Growth patterns and cardiovascular abnormalities in SGA fetuses: 2. Normal growth and progressive growth restriction.

OBJECTIVES: To characterize growth processes and their associated cardiovascular abnormalities in SGA fetuses with normal growth and progressive growth restriction patterns as defined by Individualized Growth Assessment (IGA). METHODS: A SGA cohort (EFW and BW < 10th percentile) was derived from the PORTO study that included 47 fetuses with normal growth outcome (SGA Normal) and 34 fetuses with progressive growth restriction (SGA Growth Restricted, Pattern 1). Composite fetal size parameters were used to quantify growth pathology at individual third trimester time points (individual composite Prenatal Growth Assessment Score {icPGAS}) and calculated cumulatively during the third trimester (Fetal Growth Pathology Score 1{FGPS1}). Paired Doppler evaluations of the umbilical artery (UA), middle cerebral artery (MCA), ductus venosus (DV) and myocardial performance index (MPI) were used to detect cardiovascular anomalies. Outcome variables were birth age and birth weight. RESULTS: Ranking fetuses with respect to the severity of the 3rd trimester growth pathology (-FGPS1) revealed three subgroups in each of these two groups. In SGA Normal, no (51%), minimal (19%) or minor (30%) growth abnormalities were present. Although vascular flow abnormalities occurred without growth abnormalities (UA: 38%; MCA: 35%), they increased with minor growth disturbances (UA: 64%; MCA: 50%). All fetuses delivered at term and in only 7 cases (minor growth abnormalities subgroup) were the neonates abnormally small based on IGA criteria. In SGA Growth Restricted, Pattern 1, the progression of growth restriction was slow (47%), moderate (21%) and rapid (32%). Corresponding median -FGPS1 values were -1.34%, -2.67% and -4.88%, respectively. The median age of onset was 33.6, 29.7 and 29.7 weeks in these three subgroups. UA abnormalities occurred infrequently in the first two subgroups but were found in all cases of rapidly progressing pathology. Similar results were found for the MCA and DV + MPI Doppler parameters (rapid progression: MCA = 50%; DV + MPI = 50%). Premature delivery occurred less frequently with slow progression but was nearly 100% in the moderately and rapidly progressive subgroups. CONCLUSIONS: Negative FGPS1 growth restriction patterns can be used to classify SGA fetuses. Subgroups, based on ranked -FGPS1 values in both SGA Normal and SGA Growth Restricted Pattern 1 groups had marked differences in cardiovascular abnormalities and neonatal outcomes. The characteristics of these two groups are consistent with small, normally growing fetuses and fetuses with "early" growth restriction, respectively.

Growth patterns and cardiovascular abnormalities in SGA fetuses: 3. Late, adaptive and recovering growth restriction.

OBJECTIVE: To characterize abnormal growth processes and their associated cardiovascular abnormalities in SGA fetuses using Individualized Growth Assessment (IGA). METHODS: This longitudinal investigation utilized a SGA cohort [EFW and BW <10th percentile] derived from the PORTO study. Fetuses categorized by their Fetal Growth Pathology Score [FGPS1] patterns [Pattern 2 {n = 12}, Pattern 3 {n = 11}, Pattern 5 {n = 13}] were evaluated. Growth pathology was measured using the -FGPS1 and the individual composite Prenatal Growth Assessment Score {-icPGAS]. Paired cardiovascular assessments utilized measurements of the Pulsatility Index [umbilical artery {UA}, middle cerebral artery {MCA}, ductus venosus {DV}] and the myocardial performance index [MPI; heart]. Outcome variables were birth age [preterm or, term] and birth weight [small or normal (IGA criteria)]. RESULTS: Pattern 2 was usually characterized by a single, growth abnormality (67% of cases) of variable magnitude that occurred within two weeks of delivery {median onset age: 37.6 weeks}. The incidence of UA abnormalities was low (25%) while those of MCA and DV/MPI were high {60%, 42%}. Most neonates were of normal size (67%) and delivered at term (67%).Pattern 3 had an initial progressive growth restriction phase, followed by constant but abnormally low growth. Growth pathology had an early onset (median age: 31.6 weeks), was moderate but persistently abnormal. The incidences of cardiovascular abnormalities were moderate [30-50%]. Most neonates were abnormally small (80%) but delivered at term (90%).Pattern 5 had an initial progressive phase with an early onset [onset age {median}: 31.6 weeks]. However, this process was arrested and returned toward normal. Growth pathology magnitudes were minor as were the incidences of cardiovascular abnormalities. Neonatal size was usually normal and all fetuses delivered at term. CONCLUSIONS: Characteristics of SGA Growth Restricted, Patterns 2, 3 and 5 are clearly different from those found in SGA Normal or SGA Growth Restricted Pattern 1 groups. They also differed from one another, indicating that growth restriction can manifest itself in several different ways. Pattern 2 is similar to "late" growth restriction reported previously. Patterns 3 and 5 are novel and have been designated as "adaptive" and "recovering" types of growth restriction.

Growth patterns and cardiovascular abnormalities in small for gestational age fetuses: 1. Pattern characteristics.

BACKGROUND: Fetal growth restriction is being defined as either "early" or "late" depending on age of onset. A recent investigation using individualized assessment has identified five different growth restriction patterns. No previous study has related these patterns to cardiovascular abnormalities. OBJECTIVES: To determine growth patterns in small fetuses (BW < 10th percentile) using Individualized Growth Assessment (IGA) and to relate cardiovascular abnormalities found with Doppler ultrasound to these patterns. STUDY DESIGN: A secondary analysis was carried out in 126 fetuses from the PORTO data set having both estimated weights and birth weights below the 10th percentile. Only fetuses with 2nd and 3rd trimester biometry scans appropriate for IGA and cardiovascular assessments were studied. There was one-to-one matching of biometry and Doppler evaluations in the 3rd trimester. Composite growth parameters were used to quantify growth pathology at individual time points (individual composite Prenatal Growth Assessment Score (icPGAS)) and during the 3rd trimester (Fetal Growth Pathology Score {FGPS1}). Normal and growth restriction patterns were identified using plots of FGPS1 values. Doppler measurements were classified as normal or abnormal based on published cross-sectional standards. Outcome variables were birth weight and birth age. RESULTS: In these SGA cases, 38.2% showed normal fetal growth and 61.8% had growth restriction. In the latter, seven different patterns were observed. Pattern 1 was most common (43.5%), followed by Patterns 5 (16.7%), 2 (15.4%) and 3 (14.1%). The characteristics of Pattern 1 indicated progressive growth restriction while Pattern 5 demonstrated recovery from an initial growth abnormality. Cardiovascular abnormalities were quite variable, with those in the umbilical artery being most frequent in Patterns 1 and 3. Pattern 2 had the highest incidence of middle cerebral artery abnormalities. Umbilical artery abnormalities were similar in the Normal and Pattern 5 groups as were those for the middle cerebral artery. Other cardiovascular abnormalities had low frequencies except in Pattern 2 where the ductus venosus incidence was high. Abnormally small neonates, as identified with IGA, were seen primarily in Patterns 1, 3 and 6 (80-88%). Premature deliveries occurred most frequently in Pattern 1 (56%), followed by Pattern 2 (33%). CONCLUSIONS: Growth in this SGA Group was very heterogeneous with a significant proportion of these small fetuses growing normally. Growth restriction did not appear to be a single process but was manifest as seven different FGPS1 patterns. Both growth pathology and cardiovascular abnormalities differed among patterns. Further investigation will be required to determine how specific growth abnormalities are related to fetal cardiovascular changes over time.

Reducing emergency cesarean delivery and improving the primiparous experience: Findings of the RECIPE study.

OBJECTIVE: The ability to predict the need for emergency Cesarean delivery holds the potential to facilitate birth choices. The objective of the RECIPE study (Reducing Emergency Cesarean delivery and Improving the Primiparous Experience) was to externally validate a Cesarean delivery risk prediction model. This model, developed by the Genesis study, identified five key predictive factors for emergency Cesarean delivery: maternal age, maternal height, BMI, fetal head circumference (HC) and fetal abdominal circumference (AC). STUDY DESIGN: This prospective, observational study was conducted in two tertiary referral perinatal centers. Inclusion criteria were as follows: primiparous women with a singleton, cephalic presentation fetus in the absence of fetal growth restriction (FGR), oligohydramnios, pre-eclampsia, pre-existing diabetes mellitus or an indication for planned Cesarean delivery. Between 38 + 0 and 40 + 6 weeks' gestational age, participants attended for prenatal assessment that enabled the determination of an individualized risk calculation for emergency Cesarean delivery during labour based on maternal height, BMI, fetal HC and AC, with crucially both participants and care providers being blinded to the resultant risk prediction score. Labor, delivery and postnatal outcomes were ascertained. Calibration and receiver operator curves were generated to determine the predictive capacity for emergency Cesarean delivery of the Genesis risk prediction model in this cohort. RESULTS: 559 primiparous participants were enrolled from May 2017 to April 2019, of whom 142 (25 %) had an emergency Cesarean delivery during labour. Participants with a low predicted risk score (<10 %) had a mean predicted rate of 8% (+/- standard deviation of 2%) and a similarly low actual observed rate of Cesarean delivery (8%). Participants with a high predicted risk (>50 %) had a mean predicted Cesarean delivery rate of 64 % (+/- standard deviation of 9%) and also had a high actual observed Cesarean delivery rate (62 %). The calibration curve and receiver operating characteristic curve demonstrated that this validation study had comparable discriminatory power for emergency Cesarean delivery to that described in the original Genesis study. The Area Under the Curve (AUC) in Genesis was 0.69, whereas the AUC in RECIPE was 0.72, which reflects good predictive capacity of the risk prediction model. CONCLUSION: The accuracy of the Genesis Cesarean delivery prediction tool is supported by this validation study.

The RECIPE study: reducing emergency Caesareans and improving the Primiparous experience: a blinded, prospective, observational study.

BACKGROUND: The RECIPE study aims to validate a risk prediction model for intrapartum caesarean delivery which has been developed by our group. The Genesis study was a prospective observational study carried out by the Perinatal Ireland Research Consortium across 7 clinical centres in Ireland between October 2012 and June 2015. Genesis investigated a range of maternal and fetal parameters in a prospective blinded study of 2336 singleton pregnancies between 39 + 0-41 + 0 weeks' gestational age. This resulted in the development of a risk prediction model for Caesarean Delivery in nulliparous women at term. The RECIPE study now proposes to provide external validation of this risk prediction tool. METHODS: In order to externally validate the model, we aim to include a centre which was not involved in the original study. We propose a trial of risk-assignment for intrapartum caesarean amongst nulliparous women with a singleton pregnancy between 38 + 0 and 40 + 6 weeks' gestational age who are planning a vaginal birth. Results of the risk prediction tool will be concealed from participants and from midwives and doctors providing labour care.. Participants will be invited for an ultrasound scan and delivery details will be collated postnatally. The principal aim of this study is to externally validate the risk prediction model. This prediction model holds the potential to accurately identify nulliparous women who are likely to achieve an uncomplicated vaginal birth and those at high prospect of requiring an unplanned caesarean delivery. DISCUSSION: Validation of the Genesis prediction model would enable more accurate counselling for women in the antenatal setting regarding their own likelihood of requiring an intrapartum Caesarean section. It would also provide valuable personalised information to women about the anticipated course of their own labour. We believe that this is an issue of national relevance that will impact positively on obstetric practice, and will positively empower women to make considered, personalised choices surrounding labour and delivery.

Inter-hospital comparison of Cesarean delivery rates should not be considered to reflect quality of care without consideration of patient heterogeneity: An observational study.

OBJECTIVE: Contemporary approaches to monitoring quality of care in obstetrics often focus on comparing Cesarean Delivery rates. Varied rates can complicate interpretation of quality of care. We previously developed a risk prediction tool for nulliparous women who may require intrapartum Cesarean delivery which identified five key predictors. Our objective with this study was to ascertain if patient heterogeneity can account for much of the observed variation in Cesarean delivery rates, thereby enabling Cesarean delivery rates to be a better marker of quality of care. MATERIALS AND METHODS: This is a secondary analysis of the Genesis study. This was a large prospective study of 2336 nulliparous singleton pregnancies recruited at seven hospitals. A heterogeneity score was calculated for each hospital. An adjusted Cesarean delivery rate was also calculated incorporating the heterogeneous risk score. RESULTS: A cut-off at the 90th percentile was determined for each predictive factor. Above the 90th percentile was considered to represent 'high risk' (with the exception of maternal height which identified those below the 10th percentile). The patient heterogeneous risk score was defined as the number of risk factors > 90th percentile (<10th percentile for height). An unequal distribution of high-risk patients between centers was observed (p < 0.001). The correlation between the Cesarean delivery rate and the patient heterogeneous risk score was high (0.76, p < 0.05). When adjusted for patient heterogeneity, Cesarean delivery rates became closer aligned. CONCLUSION: Inter-institutional diversity is common. We suggest that crude comparison of Cesarean delivery rates between different hospitals as a marker of care quality is inappropriate. Allowing for marked differences in patient characteristics is essential for correct interpretation of such comparisons.

An abnormal cerebroplacental ratio (CPR) is predictive of early childhood delayed neurodevelopment in the setting of fetal growth restriction.

BACKGROUND: Fetal growth restriction accounts for a significant proportion of perinatal morbidity and death. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the "at-risk" fetus in both fetal growth restriction and appropriate-for-gestational-age pregnancies. The Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction group has demonstrated previously that the presence of this "brain-sparing" effect is associated significantly with adverse perinatal outcomes in the fetal growth restriction cohort. However, data about neurodevelopment in children from pregnancies that are complicated by fetal growth restriction are sparse and conflicting. OBJECTIVE: The aim of the Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction NeuroDevelopmental Assessment Study was to determine whether children born after fetal growth-restricted pregnancies are at additional risk of adverse early childhood developmental outcomes compared with children born small for gestational age. The objective of this secondary analysis was to describe the role of cerebroplacental ratio in the prediction of adverse early childhood neurodevelopmental outcome. STUDY DESIGN: Participants were recruited prospectively from the Perinatal Ireland multicenter observational Prospective Observational Trial to Optimize Pediatric Health in Fetal Growth Restriction study cohort. Fetal growth restriction was defined as birthweight <10th percentile with abnormal antenatal umbilical artery Doppler indices. Small for gestational age was defined similarly in the absence of abnormal Doppler indices. Cerebroplacental ratio was calculated with the pulsatility indices of the middle cerebral artery and divided by umbilical artery with an abnormal value <1. Children (n=375) were assessed at 3 years with the use of the Ages and Stages Questionnaire and the Bayley Scales of Infant and Toddler Development, 3rd edition. Small-for-gestational-age pregnancies with normal Doppler indices were compared with (1) fetal growth-restricted cases with abnormal umbilical artery Doppler and normal cerebroplacental ratio or (2) fetal growth restriction cases with both abnormal umbilical artery and cerebroplacental ratio. Statistical analysis was performed with statistical software via 2-sample t-test with Bonferroni adjustment, and a probability value of .00625 was considered significant. RESULTS: Assessments were performed on 198 small-for-gestational-age children, 136 fetal growth-restricted children with abnormal umbilical artery Doppler images and normal cerebroplacental ratio, and 41 fetal growth-restricted children with both abnormal umbilical artery Doppler and cerebroplacental ratio. At 3 years of age, although there were no differences in head circumference, children who also had an abnormal cerebroplacental ratio had persistently shorter stature (P=.005) and lower weight (P=.18). Children from fetal growth restriction-affected pregnancies demonstrated poorer neurodevelopmental outcome than their small-for-gestational-age counterparts. Fetal growth-restricted pregnancies with an abnormal cerebroplacental ratio had significantly poorer neurologic outcome at 3 years of age across all measured variables. CONCLUSION: We have demonstrated that growth-restricted pregnancies with a cerebroplacental ratio <1 have a significantly increased risk of delayed neurodevelopment at 3 years of age when compared with pregnancies with abnormal umbilical artery Doppler evidence alone. This study further substantiates the benefit of routine assessment of cerebroplacental ratio in fetal growth-restricted pregnancies and for counseling parents regarding the long-term outcome of affected infants.

Trial of feasibility and acceptability of routine low-dose aspirin versus Early Screening Test indicated aspirin for pre-eclampsia prevention (TEST study): a multicentre randomised controlled trial.

OBJECTIVE: Evaluate the feasibility and acceptability of routine aspirin in low-risk women, compared with screening-test indicated aspirin for the prevention of pre-eclampsia and fetal growth restriction. DESIGN: Multicentre open-label feasibility randomised controlled trial. SETTING: Two tertiary maternity hospitals in Dublin, Ireland. PARTICIPANTS: 546 low-risk nulliparous women completed the study. INTERVENTIONS: Women underwent computerised randomisation to: Group 1-routine aspirin 75 mg from 11 until 36 weeks; Group 2-no aspirin and; Group 3-aspirin based on the Fetal Medicine Foundation screening test. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Proportion agreeing to participate; (2) compliance with protocol; (3) proportion where first trimester uterine artery Doppler was obtainable and; (4) time taken to issue a screening result. Secondary outcomes included rates of pre-eclampsia and small-for-gestational-age fetuses. RESULTS: 546 were included in the routine aspirin (n=179), no aspirin (n=183) and screen and treat (n=184) groups. 546 of 1054 were approached (51.8%) and enrolled. Average aspirin adherence was 90%. The uterine artery Doppler was obtained in 98.4% (181/184) and the average time to obtain a screening result was 7.6 (0-26) days. Of those taking aspirin, vaginal spotting was greater; n=29 (15.1%), non-aspirin n=28 (7.9%), OR 2.1 (95% CI 1.2 to 3.6). Postpartum haemorrhage >500 mL was also greater; aspirin n=26 (13.5%), no aspirin n=20 (5.6%), OR 2.6 (95% CI 1.4 to 4.8). CONCLUSION: Low-risk nulliparous women are open to taking aspirin in pregnancy and had high levels of adherence. Aspirin use was associated with greater rates of vaginal bleeding. An appropriately powered randomised controlled trial is now required to address the efficacy and safety of universal low-dose aspirin in low-risk pregnancy compared with a screening approach. TRIAL REGISTRATION NUMBER: ISRCTN (15191778); Post-results.

The Impact of Maternal Gestational Hypertension and the Use of Anti-Hypertensives on Neonatal Myocardial Performance.

BACKGROUND: Assessment of myocardial performance in neonates using advanced techniques such as deformation imaging and rotational mechanics has gained considerable interest. The applicability of these techniques for elucidating abnormal myocardial performance in various clinical scenarios is becoming established. We hypothesise that term infants born to mothers with gestational hypertension (GH) may experience impaired performance of the left and right ventricles during the early neonatal period. OBJECTIVES: We aimed to assess left and right ventricular (LV and RV) function using echocardiography in infants born to mothers with GH and compare them to a control group. METHODS: Term infants (>36+6 weeks) born to mothers with GH underwent assessment to measure biventricular function using ejection fraction (EF), deformation imaging, left-ventricle rotational mechanics (apical rotation, basal rotation, twist, twist rate, and untwist rate), and right ventricle-specific functional parameters (tricuspid annular plane systolic excursion and fractional area change) in the first 48 h after birth. A control group comprising infants born to healthy mothers was used for comparison. RESULTS: Fifteen infants with maternal GH and 30 age-matched controls were enrolled. The GH infants exhibited no differences in birthweight or LV or RV length, but they had lower EF (54 vs. 61%; p < 0.01), LV global longitudinal strain (-20 vs. -25%; p < 0.01), and LV twist (11 vs. 16°; p = 0.04). There were no differences in any of the RV functional parameters. CONCLUSION: Infants born to mothers with GH exhibited lower LV function than healthy controls, while RV function appeared to be preserved. This relationship warrants further exploration in a larger cohort.

Rab11 family expression in the human placenta: Localization at the maternal-fetal interface.

Rab proteins are a family of small GTPases involved in a variety of cellular processes. The Rab11 subfamily in particular directs key steps of intracellular functions involving vesicle trafficking of the endosomal recycling pathway. This Rab subfamily works through a series of effector proteins including the Rab11-FIPs (Rab11 Family-Interacting Proteins). While the Rab11 subfamily has been well characterized at the cellular level, its function within human organ systems is still being explored. In an effort to further study these proteins, we conducted a preliminary investigation of a subgroup of endosomal Rab proteins in a range of human cell lines by Western blotting. The results from this analysis indicated that Rab11a, Rab11c(Rab25) and Rab14 were expressed in a wide range of cell lines, including the human placental trophoblastic BeWo cell line. These findings encouraged us to further analyse the localization of these Rabs and their common effector protein, the Rab Coupling Protein (RCP), by immunofluorescence microscopy and to extend this work to normal human placental tissue. The placenta is a highly active exchange interface, facilitating transfer between mother and fetus during pregnancy. As Rab11 proteins are closely involved in transcytosis we hypothesized that the placenta would be an interesting human tissue model system for Rab investigation. By immunofluorescence microscopy, Rab11a, Rab11c(Rab25), Rab14 as well as their common FIP effector RCP showed prominent expression in the placental cell lines. We also identified the expression of these proteins in human placental lysates by Western blot analysis. Further, via fluorescent immunohistochemistry, we noted abundant localization of these proteins within key functional areas of primary human placental tissues, namely the outer syncytial layer of placental villous tissue and the endothelia of fetal blood vessels. Overall these findings highlight the expression of the Rab11 family within the human placenta, with novel localization at the maternal-fetal interface.

Non-invasive cardiac output monitoring (NICOM®) can predict the evolution of uteroplacental disease-Results of the prospective HANDLE study.

OBJECTIVES: We aimed to firstly identify the different haemodynamic profiles amongst nulliparous women who develop either gestational hypertension (GH), pre-eclampsia (PE), normotensive fetal growth restriction (FGR) versus unaffected pregnancies using non-invasive cardiac output monitoring (NICOM®). Our second primary objective was to assess the ability of NICOM® derived variables to predict the evolution of PE, GH and FGR. STUDY DESIGN: Low risk nulliparous women were enrolled in a single center prospective observational study. NICOM® assessments were performed at 14, 20 and 28 weeks' gestation and data was obtained on cardiac output (CO), total peripheral resistance (TPR), indexed TPR (adjusted for maternal body surface area; TPRi), stroke volume (SV), indexed SV (adjusted for maternal body surface area; SVi) and heart rate (HR). Logistic regression was used to model GH, PE and FGR with NICOM® measurements as predictors. Linear, non-linear and interaction terms were assessed using the Akaike Information Criterion. RESULTS: The haemodynamic profile of pregnancies complicated by uteroplacental disease- GH (n=18), PE (n=6) and FGR (n=24) were compared to 318 healthy unaffected pregnant controls. Women with evolving PE have a different haemodynamic profile to those developing either GH or FGR. The best independent predictors for the evolution of uteroplacental disease at 14 weeks' gestation were CO in the prediction of FGR (AUC=0.61; p 0.002), TPR in the prediction of GH (AUC=0.63; p<0.02) and SVi in the prediction of PE (AUC=0.62; p<0.05). The performance of haemodynamic variables was enhanced when combined in a multivariate logistic model. We demonstrated that TPR, CO and SV when combined with BP were significant predictors of pregnancies complicated by FGR (AUC=0.64, p=0.004; AUC=0.65, p=0.004; and AUC=0.65, p=0.007 respectively). Whereas in pregnancies complicated by PE, HR and SVi in combination with BP were also statistically significant predictors (AUC=0.75, p=0.017 and AUC=0.77, p=0.007 respectively). CONCLUSIONS: NICOM® derived maternal haemodynamic profile at 14 weeks' gestation has the novel potential to identify pregnancies which will ultimately develop uteroplacental disease.

Pregnancy-specific stress, fetoplacental haemodynamics, and neonatal outcomes in women with small for gestational age pregnancies: a secondary analysis of the multicentre Prospective Observational Trial to Optimise Paediatric Health in Intrauterine Growth Restriction.

OBJECTIVES: To examine associations between maternal pregnancy-specific stress and umbilical (UA PI) and middle cerebral artery pulsatility indices (MCA PI), cerebroplacental ratio, absent end diastolic flow (AEDF), birthweight, prematurity, neonatal intensive care unit admission and adverse obstetric outcomes in women with small for gestational age pregnancies. It was hypothesised that maternal pregnancy-specific stress would be associated with fetoplacental haemodynamics and neonatal outcomes. DESIGN: This is a secondary analysis of data collected for a large-scale prospective observational study. SETTING: This study was conducted in the seven major obstetric hospitals in Ireland and Northern Ireland. PARTICIPANTS: Participants included 331 women who participated in the Prospective Observational Trial to Optimise Paediatric Health in Intrauterine Growth Restriction. Women with singleton pregnancies between 24 and 36 weeks gestation, estimated fetal weight <10th percentile and no major structural or chromosomal abnormalities were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Serial Doppler ultrasound examinations of the umbilical and middle cerebral arteries between 20 and 42 weeks gestation, Pregnancy Distress Questionnaire (PDQ) scores between 23 and 40 weeks gestation and neonatal outcomes. RESULTS: Concerns about physical symptoms and body image at 35-40 weeks were associated with lower odds of abnormal UAPI (OR 0.826, 95% CI 0.696 to 0.979, p=0.028). PDQ score (OR 1.073, 95% CI 1.012 to 1.137, p=0.017), concerns about birth and the baby (OR 1.143, 95% CI 1.037 to 1.260, p=0.007) and concerns about physical symptoms and body image (OR 1.283, 95% CI 1.070 to 1.538, p=0.007) at 29-34 weeks were associated with higher odds of abnormal MCA PI. Concerns about birth and the baby at 29-34 weeks (OR 1.202, 95% CI 1.018 to 1.421, p=0.030) were associated with higher odds of AEDF. Concerns about physical symptoms and body image at 35-40 weeks were associated with decreased odds of neonatal intensive care unit admission (OR 0.635, 95% CI 0.435 to 0.927, p=0.019). CONCLUSIONS: These findings suggest that fetoplacental haemodynamics may be a mechanistic link between maternal prenatal stress and fetal and neonatal well-being, but additional research is required.

Evaluation of normalization of cerebro-placental ratio as a potential predictor for adverse outcome in SGA fetuses.

BACKGROUND: Intrauterine growth restriction accounts for a significant proportion of perinatal morbidity and mortality currently encountered in obstetric practice. The primary goal of antenatal care is the early recognition of such conditions to allow treatment and optimization of both maternal and fetal outcomes. Management of pregnancies complicated by intrauterine growth restriction remains one of the greatest challenges in obstetrics. Frequently, however, clinical evidence of underlying uteroplacental dysfunction may only emerge at a late stage in the disease process. With advanced disease the only therapeutic intervention is delivery of the fetus and placenta. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the at-risk fetus in both intrauterine growth restriction and the appropriate-for-gestational-age setting. The cerebroplacental ratio quantifies the redistribution of the cardiac output resulting in a brain-sparing effect. The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect is significantly associated with an adverse perinatal outcome in the intrauterine growth restriction cohort. OBJECTIVE: The aim of the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction study was to evaluate the optimal management of fetuses with an estimated fetal weight <10th centile. The objective of this secondary analysis was to evaluate if normalizing cerebroplacental ratio predicts adverse perinatal outcome. STUDY DESIGN: In all, 1116 consecutive singleton pregnancies with intrauterine growth restriction completed the study protocol over 2 years at 7 centers, undergoing serial sonographic evaluation and multivessel Doppler measurement. Cerebroplacental ratio was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Abnormal cerebroplacental ratio was defined as <1.0. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death. RESULTS: Data for cerebroplacental ratio calculation were available in 881 cases, with a mean gestational age of 33 (interquartile range, 28.7-35.9) weeks. Of the 87 cases of abnormal serial cerebroplacental ratio with an initial value <1.0, 52% (n = 45) of cases remained abnormal and 22% of these (n = 10) had an adverse perinatal outcome. The remaining 48% (n = 42) demonstrated normalizing cerebroplacental ratio on serial sonography, and 5% of these (n = 2) had an adverse perinatal outcome. Mean gestation at delivery was 33.4 weeks (n = 45) in the continuing abnormal cerebroplacental ratio group and 36.5 weeks (n = 42) in the normalizing cerebroplacental ratio group (P value <.001). CONCLUSION: The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect was significantly associated with an adverse perinatal outcome in our intrauterine growth restriction cohort. It was hypothesized that a normalizing cerebroplacental ratio would be a further predictor of an adverse outcome due to the loss of this compensatory mechanism. However, in this subanalysis we did not demonstrate an additional poor prognostic effect when the cerebroplacental ratio value returned to a value >1.0. Overall, this secondary analysis demonstrated the importance of a serial abnormal cerebroplacental ratio value of <1 within the <34 weeks' gestation population. Contrary to our proposed hypothesis, we recognize that reversion of an abnormal cerebroplacental ratio to a normal ratio is not associated with a heightened degree of adverse perinatal outcome.

Gestational hypertensive disease in twin pregnancy: Influence on outcomes in a large national prospective cohort.

OBJECTIVE: Gestational hypertensive disease (GHD) is associated with pregnancy-related complications and poor maternal and fetal outcomes in singleton pregnancies. We sought to examine the influence of GHD in a large prospective cohort of twin pregnancies. STUDY DESIGN: The ESPRIT study was a national multicenter observational cohort study of 1028 structurally normal twin pregnancies. Each pregnancy underwent sonographic surveillance with two-week ultrasound from 24 weeks for dichorionic and from 16 weeks for monochorionic gestations. Characteristics and demographics as well as labour and delivery outcome data were prospectively recorded. Perinatal mortality, admission to the neonatal intensive care unit (NICU) and a composite of morbidity of respiratory distress syndrome, hypoxic ischaemic encephalopathy, periventricular leukomalacia, necrotising enterocolitis and sepsis were documented for all cases. Outcomes for patients with documented GHD (pre-eclampsia and gestational hypertension) were compared with those without GHD. RESULTS: Perinatal outcome data were recorded for 977 patients. Women with GHD had a higher body mass index (27.1 ± 6.4 vs 25.2 ± 4.5, P < 0.0001) than those without and were more likely to be nulliparous (65% (59/92) vs 46% (407/885), P = 0.001). Both groups had similar mean birthweights, but those with GHD were more likely to have a birthweight discordance ≥18% (35% (32/92) vs 20% (179/885), P = 0.001). Rates of caesarean delivery were higher in those twin pregnancies affected by GHD, and while the rate of composite morbidity was similar in both groups, twins in the GHD group had higher rates of NICU admission. CONCLUSION: In twin gestations, gestational hypertension independently confers an increased risk for emergency caesarean delivery, birthweight discordance and NICU admission, such that intensive maternal-fetal monitoring is justified when hypertension develops in a twin pregnancy.

The effect of maternal obesity on sonographic fetal weight estimation and perinatal outcome in pregnancies complicated by fetal growth restriction.

PURPOSE: Maternal obesity represents a challenge in the sonographic (US) assessment of fetal weight, and is a recognized risk factor for adverse pregnancy outcome. The objective of this secondary analysis of data from the Prospective Observational Trial to Optimize Pediatric Health in fetal growth restriction (FGR) Study (PORTO) was to describe the effect of maternal obesity on the accuracy of US in determining the estimated fetal weight (EFW) and the perinatal outcome of pregnancies affected by FGR. METHODS: Between 2010 and 2012, 1,116 women with nonanomalous singleton pregnancies with an EFW in less than the tenth centile were recruited for the PORTO study. Maternal body mass index (BMI) was divided into five subcategories: normal (BMI < 24.9 kg/m(2) ), overweight (25-29.9), obese class 1 (30-34.9), obese class 2 (35-39.9), and obese class 3 (>40). The accuracy of the EFW was determined in women who delivered within 2 weeks of their last US scan. Perinatal outcomes were analyzed by BMI subcategory. RESULTS: Of the 1,074 patients with complete records, 691 (64%) were of normal weight, 258 (24%) were overweight, 93 (9%) were in obese class 1, 32 (3%) were in obese class 2, and none were in obese class 3. Overall, the EFW determined prior to delivery was within 6% of the actual birth weight in all BMI subcategories. Overweight and obese women delivered more commonly by cesarean section and at earlier gestational ages than did women with a normal BMI (p = 0.0008), resulting in lower birth weights (p = 0.0031) and significantly increased composite perinatal morbidity (p < 0.0001) and mortality (p = 0.0215) rates. CONCLUSIONS: US examination is reliable for assessing the weight of fetuses with FGR in overweight women. Maternal obesity, however, has a significant adverse effect on perinatal outcomes. Thus, health education should focus on awareness of this adverse effect, with optimization of prepregnancy weight as its main goal.

Defining the residual risk of adverse perinatal outcome in growth-restricted fetuses with normal umbilical artery blood flow.

OBJECTIVE: We sought to determine the cause of adverse perinatal outcome in fetal growth restriction (FGR) where umbilical artery (UA) Doppler was normal, as identified from the Prospective Observational Trial to Optimize Pediatric Health (PORTO). We compared cases of adverse outcome where UA Doppler was normal and abnormal. STUDY DESIGN: The PORTO study was a national multicenter study of >1100 ultrasound-dated singleton pregnancies with an estimated fetal weight <10th centile. Each pregnancy underwent intensive ultrasound, including multivessel Doppler. UA Doppler was considered abnormal when the pulsatility index was >95th centile or end-diastolic flow was absent/reversed. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, or death. RESULTS: In all, 57 (5.0%) of the 1116 fetuses had an adverse perinatal outcome. Nine (1.3%) of 698 fetuses with normal UA Doppler had an adverse outcome, compared with 48 (11.5%) of 418 with abnormal UA Doppler (P < .0001). There were 2 perinatal deaths in the normal group and 6 in the abnormal group (P = .01). The perinatal deaths in the normal group were 1 case of pulmonary hypoplasia after prolonged preterm rupture of the membranes from 12 weeks' gestation and a case of placental abruption. Gestation at delivery was 33 ± 3 vs 31 ± 4 weeks (P = .05) and mean birthweight was 1830 ± 737 vs 1146 ± 508 g (P = .001) in the respective groups. Neonatal sepsis was the commonest adverse outcome in both groups: 0.1% and 0.4%, respectively (P = .01). CONCLUSION: Adverse perinatal outcome is uncommon in FGR with normal UA Doppler. The cases we identified were associated with heterogenous pathologies. FGR with normal UA blood flow is a largely benign condition.

The role of brain sparing in the prediction of adverse outcomes in intrauterine growth restriction: results of the multicenter PORTO Study.

OBJECTIVE: The aim of the Prospective Observational Trial to Optimize Pediatric Health in IUGR Study was to evaluate the optimal management of fetuses with an estimated fetal weight less than the 10th centile. The objective of this secondary analysis was to describe the role of the cerebroplacental ratio (CPR) in the prediction of adverse perinatal outcome. STUDY DESIGN: More than 1100 consecutive singleton pregnancies with intrauterine growth restriction (IUGR) were recruited over 2 years at 7 centers, undergoing serial sonographic evaluation including multivessel Doppler measurement. CPR was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death. RESULTS: Data for CPR calculation was available in 881 cases, which was performed at a mean gestational age of 33 weeks (interquarile range, 28.7-35.9). Of the 146 cases with CPR less than 1, 18% (n = 27) had an adverse perinatal outcome. This conferred an 11-fold increased risk (odds ratio, 11.7; P < .0001) when compared with cases with normal CPR (2%; 14 of 735). An abnormal CPR was present in all 3 cases of mortality. Prediction of adverse outcomes was comparable when using all definitions of abnormal CPR. CONCLUSION: Irrespective of the CPR calculation used, brain sparing is significantly associated with an adverse perinatal outcome in IUGR. This adds further weight to integrating CPR evaluation into the clinical assessment of IUGR pregnancies. The impact of this finding on long-term neurodevelopmental outcomes in this patient cohort is underway.

Fetal growth restriction and the risk of perinatal mortality-case studies from the multicentre PORTO study.

BACKGROUND: Intrauterine growth restriction (IUGR) is the single largest contributing factor to perinatal mortality in non-anomalous fetuses. Advances in antenatal and neonatal critical care have resulted in a reduction in neonatal deaths over the past decades, while stillbirth rates have remained unchanged. Antenatal detection rates of fetal growth failure are low, and these pregnancies carry a high risk of perinatal death. METHODS: The Prospective Observational Trial to Optimize Paediatric Health in IUGR (PORTO) Study recruited 1,200 ultrasound-dated singleton IUGR pregnancies, defined as EFW <10th centile, between 24+0 and 36+6 weeks gestation. All recruited fetuses underwent serial sonographic assessment of fetal weight and multi-vessel Doppler studies until birth. Perinatal outcomes were recorded for all pregnancies. Case records of the perinatal deaths from this prospectively recruited IUGR cohort were reviewed, their pregnancy details and outcome were analysed descriptively and compared to the entire cohort. RESULTS: Of 1,116 non-anomalous singleton infants with EFW <10th centile, 6 resulted in perinatal deaths including 3 stillbirths and 3 early neonatal deaths. Perinatal deaths occurred between 24+6 and 35+0 weeks gestation corresponding to birthweights ranging from 460 to 2260 grams. Perinatal deaths occurred more commonly in pregnancies with severe growth restriction (EFW <3rd centile) and associated abnormal Doppler findings resulting in earlier gestational ages at delivery and lower birthweights. All of the described pregnancies were complicated by either significant maternal comorbidities, e.g. hypertension, systemic lupus erythematosus (SLE) or diabetes, or poor obstetric histories, e.g. prior perinatal death, mid-trimester or recurrent pregnancy loss. Five of the 6 mortalities occurred in women of non-Irish ethnic backgrounds. All perinatal deaths showed abnormalities on placental histopathological evaluation. CONCLUSIONS: The PNMR in this cohort of prenatally identified IUGR cases was 5.4/1,000 and compares favourably to the overall national rate of 4.1/1,000 births, which can be attributed to increased surveillance and timely delivery. Despite antenatal recognition of IUGR and associated maternal risk factors, not all perinatal deaths can be prevented.

Definition and management of fetal growth restriction: a survey of contemporary attitudes.

OBJECTIVE: To evaluate opinions among Irish obstetricians and obstetric trainees regarding the optimal definition, assessment and management of pregnancies affected by intrauterine growth restriction (IUGR). STUDY DESIGN: An anonymous, structured, web-based survey that comprised 14 questions was sent to 200 obstetricians and obstetric trainees in Ireland. RESULTS: Of the 113 participants (57% response rate), the majority (50%) were consultants, with over 10 years' clinical experience (46%), who worked in large maternity units (58%) with neonatal units providing care for preterm IUGR fetuses (94%). Eighty-three clinicians (74%) agreed that an estimated fetal weight (EFW) below the 10th centile constitutes small-for-gestational age (SGA). The majority (n=93; 82%) would deliver the SGA fetus between 37(+0) and 39(+6) weeks gestation. In total, the survey yielded 30 different IUGR definitions; the top three definitions were (i) an EFW below the 5th centile (n=18; 16%), (ii) an EFW below the 10th centile with oligohydramnios and abnormal umbilical artery (UA) Doppler (n=16; 14%), and (iii) an EFW below the 10th centile (n=12; 11%). In the evaluation of the preterm IUGR fetus with abnormal UA Doppler, the assessment of amniotic fluid volume, middle cerebral artery, ductus venosus, cardiotocograph (CTG) and biophysical profiling was performed in 74%, 60%, 60%, 54% and 52% respectively. The majority of clinicians applied three or more assessment modalities and 60% referred to a maternal-fetal medicine (MFM) subspecialist. Interestingly, even among MFM subspecialists there was no common consistent management approach. Most doctors (81%) would deliver the IUGR fetus for CTG abnormalities but MFM subspecialists more commonly deliver on the basis of absent end-diastolic flow in the UA alone (37% vs. 10%; p=0.006). Two-thirds of doctors (n=74) would implement customised growth charts if they became available for their population and over 80% thought that a national guideline on IUGR would be beneficial. CONCLUSION: The results of this survey confirm the inconsistencies surrounding the clinical management of IUGR pregnancies and highlight the need for standardisation of terminology and antenatal surveillance, implementation of fetal weight customisation and national guidance for Ireland.

The role of growth trajectories in classifying fetal growth restriction.

OBJECTIVE: To examine the validity of a growth trajectory method to discriminate between pathologically and constitutionally undergrown fetuses using repeated measures of estimated fetal weight. METHODS: In a prospective, observational, multicenter study in Ireland, 1,116 women with a growth-restricted fetus diagnosed participated with the objective of evaluating ultrasound findings as predictors of pediatric morbidity and mortality. Fetal growth trajectories were based on estimated fetal weight. RESULTS: Between 22 weeks of gestation and term, two fetal growth trajectories were identified: normal (96.7%) and pathologic (3.3%). Compared with the normal trajectory, the pathologic trajectory was associated with an increased risk for preeclampsia (odds ratio [OR] 8.1, 95% confidence interval [CI] 2.6-23.4), increased umbilical artery resistance at 30 weeks of gestation (OR 12.6, 95% CI 4.6-34.1) or 34 weeks of gestation (OR 28.0, 95% CI 8.9-87.7), reduced middle cerebral artery resistance at 30 weeks of gestation (OR 0.33, 95% CI 0.12-0.96) or 34 weeks of gestation (OR 0.14, 95% CI 0.03-0.74), lower gestational age at delivery (mean 32.02 weeks of gestation compared with 38.02 weeks of gestation; P<.001), and higher perinatal complications (OR 21.5, 95% CI 10.5-44.2). In addition, 89.2% of newborns with pathologic fetal growth were admitted to neonatal intensive care units compared with 25.9% of those with normal growth. CONCLUSIONS: Fetal growth trajectory analysis reliably differentiated fetuses with a pathologic growth pattern among a group of women with growth-restricted fetuses. With further development, this approach could provide clarity to how we define, identify, and ultimately manage pathologic fetal growth. LEVEL OF EVIDENCE: II.