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Background: No fetal growth standard is currently endorsed for universal use in the United States. Newer standards improve upon the methodologic limitations of older studies; however, before adopting into practice, it is important to know how recent standards perform at identifying fetal undergrowth or overgrowth and at predicting subsequent neonatal morbidity or mortality in US populations., Objective: To compare classification of estimated fetal weight that is <5th or 10th percentile or >90th percentile by 6 population-based fetal growth standards and the ability of these standards to predict a composite of neonatal morbidity and mortality., Study Design: We used data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be cohort, which recruited nulliparous women in the first trimester at 8 US clinical centers (2010-2014). Estimated fetal weight was obtained from ultrasounds at 16 to 21 and 22 to 29 weeks of gestation (N=9534 women). We calculated rates of fetal growth restriction (estimated fetal weight <5th and 10th percentiles; fetal growth restriction<5 and fetal growth restriction<10) and estimated fetal weight >90th percentile (estimated fetal weight>90) from 3 large prospective fetal growth cohorts with similar rigorous methodologies: INTERGROWTH-21, World Health Organization-sex-specific and combined, Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific and unified, and the historic Hadlock reference. To determine whether differential classification of fetal growth restriction or estimated fetal weight >90 among standards was clinically meaningful, we then compared area under the curve and sensitivity of each standard to predict small for gestational age or large for gestational age at birth, composite perinatal morbidity and mortality alone, and small for gestational age or large for gestational age with composite perinatal morbidity and mortality., Results: The standards classified different proportions of fetal growth restriction and estimated fetal weight>90 for ultrasounds at 16 to 21 (visit 2) and 22 to 29 (visit 3) weeks of gestation. At visit 2, the Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific, World Health Organization sex-specific and World Health Organization-combined identified similar rates of fetal growth restriction<10 (8.4%-8.5%) with the other 2 having lower rates, whereas Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific identified the highest rate of fetal growth restriction<5 (5.0%) compared with the other references. At visit 3, World Health Organization sex-specific classified 9.2% of fetuses as fetal growth restriction<10, whereas the other 5 classified a lower proportion as follows: World Health Organization-combined (8.4%), Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific (7.7%), INTERGROWTH (6.2%), Hadlock (6.1%), and Eunice Kennedy Shriver National Institute of Child Health and Human Development unified (5.1%). INTERGROWTH classified the highest (21.3%) as estimated fetal weight>90 whereas Hadlock classified the lowest (8.3%). When predicting composite perinatal morbidity and mortality in the setting of early-onset fetal growth restriction, World Health Organization had the highest area under the curve of 0.53 (95% confidence interval, 0.51-0.53) for fetal growth restriction<10 at 22 to 29 weeks of gestation, but the areas under the curve were similar among standards (0.52). Sensitivity was generally low across standards (22.7%-29.1%). When predicting small for gestational age birthweight with composite neonatal morbidity or mortality, for fetal growth restriction<10 at 22 to 29 weeks of gestation, World Health Organization sex-specific had the highest area under the curve (0.64; 95% confidence interval, 0.60-0.67) and INTERGROWTH had the lowest (area under the curve=0.58; 95% confidence interval 0.55-0.62), though all standards had low sensitivity (7.0%-9.6%)., Conclusion: Despite classifying different proportions of fetuses as fetal growth restriction or estimated fetal weight>90, all standards performed similarly in predicting perinatal morbidity and mortality. Classification of different percentages of fetuses as fetal growth restriction or estimated fetal weight>90 among references may have clinical implications in the management of pregnancies, such as increased antenatal monitoring for fetal growth restriction or cesarean delivery for suspected large for gestational age. Our findings highlight the importance of knowing how standards perform in local populations, but more research is needed to determine if any standard performs better at identifying the risk of morbidity or mortality., (Published by Elsevier Inc.)

Background: Research on the definition of fetal growth restriction (FGR) has focused on predicting adverse perinatal outcomes. A significant limitation of this approach is that the individual outcomes of interest could be related to the condition and the treatment. Evaluation of outcomes that reflect the pathophysiology of FGR may overcome this limitation., Objective: To compare the diagnostic performance of the FGR definitions established by the International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) and the Society for Maternal-Fetal Medicine (SMFM) to predict placental histopathological findings associated with placental insufficiency and a composite adverse neonatal outcome (ANeO)., Study Design: In this retrospective cohort study of singleton pregnancies, the ISUOG and the SMFM guidelines were used to identify pregnancies with FGR and a corresponding control group. The primary outcome was the prediction of placental histopathological findings associated with placental insufficiency, defined as lesions associated with maternal vascular malperfusion (MVM). A composite ANeO (ie, umbilical artery pH≤7.1, Apgar score at 5 minutes ≤4, neonatal intensive care unit admission, hypoglycemia, respiratory distress syndrome requiring mechanical ventilation, intrapartum fetal distress requiring expedited delivery, and perinatal death) was investigated as a secondary outcome. Sensitivity, specificity, positive and negative predictive values, and the areas under the receiver-operating-characteristics curves were determined for each FGR definition. Logistic regression models were used to assess the association between each definition and the studied outcomes. A subgroup analysis of the diagnostic performance of both definitions stratifying the population in early and late FGR was also performed., Results: Both societies' definitions showed a similar diagnostic performance as well as a significant association with the primary (ISUOG adjusted odds ratio 3.01 [95% confidence interval 2.42, 3.75]; SMFM adjusted odds ratio 2.85 [95% confidence interval 2.31, 3.51]) and secondary outcomes (ISUOG adjusted odds ratio 1.95 [95% confidence interval 1.56, 2.43]; SMFM adjusted odds ratio 2.12 [95% confidence interval 1.70, 2.65]). Furthermore, both FGR definitions had a limited discriminatory capacity for placental histopathological findings of MVM and the composite ANeO (area under the receiver-operating-characteristics curve ISUOG 0.63 [95% confidence interval 0.61, 0.65], 0.59 [95% confidence interval 0.56, 0.61]; area under the receiver-operating-characteristics SMFM 0.63 [95% confidence interval 0.61, 0.66], 0.60 [95% confidence interval 0.57, 0.62])., Conclusion: The ISUOG and the SMFM FGR definitions have limited discriminatory capacity for placental histopathological findings associated with placental insufficiency and a composite ANeO. El resumen está disponible en Español al final del artículo., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To assess the utility of placental growth factor (PlGF) levels and the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA)., Design: Prospective, observational cohort study., Setting: Tertiary maternity hospital in Australia., Population: There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32 +0  weeks) and 109 (30.0%) late FGR (≥32 +0  weeks)., Methods: Maternal serum PlGF and sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt-1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt-1/PlGF ratio to the time of birth or censoring., Main Outcome Measures: The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained., Results: The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt-1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt-1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt-1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt-1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48-175.46)., Conclusions: Low maternal PlGF levels and elevated sFlt-1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To assess the association of the umbilicocerebral ratio (UCR) with adverse perinatal outcome in late preterm small-for-gestational age (SGA) fetuses and to investigate the effect on perinatal outcomes of immediate delivery., Design: Multicentre cohort study with nested randomised controlled trial (RCT)., Setting: Nineteen secondary and tertiary care centres., Population: Singleton SGA pregnancies (estimated fetal weight [EFW] or fetal abdominal circumference [FAC] <10th centile) from 32 to 36 +6  weeks., Methods: Women were classified: (1) RCT-eligible: abnormal UCR twice consecutive and EFW below the 3 rd centile at/or below 35 weeks or below the 10 th centile at 36 weeks; (2) abnormal UCR once or intermittent; (3) never abnormal UCR. Consenting RCT-eligible patients were randomised for immediate delivery from 34 weeks or expectant management until 37 weeks., Main Outcome Measures: A composite adverse perinatal outcome (CAPO), defined as perinatal death, birth asphyxia or major neonatal morbidity., Results: The cohort consisted of 690 women. The study was halted prematurely for low RCT-inclusion rates (n = 40). In the RCT-eligible group, gestational age at delivery, birthweight and birthweight multiple of the median (MoM) (0.66, 95% confidence interval [CI] 0.59-0.72) were significantly lower and the CAPO (n = 50, 44%, p < 0.05) was more frequent. Among patients randomised for immediate delivery there was a near-significant lower birthweight (p = 0.05) and higher CAPO (p = 0.07). EFW MoM, pre-eclampsia, gestational hypertension and Doppler classification were independently associated with the CAPO (area under the curve 0.71, 95% CI 0.67-0.76)., Conclusions: Perinatal risk was effectively identified by low EFW MoM and UCR. Early delivery of SGA fetuses with an abnormal UCR at 34-36 weeks should only be performed in the context of clinical trials., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Assessing the umbilical artery pulsatility index via Doppler measurements plays a crucial role in evaluating fetal growth impairment., Objective: This study aimed to investigate perinatal outcomes associated with discordant pulsatility indices of umbilical arteries in fetuses with growth restriction., Study Design: In this retrospective cohort study, all singleton pregnancies were included if their estimated fetal weight and/or abdominal circumference fell below the 10th percentile for gestational age (2017-2022). Eligible cases included singleton pregnancies with concurrent sampling of both umbilical arteries within 14 days of birth at the ultrasound evaluation closest to delivery. The exclusion criteria included births before 22 weeks of gestation, evidence of absent or reverse end-diastolic flow in either umbilical artery, and known fetal genetic or structural anomalies. The study compared cases with discordant umbilical artery pulsatility index values (defined as 1 umbilical artery pulsatility index at ≤95th percentile and the other umbilical artery pulsatility index at >95th percentile for gestational age) to pregnancies where both umbilical artery pulsatility indices had normal pulsatility index values and those with both umbilical arteries displaying abnormal pulsatility index values. The primary outcome assessed was the occurrence of composite adverse neonatal outcomes. Multivariable logistic regressions were performed, adjusting for relevant covariates., Results: The study encompassed 1014 patients, including 194 patients (19.1%) with discordant umbilical artery pulsatility index values among those who had both umbilical arteries sampled close to delivery, 671 patients (66.2%) with both umbilical arteries having normal pulsatility index values, and 149 patients (14.7%) with both umbilical arteries exhibiting abnormal values. Pregnancies with discordant umbilical artery pulsatility index values displayed compromised sonographic parameters compared with those with both umbilical arteries showing normal pulsatility index values. Similarly, the number of abnormal umbilical artery pulsatility index values was associated with adverse perinatal outcomes in a dose-response manner. Cases with 1 abnormal (discordant) umbilical artery pulsatility index value showed favorable sonographic parameters and perinatal outcomes compared with cases with both abnormal umbilical artery pulsatility index values, and cases with both abnormal umbilical artery pulsatility index values showed worse sonographic parameters and perinatal outcomes compared with cases with discordant UA PI values. Multivariate analysis revealed that discordant umbilical artery pulsatility indices were significantly and independently associated with composite adverse perinatal outcomes, with an adjusted odds ratio of 1.75 (95% confidence interval, 1.24-2.47; P = .002)., Conclusion: Evaluating the resistance indices of both umbilical arteries may provide useful data and assist in assessing adverse perinatal outcomes among fetuses with growth restriction., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Small for gestational age (SGA) neonates are known to be at an elevated risk for neonatal morbidity. Despite this, there is a growing array of proposed size standards for identifying SGA fetuses. Given the inherent differences in design, acquisition methods, and the characteristics of the populations they represent, the generalizability of these standards to diverse populations remains uncertain., Introduction: This study aimed to assess variations in rates of SGA and severe SGA using six distinct size standards: Hadlock, Fetal Medicine Foundation (FMF), World Health Organization (WHO), Intergrowth-21 (IG-21), and two locally derived population-based size standards. The objective was to examine the differences in SGA and severe SGA rates among these size standards., Methods: A retrospective cohort study was conducted, encompassing all singleton deliveries in two tertiary referral hospital campuses with an annual birth count exceeding 10,000, from January 2019 to July 2022. SGA and severe SGA were defined as birthweights below the 10th or 3rd percentile, respectively, based on each growth standard. The study design included details on the setting, subjects (singleton deliveries), and the chosen size standards. Comparative analyses were performed to assess variations in SGA and severe SGA rates among these size standards., Results: Our study analyzed 32,912 singleton deliveries. We found that the choice of growth standard significantly impacted the rates of both SGA and severe SGA infants. Notably, the WHO criteria identified 5,548 (16.9 %) fetuses as SGA, compared to only 1,716 (5.2 %) using the INTERGROWTH-21 standard (p < 0.001). Similarly, for severe SGA, the FMF charts classified 2098 (6.37 %) infants, significantly higher than the 320 (1 %) identified by Dolberg's local population-based charts (p < 0.001)., Conclusion: Our study demonstrates a significant variety of SGA and severe SGA rates using different size standards. Therefore, the decision on the size standards in use is critical given the significant influence on clinical management., Synopsis: There are significant variations in SGA and Severe SGA rates depending on the chosen size standard., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fetal growth restriction (FGR) increases cardiovascular risk by cardiac remodeling and programming. This systematic review and meta-analysis across species examines the use of echocardiography in FGR offspring at different ages. PubMed and Embase.com were searched for animal and human studies reporting on echocardiographic parameters in placental insufficiency-induced FGR offspring. We included six animal and 49 human studies. Although unable to perform a meta-analysis of animal studies because of insufficient number of studies per individual outcome, all studies showed left ventricular dysfunction. Our meta-analyses of human studies revealed a reduced left ventricular mass, interventricular septum thickness, mitral annular peak velocity, and mitral lateral early diastolic velocity at neonatal age. No echocardiographic differences during childhood were observed, although the small age range and number of studies limited these analyses. Only two studies at adult age were performed. Meta-regression on other influential factors was not possible due to underreporting. The few studies on myocardial strain analysis showed small changes in global longitudinal strain in FGR offspring. The quality of the human studies was considered low and the risk of bias in animal studies was mostly unclear. Echocardiography may offer a noninvasive tool to detect early signs of cardiovascular predisposition following FGR. Clinical implementation yet faces multiple challenges including identification of the most optimal timing and the exact relation to long-term cardiovascular function in which echocardiography alone might be limited to reflect a child's vascular status. Future research should focus on myocardial strain analysis and the combination of other (non)imaging techniques for an improved risk estimation. NEW & NOTEWORTHY Our meta-analysis revealed echocardiographic differences between fetal growth-restricted and control offspring in humans during the neonatal period: a reduced left ventricular mass and interventricular septum thickness, reduced mitral annular peak velocity, and mitral lateral early diastolic velocity. We were unable to pool echocardiographic parameters in animal studies and human adults because of an insufficient number of studies per individual outcome. The few studies on myocardial strain analysis showed small preclinical changes in FGR offspring.

Introduction: To assess the rate of change in soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio and PlGF levels per week compared to a single sFlt-1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction., Material and Methods: A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt-1/PlGF ratio, change in PlGF levels per week or sFlt-1/PlGF ratio per week. Cox-proportional hazard models and Harrell's C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth., Results: The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt-1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell's C: 0.85-0.76). The rate of increase per week of the sFlt-1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39-10.99, p = 0.01, Harrell's C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25-1.67, p = 0.37, Harrell's C: 0.68)., Conclusions: Both a high sFlt-1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt-1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt-1/PlGF ratio or low PlGF level., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Accurate identification of fetal growth restriction in fetal autopsy is critical for assessing causes of death. We examined the impact of using a chart derived from ultrasound measurements of healthy fetuses (World Health Organization fetal growth chart) versus a chart commonly used by pathologists (Archie et al.) derived from fetal autopsy-based populations in diagnosing small-for-gestational-age (SGA) birth in perinatal deaths. Study Design: We examined perinatal deaths that underwent autopsy at BC Women's Hospital, 2015-2021. Weight centiles were assigned using the ultrasound-based fetal growth chart for birthweight and autopsy-based growth chart for autopsy weight. Results: Among 352 fetuses, 30% were SGA based on the ultrasound-based fetal growth chart versus 17% using the autopsy-based growth chart ( p  < 0.001). Weight centiles were lower when using the ultrasound-based versus autopsy-based growth chart (median difference of 9 centiles [IQR 2, 20]). Conclusions: Autopsy-based growth charts may under-classify SGA status compared to ultrasound-based fetal growth charts.

Introduction: The inaccuracy of late pregnancy dating is often discussed, and the impact on diagnosis of fetal growth restriction is a concern. However, the magnitude and direction of this effect has not previously been demonstrated. In this study, we aimed to investigate the effect of late pregnancy dating by head circumference on the detection of late onset growth restriction, compared to first trimester crown-rump length dating., Material and Methods: This was a cohort study of 14 013 pregnancies receiving obstetric care at a tertiary center over a three-year period. Universal scans were performed at 12 weeks, including crown-rump length; at 20 weeks including fetal biometry; and at 36 weeks, where biometry, umbilical artery doppler and cerebroplacental ratio were used to determine the incidence of fetal growth restriction according to the Delphi consensus. For the entire cohort, the gestational age was first calculated using T1 dating; and was then recalculated using head circumference at 20 weeks (T2 dating); and at 36 weeks (T3 dating). The incidence of fetal growth restriction following T2 and T3 dating was compared to T1 dating using four-by-four sensitivity tables., Results: When the cohort was redated from T1 to T2, the median gestation at delivery changed from 40 + 0 to 40 + 2 weeks (p < 0.001). When the cohort was redated from T1 to T3, the median gestation at delivery changed from 40 + 0 to 40 + 3 weeks (p < 0.001). T2 dating resulted in fetal growth restriction sensitivity of 80.2% with positive predictive value of 78.8% compared to T1 dating. T3 dating resulted in sensitivity of 8.6% and positive predictive value of 27.7%, respectively. The sensitivity of abnormal CPR remained high despite T2 and T3 redating; 98.0% and 89.4%, respectively., Conclusions: Although dating at 11-14 weeks is recommended, late pregnancy dating is sometimes inevitable, and this can prolong the estimated due date by an average of two to three days. One in five pregnancies which would be classified as growth restricted if the pregnancy was dated in the first trimester, will be reclassified as nongrowth restricted following dating at 20 weeks, whereas nine out of 10 pregnancies will be reclassified as non-growth restricted with 36-week dating., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: Cerebroplacental ratio (CPR) has been shown to be an independent predictor of adverse perinatal outcome at term and a marker of failure to reach the growth potential (FRGP) regardless of fetal size, being abnormal in compromised fetuses with birthweight above the 10th centile. The main aim of this study was to propose a risk-based approach for the management of pregnancies with normal estimated fetal weight (EFW) and abnormal CPR near term., Material and Methods: This was a retrospective study of 943 pregnancies, that underwent an ultrasound evaluation of EFW and CPR at or beyond 34 weeks. CPR values were converted into multiples of the median (MoM) and EFW into centiles according to local references. Pregnancies were then divided into four groups: normal fetuses (defined as EFW ≥10th centile and CPR ≥0.6765 MoM), small for gestational age (EFW <10th centile and CPR ≥0.6765 MoM), fetal growth restriction (EFW <10th centile and CPR <0.6765 MoM), and fetuses with apparent normal growth (EFW ≥10th centile) and abnormal CPR (<0.6765 MoM), that present FRGP. Intrapartum fetal compromise (IFC) was defined as an abnormal intrapartum cardiotocogram or pH requiring cesarean delivery. Risk comparisons were performed among the four groups, based on the different frequencies of IFC. The risks of IFC were subsequently extrapolated into a gestational age scale, defining the optimal gestation to plan the birth for each of the four groups., Results: Fetal growth restriction was the group with the highest frequency of IFC followed by FRGP, small for gestational age, and normal groups. The "a priori" risks of the fetal growth restriction and normal groups were used to determine the limits of two scales. One defining the IFC risk and the other defining the appropriate gestational age for delivery. Extrapolation of the risk between both scales placed the optimal gestational age for delivery at 39 weeks of gestation in the case of FRGP and at 40 weeks in the case of small for gestational age., Conclusions: Fetuses near term may be evaluated according to the CPR and EFW defining four groups that present a progressive risk of IFC. Fetuses in pregnancies complicated by FRGP are likely to benefit from being delivered at 39 weeks of gestation., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

This study aimed to develop and externally validate a prognostic prediction model for screening fetal growth restriction (FGR)/small for gestational age (SGA) using medical history. From a nationwide health insurance database (n=1,697,452), we retrospectively selected visits of 12-to-55-year-old females to healthcare providers. This study used machine learning (including deep learning) and 54 medical-history predictors. The best model was a deep-insight visible neural network (DI-VNN). It had area under the curve of receiver operating characteristics (AUROC) 0.742 (95% CI 0.734 to 0.750) and a sensitivity of 49.09% (95% CI 47.60% to 50.58% at with 95% specificity). Our model used medical history for screening FGR/SGA with moderate accuracy by DI-VNN. In future work, we will compare this model with those from systematically-reviewed, previous studies and evaluate if this model's usage impacts patient outcomes.

Introduction: Restriction in the growth of the fetus is a leading cause of stillbirth, neonatal mortality, and short- and long-term morbidity. Documented existing scientific evidence have shown the effects of maternal drugs use, alcohol drinking, tobacco smoking, cocaine use and heroin use on fetal growth restriction. However, data is lacking on the effects of khat chewing during pregnancy on fetal growth status and newborn size at birth. Therefore, the aim of the present study was to measure the effect of chewing khat during pregnancy on fetal growth and size at birth in eastern Ethiopia., Method: A cohort study was conducted in selected health institutions in eastern Ethiopia. All pregnant women fulfilled the eligibility criteria in the selected health institutions was the source population. The calculated sample size of exposed and unexposed groups included in the study, in total, was 344. Data collection was performed prospectively by interviewers administered questionnaires, and anthropometric, clinical and ultrasound measurements. Data was analyzed using SPSS version 27 and STATA version 16 software. The survival analysis (cox proportional hazards model) and generalized linear model (GLM) for the binomial family analysis were performed to estimate the crude and adjusted relative risk and attributable risk (AR) with corresponding 95% CI of chewing khat on fetal growth restriction. The mediation effect has been examined through Generalized Structural Equation Modeling (GSEM) analysis using the Stata 'gsem' command. Statistically significant association was declared at p-value less than 5%., Results: In the present study, the incidence of fetal growth restriction (FGR) among the study cohorts was 95 (29.7%); of this, 81 (85.3%) were among khat chewer cohorts. The relative risk of fetal growth restriction among khat chewer cohort mothers was significantly higher (aRR = 4.32; 95%CI 2.62-7.12). Moreover, the incidence of small for gestational age at birth among the present study cohorts was 100 (31.3%); 84 (84%) were from khat chewer cohorts' deliveries. More importantly, in the present study, 98.95% of the ultrasound-identified fetuses with FGR were found to be SGA at birth. Hence, in the current study, FGR was highly associated with SGA at birth. In additional analysis, the regression coefficient of khat chewing during pregnancy on fetal growth restriction has been decreased in size from path o, β = 0.43, p < 0.001 to path o', β = 0.32, p < 0.001, after adjusting for gestational hypertension and maternal anemia., Conclusion: In sum, the present study showed khat chewing during pregnancy is not simply affected the mothers, but it also affected the unborn fetuses. Therefore, the health workers as well as the local community and religious leaders should give high emphasis on provision of health education regarding the damage of chewing khat by pregnant mothers, with especial focus of the effects on their fetuses., (© 2024. The Author(s).)

Objective: Fetal growth restriction is an independent risk factor for fetal death and adverse neonatal outcomes. The main aim of this study was to investigate the diagnostic performance of 32 vs 36 weeks ultrasound of fetal biometry in detecting late-onset fetal growth restriction and predicting small-for-gestational-age neonates., Data Sources: A systematic search was performed to identify relevant studies published until June 2022, using the databases PubMed, Web of Science, and Scopus., Study Eligibility Criteria: Cohort studies in low-risk or unselected singleton pregnancies with screening ultrasound performed at ≥32 weeks of gestation were used., Methods: The estimated fetal weight and abdominal circumference were assessed as index tests for the prediction of small for gestational age (birthweight of <10th percentile) and detecting fetal growth restriction (estimated fetal weight of <10th percentile and/or abdominal circumference of <10th percentile). The quality of the included studies was independently assessed by 2 reviewers using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. For the meta-analysis, hierarchical summary area under the receiver operating characteristic curves were constructed, and quantitative data synthesis was performed using random-effects models., Results: The analysis included 25 studies encompassing 73,981 low-risk pregnancies undergoing third-trimester ultrasound assessment for growth, of which 5380 neonates (7.3%) were small for gestational age at birth. The pooled sensitivities for estimated fetal weight of <10th percentile and abdominal circumference of <10th percentile in predicting small for gestational age were 36% (95% confidence interval, 27%-46%) and 37% (95% confidence interval, 19%-60%), respectively, at 32 weeks ultrasound and 48% (95% confidence interval, 41%-56%) and 50% (95% confidence interval, 25%-74%), respectively, at 36 weeks ultrasound. The pooled specificities for estimated fetal weight of <10th percentile and abdominal circumference of <10th percentile in detecting small for gestational age were 93% (95% confidence interval, 91%-95%) and 95% (95% confidence interval, 85%-98%), respectively, at 32 weeks ultrasound and 93% (95% confidence interval, 91%-95%) and 97% (95% confidence interval, 85%-98%), respectively, at 36 weeks ultrasound. The observed diagnostic odds ratios for an estimated fetal weight of <10th percentile and an abdominal circumference of <10th percentile in detecting small for gestational age were 8.8 (95% confidence interval, 5.4-14.4) and 11.6 (95% confidence interval, 6.2-21.6), respectively, at 32 weeks ultrasound and 13.3 (95% confidence interval, 10.4-16.9) and 36.0 (95% confidence interval, 4.9-260.0), respectively, at 36 weeks ultrasound. The pooled sensitivity, specificity, and diagnostic odds ratio in predicting fetal growth restriction were 71% (95% confidence interval, 52%-85%), 90% (95% confidence interval, 79%-95%), and 25.8 (95% confidence interval, 14.5-45.8), respectively, at 32 weeks ultrasound and 48% (95% confidence interval, 41%-55%), 94% (95% confidence interval, 93%-96%), and 16.9 (95% confidence interval, 10.8-26.6), respectively, at 36 weeks ultrasound. Abdominal circumference of <10th percentile seemed to have comparable sensitivity to estimated fetal weight of <10th percentile in predicting small-for-gestational-age neonates., Conclusion: An ultrasound assessment of the fetal biometry at 36 weeks of gestation seemed to have better predictive accuracy for small-for-gestational-age neonates than an ultrasound assessment at 32 weeks of gestation. However, an opposite trend was noted when the outcome was fetal growth restriction. Fetal abdominal circumference had a similar predictive accuracy to that of estimated fetal weight in detecting small-for-gestational-age neonates., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Fetal growth nomograms were developed to screen for fetal growth restriction and guide clinical care to improve perinatal outcomes; however, existing literature remains inconclusive regarding which nomogram is the gold standard., Objective: This study aimed to compare the ability of 4 commonly used nomograms (Hadlock, International Fetal and Newborn Growth Consortium for the 21st Century, Eunice Kennedy Shriver National Institute of Child Health and Human Development-unified standard, and World Health Organization fetal growth charts) and 1 institution-specific reference to predict small for gestational age and poor neonatal outcomes., Study Design: This was a retrospective cohort study of all nonanomalous singleton pregnancies undergoing ultrasound at ≥20 weeks of gestation between 2013 and 2020 and delivering at a single academic center. Using random selection methods, the study sample was restricted to 1 pregnancy per patient and 1 ultrasound per pregnancy completed at ≥22 weeks of gestation. Fetal biometry data were used to calculate estimated fetal weight and percentiles according to the aforementioned 5 nomograms. Maternal and neonatal data were extracted from electronic medical records. Logistic regression was used to estimate the association between estimated fetal weight of <10th and <3rd percentiles compared with estimated fetal weight of 10th to 90th percentile as the reference group for small for gestational age and the neonatal composite outcomes (perinatal mortality, hypoxic-ischemic encephalopathy or seizures, respiratory morbidity, intraventricular hemorrhage, necrotizing enterocolitis, hyperbilirubinemia or hypoglycemia requiring neonatal intensive care unit admission, and retinopathy of prematurity). Receiver operating characteristic curve contrast estimation (primary analysis) and test characteristics were calculated for all nomograms and the prediction of small for gestational age and the neonatal composite outcomes. We restricted the sample to ultrasounds performed within 28 days of delivery; moreover, similar analyses were completed to assess the prediction of small for gestational age and neonatal composite outcomes., Results: Among 10,045 participants, the proportion of fetuses classified as <10th percentile varied across nomograms from 4.9% to 9.7%. Fetuses with an estimated fetal weight of <10th percentile had an increased risk of small for gestational age (odds ratio, 9.9 [95% confidence interval, 8.5-11.5] to 12.8 [95% confidence interval, 10.9-15.0]). In addition, the estimated fetal weight of <10th and <3rd percentile was associated with increased risk of the neonatal composite outcome (odds ratio, 2.4 [95% confidence interval, 2.0-2.8] to 3.5 [95% confidence interval, 2.9-4.3] and 5.7 [95% confidence interval, 4.5-7.2] to 8.8 [95% confidence interval, 6.6-11.8], respectively). The prediction of small for gestational age with an estimated fetal weight of <10th percentile had a positive likelihood ratio of 6.3 to 8.5 and an area under the curve of 0.62 to 0.67. Similarly, the prediction of the neonatal composite outcome with an estimated fetal weight of <10th percentile had a positive likelihood ratio of 2.1 to 3.1 and an area under the curve of 0.55 to 0.57. When analyses were restricted to ultrasound within 4 weeks of delivery, among fetuses with an estimated fetal weight of <10th percentile, the risk of small for gestational age increased across all nomograms (odds ratio, 16.7 [95% confidence interval, 12.6-22.3] to 25.1 [95% confidence interval, 17.0-37.0]), and prediction improved (positive likelihood ratio, 8.3-15.0; area under the curve, 0.69-0.75). Similarly, the risk of neonatal composite outcome increased (odds ratio, 3.2 [95% confidence interval, 2.4-4.2] to 5.2 [95% confidence interval, 3.8-7.2]), and prediction marginally improved (positive likelihood ratio, 2.4-4.1; area under the curve, 0.60-0.62). Importantly, the risk of both being small for gestational age and having the neonatal composite outcome further increased (odds ratio, 21.4 [95% confidence interval, 13.6-33.6] to 28.7 (95% confidence interval, 18.6-44.3]), and the prediction of concurrent small for gestational age and neonatal composite outcome greatly improved (positive likelihood ratio, 6.0-10.0; area under the curve, 0.80-0.83)., Conclusion: In this large cohort, Hadlock, recent fetal growth nomograms, and a local population-derived fetal growth reference performed comparably in the prediction of small for gestational age and neonatal composite outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The aim of our study was to investigate the causes of fetal growth <10th centile diagnosed <26 weeks' gestation in singleton pregnancies and compare pregnancy outcomes in relation to the identified etiology., Material and Methods: Historical cohort study conducted in two Italian hospitals which included all small-for-gestational-age fetuses diagnosed between 18+0 and 26+0 weeks over a 10-year period. Fetuses were divided into three groups depending on the prenatally suspected etiology: chromosomal abnormalities (Group 1), malformations (Group 2) and isolated (Group 3). These groups were compared regarding pregnancy outcomes. Fetuses in Group 3 were divided into small-for-gestational-age and fetal growth restriction following the Delphi Consensus criteria and the outcomes were further compared. Fisher's Exact or Mann-Whitney test were used for comparison of groups., Results: In all, 435 fetuses were included. Of these, 20 cases (4.6%) were associated with chromosomal abnormalities (Group 1), 98 (22.5%) with fetal malformations (Group 2) and 317 (72.9%) were isolated (Group 3). A higher percentage of live births was reported for Group 3 (P < 0.001). Termination of pregnancy was more common in Group 1 (P < 0.001). No differences in gestational age at delivery, birthweight, intrauterine death or neonatal death were detected within groups. Growth-restricted fetuses had lower gestational age at delivery, birthweight and number of live births (P < 0.001), higher rates of termination of pregnancy, intrauterine death (P < 0.001) and neonatal death <10 days (P = 0.002) compared to small-for-gestational-age. In 17 cases a chromosomal abnormality, genetic syndrome or adverse neurological outcome was diagnosed after birth: six from Group 2 (11.3% of live births in this group) and 11 from Group 3 (4.3%)., Conclusions: We report that fetal growth <10th percentile diagnosed before 26 weeks is not isolated before birth in 27% of cases. Malformations and chromosomal abnormalities are common etiologies; therefore, detailed anomaly scans and invasive testing should be offered. In addition, there is a residual risk of neonatal death and postnatal diagnosis of a genetic syndrome or neurodevelopmental impairment despite normal prenatal tests. These results expand the small amount of information on the outcome of cases with very early diagnosis of impaired fetal growth currently available and highlight the importance of detailed counseling with couples., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: To investigate the afamin concentration in the serum of pregnant women diagnosed with late fetal growth restriction (FGR) or small for gestational age (SGA) in the third trimester., Methods: This prospective case-control study was conducted on 126 pregnant women, 42 of whom were diagnosed with late FGR in the third trimester, 43 were SGA, and 41 were healthy controls. The groups were compared in terms of maternal serum afamin concentrations., Results: Three groups were similar in terms of demographic characteristics and gestational age at blood sampling for afamin ( p  < .05). The median afamin concentration was determined as 199 ng/mL in the late FGR group, 153 ng/mL in the SGA group, and 108 ng/mL in the control group ( p  = .000). In the post-hoc analysis, while maternal serum afamin concentrations were found to be significantly higher in the late FGR group and SGA group compared to the control group but, this significance could not be shown between the FGR group and the SGA group ( p  = .00001, p  = .005, p  = .137, respectively). In the ROC analysis, the optimal cutoff value of serum afamin concentration to predict late FGR was determined as 141 ng/mL, with a sensitivity of 66.6% and a specificity of 85.3%., Conclusions: The serum afamin concentration in the third trimester was found to be higher in pregnant women with late FGR compared to the SGA and control groups. Although afamin is seen as a promising molecule in the clinical prediction of late FGR, this needs to be supported by large series of studies.

Background: Lipid disorders are one of the risk factors for cardiovascular diseases. The aim of the study was to estimate the lipid profile in early childhood in the population of Polish children born small for gestational age (SGA)., Materials and Methods: The study included 140 patients (93 SGA children and 47 controls) aged 5 to 11 years. All the subjects underwent a physical examination and blood laboratory tests for the glucose and lipid profiles. The SGA group was divided into subgroups, i.e., symmetrical and asymmetrical intrauterine growth restriction (IUGR)., Results: Blood sample analysis revealed higher levels of total cholesterol (SGA group 190.61 ± 24.66 mg/dL vs. controls 143.23 ± 23.90; p < 0.001). The analysis of particular cholesterol fractions showed significantly higher mean values of triglycerides and LDL cholesterol as well as lower mean values of HDL cholesterol in SGA children. Children in both groups did not differ significantly in terms of weight or body mass index. A statistically significantly higher glucose concentration was observed in SGA patients with the symmetrical type of IUGR. Analyzing the differences regarding metabolic factors, we obtained a statistically significant difference only in fasting glucose concentration (asymmetrical IUGR = 90.56 ± 10.21 vs. symmetrical IUGR = 98.95 ± 14.79; p < 0.001)., Conclusions: Children born SGA, even those not suffering from overweight or obesity in their early childhood, have an abnormal lipid profile, which may contribute to the development of cardiovascular diseases in adulthood.

Background: Criteria for diagnosis of fetal growth restriction differ widely according to national and international guidelines, and further heterogeneity arises from the use of different biometric and Doppler reference charts, making the diagnosis of fetal growth restriction highly variable., Objective: This study aimed to compare fetal growth restriction definitions between Delphi consensus and Society for Maternal-Fetal Medicine definitions, using different standards/charts for fetal biometry and different reference ranges for Doppler velocimetry parameters., Study Design: From the TRUFFLE 2 feasibility study (856 women with singleton pregnancy at 32 +0 to 36 +6 weeks of gestation and at risk of fetal growth restriction), we selected 564 women with available mid-pregnancy biometry. For the comparison, we used standards/charts for estimated fetal weight and abdominal circumference from Hadlock, INTERGROWTH-21 st , and GROW and Chitty. Percentiles for umbilical artery pulsatility index and its ratios with middle cerebral artery pulsatility index were calculated using Arduini and Ebbing reference charts. Sensitivity and specificity for low birthweight and adverse perinatal outcome were evaluated., Results: Different combinations of definitions and reference charts identified substantially different proportions of fetuses within our population as having fetal growth restriction, varying from 38% (with Delphi consensus definition, INTERGROWTH-21 st biometric standards, and Arduini Doppler reference ranges) to 93% (with Society for Maternal-Fetal Medicine definition and Hadlock biometric standards). None of the different combinations tested appeared effective, with relative risk for birthweight <10th percentile between 1.4 and 2.1. Birthweight <10th percentile was observed most frequently when selection was made with the GROW/Chitty charts, slightly less with the Hadlock standard, and least frequently with the INTERGROWTH-21 st standard. Using the Ebbing Doppler reference ranges resulted in a far higher proportion identified as having fetal growth restriction compared with the Arduini Doppler reference ranges, whereas Delphi consensus definition with Ebbing Doppler reference ranges produced similar results to those of the Society for Maternal-Fetal Medicine definition. Application of Delphi consensus definition with Arduini Doppler reference ranges was significantly associated with adverse perinatal outcome, with any biometric standards/charts. The Society for Maternal-Fetal Medicine definition could not accurately detect adverse perinatal outcome irrespective of estimated fetal weight standard/chart used., Conclusion: Different combinations of fetal growth restriction definitions, biometry standards/charts, and Doppler reference ranges identify different proportions of fetuses with fetal growth restriction. The difference in adverse perinatal outcome may be modest, but can have a significant impact in terms of rate of intervention., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Recent studies have demonstrated that a routine third-trimester ultrasound scan may improve the detection of small for gestational age infants when compared with clinically indicated ultrasound scans but with no reported reduction in severe perinatal morbidity. Establishing the optimal gestational age for the third-trimester examination necessitates evaluation of the ability to detect small for gestational age infants and to predict maternal and perinatal outcomes. Intrauterine growth restriction most often corresponds with small for gestational age infants associated with pathologic growth patterns., Objective: This study aimed to assess the performance of routine early ultrasound scans vs late ultrasound scans during the third trimester of pregnancy to identify small for gestational age infants and fetuses with intrauterine growth restriction., Study Design: This was an open-label, randomized, parallel trial conducted in Upper Normandy, France, from 2012 to 2015. The study eligibility criteria were heathy, nulliparous women older than 18 years with gestational age determined using the crown-rump length at the first trimester routine scan and with no fetal malformation or suspected small for gestational age fetus at the routine second trimester scan. Pregnant women were randomly assigned to a third-trimester scan group at 31 weeks gestational age ±6 days (early ultrasound scan) or at 35 weeks gestational age ±6 days (late ultrasound scan). The primary outcome of this trial was the ability of a third trimester scan to predict small for gestational age infants (customized birth weight <10th percentile) and intrauterine growth restriction (customized birth weight

Background: Previous research endeavors examining the association between clinical characteristics, sonographic indices, and the risk of adverse perinatal outcomes in pregnancies complicated by fetal growth restriction have been hampered by a lack of agreement regarding its definition. In 2016, a consensus definition was reached by an international panel of experts via the Delphi procedure, but as it currently stands, this has not been endorsed by all professional organizations., Objective: This study aimed to assess whether an independent association exists between estimated fetal weight and/or abdominal circumference of <10th percentile and adverse perinatal outcomes when consensus criteria for growth restriction are not met., Study Design: Data were derived from a passive prospective cohort of singleton nonanomalous pregnancies at a single academic tertiary care institution (2010-2022) that fell into 3 groups: (1) consecutive fetuses that met the Delphi criteria for fetal growth restriction, (2) small-for-gestational-age fetuses that failed to meet the consensus criteria, and (3) fetuses with birthweights of 20th to 80th percentile randomly selected as an appropriately grown (appropriate-for-gestational-age) comparator group. This nested case-control study used 1:1 propensity score matching to adjust for confounders among the 3 groups: fetal growth restriction cases, small-for-gestational-age cases, and controls. Our primary outcome was a composite: perinatal demise, 5-minute Apgar score of <7, cord pH of ≤7.10, or base excess of ≥12. Pregnancy characteristics with a P value of <.2 on univariate analyses were considered for incorporation into a multivariable model along with fetal growth restriction and small-for-gestational-age to evaluate which outcomes were independently predictive of adverse perinatal outcomes., Results: Overall, 2866 pregnancies met the inclusion criteria. After propensity score matching, there were 2186 matched pairs, including 511 (23%), 1093 (50%), and 582 (27%) patients in the small-for-gestational-age, appropriate-for-gestational-age, and fetal growth restriction groups, respectively. Moreover, 210 pregnancies (10%) were complicated by adverse perinatal outcomes. None of the pregnancies with small-for-gestational-age OR appropriate-for-gestational-age fetuses resulted in perinatal demise. Twenty-three of 511 patients (5%) in the small-for-gestational-age group had adverse outcomes based on 5-minute Apgar scores and/or cord gas results compared with 77 of 1093 patients (7%) in the appropriate-for-gestational-age group (odds ratio, 0.62; 95% confidence interval, 0.39-1.00). Furthermore, 110 of 582 patients (19%) with fetal growth restriction that met the consensus criteria had adverse outcomes (odds ratio, 3.08; 95% confidence interval, 2.25-4.20), including 34 patients with perinatal demise or death before discharge. Factors independently associated with increased odds of adverse outcomes included chronic hypertension, hypertensive disorders of pregnancy, and early-onset fetal growth restriction. Small-for-gestational age was not associated with the primary outcome after adjustment for 6 other factors included in a model predicting adverse perinatal outcomes. The bias-corrected bootstrapped area under the receiver operating characteristic curve for the model was 0.72 (95% confidence interval, 0.66-0.74). The bias-corrected bootstrapped area under the receiver operating characteristic curve for a 7-factor model predicting adverse perinatal outcomes was 0.72 (95% confidence interval, 0.66-0.74)., Conclusion: This study found no evidence that fetuses with an estimated fetal weight and/or abdominal circumference of 3rd to 9th percentile that fail to meet the consensus criteria for fetal growth restriction (based on Doppler waveforms and/or growth velocity of ≥32 weeks) are at increased risk of adverse outcomes. Although the growth of these fetuses should be monitored closely to rule out evolving growth restriction, most cases are healthy constitutionally small fetuses. The management of these fetuses in the same manner as those with suspected pathologic growth restriction may result in unnecessary antenatal testing and increase the risk of iatrogenic complications resulting from preterm or early term delivery of small fetuses that are at relatively low risk of adverse perinatal outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

(1) Intrauterine growth restriction (IUGR) is associated with multiple morbidities including growth restriction and impaired neurodevelopment. Small for gestational age (SGA) is defined as a birth weight <10th percentile, regardless of the etiology. The term is commonly used as a proxy for IUGR, but it may represent a healthy constitutionally small infant. Differentiating between IUGR and constitutionally small infants is essential for the nutritional management. (2) Infants born at <37 weeks of gestation between 2017 and 2022, who underwent body composition measurement (FFM: fat-free mass; FM: fat mass) at term-equivalent age, were included in this study. Infants with IUGR and constitutionally small infants (SGA) were compared to infants appropriate for gestational age (AGA). (3) A total of 300 infants (AGA: n = 249; IUGR: n = 40; SGA: n = 11) were analyzed. FFM ( p < 0.001) and weight growth velocity ( p = 0.022) were significantly lower in IUGR compared to AGA infants, but equal in SGA and AGA infants. FM was not significantly different between all groups. (4) The FFM Z-score was significantly lower in IUGR compared to AGA infants ( p = 0.017). Being born constitutionally small compared to AGA had no impact on growth and body composition. These data showed that early aggressive nutritional management is essential in IUGR infants to avoid impaired growth and loss of FFM.

Studies have shown that exposure to extreme ambient temperature can contribute to adverse pregnancy outcomes, however, results across studies have been inconsistent. We aimed to evaluate the relationships between trimester-specific extreme temperature exposures and fetal growth restriction indicated by small for gestational age (SGA) in term pregnancies, and to assess whether and to what extent this relationship varies between different geographic regions. We linked 1,436,480 singleton term newborns (2014-2016) in Hubei Province, China, with a sub-district-level temperature exposures estimated by a generalized additive spatio-temporal model. Mixed-effects logistic regression models were employed to estimate the effects of extreme cold (temperature ≤5th percentile) and heat exposures (temperature >95th percentile) on term SGA in three different geographic regions, while adjusting for the effects of maternal age, infant sex, the frequency of health checks, parity, educational level, season of birth, area-level income, and PM 2.5 exposure. We also stratified our analyses by infant sex, maternal age, urban‒rural type, income categories and PM 2.5 exposure for robustness analyses. We found that both cold (OR:1.32, 95% CI: 1.25-1.39) and heat (OR:1.17, 95% CI: 1.13-1.22) exposures during the third trimester significantly increased the risk of SGA in the East region. Only extreme heat exposure (OR:1.29, 95% CI: 1.21-1.37) during the third trimester was significantly related to SGA in the Middle region. Our findings suggest that extreme ambient temperature exposure during pregnancy can lead to fetal growth restriction. Governments and public health institutions should pay more attention to environmental stresses during gestation, especially in the late stage of the pregnancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Deoxynivalenol (DON), one of the most prevalent mycotoxins, has been found to cause fetal growth retardation in animals. However, limited evidence exists regarding its effects on pregnant women., Methods: Maternal urinary concentration of total DON (tDON) and free DON (fDON) in the second trimester was measured using liquid chromatography with tandem mass spectrometry. Provisional daily intake (PDI) of DON was calculated based on tDON concentration. Linear and logistic regression models were used to evaluate the association between DON exposure levels and birth weight, birth length, and the risk of small for gestational age (SGA)., Results: Among 1538 subjects, the median concentrations of tDON and fDON were 12.1 ng/mL and 5.1 ng/mL, respectively. The PDI values revealed that the median DON intake was 0.7 µg/kg bw, and 35.9% of the total population exceeded the provisional maximum tolerable daily intake (PMTDI) of 1 µg/kg bw. Compared with the lowest tertile, birth weight decreased by 81.11 g (95% CI: -127.00, -35.23) for tDON (P-trend < 0.001) and 63.02 g (95% CI: -108.72, -17.32) for fDON (P-trend = 0.004) in the highest tertile. Each unit increase in Ln-tDON and Ln-fDON was also inversely associated with birth weight. Furthermore, compared to those who did not exceed PMTDI, pregnant women whose PDI exceeded PMTDI had lower birth weight (β = -79.79 g; 95% CI: -119.09, -40.49) and birth length (β = -0.21 cm; 95% CI: -0.34, -0.07), and a higher risk of SGA (OR = 1.48; 95% CI: 1.02, 2.15) in their offspring. Similar associations with birth weight, birth length, and SGA were found when comparing the highest tertile of PDI to the lowest tertile (all P-trend < 0.05)., Conclusions: Maternal DON exposure is related to decreased birth weight. Our findings implicate that DON exposure during pregnancy may cause fetal growth faltering, and measures should be taken to reduce DON exposure in pregnant women., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Infants born small for gestational age (SGA) have an increased risk of developing various cardiovascular complications. While many influencing factors can be adjusted or adapt over time, congenital factors also have a significant role. This study, therefore, seeks to explore the effect of perinatal factors on the left ventricular (LV) parameters in SGA infants, as assessed immediately after birth., Methods and Materials: This single-center prospective cohort study, conducted between 2014 and 2018, involved healthy SGA newborns born > 35 weeks' gestation, delivered at New York-Presbyterian Brooklyn Methodist Hospital, and a gestational age (GA)-matched control group of appropriate for gestational age (AGA) infants. Data analysis was performed using multivariate linear regression in STATA., Results: The study enrolled 528 neonates, 114 SGA and 414 AGA. SGA infants exhibited a mean GA of 38.05 weeks (vs. 38.54), higher male representation (69.3% vs. 51.5%), lower birth weight (BW) (2318g vs 3381g), lower Apgar scores at birth, and a higher rate of neonatal intensive care unit admission compared to AGA infants (41.2% vs.18.9%; p<0.001). Furthermore, SGA infants were more likely to be born to nulliparous women (63.16% vs. 38.16%; p<0.001), with lower body mass index (BMI) (29.8 vs. 31.7; p=0.004), a lower prevalence of gestational maternal diabetes (GDM) (14.9 % vs. 35.5%; p<0.001), and a higher prevalence of preeclampsia (18.4 % vs. 6.52%; p<0.001). BW was identified as the most significant predictor affecting most LV parameters in this study (p<0.001), except shortening fraction, asymmetric interventricular septal hypertrophy and Inter-ventricular septal thickness/LV posterior wall ratio (IVS/LVPW). Lower GA (coefficient = -0.09, p=0.002), insulin use in GDM (coefficient = 0.39, p=0.014), and low APGAR scores at 1 minute (coefficient = -0.07, p<0.001) were significant predictors of IVS during diastole (R-squared [R 2 ]=0.24). High maternal BMI is marginally associated with LVPW during systole (R 2 =0.27, coefficient = 0.01, p=0.050), while male sex was a significant predictor of LV internal dimension during diastole (R 2 =0.29, p=0.033)., Conclusion: This study highlights the significant influence of perinatal factors on LV parameters in SGA infants, with BW being the most influential factor. Although LV morphology alone may not predict future cardiovascular risk in the SGA population, further research is needed to develop effective strategies for long-term cardiovascular health management in this population., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Antenatal detection of fetal growth restriction allows the opportunity to increase surveillance and initiate intervention to prevent adverse outcomes. Detection of small for gestational age (SGA) fetuses with risk factor screening and selective ultrasonography is the standard of care in Australia, but evidence regarding performance is lacking., Aims: To evaluate the diagnostic performance of a risk factor-based screening approach in detection of SGA neonates., Materials and Methods: Retrospective cohort study conducted in a metropolitan maternity service, including all consecutive singleton deliveries over 20 weeks gestation from July 2016 to December 2017, and excluding terminations of pregnancy. An SGA neonate was defined by birthweight below the tenth percentile according to Australian reference ranges. Antenatally detected SGA cases were defined by estimated fetal weight or abdominal circumference below the tenth percentile for gestational age, or abnormal symphysio-fundal height. The diagnostic accuracy of the screening protocol was calculated using detection rates and false-positive rates., Results: There were 13 384 singleton pregnancies included. There were 1330 infants (10.0%) who were SGA at birth. Antenatal detection rate of SGA neonates was 39.6% (95% confidence interval (CI) 37.0-42.3%), with a false-positive rate of 10.2% (95% CI 9.6-10.7%). There were 10 266 pregnancies (77.0%) which had at least one risk factor for an SGA infant. Of these, 6650 (64.8%) underwent at least one fetal growth ultrasound after 24 weeks gestation., Conclusions: Antenatal recognition of poor fetal growth is suboptimal using our current screening protocol. Three-quarters of pregnancies demonstrated risk factors for delivering an SGA infant, but growth ultrasonography may be underutilised., (© 2022 Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objective: To assess whether standardised longitudinal reporting of growth monitoring information improves antenatal detection of infants who are small for gestational age (SGA), compared with usual care., Design: Cluster-randomised controlled trial., Setting: Sixteen French level-3 units in 2018-2019., Population: Singleton pregnancies., Methods: The intervention consisted of the serial plotting of symphysis-fundal height (SFH) and estimated fetal weight (EFW) measurements on customised growth charts using a software program, compared with standard antenatal care. We estimated relative risks (RR) adjusted for known risk factors for fetal growth restriction (FGR)., Main Outcome Measures: The primary outcome was antenatal detection of FGR among SGA births (with birthweights below the tenth centile of French customised curves), defined as the mention of suspected FGR in medical records and either referral ultrasounds for growth monitoring or indicated delivery for FGR. Secondary outcomes were false-positive rates, mode of delivery, perinatal morbidity and mortality, and number of antenatal visits and ultrasounds., Results: In total, seven intervention clusters (n = 4349) and eight control clusters (n = 4943) were analysed, after the exclusion of one intervention centre for a major deviation in protocol. SGA births represented 613 (14.1%) and 626 (12.7%) of all births, respectively. The rates of antenatal detection of FGR among SGA births were 40.0% in the intervention arm versus 37.1% in the control arm (crude RR 1.08, 95% CI 0.87-1.34; adj RR 1.09, 95% CI 0.88-1.35). No benefits of the intervention were detected in the analyses of secondary outcomes., Conclusions: Serial plotting of SFH and EFW measurements on customised growth charts did not improve the antenatal detection of FGR among SGA births., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To evaluate the performance of INTERGROWTH-21 st (IG-21 st ) and World Health Organization (WHO) fetal growth charts to identify small-for-gestational-age (SGA) and fetal growth restriction (FGR) neonates, as well as their specific risks for adverse neonatal outcomes., Methods: Multicenter cross-sectional study including 67 968 live births from 10 maternity units across four Latin American countries. According to each standard, neonates were classified as SGA and FGR (birth weight <10 th and less than third centiles, respectively). The relative risk (RR) and diagnostic performance for a low APGAR score and low ponderal index were calculated for each standard., Results: WHO charts identified more neonates as SGA than IG-21 st (13.9% vs 7%, respectively). Neonates classified as having FGR by both standards had the highest RR for a low APGAR (RR, 5.57 [95% confidence interval (CI), 3.99-7.78]), followed by those who were SGA by both curves (RR, 3.27 [95% CI, 2.52-4.24]), while neonates with SGA identified by WHO alone did not have an additional risk (RR, 0.87 [95% CI, 0.55-1.39]). Furthermore, the diagnostic odds ratio for a low APGAR was higher when IG-21 st was used., Conclusion: In a population from Latin America, the WHO charts seem to identify more SGA neonates, but the diagnostic performance of the IG-21 st charts for low APGAR score and low ponderal index is better., (© 2023 International Federation of Gynecology and Obstetrics.)

Reduced birthweight is a marker of pathologies that impair growth and also decrease survival. However, "fetal growth restriction" remains poorly defined. Assuming that birthweight itself has no causal effect on neonatal mortality, we can estimate the features of pathological fetal growth that would be required to produce the observed pattern of weight-specific mortality. Under the simplest possible scenario, we find that at 39-41 weeks, pathological fetal growth restriction affects only about 0.5% of U.S. births, with a neonatal mortality risk up to 220-fold. This surprising concentration of pathology among a tiny subset of babies would account for roughly half of neonatal deaths at term. Moreover, the prevalence of these pathological births appears to have remained relatively stable over recent decades, even as neonatal mortality in the U.S. has declined by 90%. In our model, the decline has been driven by the reduction in baseline mortality (i.e., mortality among babies unaffected by growth pathologies), while the relative risk of death among pathologically grown infants has apparently remained stable. Fetal growth restriction is conventionally regarded as common and preventable. In contrast, our observations suggest that pathological fetal growth is rare and constant over time, perhaps the result of unpreventable stochastic errors in embryonic development. Public health strategies may be more effective by setting aside attempts to increase birthweight, and focusing instead on the discovery and support of factors (unrelated to birthweight) that have produced the striking reductions in neonatal mortality over time., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Fetal growth restriction (FGR) leading to low birth weight (LBW) is a major cause of neonatal morbidity and mortality worldwide. Normal placental development involves a series of highly regulated processes involving a multitude of hormones, transcription factors, and cell lineages. Failure to achieve this leads to placental dysfunction and related placental diseases such as pre-clampsia and FGR. Early recognition of at-risk pregnancies is important because careful maternal and fetal surveillance can potentially prevent adverse maternal and perinatal outcomes by judicious pregnancy surveillance and careful timing of birth. Given the association between a variety of circulating maternal biomarkers, adverse pregnancy, and perinatal outcomes, screening tests based on these biomarkers, incorporating maternal characteristics, fetal biophysical or circulatory variables have been developed. However, their clinical utility has yet to be proven. Of the current biomarkers, placental growth factor and soluble fms-like tyrosine kinase 1 appear to have the most promise for placental dysfunction and predictive utility for FGR., (© 2023 The Author(s).)

Research Question: What part do maternal context and medically assisted reproduction (MAR) techniques play in the risk of fetal growth disorders?, Design: This retrospective nationwide cohort study uses data available in the French National Health System database and focuses on the period from 2013 to 2017. Fetal growth disorders were divided into four groups according to the origin of pregnancy: fresh embryo transfer (n = 45,201), frozen embryo transfer (FET, n = 18,845), intrauterine insemination (IUI, n = 20,179) and natural conceptions (n = 3,412,868). Fetal growth disorders were defined from the percentiles of the weight distribution according to gestational age and sex: small and large for gestational age (SGA and LGA) if <10th and >90th percentiles, respectively. Analyses were performed using univariate and multivariate logistic models., Results: Compared with births following natural conception, multivariate analysis showed that the risk of SGA was higher for births following fresh embryo transfer and IUI (adjusted odds ratio [aOR] 1.26 [1.22-1.29] and 1.08 [1.03-1.12], respectively) and significantly lower following FET (aOR 0.79 [0.75-0.83]). The risk of LGA was higher for births following FET (aOR 1.32 [1.27-1.38]), especially in artificial cycles when compared with ovulatory cycles (aOR 1.25 [1.15-1.36]). In the subgroup of births without any obstetrical or neonatal morbidity, the same increased risk of SGA and LGA were observed following fresh embryo transfer or IUI and FET (aOR 1.23 [1.19-1.27] or 1.06 [1.01-1.11] and aOR 1.36 [1.30-1.43], respectively)., Conclusions: An effect of MAR techniques on the risks for SGA and LGA is suggested independently from maternal context and obstetrical or neonatal morbidities. Pathophysiological mechanisms remain poorly understood and should be further evaluated, as well as the influence of embryonic stage and freezing techniques., (Copyright © 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: To systematically identify and critically assess the quality of clinical practice guidelines (CPGs) on management fetal growth restriction (FGR)., Content: Medline, Embase, Google Scholar, Scopus and ISI Web of Science databases were searched to identify all relevant CPGs on FGR., Summary: Diagnostic criteria of FGR, recommended growth charts, recommendation for detailed anatomical assessment and invasive testing, frequency of fetal growth scans, fetal monitoring, hospital admission, drugs administrations, timing at delivery, induction of labor, postnatal assessment and placental histopathological were assessed. Quality assessment was evaluated by AGREE II tool. Twelve CPGs were included. Twenty-five percent (3/12) of CPS adopted the recently published Delphi consensus, 58.3% (7/12) an estimated fetal weight (EFW)/abdominal circumference (AC) EFW/AC <10th percentile, 8.3% (1/12) an EFW/AC <5th percentile while one CPG defined FGR as an arrest of growth or a shift in its rate measured longitudinally. Fifty percent (6/12) of CPGs recommended the use of customized growth charts to assess fetal growth. Regarding the frequency of Doppler assessment, in case of absent or reversed end-diastolic flow in the umbilical artery 8.3% (1/12) CPGs recommended assessment every 24-48, 16.7% (2/12) every 48-72 h, 1 CPG generically recommended assessment 1-2 times per week, while 25 (3/12) did not specifically report the frequency of assessment. Only 3 CPGs reported recommendation on the type of Induction of Labor to adopt. The AGREE II standardized domain scores for the first overall assessment (OA1) had a mean of 50%., Outlook: There is significant heterogeneity in the management of pregnancies complicated by FGR in published CPGs., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Although fetal size is associated with adverse perinatal outcome, the relationship between fetal growth velocity and adverse perinatal outcome is unclear., Objective: This study aimed to evaluate the relationship between fetal growth velocity and signs of cerebral blood flow redistribution, and their association with birthweight and adverse perinatal outcome., Study Design: This study was a secondary analysis of the TRUFFLE-2 multicenter observational prospective feasibility study of fetuses at risk of fetal growth restriction between 32 +0 and 36 +6 weeks of gestation (n=856), evaluated by ultrasound biometry and umbilical and middle cerebral artery Doppler. Individual fetal growth velocity was calculated from the difference of birthweight and estimated fetal weight at 3, 2, and 1 week before delivery, and by linear regression of all available estimated fetal weight measurements. Fetal estimated weight and birthweight were expressed as absolute value and as multiple of the median for statistical calculation. The coefficients of the individual linear regression of estimated fetal weight measurements (growth velocity; g/wk) were plotted against the last umbilical-cerebral ratio with subclassification for perinatal outcome. The association of these measurements with adverse perinatal outcome was assessed. The adverse perinatal outcome was a composite of abnormal condition at birth or major neonatal morbidity., Results: Adverse perinatal outcome was more frequent among fetuses whose antenatal growth was <100 g/wk, irrespective of signs of cerebral blood flow redistribution. Infants with birthweight <0.65 multiple of the median were enrolled earlier, had the lowest fetal growth velocity, higher umbilical-cerebral ratio, and were more likely to have adverse perinatal outcome. A decreasing fetal growth velocity was observed in 163 (19%) women in whom the estimated fetal weight multiple of the median regression coefficient was <-0.025, and who had higher umbilical-cerebral ratio values and more frequent adverse perinatal outcome; 67 (41%; 8% of total group) of these women had negative growth velocity. Estimated fetal weight and umbilical-cerebral ratio at admission and fetal growth velocity combined by logistic regression had a higher association with adverse perinatal outcome than any of those parameters separately (relative risk, 3.3; 95% confidence interval, 2.3-4.8)., Conclusion: In fetuses at risk of late preterm fetal growth restriction, reduced growth velocity is associated with an increased risk of adverse perinatal outcome, irrespective of signs of cerebral blood flow redistribution. Some fetuses showed negative growth velocity, suggesting catabolic metabolism., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to explore the association between maternity formula supplementation and small for gestational age (SGA) status in Chinese newborns., Methods: Data were from a population-based cross-sectional survey conducted in Shaanxi, Northwest China between August and December 2013. A total of 27 780 women pregnant with singletons and 356 with twins were included in this survey. Information on use of maternity formulas fortified with vitamins, folic acid, pantothenic acid, calcium, iron, zinc, and docosahexaenoic acid (DHA) was collected. SGA was defined as birthweight <10th percentile of fetal growth. Generalized linear models and estimating equation models were used to estimate crude odds ratios (ORs) or adjusted ORs with 95% confidence intervals (CIs) for SGA., Results: The rate of maternity formula supplementation during the entire pregnancy was 13.0% in the overall population. There was no significant association between maternal formula supplementation during pregnancy and the risk of total SGA birth (OR: 1.00; 95% CI, 0.90-1.11; P = 0.950). However, maternity formula supplementation during pregnancy was related to a lower risk of SGA for twins (OR: 0.49; 95% CI, 0.31-0.80; P = 0.004), twin A (OR: 0.50; 95% CI, 0.25-0.98; P = 0.045), and twin B (OR: 0.48; 95% CI, 0.25-0.95; P = 0.034). Furthermore, maternity formula supplementation during the first trimester was inversely associated with the risk of SGA birth of twins (OR: 0.32; 95% CI, 0.15-0.65; P = 0.002)., Conclusions: No significant association was observed between maternity formula supplementation and total SGA birth. However, women supplemented with maternal formula during pregnancy, especially during the first trimester, may have a reduced risk of SGA birth of twins., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Children with late fetal growth restriction (FGR) are at high risk of being born small for gestational age (SGA). These categories of newborns are at increased risk for neurodevelopment impairment. The general movements assessment, in particular at fidgety age, has been used to predict neurological dysfunctions. This study aimed to evaluate growth recovery, presence of fidgety movements at 3 months, and neurodevelopmental outcome at 2 years of age in term late FGR infants and adequate for gestational age (AGA) controls., Methods: Prospective clinical evaluation. At 3 months auxological parameters (AP) and neurological examination were evaluated while at 24 months neurodevelopment outcome by Griffiths Mental Development Scales (GMDS-R) was evaluated., Results: 38 late FGR and 20 AGA controls completed the study. Despite a significant catch up, at 3 months 13% of late FGR presented at least one auxological parameter <3° percentile. Moreover, 23.7% of late FGR infants did not show fidgety movements compared to 100% AGA controls ( p  < .001). Cranial circumference at birth resulted a positive predictive factor for FMs ( p  = .039). At 2 years of age, a difference statistically significant between late FGR and AGA was detected in GMDS-R., Conclusion: Independently from growth recovery, fidgety movements resulted less expressed in late FGR infants, and at 2 years of age the neurodevelopmental assessment revealed differences in each domain of evaluation between late FGR and AGA infants, although within normal ranges.

Objective: To investigate the characteristics of dendritic cells (DC) and natural killer cells (NK) in umbilical cord blood of pregnant patients diagnosed with idiopathic fetal growth restriction (IFGR)., Methods: A prospective study cohort of IFGR patients was established who were in the third trimester (28-36 weeks), with a healthy, pregnant woman cohort selected as controls. Umbilical cord blood was collected., Results: The study included 50 pregnant women in the IFGR group and 50 pregnant women in the healthy, control group. The incidence of SGA in the IFGR group was 52.0%, and the incidence of preterm birth was 18.0%. The incidence of neonatal complications in neonates with live birth in the IFGR group was 12.0%. The birth weight, body length and placental weight of the newborns in the IFGR group were significantly lower than those in the control group ( p  < .05). Flow cytometry revealed no significant difference in the proportion or maturity of DC in umbilical cord blood between IFGR group and control group ( p  > .05). The proportion of NK cells in umbilical cord blood of IFGR group was significantly higher than that of normal control group. The proportion of CD56dimCD16+ NK cells was also significantly higher than that of the normal control group ( p  < .05), but the expression of NK cell surface killing activator receptor NKG2D and inhibitory receptor NKG2A was not statistically significant ( p  > .05)., Conclusion: The number and proportion of DC cells in cord blood may not be the key factors affecting the outcomes observed during FGR pregnancies. However, we found the proportion of NK cells in cord blood to be significantly increased, as well as the ratio of CD56dimCD16 + NK to CD56highCD16-NK to be imbalanced, which may be one of the pathogenesis of the pathological pregnancy leading to IFGR.

Objectives: To improve identification of fetal growth restriction (FGR) by means of umbilical venous flow (QUV) and maternal hemodynamics, including systemic vascular resistance (SVR) and cardiac output (CO), in order to distinguish between FGR and SGA., Methods: We enrolled 68 pregnancies (36 SGA, 8 early FGR and 24 late FGR) who underwent a complete fetal hemodynamic examination including QUV and a noninvasive maternal hemodynamics assessment by means of USCOM., Results: In comparison with SGA, QUV and corrected for estimated fetal weight QUV (cQUV) were significantly lower in early and late-FGR. In addition, maternal CO was lower in early and late-FGR, while SVR was lower only in early-onset FGR. According to ROC analysis, cQUV centile (AUC 0.92, 0.72) was the best parameter for the prediction of SGA before and after 32 weeks, followed by SVR and CO. For all parameters, the prediction was always better in the case of early-onset FGR <32 weeks., Conclusions: UV flow and maternal hemodynamics examination are useful tools to accurately discern between SGA and FGR.

Objective: The ductus venosus, a small blood vessel in the fetal venous system, has extraordinary physiologic significance because it connects the umbilical vein to the inferior vena cava in the fetus circulation system and transports highly oxygenated blood from the placenta to the fetus' heart. Hence, assessment of ductus venosus flows is helpful in evaluating fetal hemodynamics. Considering the critical function of the ductus venosus, we hypothesized that the diameter of the midtrimester ductus venosus and its peak velocity index can be related to adequate fetal growth; therefore, the aim of this study was to evaluate the role of the midtrimester umbilical venous blood flow, ductus venosus diameter, and ductus venosus peak systolic velocity to help predict uncomplicated deliveries of late onset small for gestational age (SGA) fetuses., Methods: In this prospective study we analyzed the pregnancies and deliveries of 398 pregnant women who met the inclusion criteria and divided them into three groups according to fetal birth weight as follows: birth weight <3 percentile SGA group ( n  = 16), birth weight 3-10 percentile SGA group ( n  = 42), and appropriate for the gestational age (AGA) group ( n  = 340). The midtrimester ductus venosus diameter and peak sistolic velocity, umbilical venous blood flow, and umbilical artery pulsatility index (PI) were recorded. In the absence of congenital anomalies, the diagnosis of fetal growth restriction (FGR) is made according to Delphi consensus criteria. In the absence of abnormal Doppler findings, late FGR was defined as occurring ≥32 weeks., Results: Maternal age, nulliparity, mean gestational age at ultrasound evaluation, ethnicity, body mass index, and previous cesarean delivery rates were similar among the groups. In addition, mid-trimester fetal biometric measurements and amniotic fluid volume were similar among the groups. The gestational age at delivery, prematurity, fetal birth weight, vaginal delivery rates, and rate of admission to the neonatal intensive care unit were significantly different among the groups. The mean mid-trimester umbilical vein blood flow to abdominal circumference ratio (UVBF/AC) was similar among the groups ( p =.740). In the <3 group, the mean peak systolic velocity of the ductus venosus was significantly lower and the mean diameter of the ductus venosus significantly higher than those in the 3-10 and AGA groups (both p <.001). Although the values are below the 95th percentile mid-trimester umbilical artery PI was significantly higher in the <3 percentile SGA group than in the 3-10 percentile SGA and AGA groups., Conclusion: Our results suggest that the diameter and peak systolic velocity of the mid-trimester ductus venosus are useful noninvasive measurements that provide prediction of late onset SGA fetuses.

Objective: The aim of this study was to assess the added value of the soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio for adjusting the periodicity of ultrasound examinations in early-onset fetal growth restriction (FGR) and small for gestational age (SGA)., Design: A prospective, observational study., Setting: Tertiary referral hospital., Population: One hundred and thirty-four single pregnancies with ultrasonographic estimated fetal weight (EFW) below the 10th centile between 20 +0 and 31 +6  weeks of gestation with antegrade umbilical artery flow., Methods: The time from Doppler and sFlt-1/PlGF assessment to delivery was recorded and classified into four ranges: <1, <2, <3 and <4 weeks., Main Outcome Measures: Sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of sFlt-1/PlGF values to predict the time to delivery., Results: In the SGA cohort, the NPV calculated for an sFlt-1/PlGF cut-off value of 38 was 100% for delivery before 3 weeks, and 98% for delivery before 4 weeks after diagnosis (95% CI 0.89-1.00). In the FGR cohort, the NPV calculated for an sFlt-1/PlGF cut-off value of 38 was 100% for delivery before 2 weeks after diagnosis (95% CI 0.92-1.00). By contrast, more than 50% of cases with an sFlt-1/PlGF value of >85 required an elective delivery before 1 week., Conclusions: sFlt-1/PlGF values in early-onset SGA and FGR are predictive of the time to delivery and could be used for planning fetal surveillance, by reducing the frequency of ultrasound in cases with sFlt-1/PlGF < 38 and by providing closer follow-up in cases with sFlt-1/PlGF >85., Tweetable Abstract: sFlt-1/PlGF values in early-onset SGA/FGR could be used in addition to Doppler for planning fetal surveillance., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Purpose: Being born small for gestational age (SGA) is associated with a higher frequency and more severe forms of hypospadias as well as with potential developmental differences. This study aims to characterize operative outcomes in SGA boys compared to boys born with normal weight and length for gestational age (appropriate/large for gestational age, AGA/LGA)., Methods: Demographic data, hypospadias characteristics, associated pathologies and operative outcomes of boys who underwent hypospadias repair at a single center (10/2012-10/2019) were evaluated. Boys were categorized into SGA and non-SGA, which were then compared using unpaired t-tests and chi square tests. To examine the effect of SGA on reoperative risk, a logistic regression model was applied integrating surgical technique, meatal localization and complex hypospadias (narrow glans/plate, curvature, micropenis, bilateral cryptorchidism)., Results: SGA boys accounted for 13.7% (n = 80) of the total cohort (n = 584) and 33% of all proximal hypospadias (n = 99, SGA vs. non-SGA 41.3% vs. 13%, p < 0.001). After a mean follow-up of 18.6 months the reoperation rate for all hypospadias was 17.9% (n = 105). In distal hypospadias there was no difference in reoperation rate between SGA and AGA/LGA boys (p = 0.548, multivariate regression model). For each meatal localization in proximal hypospadias SGA was a significant, independent factor predicting higher reoperation rates (p = 0.019, OR 3.21) in a logistic regression model (Figure ROC)., Discussion: Hypospadias surgery carries a substantial risk for unplanned reinterventions. Apart from meatal localization, there are only a few factors (urethral plate quality, glandular diameter, curvature) reported in literature to be associated with reoperative risk. Intrauterine growth retardation associated with SGA might lead to not only a higher probability of proximal hypospadias but also contribute to a higher risk for complications mediated by developmental differences. Whether these findings could help to tailor surgical strategies or adjuvant measures, as for example the application of preoperative hormonal stimulation remains to be determined in future studies. This study is limited by being a single-center series with limited follow-up resulting in some complications probably not yet detected - however, in the same extent in both groups., Conclusion: Based on this study, 33% of all proximal hypospadias cases occur in boys born SGA. While the reoperation rate in boys with distal hypospadias was not influenced by SGA status, SGA proved to be an independent predictor of a higher risk of reoperation in those with proximal hypospadias. After validation of these findings in other centers, this could be integrated into counseling and risk-stratification., Competing Interests: Conflict of Interest All authors indicate no conflicts of interest and received no funding for this project., (Copyright © 2022 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: There are multiple etiologies for being born small for gestational age (SGA). However, extended familial data in idiopathic cases have been scarcely reported., Objective: Our aim was to explore the familial history of SGA newborns and describe the proportion and distribution of SGA in their parents and parental siblings., Methods: This was a retrospective study performed at an obstetrics clinic holding a detailed reliable electronic database. Between 2008 and 2017, data of 14,003 patients and 20,617 pregnancies were recorded. Parents of SGA infants were identified and extended familial history was obtained by questionnaires, including birth weights (BWs) and gestational age at birth of the parents and parents' siblings. SGA was defined as a BW below the 10th percentile. Proportions of maternal, paternal, and parental siblings' SGA were calculated. Chi-square test was performed to assess the relationship between SGA family member's gender and SGA infants' gender, and between the relative's gender and their family relationship to the infant., Results: About 2100 women had a history of a previous infant born SGA, however, after exclusion the final cohort comprised 926 women with a previous SGA infant. In 473 cases there was at least one other family member of the infant born SGA: father, mother, aunt, or uncle of the infant, representing a prevalence of 51% (473/926) of familial SGA. Out of familial SGA cases, maternal SGA was found in 55% (260/473), and paternal SGA was found in 28.1% (133/473). 27.6% had more than one SGA relative. Eighteen infants had both an SGA father and an SGA mother (3.8%). A history of an SGA aunt or uncle was found in 44% (209/473) of familial SGA cases, which was 22.5% (209/926) of the entire cohort. Parental sibling SGA occurred almost twice in mother's siblings as compared to father's siblings. Chi-square test revealed no association between the SGA relative's gender and their family relationship to the infant. There was no association between the SGA infant's gender and the SGA relative's gender., Conclusions: A family history of SGA is common in SGA infants, and occurs most often in mothers. This study found 22% SGA in parental siblings, in maternal siblings more than paternal siblings, supporting the possibility of a genetic component in SGA trait transmission. In clinical practice, when counseling parents with a growth-restricted fetus from an unknown etiology, extended familial birthweight history should be obtained and taken into account, which may be helpful in reducing parental anxiety.

Objectives: Fetal growth restriction (FGR) is a condition characterized by its complexity in diagnosis and management. There is a need for early accurate diagnosis, evidence-based monitoring and management of FGR to improve neonatal outcomes. This study evaluated differences and similarities in protocols of Dutch hospitals in the approach of (suspected) FGR in the context of the national guideline., Study Design: FGR protocols were collected from Dutch hospitals between November 2019 and June 2020. Collected data were coded for further analysis and categorized in eight predetermined key domains of definition, preventive measures, testing, referral, monitoring strategies, interventions, mode of delivery and pathologic placenta examination., Results: 55 of 71 approached hospitals (78 %) responded to the request and 54 protocols (76 %) were obtained. Protocols used variable definitions of FGR, and management was mostly based on fetal biometry results in combination with Doppler results (n = 47, 87 %). In pregnancies with an abdominal circumference (AC) or an estimated fetal weight (EFW) <10th percentile with normal Doppler results, induction of labour was recommended ≥37 weeks (n = 1, 2 %), ≥38-40 weeks (n = 23, 43 %); ≥41 weeks (n = 1, 2 %) or not specified (n = 29, 54 %). In case of an umbilical artery (UA) Doppler pulsatility index >95th percentile, (preterm) labour induction was recommended in the majority of the protocols regardless of fetal size (≥36 weeks: n = 2, 4 %; ≥37 weeks: n = 41, 76 %, not stated: n = 11, 20 %)., Conclusion: This study found practice variation in all predetermined domains of FGR protocols of Dutch hospitals, underscoring the complexity of the condition. The differences found in this study feed the research agenda that informs the process of improving obstetric care by better identification of the fetus at risk for consequences of FGR, improving evidence-based monitoring strategies to identify (imminent) fetal hypoxia, and more accurate timing of delivery., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The clinical inability to correctly identify late fetal growth restriction (FGR) within a group of fetuses who are identified as small for gestational age (SGA) is an everyday problem for all obstetrician-gynecologists. This leads to substantial overtreatment of healthy small fetuses but also inadequate detection of the growth-restricted fetuses that may benefit from timely delivery. Redistribution of the fetal circulation, signaled by an abnormal ratio of the Doppler velocity flow profiles of the umbilical artery and the middle cerebral artery, more specifically an increased umbilicocerebral ratio (UCR) (or its inverse: a decreased cerebroplacental ratio (CPR)), is an adaptation to chronic hypoxemia and nutritional scarcity with long-term consequences in survivors. The relevance of an abnormal UCR has been signaled extensively, and there is a general consensus that it is a signal of FGR, independent of size, with a strong association with poor outcomes. Yet, in the current literature, no comparisons of a monitoring-delivery strategy based on unfavorable UCR have been published. The objective of the Doppler Ratio In fetal Growth restriction Intervention Trial At (near) Term (DRIGITAT) is to evaluate if the timing of the delivery based on an abnormal UCR in late preterm fetuses identified as SGA improves neurodevelopmental outcomes at 2 years of age., Methods: The DRIGITAT study is a national multicenter cohort study of women with singleton pregnancies between 32 and 37 weeks of gestation identified as SGA, with a nested randomized controlled trial (RCT) in case of an abnormal UCR (> 0.8). Recruiting centers are in The Netherlands. In the nested RCT, women are randomized to either immediate induction of labor or expectant management from 34 weeks in case of severely abnormal size (EFW or FAC < p3) and from 36 weeks in case of mildly abnormal size (EFW or FAC p3-p10). The primary outcome measure is the 7-point average difference in the composite cognitive score (CCS) and composite motor score (CMS) on the Bayley-3 at 2 years. Secondary outcome measures include a composite outcome of neonatal morbidity, perinatal mortality, mode of delivery, maternal quality of life, costs, and predictive value of serum biomarkers. Analyses will be by intention to treat. The required sample size is determined for the nested RCT as 185 patients., Discussion: This study will provide insight into the diagnostic efficacy of UCR measurement in the evaluation of SGA fetuses in order to differentiate the healthy SGA fetus from the growth-restricted fetus and to determine if a fetus with abnormal UCR benefits from early delivery., Trial Registration: Healthcare Evaluation Netherlands NTR6663 . Registered on 14 August 2017., (© 2022. The Author(s).)

Objective: To explore the relationship between changes in blood high-density lipoprotein cholesterol (HDL-C) levels in advanced pregnancy and the risk of small for gestational age (SGA) in healthy full-term pregnant women., Methods: In this retrospective nested case-control study, pregnant women who got antenatal visits and experienced a healthy full-term delivery in Affiliated Women's Hospital, Zhejiang University School of Medicine in 2017 were enrolled. From the cohort, 249 women delivered SGA infants with completed clinical data were set as SGA group, 996 women who delivered normal neonates were randomly selected as matched controls (1∶4). The data of baseline characteristics, the HDL-C levels in 24 th -27 th week and after 37 th week were collected, the average HDL-C changes every four weeks in the third trimester (ΔHDL-C) were calculated. Paired t test was used to compare the differences of HDL-C and ΔHDL-C between cases and controls, and a conditional logistic regression model was applied to analyze the association between ΔHDL-C and the risk of SGA., Results: HDL-C levels after the 37 th week in both groups were lower than those in mid-pregnancy (ΔHDL-C<0 and P <0.05 for both groups), while the ΔHDL-C levels in SGA group were significantly higher ( P <0.05). Compared with women with low ΔHDL-C, the risk of SGA was higher for women with middle and high ΔHDL-C ( OR =1.74, 95% CI ：1.22-2.50; OR =2.48, 95% CI ：1.65-3.70, both P <0.05)., Conclusion: In healthy full-term pregnant women, the risk of SGA is associated with the HDL-C changing trend, HDL-C level decreasing slowly or even raising in the third trimester indicate that SGA may be likely to occur.

Intrauterine growth restriction (IUGR) is linked to lifelong reductions in muscle mass due to intrinsic functional deficits in myoblasts, but the mechanisms underlying these deficits are not known. Our objective was to determine if the deficits were associated with changes in inflammatory and adrenergic regulation of IUGR myoblasts, as was previously observed in IUGR muscle. Primary myoblasts were isolated from IUGR fetal sheep produced by hyperthermia-induced placental insufficiency (PI-IUGR; n = 9) and their controls (n = 9) and from IUGR fetal sheep produced by maternofetal inflammation (MI-IUGR; n = 6) and their controls (n = 7). Proliferation rates were less (P < 0.05) for PI-IUGR myoblasts than their controls and were not affected by incubation with IL-6, TNF-α, norepinephrine, or insulin. IκB kinase inhibition reduced (P < 0.05) proliferation of control myoblasts modestly in basal media but substantially in TNF-α-added media and reduced (P < 0.05) PI-IUGR myoblast proliferation substantially in basal and TNF-α-added media. Proliferation was greater (P < 0.05) for MI-IUGR myoblasts than their controls and was not affected by incubation with TNF-α. Insulin increased (P < 0.05) proliferation in both MI-IUGR and control myoblasts. After 72-h differentiation, fewer (P < 0.05) PI-IUGR myoblasts were myogenin+ than controls in basal and IL-6 added media but not TNF-α-added media. Fewer (P < 0.05) PI-IUGR myoblasts were desmin+ than controls in basal media only. Incubation with norepinephrine did not affect myogenin+ or desmin+ percentages, but insulin increased (P < 0.05) both markers in control and PI-IUGR myoblasts. After 96-h differentiation, fewer (P < 0.05) MI-IUGR myoblasts were myogenin+ and desmin+ than controls regardless of media, although TNF-α reduced (P < 0.05) desmin+ myoblasts for both groups. Differentiated PI-IUGR myoblasts had greater (P < 0.05) TNFR1, ULK2, and TNF-α-stimulated TLR4 gene expression, and PI-IUGR semitendinosus muscle had greater (P < 0.05) TNFR1 and IL6 gene expression, greater (P < 0.05) c-Fos protein, and less (P < 0.05) IκBα protein. Differentiated MI-IUGR myoblasts had greater (P < 0.05) TNFR1 and IL6R gene expression, tended to have greater (P = 0.07) ULK2 gene expression, and had greater (P < 0.05) β-catenin protein and TNF-α-stimulated phosphorylation of NFκB. We conclude that these enriched components of TNF-α/TNFR1/NFκB and other inflammatory pathways in IUGR myoblasts contribute to their dysfunction and help explain impaired muscle growth in the IUGR fetus., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We aimed to examine the contribution of splenic artery (SA) Doppler parameters in the detection of foetuses with late-onset foetal growth restriction (LO-FGR) and to evaluate its power in predicting adverse perinatal outcomes. Within the study's scope, 52 cases in the LO-FGR group and 92 cases in the control group were evaluated. The criteria determined in the Delphi procedure by an international consensus were used to define the LO-FGR. Middle cerebral artery (MCA) pulsatility index (PI) and SA PI were significantly lower in the LO-FGR group ( p : .002, p <.001, respectively). Likewise, cerebroplacental ratio (CPR) was significantly lower in the LO-FGR group ( p <.001). Decreased CPR and decreased SA PI were significantly and positively associated with an increased likelihood of exhibiting adverse obstetric outcome ( p <.001, p : .012, respectively). The receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off value for SA PI was 1.41 to predict LO-FGR with 70.7% sensitivity and 61.5% specificity (AUC = 0.684; 95% CI, 0.594-0.774).Impact Statement What is already known on this subject? The main clinical difficulty in late-onset foetal growth restriction (LO-FGR) is the detection of the disease. What do the results of this study add? The splenic artery (SA) pulsatility index (PI) may contribute to both diagnostic and the prediction of adverse perinatal outcomes in LO-FGR cases. Our results showed that the SA PI value, as well as cerebroplacental ratio (CPR), can be a useful parameter in predicting negative outcomes. What are the implications of these findings for clinical practice and /or further research? Various degrees of uteroplacental insufficiency in foetuses with LO-FGR may be associated with abnormalities in SA Doppler velocimetry. Splenic artery Doppler velocimetry can be used for the clinical management of LO-FGR.