Etiologic evaluation and pregnancy outcomes of fetal growth restriction (FGR) associated with structural malformations.

This study aimed to evaluate the etiology and pregnancy outcomes of fetuses underwent invasive prenatal diagnosis for fetal growth restriction (FGR) accompanied by structural malformations. Data from 130 pregnancies referred for prenatal diagnosis for FGR accompanied by structural malformations were obtained between July 2011 and July 2023. Traditional karyotyping was conducted for all the subjects. A total of 37 (28.5%) cases of chromosomal abnormalities were detected by karyotyping, including 30 cases of numerical anomalies and seven cases of unbalanced structural anomalies. Trisomy 18 was the most common abnormalities, accounting for 51.4%, significantly higher than any other chromosomal abnormality. The cohort was predominantly comprised of early-onset FGR (88.5%) compared to late-onset FGR (11.5%). The incidences of chromosomal abnormalities in this two groups were 29.6% (34/115) and 20.0% (3/15), respectively (p > 0.05). The majority (74.6%, 97/130) of the cohort were affected by a single system malformation, with chromosomal abnormalities found in 19.6% (19/97) of cases. In pregnancies of structural malformations involving two and multiple systems, the frequencies were 56.5% (13/23), and 50.0% (5/10), respectively. Single nucleotide polymorphism array (SNP array) was performed in parallel for 65 cases, revealing additional 7.7% cases of copy number variants (CNVs) compared to karyotyping. Polymerase chain reaction (PCR) was used for detection of cytomegalovirus (CMV) DNA in 92 cases. All fetuses with FGR associated with two or more system malformations were either terminated or stillborn, irrespective of chromosomal aberrations. Conversely, 71.8% of pregnancies with a single-system malformation and normal genetic testing results resulted in live births. Furthermore, two (2.2%) cases tested positive for CMV DNA, leading to one termination and one case of serious developmental disorder after birth. Our study suggests that structural malformations associated with FGR are more likely to affect a single organ system. When multiple systems are involved, the incidence of chromosomal abnormalities and termination rates are notably high. We advocate for the use of CMA and CMV DNA examinations in FGR cases undergo invasive prenatal diagnosis, as these tests can provide valuable insights for etiological exploration and pregnancy management guidance.

Role of the brain-sparing effect on retinopathy of prematurity in newborns with fetal growth restriction.

INTRODUCTION: This study aimed to investigate the role of the brain-sparing effect (BSE) on retinopathy of prematurity (ROP) in fetal growth restriction (FGR). METHODS: In this retrospective study, 127 pregnant women were divided into two groups considering the cerebroplacental ratio (CPR): FGR with abnormal CPR group (n = 74) and the appropriate for gestational age with normal Doppler group (n = 53). CPR was computed using the pulsatility index (PI) and resistance index (RI) to quantitate the waveforms [middle cerebral artery (MCA) PI/umbilical artery (UA) PI and MCA RI/UA RI: a result <1 was taken into account as abnormal]. ROP screening results of newborns were recorded from electronic files. RESULTS: After adjusting for co-variants, BSE was not related to ROP (adjusted odds ratio [aOR], 1.06; 95% confidence interval [CI], 0.23-4.95). Gestational age at delivery <30 weeks (aOR, 2.55; 95% CI, 1.04-6.93) and birth weight <1500 g (aOR, 5.15; 95% CI, 1.15-25.2) were independently associated with ROP. Preeclampsia, emergency cesarean section birth, or 48 h completion after the first steroid administration were not associated with ROP. CONCLUSIONS: Gestational age at delivery <30 weeks and birth weight <1500 g are independent risk factors for ROP in FGR whereas the BSE is not a risk factor.

Assessment of vitamin status; A, E and D in Egyptian neonates with IUGR: a cross sectional study.

BACKGROUND: Neonates with intrauterine growth retardation (IUGR) may present with fatal complications and permanent serious consequences. Vitamin status may influence fetal development. In this study we assessed vitamin A, E and D concentrations in umbilical cord blood in newborns with IUGR. METHODS: Maternal data were obtained. Neonatal assessment included; age of gestation calculated from last menstrual period, Ultrasound (U/S), new Ballard, Apgar scores and anthropometric measurements including; Head circumference, length and weight. WHO growth percentile curves were used. Vitamin A, E and D in cord blood samples were measured by high performance liquid chromatography (HPLC) and ELISA consecutively. RESULTS: A total of 86 full term newborns were enrolled in this study, 42 (48.8%) with IUGR with gestational age (33.59 ± 1.20) week by U/S and 44 (51.2%) appropriate for gestational age neonates with gestational age (38.70 ± 1.50). Ballard and Apgar scores (p < 0.05) and Z scores for weight, length and head circumference (p < 0.001) at birth were significantly lower in neonates with Intrauterine growth retardation (IUGR) than appropriate for gestational age (AGA) neonates. The levels of Vitamin A, E and D were significantly lower in the IUGR group than the AGA (p < 0.05) for all. Significant positive correlations of weight with vitamin A, and E cord blood levels were found (p < 0.05), while length was significantly positively correlated only with vitamin A (p < 0.05). Head circumference showed significant positive correlations with the three vitamins (p < 0.05) for all. CONCLUSION: Neonates with IUGR had significantly lower levels of Vitamin A, E and D than AGA neonates. Significant positive correlations of weight with vitamin A, and E cord blood levels was detected, while neonatal length was associated only with vitamin A level. The present study highlights the significance of nutritional policies for inhibiting deficiency of these vitamins during pregnancy and childhood.

The role of confined placental mosaicism in fetal growth restriction: A retrospective cohort study.

OBJECTIVE: To evaluate which cytogenetic characteristics of confined placental mosaicism (CPM) detected in the first trimester chorionic villi and/or placentas in terms of chromosome aberration, cell lineage involved and trisomy origin will lead to fetal growth restriction and low birthweight. METHODS: Cohort study using routinely collected perinatal data and cytogenetic data of non-invasive prenatal testing, the first trimester chorionic villi sampling and postnatal placentas. RESULTS: 215 CPM cases were found. Fetal growth restriction (FGR) and low birthweight below the 10th percentile (BW < p10) were seen in 34.0% and 23.1%, respectively. Excluding cases of trisomy 16, 29.1% showed FGR and 17.9% had a BW < p10. The highest rate of FGR and BW < p10 was found in CPM type 3, but differences with type 1 and 2 were not significant. FGR and BW < p10 were significantly more often observed in cases with meiotic trisomies. CONCLUSION: There is an association between CPM and FGR and BW < p10. This association is not restricted to trisomy 16, neither to CPM type 3, nor to CPM involving a meiotic trisomy. Pregnancies with all CPM types and origins should be considered to be at increased risk of FGR and low BW < p10. A close prenatal fetal monitoring is indicated in all cases of CPM.

Lipid profile of circulating placental extracellular vesicles during pregnancy identifies foetal growth restriction risk.

Small-for-gestational age (SGA) neonates exhibit increased perinatal morbidity and mortality, and a greater risk of developing chronic diseases in adulthood. Currently, no effective maternal blood-based screening methods for determining SGA risk are available. We used a high-resolution MS/MSALL shotgun lipidomic approach to explore the lipid profiles of small extracellular vesicles (sEV) released from the placenta into the circulation of pregnant individuals. Samples were acquired from 195 normal and 41 SGA pregnancies. Lipid profiles were determined serially across pregnancy. We identified specific lipid signatures of placental sEVs that define the trajectory of a normal pregnancy and their changes occurring in relation to maternal characteristics (parity and ethnicity) and birthweight centile. We constructed a multivariate model demonstrating that specific lipid features of circulating placental sEVs, particularly during early gestation, are highly predictive of SGA infants. Lipidomic-based biomarker development promises to improve the early detection of pregnancies at risk of developing SGA, an unmet clinical need in obstetrics.

The changing Doppler patterns and perinatal outcomes of monochorionic diamniotic twins with selective fetal growth restriction.

OBJECTIVES: To investigate the clinical outcomes and Doppler patterns changes in monochorionic diamniotic (MCDA) twins with selective fetal growth restriction (sFGR). METHODS: We retrospectively analyzed 362 sFGR cases from January 2010 to May 2016 at a single tertiary referral center. The Doppler waveforms of umbilical artery end-diastolic flow were collected, and all neonates were subjected to an early neonatal brain scan. RESULTS: A total of 66/100 (66 %) type I cases were stable, whereas 25/100 (25 %) cases changed to type II and 9/100 (9 %) changed to sFGR complicated twin-twin transfusion syndrome (TTTS). A total of 48.9 % (22/45) sFGR cases were complicated with polyhydramnios and 30.4 % (7/23) sFGR cases were complicated with oligohydramnios, both of which were progressed to sFGR with TTTS. Mild cerebral injury was significantly associated with Doppler flow abnormalities, earlier gestational age at delivery and type of sFGR diagnosis. Severe cerebral injury was significantly associated with gestational age at delivery (31.6 vs. 34.1, p=0.002) and larger birthweight discordance (43.9 vs. 29.3 %, p=0.011). CONCLUSIONS: Doppler patterns in sFGR can gradually change, with important consequences with regard to management and outcomes. Along with abnormal Doppler findings, earlier occurrence of sFGR and delivery are associated with subsequent neonatal cerebral injury.

Evolution of Fetal Growth in Symptomatic Sars-Cov-2 Pregnancies.

INTRODUCTION: SARS-CoV-2 is a viral disease with potentially devastating effects. Observational studies of pregnant women infected with SARS-CoV-2 report an increased risk for FGR. This study utilizes data from a prospective SARS-CoV-2 registry in pregnancy, investigating the progression of fetuses to fetal growth restriction (FGR) at birth following maternal SARS-CoV-2 and evaluating the hypothesis of whether the percentage of SGA at birth is increased after maternal SARS-CoV-2 taking into account the time interval between infection and birth. MATERIALS & METHODS: CRONOS is a prospective German registry enrolling pregnant women with confirmed SARS-CoV-2 infection during their pregnancy. SARS-CoV-2 symptoms, pregnancy- and delivery-specific information were recorded. The data evaluated in this study range from March 2020 until August 2021. Women with SARS-CoV-2 were divided into three groups according to the time of infection/symptoms to delivery: Group I<2 weeks, Group II 2-4 weeks, and Group III>4 weeks. FGR was defined as estimated and/or birth weight<10% ile, appropriate for gestational age (AGA) was within 10 and 90%ile, and large for gestational age (LGA) was defined as fetal or neonatal weight>90%ile. RESULTS: Data for a total of 2,650 SARS-CoV-2-positive pregnant women were available. The analysis was restricted to symptomatic cases that delivered after 24+0 weeks of gestation. Excluding those cases with missing values for estimated fetal weight at time of infection and/or birth weight centile, 900 datasets remained for analyses. Group I consisted of 551 women, Group II of 112 women, and Group III of 237 women. The percentage of changes from AGA to FGR did not differ between groups. However, there was a significantly higher rate of large for gestational age (LGA) newborns at the time of birth compared to the time of SARS-CoV-2 infection in Group III (p=0.0024), respectively. CONCLUSION: FGR rates did not differ between symptomatic COVID infections occurring within 2 weeks and>4 weeks before birth. On the contrary, it presented a significant increase in LGA pregnancies in Group III. However, in this study population, an increase in the percentage of LGA may be attributed to pandemic measures and a reduction in daily activity.

The impact of late pregnancy dating on the detection of fetal growth restriction at term.

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.

Rate of deterioration of umbilical artery Doppler indices in fetuses with severe early-onset fetal growth restriction.

BACKGROUND: Incorporation of umbilical artery Doppler in the surveillance of fetal growth restriction has been shown to reduce the risk of perinatal deaths. Systole/Diastole ratio, Pulsatility Index and Resistance Index are obtained upon Doppler interrogation of the umbilical artery however it is unknown which index predicts more advanced stages of placental deterioration. OBJECTIVE: This study aimed to examine risk factors for the development of absent or reversed end-diastolic velocity and the time intervals of deterioration from normal umbilical artery end-diastolic velocity (indicated by systole/diastole ratio, pulsatility index, or resistance index) to decreased and absent or reversed end-diastolic velocity in fetuses with early-onset severe fetal growth restriction. STUDY DESIGN: This was a retrospective cohort study performed from 2005 to 2020. All singleton pregnancies with severe (estimated fetal weight or abdominal circumference below the third percentile) and early-onset (diagnosed between 20 0/7 and 31 6/7 weeks of gestation) fetal growth restriction were included. Patients with fetal genetic or structural anomalies, suspected congenital infections, absent or reversed end-diastolic velocity at diagnosis, poor pregnancy dating, and absence of follow-up ultrasounds were excluded. Estimated fetal weight, abdominal circumference, and Doppler indices were reviewed longitudinally from diagnosis to delivery. To examine risk factors for absent or reversed end-diastolic velocity, we performed backward stepwise logistic regression and calculated odds ratios with 95% confidence intervals. Kaplan-Meier curves were compared using log-rank tests. RESULTS: A total of 985 patients met the inclusion criteria, and 79 (8%) progressed to absent or reversed end-diastolic velocity. Factors associated with development of absent or reversed end-diastolic velocity included gestational age at diagnosis (adjusted odds ratio, 4.88 [95% confidence interval, 2.55-9.37] at 20 0/7 to 23 6/7 weeks; adjusted odds ratio, 1.56 [95% confidence interval, 0.86-2.82] at 24 0/7 to 27 6/7 weeks compared with 28 0/7 to 31 6/7 weeks) and presence of chronic hypertension (adjusted odds ratio, 2.37 [95% confidence interval, 1.33-4.23]). Rates of progression from diagnosis of fetal growth restriction with normal umbilical artery Doppler to absent or reversed end-diastolic velocity were significant after 4 weeks from diagnosis (5.84% [95% confidence interval, 4.50-7.57]). Regarding the Doppler indices, the progression from normal values to abnormal indices was similar at 1 and 2 weeks. However, the rate of progression from normal to abnormal systole/diastole ratio compared with the rates of progression from normal to abnormal pulsatility index or resistance index was higher at 4 and 6 weeks. Deterioration from abnormal indices to absent or reversed end-diastolic velocity was shorter with abnormal resistance index and pulsatility index when compared with the systole/diastole ratio at 2, 4, and 6 weeks after diagnosis and at 6 weeks, respectively. CONCLUSION: Earlier gestational age at diagnosis and chronic hypertension are considered as risk factors for Doppler deterioration and development of absent or reversed end-diastolic velocity in the umbilical artery. With normal Doppler indices, significant deterioration and progression to absent or reversed end-diastolic velocity is unlikely until 4 weeks after diagnosis. Abnormal systole/diastole ratio seems to appear first. However, abnormal pulsatility index or resistance index was associated with absent or reversed end-diastolic velocity.

Prognosticating Fetal Growth Restriction and Small for Gestational Age by Medical History.

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.

The role of the PLGF in the management of pregnancies complicated with fetal microsomia.

PURPOSE: To explore the contribution of maternal and fetal parameters in predicting the time interval between diagnosis and development of adverse events leading to delivery in singleton pregnancies complicated with fetal microsomia. METHODS: Prospective study on singleton pregnancies referred to a tertiary center because of suspicion of fetal smallness in the third trimester. The study cohort included cases with fetal abdominal circumference (AC) ≤ 10th centile or estimated fetal weight ≤ 10th centile or umbilical artery pulsatitlity index ≥ 90th centile. Development of pre-eclampsia, fetal demise, and fetal deterioration diagnosed by fetal Doppler studies or fetal heart rate monitoring and leading to delivery were considered as adverse events. Maternal demographics, obstetric history, blood pressure, serum PLGF, and fetal Doppler studies were explored as predictors of the time interval between the first visit to the clinic and the diagnosis of complications. RESULTS: In 59 women, the median incubation period from presentation to the clinic to an adverse event was 6, 2 weeks, whereas half of the pregnancies (52.5%) did not develop any adverse event. PLGF was the strongest predictor of adverse events. Both PLGF in raw values and PLGF MOM had equally good predictive ability (AUC 0.82 and 0.78 respectively). Optimal cut-off points were 177.7 pg/ml for PLGF raw values (sensitivity 83% and specificity 66.7%) and 0.277 MoM (sensitivity 76% and specificity 86.7%). On multiple Cox regression analysis, maternal systolic blood pressure, PLGF, fetal increased umbilical artery PI, and reduced CP ratio were independently associated with adverse events. Half of the pregnancies with low PLGF and only one in ten with high PLGF were delivered within two weeks after the initial visit. CONCLUSION: Half of the pregnancies carrying a small fetus in the third trimester will not develop maternal or fetal complications. PLGF is a strong predictor of adverse events that can be used to customize antenatal care.

Patients with autoimmune skin diseases are at increased risk of adverse pregnancy outcomes.

BACKGROUND: Increased rates of adverse pregnancy outcomes have been reported in association with rheumatologic diseases such as systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis. However, little is known about pregnancy outcomes in patients with autoimmune skin diseases. OBJECTIVE: This study aimed to determine the frequency of adverse pregnancy outcomes in patients with autoimmune skin diseases. We hypothesized that similar to rheumatic diseases, the rate of adverse pregnancy outcomes in patients with autoimmune skin diseases would be higher than the general population. STUDY DESIGN: This is a case control study using the TriNetX US Collaborative Network, which is a database of electronic medical records of >95 million patients seen at 57 healthcare organizations in the United States. All pregnant women between the ages of 15 and 44 years who were seen at a healthcare organization between January 1, 2016 and December 31, 2021 were included. Participants with autoimmune skin disease were matched to healthy controls and controls with systemic rheumatologic conditions (systemic lupus erythematosus or rheumatoid arthritis). For both the autoimmune skin disease and healthy control groups, those with systemic rheumatologic condition or hidradenitis suppurativa were excluded. The primary outcomes were adverse pregnancy outcomes defined as spontaneous abortion, gestational hypertension, preeclampsia or eclampsia, gestational diabetes mellitus, intrauterine growth restriction, preterm premature rupture of membranes, preterm birth, and stillbirth. Patients with autoimmune skin diseases and controls were 1:1 propensity score-matched by age, race, ethnicity, comorbidities, obesity, and substance use. For each outcome, odds ratio with a 95% confidence interval was calculated. RESULTS: A total of 2788 patients with autoimmune skin diseases were matched to 2788 healthy controls. Patients with autoimmune skin diseases were at a higher risk of spontaneous abortions than controls (odds ratio, 1.54; 95% confidence interval, 1.36-1.75; P<.001). Compared with patients with systemic lupus erythematosus, patients with autoimmune skin diseases were at lower risk of having infants with intrauterine growth restriction (odds ratio, 0.59; 95% confidence interval, 0.4-0.87; P=.01), preterm birth (odds ratio, 0.68; 95% confidence interval, 0.47-0.98; P=.04), and stillbirth (odds ratio, 0.50; 95% confidence interval, 0.25-0.97; P=.04). The differences in adverse pregnancy outcomes between patients with autoimmune skin diseases and those with rheumatoid arthritis were not statistically significant. CONCLUSION: Patients with autoimmune skin diseases are at a higher risk of spontaneous abortions than patients without autoimmune skin diseases. When analyzed by each autoimmune skin disease, patients with cutaneous lupus erythematosus or vitiligo remained at increased risk of spontaneous abortions compared with patients without autoimmune skin diseases. Patients with autoimmune skin diseases have similar risks of adverse pregnancy outcomes as patients with rheumatoid arthritis, but lower risks than patients with systemic lupus erythematosus.

Predictive ability of fetal growth charts in identifying kindergarten-age developmental challenges: a cohort study.

BACKGROUND: The Society for Maternal-Fetal Medicine recommends defining fetal growth restriction as an estimated fetal weight or abdominal circumference <10th percentile of a population-based reference. However, because multiple references are available, an understanding of their ability to identify infants at increased risk due to fetal growth restriction is critical. Previous studies have focused on the ability of different population references to identify short-term outcomes, but fetal growth restriction also has longer-term consequences for child development. OBJECTIVE: This study aimed to estimate the association between estimated fetal weight percentiles on the INTERGROWTH-21st and World Health Organization fetal growth charts and kindergarten-age childhood development, and establish the charts' discriminatory ability in predicting kindergarten-age developmental challenges. STUDY DESIGN: We conducted a retrospective cohort study linking obstetrical ultrasound scans conducted at BC Women's Hospital, Vancouver, Canada, with population-based standardized kindergarten test results. The cohort was limited to nonanomalous, singleton fetuses scanned at ≥28 weeks' gestation from 2000 to 2011, with follow-up until 2017. We classified estimated fetal weight into percentiles using the INTERGROWTH-21st and World Health Organization charts. We used generalized additive modeling to link estimated fetal weight percentile with routine province-wide kindergarten readiness test results. We calculated the area under the receiver-operating characteristic curve and other measures of diagnostic accuracy with 95% confidence intervals at select percentile cut-points of the charts. We repeated analyses using the Hadlock chart to help contextualize findings. The main outcome measure was the total Early Development Instrument score (/50). Secondary outcomes were Early Development Instrument subdomain scores for language and cognitive development, and for communication skills and general knowledge, as well as designation of "developmentally vulnerable" or "special needs". RESULTS: Among 3418 eligible fetuses, those with lower estimated fetal weight percentiles had systematically lower Early Development Instrument scores and increased risks of developmental vulnerability. However, the clinical significance of differences was modest in magnitude (eg, total Early Development Instrument score -2.8 [95% confidence interval, -5.1 to -0.5] in children with an estimated fetal weight in 3rd-9th percentile of INTERGROWTH-21st chart [vs reference of 31st-90th]). The charts' predictive abilities for adverse child development were limited (eg, area under the receiver-operating characteristic curve <0.53 for all 3 charts). CONCLUSION: Lower estimated fetal weight percentiles on the INTERGROWTH-21st and World Health Organization charts indicate increased risks of adverse kindergarten-age child development at the population level, but are not accurate individual-level predictors of adverse child development.

Blood Biomarkers in the Fetally Growth Restricted and Small for Gestational Age Neonate: Associations with Brain Injury.

Fetal growth restriction (FGR) and small for gestational age (SGA) infants have increased risk of mortality and morbidity. Although both FGR and SGA infants have low birthweights for gestational age, a diagnosis of FGR also requires assessments of umbilical artery Doppler, physiological determinants, neonatal features of malnutrition, and in utero growth retardation. Both FGR and SGA are associated with adverse neurodevelopmental outcomes ranging from learning and behavioral difficulties to cerebral palsy. Up to 50% of FGR, newborns are not diagnosed until around the time of birth, yet this diagnosis lacks further indication of the risk of brain injury or adverse neurodevelopmental outcomes. Blood biomarkers may be a promising tool. Defining blood biomarkers indicating an infant's risk of brain injury would provide the opportunity for early detection and therefore earlier support. The aim of this review was to summarize the current literature to assist in guiding the future direction for the early detection of adverse brain outcomes in FGR and SGA neonates. The studies investigated potential diagnostic blood biomarkers from cord and neonatal blood or serum from FGR and SGA human neonates. Results were often conflicting with heterogeneity common in the biomarkers examined, timepoints, gestational age, and definitions of FGR and SGA used. Due to these variations, it was difficult to draw strong conclusions from the results. The search for blood biomarkers of brain injury in FGR and SGA neonates should continue as early detection and intervention is critical to improve outcomes for these neonates.

Investigation of Serum Amphiregulin Concentrations in Pregnant Women Diagnosed with Isolated Fetal Growth Restriction in the Third Trimester.

OBJECTIVE: We aimed to investigate serum amphiregulin (AREG) concentrations in pregnant women with isolated fetal growth restriction (FGR) in the third trimester. MATERIALS AND METHODS: This cross-sectional study was conducted with 90 pregnant women who applied to the Umraniye Training and Research Hospital Gynecology and Obstetrics Clinic between January 2022 and May 2022. The FGR group consisted of 45 pregnant women diagnosed with FGR in the third trimester, and the control group consisted of 45 healthy pregnant women matched with the FGR group in terms of age and body mass index (BMI). Demographic characteristics, ultrasound findings, and neonatal outcomes were noted. As a primary outcome, the two groups were compared for maternal serum AREG concentrations. RESULTS: Both groups were similar in terms of demographic characteristics (p>0.05). While fetal BPD, AC, and FL measurements in the group diagnosed with FGR were significantly lower than in the control group, umbilical artery Doppler PI and S/D were higher (p=0.000, for all). Gestational age at birth, newborn birth weight, birth height, and 1-minute Apgar score were significantly lower and the NICU admission rate was higher in the FGR group (p=0.000, p=0.000, p=0.000, p=0.027, p=0.011 respectively). Gestational age at blood sampling for AREG was similar in both groups (p=0.869). While maternal serum AREG concentration was 969.39 ng/L in the FGR group, it was 795.20 ng/L in the control group (p=0.018). AUC analysis of AREG for estimation of FGR in ROC analysis was 0.57 (p<0.247, 95% CI=0.44-0.69). The optimal threshold value for FGR estimation of maternal serum AREG concentration was determined as 874.03 ng/L with 55% sensitivity and 55% specificity. CONCLUSION: High maternal serum AREG concentrations appear to be associated with isolated FGR in the third trimester. The pathways through which AREG modulates fetal growth remain to be investigated.

Fetal heart rate spectral analysis in raw signals and PRSA-derived curve: normal and pathological fetuses discrimination.

Cardiotocography (CTG) is the most common technique for electronic fetal monitoring and consists of the simultaneous recording of fetal heart rate (FHR) and uterine contractions. In analogy with the adult case, spectral analysis of the FHR signal can be used to assess the functionality of the autonomic nervous system. To do so, several methods can be employed, each of which has its strengths and limitations. This paper aims at performing a methodological investigation on FHR spectral analysis adopting 4 different spectrum estimators and a novel PRSA-based spectral method. The performances have been evaluated in terms of the ability of the various methods to detect changes in the FHR in two common pregnancy complications: intrauterine growth restriction (IUGR) and gestational diabetes. A balanced dataset containing 2178 recordings distributed between the 32nd and 38th week of gestation was used. The results show that the spectral method derived from the PRSA better differentiates high-risk pregnancies vs. controls compared to the others. Specifically, it more robustly detects an increase in power percentage within the movement frequency band and a decrease in high frequency between pregnancies at high risk in comparison to those at low risk.

Performance of fetal ultrasound and magnetic resonance imaging in predicting birthweight according to the test-to-delivery interval: A cohort study.

OBJECTIVE: To assess the influence of the test-to-delivery interval (TDI) on the performance of ultrasound (US) and magnetic resonance imaging (MRI) for predicting birthweight (BW). STUDY DESIGN: This is a secondary analysis of a prospective, single center, blinded cohort study that compared MRI and US for the prediction of BW ≥ 95th percentile in singleton pregnancies. Patients that were included in the initial study underwent US and MRI for estimation of fetal weight between 36 + 0/7 and 36 + 6/7 weeks of gestation (WG). The primary outcome of the current study was to report the changes of US and MRI sensitivity and specificity in the prediction of BW > 95th percentile, BW > 90th percentile, BW < 10th percentile, and BW < 5th percentile, according to the TDI. The secondary outcome was to represent the performance of both tools in the prediction of BW > 90th percentile when TDI is<2 weeks, between 2 and 4 weeks, and>4 weeks. Receiver operating characteristic (ROC) curves were constructed accordingly. RESULTS: 2378 patients were eligible for final analysis. For the prediction of BW > 95th or 90th percentile, the sensitivity of MRI remains high until 2 weeks, and it decreases slowly between 2 and 4 weeks, in contrast to the sensitivity of US which decreases rapidly 2 weeks after examination (p < 0.001). For the prediction of BW < 10th or 5th percentile, the sensitivity of both tools decreases in parallel between 1 and 2 weeks. The specificities of both tools remain high from examination till delivery. These findings are reproducible with the use of the antenatal customized and the postnatal national growth charts. CONCLUSION: The performance of MRI in the prediction of BW, especially in large-for-gestational age, is maximal when delivery occurs within two weeks of the examination, decreasing slightly thereafter, in contrast with the performance of US which decreases drastically over time.

Association of low pregnancy associated plasma protein-A with increased umbilical artery pulsatility index in cases of fetal weight between the 3rd and 10th percentiles: a retrospective cohort study.

OBJECTIVES: This study aims to evaluate if low levels of serum maternal pregnancy associated plasma protein-A (PAPP-A) during the first trimester are related to increased umbilical artery pulsatility index (UA PI) later in pregnancy, in cases of estimated fetal weight between the 3rd and 10th percentiles, in order to establish PAPP-A as a predictor of this particular cases of fetal growth restriction (FGR). METHODS: An observational, retrospective cohort study, conducted at a tertiary University Hospital located in Oporto, Portugal. Pregnant women who did the first trimester combined screening, between May 2013 and June 2020 and gave birth in the same hospital, with an estimated fetal weight (EFW) between the 3rd and 10th percentiles were included. The primary outcome is the difference in increased UA PI prevalence between two groups: PAPP-A<0.45 MoM and PAPP-A≥0.45 MoM. As secondary outcomes were evaluated differences in neonatal weight, gestational age at delivery, cesarean delivery, neonatal intensive care unit hospitalization, 5-min Apgar score below 7 and live birth rate between the same two groups. RESULTS: We included 664 pregnancies: 110 cases of PAPP-A<0.45 MoM and 554 cases with PAPP-A≥0.45 MoM. Increased UA PI prevalence, which was the primary outcome of this study, was significantly different between the two groups (p=0.005), as the PAPP-A<0.45 MoM group presents a higher prevalence (12.7 %) when compared to the PAPP-A≥0.45 MoM group (5.4 %). The secondary outcome cesarean delivery rate was significantly different between the groups (p=0.014), as the PAPP-A<0.45 MoM group presents a higher prevalence (42.7 %) than the PAPP-A≥0.45 MoM group (30.1 %). No other secondary outcomes showed differences between the two groups. CONCLUSIONS: There is an association of low serum maternal PAPP-A (<0.45 MoM) during the first trimester and increased UA PI (>95th percentile) later in pregnancy, in cases of EFW between the 3rd and 10th percentiles. However, this association is not strong enough alone for low PAPP-A to be a reliable predictor of increased UA PI in this population.

Placental growth factor testing at 19-23 weeks of gestation as a guide to subsequent care in pregnancy: A prospective observational study.

OBJECTIVE: To determine whether serum placental growth factor (PlGF) at 19-23 weeks of gestation can improve the identification of risk for adverse outcomes. DESIGN: Prospective observational cohort study. SETTING: Two English maternity units. POPULATION: Unselected singleton pregnancies attending routine ultrasound at 19-23 weeks of gestation. METHODS: Outcomes ascertained by health record review. Diagnostic test properties evaluated clinical risk factors for pre-eclampsia (according to National Institute of Care Excellence) or fetal growth restriction (according to Royal College of Obstetricians and Gynaecologists), low PlGF at 19-23 weeks of gestation (<5th percentile) or both. MAIN OUTCOME MEASURES: Pre-eclampsia, gestational hypertension, stillbirth, birthweight below third percentile or neonatal intensive care unit (NICU) admission for ≥48 h. RESULTS: In 30 013 pregnancies, risk factors were present in 9941 (33.1%), low PlGF was present in 1501 (5.0%) and both ('two-stage' screening) were present in 547 (1.8%) pregnancies. Risk factors detected 41.7%-54.7% of adverse outcomes, and could not meaningfully revise the risk (all positive likelihood ratios, +LR, <5.0; all negative likelihood ratios, -LR, ≥0.2). Low PlGF detected 8.5%-17.4% of adverse outcomes, but meaningfully increased risks (other than NICU admission) associated with delivery <37 weeks of gestation (+LR = 5.03-15.55); all -LRs were ≥0.2. 'Two-stage' screening detected 4.2%-8.9% of adverse outcomes, with meaningful +LRs (6.28-18.61) at <37 weeks of gestation, except for NICU admission of ≥48 h, which had an +LR of 7.56 at <34 weeks of gestation; all -LRs were ≥0.2. No screening strategy meaningfully increased or decreased the detection of adverse outcome risk at term. CONCLUSIONS: Clinical risk factor screening has a high screen-positive rate and a poor detection of adverse outcomes. False positives cannot be reduced by PlGF testing at 19-23 weeks of gestation; therefore, this cannot be recommended as a useful strategy on its own.