (157/3 781), P &lt; 0.001), and higher cesarean section rate (82.5% (553/670) vs. 70.2% (2 656/3 781), P &lt; 0.001). In the FGR group, more neonates had 5-minute Apgar score ≤7 (7.9% (53/670) vs. 3.9% (149/3 780), P &lt; 0.001), with higher neonatal intensive care unit admission rate (48.1% (322/670) vs. 23.3% (881/3 781), P &lt; 0.001). More cases of HELLP syndrome occurred in the FGR group (6.9% (46/670) vs. 3.2% (122/3 781), P &lt; 0.001). Women with FGR had heavier 24-hour urinary protein excretion than those without FGR ((3.9 ± 3.7) g vs. (3.1 ± 4.2) g, P = 0.005). Conclusion: In pregnancies with hypertensive disorders, increased risks of FGR are associated with preterm birth, birth before 34 weeks, and a previous FGR history. FGR is related to higher occurrence of abnormal uterine artery Doppler and umbilical artery Doppler. When hypertensive disorders is complicated by FGR, there appears to be higher maternal morbidity including higher rate of HELLP syndrome, cesarean section, and heavier proteinuria, as well as worse neonatal outcomes.

284 Umbilical vein flow in fetal growth restriction versus small for gestational age fetuses

Pregnancies complicated by fetal growth restriction (FGR) have a worse outcome than those with a small-for-gestational-age (SGA) fetus. There is increasing evidence of a maternal cardiovascular role in the pathophysiology of FGR. We aimed to compare maternal hemodynamic indices between pregnancies complicated by FGR and those delivering a SGA neonate, using a non-invasive device. This was a prospective study of normotensive pregnancies complicated by FGR (defined as estimated fetal weight (EFW) < 3rd centile or Doppler evidence of impaired placental-fetal blood flow), those with a SGA fetus (defined as EFW < 10th centile) and control pregnancies with an appropriately grown fetus. Assessment of maternal hemodynamics (heart rate (HR), cardiac output (CO), mean arterial pressure (MAP), systemic vascular resistance (SVR) and stroke volume) was performed using a non-invasive device (USCOM-1A®). Uterine artery (UtA) pulsatility index (PI) was measured using transabdominal ultrasound. Hemodynamic variables that are affected by gestational age and maternal characteristics were corrected for using device-specific reference ranges. Comparison between groups was performed using the chi-square test or the Mann-Whitney U-test, as appropriate. A total of 102 FGR, 64 SGA and 401 control pregnancies, with a median gestational age of 36 weeks, were included in the analysis. Women with a pregnancy complicated by FGR and those with a SGA fetus were shorter and weighed less than did controls. Compared with controls, the FGR group had significantly lower median maternal HR (80 beats per min (bpm) vs 85 bpm; P = 0.001) and CO multiples of the median (MoM; 0.91 vs 0.98; P = 0.003), and higher median maternal MAP (90 mmHg vs 87 mmHg; P = 0.040), SVR MoM (1.2 vs 1.0; P < 0.001) and UtA-PI MoM (1.1 vs 0.96; P < 0.001), but there was no significant difference in stroke volume MoM (1.0 vs 0.98; P = 0.647). Compared with the SGA group, the FGR group had a significantly lower median HR (80 bpm vs 87 bpm; P = 0.022), and higher median maternal MAP (90 mmHg vs 85 mmHg; P = 0.025), SVR MoM (1.2 vs 1.0; P = 0.002) and UtA-PI MoM (1.1 vs 0.98; P = 0.005), but there was no significant difference in CO MoM (0.91 vs 0.96; P = 0.092) or stroke volume MoM (1.0 vs 1.0; P = 0.806). There were no significant differences in adjusted maternal hemodynamic indices between the SGA group and controls. Pregnancies complicated by FGR presented with impaired maternal hemodynamic function, as evidenced by lower HR and CO, as well as higher MAP, SVR and UtA resistance. Pregnancies delivering a SGA neonate, without evidence of FGR, had normal maternal hemodynamic function. Maternal hemodynamic indices may therefore be of value in distinguishing FGR from SGA pregnancies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Fetal growth restriction and intra-uterine growth restriction: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians