Fetal cerebral blood-flow redistribution: analysis of Doppler reference charts and association of different thresholds with adverse perinatal outcome.

OBJECTIVES: First, to compare published Doppler reference charts of the ratios of flow in the fetal middle cerebral and umbilical arteries (i.e. the cerebroplacental ratio (CPR) and umbilicocerebral ratio (UCR)). Second, to assess the association of thresholds of CPR and UCR based on these charts with short-term composite adverse perinatal outcome in a cohort of pregnancies considered to be at risk of late preterm fetal growth restriction. METHODS: Studies presenting reference charts for CPR or UCR were searched for in PubMed. Formulae for plotting the median and the 10th percentile (for CPR) or the 90th percentile (for UCR) against gestational age were extracted from the publication or calculated from the published tables. Data from a prospective European multicenter observational cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks' gestation, in which fetal arterial Doppler measurements were collected longitudinally, were used to compare the different charts. Specifically, the association of UCR and CPR thresholds (CPR < 10th percentile or UCR ≥ 90th percentile and multiples of the median (MoM) values) with composite adverse perinatal outcome was analyzed. The association was also compared between chart-based thresholds and absolute thresholds. Composite adverse perinatal outcome comprised both abnormal condition at birth and major neonatal morbidity. RESULTS: Ten studies presenting reference charts for CPR or UCR were retrieved. There were large differences between the charts in the 10th and 90th percentile values of CPR and UCR, respectively, while median values were more similar. In the gestational-age range of 28-36 weeks, there was no relationship between UCR or CPR and gestational age. From the prospective observational study, 856 pregnancies at risk of late-onset preterm fetal growth restriction were included in the analysis. The association of abnormal UCR or CPR with composite adverse perinatal outcome was similar for percentile thresholds or MoM values, as calculated from the charts, and for absolute thresholds, both on univariable analysis and after adjustment for gestational age at measurement, estimated fetal weight MoM and pre-eclampsia. The adjusted odds ratio for composite adverse perinatal outcome was 3.3 (95% CI, 1.7-6.4) for an absolute UCR threshold of ≥ 0.9 or an absolute CPR threshold of < 1.11 (corresponding to ≥ 1.75 MoM), and 1.6 (95% CI, 0.9-2.9) for an absolute UCR threshold of ≥ 0.7 to < 0.9 or an absolute CPR threshold of ≥ 1.11 to < 1.43 (corresponding to ≥ 1.25 to < 1.75 MoM). CONCLUSIONS: In the gestational-age range of 32 to 36 weeks, adjustment of CPR or UCR for gestational age is not necessary when assessing the risk of adverse outcome in pregnancies at risk of fetal growth restriction. The adoption of absolute CPR or UCR thresholds, independent of reference charts, is feasible and makes clinical assessment simpler than if using percentiles or other gestational-age normalized units. The high variability in percentile threshold values among the commonly used UCR and CPR reference charts hinders reliable diagnosis and clinical management of late preterm fetal growth restriction. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Pregnancy and neonatal outcomes of COVID-19: coreporting of common outcomes from PAN-COVID and AAP-SONPM registries.

OBJECTIVE: Few large cohort studies have reported data on maternal, fetal, perinatal and neonatal outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy. We report the outcome of infected pregnancies from a collaboration formed early during the pandemic between the investigators of two registries, the UK and Global Pregnancy and Neonatal outcomes in COVID-19 (PAN-COVID) study and the American Academy of Pediatrics (AAP) Section on Neonatal-Perinatal Medicine (SONPM) National Perinatal COVID-19 Registry. METHODS: This was an analysis of data from the PAN-COVID registry (1 January to 25 July 2020), which includes pregnancies with suspected or confirmed maternal SARS-CoV-2 infection at any stage in pregnancy, and the AAP-SONPM National Perinatal COVID-19 registry (4 April to 8 August 2020), which includes pregnancies with positive maternal testing for SARS-CoV-2 from 14 days before delivery to 3 days after delivery. The registries collected data on maternal, fetal, perinatal and neonatal outcomes. The PAN-COVID results are presented overall for pregnancies with suspected or confirmed SARS-CoV-2 infection and separately in those with confirmed infection. RESULTS: We report on 4005 pregnant women with suspected or confirmed SARS-CoV-2 infection (1606 from PAN-COVID and 2399 from AAP-SONPM). For obstetric outcomes, in PAN-COVID overall and in those with confirmed infection in PAN-COVID and AAP-SONPM, respectively, maternal death occurred in 0.5%, 0.5% and 0.2% of cases, early neonatal death in 0.2%, 0.3% and 0.3% of cases and stillbirth in 0.5%, 0.6% and 0.4% of cases. Delivery was preterm (< 37 weeks' gestation) in 12.0% of all women in PAN-COVID, in 16.1% of those women with confirmed infection in PAN-COVID and in 15.7% of women in AAP-SONPM. Extreme preterm delivery (< 27 weeks' gestation) occurred in 0.5% of cases in PAN-COVID and 0.3% in AAP-SONPM. Neonatal SARS-CoV-2 infection was reported in 0.9% of all deliveries in PAN-COVID overall, in 2.0% in those with confirmed infection in PAN-COVID and in 1.8% in AAP-SONPM; the proportions of neonates tested were 9.5%, 20.7% and 87.2%, respectively. The rates of a small-for-gestational-age (SGA) neonate were 8.2% in PAN-COVID overall, 9.7% in those with confirmed infection and 9.6% in AAP-SONPM. Mean gestational-age-adjusted birth-weight Z-scores were -0.03 in PAN-COVID and -0.18 in AAP-SONPM. CONCLUSIONS: The findings from the UK and USA registries of pregnancies with SARS-CoV-2 infection were remarkably concordant. Preterm delivery affected a higher proportion of women than expected based on historical and contemporaneous national data. The proportions of pregnancies affected by stillbirth, a SGA infant or early neonatal death were comparable to those in historical and contemporaneous UK and USA data. Although maternal death was uncommon, the rate was higher than expected based on UK and USA population data, which is likely explained by underascertainment of women affected by milder or asymptomatic infection in pregnancy in the PAN-COVID study, although not in the AAP-SONPM study. The data presented support strong guidance for enhanced precautions to prevent SARS-CoV-2 infection in pregnancy, particularly in the context of increased risks of preterm delivery and maternal mortality, and for priority vaccination of pregnant women and women planning pregnancy. Copyright © 2021 ISUOG. Published by John Wiley & Sons Ltd.

Etiology and perinatal outcome of periviable fetal growth restriction associated with structural or genetic anomaly.

OBJECTIVE: To investigate the etiology and perinatal outcome of periviable fetal growth restriction (FGR) associated with a structural defect or genetic anomaly. METHODS: This was a retrospective study of singleton pregnancies seen at a referral fetal medicine unit between 2005 and 2018, in which FGR (defined as fetal abdominal circumference ≤ 3rd percentile for gestational age) was diagnosed between 22 + 0 and 25 + 6 weeks of gestation. The study group included pregnancies with periviable FGR associated with a genetic or structural anomaly (anomalous FGR), while the control group consisted of structurally and genetically normal pregnancies with periviable FGR (non-anomalous FGR). Results of genetic testing, TORCH screen and postmortem examination, as well as perinatal outcome, were investigated. RESULTS: Of 255 pregnancies complicated by periviable FGR, 188 were eligible; of which 52 (28%) had anomalous FGR and 136 (72%) had non-anomalous FGR. A confirmed genetic abnormality accounted for 17/52 cases (33%) of anomalous FGR, with trisomy 18 constituting over 50% (9/17; 53%). The most common structural defects associated with FGR were central nervous system abnormalities (13/35; 37%). Overall, 12 (23%) cases of anomalous FGR survived the neonatal period. No differences were found in terms of perinatal survival between pregnancies with anomalous and those with non-anomalous FGR. CONCLUSIONS: Most pregnancies complicated by anomalous FGR were associated with a structural defect. The presence of an associated genetic defect was invariably lethal, while those with a structural defect, in the absence of a confirmed genetic abnormality, survived into infancy in over 90% of cases, with an overall one in three chance of perinatal survival. These data can be used for counseling prospective parents. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Fetal cerebral Doppler changes and outcome in late preterm fetal growth restriction: prospective cohort study.

OBJECTIVES: To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction. METHODS: This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored. RESULTS: The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37-39) weeks and birth weight was 2478 (IQR, 2140-2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32-33 weeks and 1.0 at 34-36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5-3.2) and RR 2.0 (95% CI, 1.4-3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association. CONCLUSION: In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal Management of Pregnancies at Risk of Fetal Neonatal Alloimmune Thrombocytopenia (FNAIT): Scientific Impact Paper No. 61.

WHAT IS IT?: Fetal neonatal alloimmune thrombocytopenia (FNAIT), also known as neonatal alloimmune thrombocytopenia (NAIT) or fetomaternal alloimmune thrombocytopenia (FMAIT), is a rare condition which affects a baby's platelets. This can put them at risk of problems with bleeding, particularly into the brain. One baby per week in the UK may be seriously affected and milder forms can affect one in every 1000 births. HOW IS IT CAUSED?: Platelets are blood cells that are very important in helping blood to clot. All platelets have natural proteins on their surface called human platelet antigens (HPAs). In babies, half of these antigens are inherited from the mother and half from the father. During pregnancy, some of the baby's platelets can cross into the mother's bloodstream. In most cases, this does not cause a problem. But in cases of FNAIT, the mother's immune system does not recognise the baby's HPAs that were inherited from the father and develops antibodies, which can cross the placenta and attack the baby's platelets. These antibodies are called anti-HPAs, and the commonest antibody implicated is anti-HPA-1a, but there are other rarer antibody types. If this happens, the baby's platelets may be destroyed causing their platelet count to fall dangerously low. If the platelet count is very low there is a risk to the baby of bleeding into their brain before they are born. This is very rare but if it happens it can have serious effects on the baby's health. HOW IS IT INHERITED?: A baby inherits half of their HPAs from its mother and half from its father. Consequently, a baby may have different HPAs from its mother. As the condition is very rare, and even if the baby is at risk of the condition we have no way of knowing how severely they will be affected, routine screening is not currently recommended. WHAT CAN BE DONE?: FNAIT is usually diagnosed if a previous baby has had a low platelet count. The parents are offered blood tests and the condition can be confirmed or ruled out. There are many other causes of low platelets in babies, which may also need to be tested for. As the condition is so rare, expertise is limited to specialist centres and normally a haematologist and fetal medicine doctor will perform and interpret the tests together. Fortunately, there is an effective treatment for the vast majority of cases called immunoglobulin, or IVIg. This 'blood product' is given intravenously through a drip every week to women at risk of the condition. It may be started from as early as 16 weeks in the next pregnancy, until birth, which would be offered at around 36-37 weeks. Less common treatments that may be considered depending on individual circumstances include steroid tablets or injections, or giving platelet transfusions to the baby. WHAT DOES THIS PAPER TELL YOU?: This paper considers the latest evidence in relation to treatment options in the management of pregnancies at risk of FNAIT. Specifically, we discuss the role of screening, when IVIg should be started, what dose should be used, and what evidence there is for maternal steroids. We also consider in very rare selected cases, the use of fetal blood sampling and giving platelet transfusions to the baby before birth. Finally, we consider the approaches to blood testing mothers to tell if babies are at risk, which is offered in some countries, and development of new treatments to reduce the risk of FNAIT.

Descent of fetal head during active pushing: secondary analysis of prospective cohort study investigating ultrasound examination before operative vaginal delivery.

OBJECTIVES: To investigate if descent of the fetal head during active pushing is associated with duration of operative vaginal delivery, mode of delivery and neonatal outcome in nulliparous women with prolonged second stage of labor. METHODS: This was a prospective cohort study of nulliparous women with prolonged second stage of labor, conducted between November 2013 and July 2016 in five European countries. Fetal head descent was measured using transperineal ultrasound. Head-perineum distance (HPD) was measured between contractions and on maximum contraction during active pushing, and the difference between these values (ΔHPD) was calculated. The main outcome was duration of operative vaginal delivery, estimated using survival analysis to calculate hazard ratios (HRs) for vaginal delivery, with values > 1 indicating a shorter duration. HR was adjusted for prepregnancy body mass index, maternal age, induction of labor, augmentation with oxytocin and use of epidural analgesia. Pregnancies were grouped according to ΔHPD quartile, and delivery mode and neonatal outcome were compared between groups. RESULTS: The study population comprised 204 women. Duration of vacuum extraction was shorter with increasing ΔHPD. Estimated mean duration was 10.0, 9.0, 8.8 and 7.5 min in pregnancies with ΔHPD in the first to fourth quartiles, respectively, and the adjusted HR for vaginal delivery, using increasing ΔHPD as a continuous variable, was 1.04 (95% CI, 1.01-1.08). Mean ΔHPD was 7 mm (range, -10 to 37 mm). ΔHPD was either negative or ≤ 2 mm in the lowest quartile. In this group, 7/50 (14%) pregnancies were delivered by Cesarean section, compared with 8/154 (5%) of those with ΔHPD > 2 mm (P < 0.05). There was no significant association between umbilical artery pH < 7.10 or 5-min Apgar score < 7 and ΔHPD quartile. CONCLUSION: Minimal or no fetal head descent during active pushing was associated with longer duration of operative vaginal delivery and higher frequency of Cesarean section in nulliparous women with prolonged second stage of labor. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Altered autonomic control of heart rate variability in the chronically hypoxic fetus.

KEY POINTS: Fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, and a decrease in FHRV is associated with fetal compromise. However, the mechanisms by which FHRV is reduced in the chronically hypoxic fetus have yet to be established. The sympathetic and parasympathetic influences on heart rate mature at different rates throughout fetal life, and can be assessed by time domain and power spectral analysis of FHRV. In this study of chronically instrumented fetal sheep in late gestation, we analysed FHRV daily over a 16 day period towards term, and compared changes between fetuses of control and chronically hypoxic pregnancy. We show that FHRV in sheep is reduced by chronic hypoxia, predominantly due to dysregulation of the sympathetic control of the fetal heart rate. This presents a potential mechanism by which a reduction in indices of FHRV predicts fetuses at increased risk of neonatal morbidity and mortality in humans. Reduction in overall FHRV may therefore provide a biomarker that autonomic dysregulation of fetal heart rate control has taken place in a fetus where uteroplacental dysfunction is suspected. ABSTRACT: Although fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, the mechanisms by which it is reduced in the chronically hypoxic fetus have yet to be established. In particular, the physiological mechanism underlying the reduction of short term variation (STV) in fetal compromise remains unclear. In this study, we present a longitudinal study of the development of autonomic control of FHRV, assessed by indirect indices, time domain and power spectral analysis, in normoxic and chronically hypoxic, chronically catheterised, singleton fetal sheep over the last third of gestation. We used isobaric chambers able to maintain pregnant sheep for prolonged periods in hypoxic conditions (stable fetal femoral arterial PO2 10-12 mmHg), and a customised wireless data acquisition system to record beat-to-beat variation in the fetal heart rate. We determined in vivo longitudinal changes in overall FHRV and the sympathetic and parasympathetic contribution to FHRV in hypoxic (n = 6) and normoxic (n = 6) ovine fetuses with advancing gestational age. Normoxic fetuses show gestational age-related increases in overall indices of FHRV, and in the sympathetic nervous system contribution to FHRV (P < 0.001). Conversely, gestational age-related increases in overall FHRV were impaired by exposure to chronic hypoxia, and there was evidence of suppression of the sympathetic nervous system control of FHRV after 72 h of exposure to hypoxia (P < 0.001). This demonstrates that exposure to late gestation isolated chronic fetal hypoxia has the potential to alter the development of the autonomic nervous system control of FHRV in sheep. This presents a potential mechanism by which a reduction in indices of FHRV in human fetuses affected by uteroplacental dysfunction can predict fetuses at increased risk.

Preconception and early pregnancy maternal haemodynamic changes in healthy women in relation to pregnancy viability.

STUDY QUESTION: Are there differences in preconception cardiovascular function between women who have a viable pregnancy and those who have a first trimester miscarriage? SUMMARY ANSWER: Preconception cardiovascular function of central haemodynamics and arterial function are similar between women who have a viable pregnancy and those who have a first trimester miscarriage. WHAT IS KNOWN ALREADY: Miscarriages have been associated with increased long-term cardiovascular disease risk, and arterial and cardiovascular dysfunction has been hypothesised as the common link. It is not known if these risks are present prior to pregnancy or are a reflection of poor arterial and haemodynamic adaptation to pregnancy. STUDY DESIGN, SIZE, DURATION: This prospective longitudinal preconception cohort study was conducted over 18 months. In total, 367 participants were recruited pre-pregnancy, from which 197 pregnancies were recorded; 39 of these pregnancies ended in first trimester miscarriage. Complete longitudinal data were available for 172 pregnancies (140 viable pregnancies, 32 first trimester miscarriages) from pre-pregnancy to 6 weeks gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: This was a single site study based at a maternity hospital in London. Healthy women were recruited prior to natural conception and followed up once they became pregnant. All underwent haemodynamic [cardiac output (CO), peripheral vascular resistance (PVR)] and arterial function [aortic augmentation index (AIx) and pulse wave velocity (PWV)] testing prior to pregnancy and at 6 weeks gestation, using non-invasive devices (gas re-breathing method, Innocor® and an occilometric device, Vicorder®). Cross-sectional measurements at pre-pregnancy and 6 weeks gestation and a longitudinal analysis of changes were compared between women who had a subsequent viable pregnancy, and those who had a subsequent first trimester miscarriage. MAIN RESULTS AND THE ROLE OF CHANCE: There were no differences between women destined to have a healthy ongoing pregnancy compared to those who miscarried, in terms of baseline cardiovascular function, assessed by CO, PVR, PWV or AIx. Similarly, between the groups, there were no differences in pregnancy adaptation with similar trends in cardiovascular function changes from pre-pregnancy to 6 weeks gestation. LIMITATIONS, REASONS FOR CAUTION: Whilst this is the first study to investigate preconception and early pregnancy haemodynamic and arterial function in relation to viability, the relatively modest number of miscarriages may not be sufficient to show subtle differences in haemodynamic changes if these were present. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that pre-pregnancy haemodynamic and arterial function is unlikely to be the causal link between miscarriages and future cardiovascular disease. Our findings suggests that factors other than the presence of a viable embryo drive cardiovascular changes in early pregnancy. This study raises new questions about miscarriages as an independent risk event which predisposes women to increased cardiovascular risk later in life. STUDY FUNDING/COMPETING INTEREST(S): The investigators are funded by NIHR Imperial BRC, NIHR Cambridge BRC, Action Medical Research, Imperial College Healthcare Charity and Tommy's Charity. We acknowledge the loan of ultrasound equipment from Samsung Medison (South Korea)/MIS Ltd and provision of fertility monitors from SPD Development Company Ltd (Bedford, UK). There are no competing interests. C.C.L. is supported by the UK National Institute for Health Research Biomedical Research Centre based at Imperial College Healthcare National Health Service Trust and Imperial College London. TRIAL REGISTRATION NUMBER: N/A.

Change in maternal cardiac output from preconception to mid-pregnancy is associated with birth weight in healthy pregnancies.

OBJECTIVE: Birth weight (BW) is thought to be determined by maternal health and genetic, nutritional and placental factors, the latter being influenced by anatomical development and perfusion. Maternal cardiovascular changes contribute to uteroplacental perfusion; however, they have not yet been investigated in relation to fetal growth or BW. Our aim was to explore the relationship between maternal cardiovascular adaptation, fetal growth and BW in healthy pregnancies. METHODS: This was a longitudinal prospective study of women planning to conceive a pregnancy. Maternal cardiac output (CO), cardiac index (CI), pulse-wave velocity, aortic augmentation index, central blood pressure and peripheral vascular resistance were assessed prior to pregnancy and at 6, 23 and 33 weeks' gestation. Fetal growth was assessed using serial ultrasound measurements of biometry. RESULTS: In total, 143 women volunteered to participate and were eligible for study inclusion. A total of 101 women conceived within 18 months and there were 64 live births with normal pregnancy outcome. There were positive correlations between BW and the pregnancy-induced changes in CO (ρ = 0.4, P = 0.004), CI (ρ = 0.3, P = 0.02) and peripheral vascular resistance (ρ = 0.3, P = 0.02). There were significant associations between second-to-third-trimester fetal weight gain and the prepregnancy-to-second-trimester increase in CO (Δ, 0.8 ± 1.2 L/min; ρ = 0.3, P = 0.02) and CI (Δ, 0.4 ± 0.6 L/min/m2 ; ρ = 0.3, P = 0.04) and reduction in aortic augmentation index (Δ, -10 ± 9%; ρ = -0.3, P = 0.04). CONCLUSIONS: In healthy pregnancy, incremental changes in maternal CO in early pregnancy are associated with third-trimester fetal growth and BW. It is plausible that this association is causative as the changes predate third-trimester fetal growth and eventual BW. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Fetal monitoring indications for delivery and 2-year outcome in 310 infants with fetal growth restriction delivered before 32 weeks' gestation in the TRUFFLE study.

OBJECTIVE: In the TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe) study on the outcome of early fetal growth restriction, women were allocated to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate (FHR) short-term variation (STV) on cardiotocography (CTG); (2) early changes in fetal ductus venosus (DV) waveform (DV-p95); and (3) late changes in fetal DV waveform (DV-no-A). However, many infants per monitoring protocol were delivered because of safety-net criteria, for maternal or other fetal indications, or after 32 weeks of gestation when the protocol was no longer applied. The objective of the present posthoc subanalysis was to investigate the indications for delivery in relation to 2-year outcome in infants delivered before 32 weeks to further refine management proposals. METHODS: We included all 310 cases of the TRUFFLE study with known outcome at 2 years' corrected age and seven fetal deaths, excluding seven cases with inevitable perinatal death. Data were analyzed according to the allocated fetal monitoring strategy in combination with the indication for delivery. RESULTS: Overall, only 32% of liveborn infants were delivered according to the specified monitoring parameter for indication for delivery; 38% were delivered because of safety-net criteria, 15% for other fetal reasons and 15% for maternal reasons. In the CTG-STV group, 51% of infants were delivered because of reduced STV. In the DV-p95 group, 34% of infants were delivered because of abnormal DV and, in the DV-no-A group, only 10% of infants were delivered accordingly. The majority of infants in the DV groups were delivered for the safety-net criterion of spontaneous decelerations in FHR. Two-year intact survival was highest in the DV groups combined compared with the CTG-STV group (P = 0.05 for live births only, P = 0.21 including fetal death), with no difference between DV groups. A poorer outcome in the CTG-STV group was restricted to infants delivered because of FHR decelerations in the safety-net subgroup. Infants delivered because of maternal reasons had the highest birth weight and a non-significantly higher intact survival. CONCLUSIONS: In this subanalysis of infants delivered before 32 weeks, the majority were delivered for reasons other than the allocated monitoring strategy indication. Since, in the DV group, CTG-STV criteria were used as a safety net but in the CTG-STV group, no DV safety-net criteria were applied, we speculate that the slightly poorer outcome in the CTG-STV group might be explained by the absence of DV data. The optimal timing of delivery of fetuses with early intrauterine growth restriction may therefore be best determined by monitoring them longitudinally, with both DV and CTG monitoring. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal study of computerized cardiotocography in early fetal growth restriction.

OBJECTIVES: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome. METHODS: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome. RESULTS: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42% and specificity of 91%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4% (interquartile range (IQR), 2-7%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5% (IQR, 4-7%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the median and gestational age did not usefully improve daily risk prediction. There was no association of STV regression coefficients, a low last STV and/or recurrent FHR decelerations with short- or long-term infant outcomes. CONCLUSION: The TRUFFLE study showed that a strategy of DV monitoring with safety-net criteria of very low STV and/or recurrent FHR decelerations for delivery indication could increase 2-year infant survival without neurological impairment. This post-hoc analysis demonstrates that, in early FGR, the daily risk of abnormal CTG, as defined by the DV group safety-net criteria, is 5%, and that prediction is not possible. This supports the rationale for CTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent FHR decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DV-PI is within normal range. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study.

OBJECTIVES: In the recent TRUFFLE study, it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks' gestation, monitoring of the fetal ductus venosus (DV) waveform combined with computed cardiotocography (CTG) to determine timing of delivery increased the chance of infant survival without neurological impairment. However, concerns with the interpretation were raised, as DV monitoring appeared to be associated with a non-significant increase in fetal death, and some infants were delivered after 32 weeks, at which time the study protocol no longer applied. This secondary sensitivity analysis of the TRUFFLE study focuses on women who delivered before 32 completed weeks' gestation and analyzes in detail the cases of fetal death. METHODS: Monitoring data of 317 pregnancies with FGR that delivered before 32 weeks were analyzed, excluding those with absent outcome data or inevitable perinatal death. Women were allocated randomly to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate short-term variation (STV) on CTG; (2) early changes in fetal DV waveform; and (3) late changes in fetal DV waveform. Primary outcome was 2-year survival without neurological impairment. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis. RESULTS: Two-year survival without neurological impairment occurred more often in the two DV groups (both 83%) than in the CTG-STV group (77%), however, the difference was not statistically significant (P = 0.21). Among the surviving infants in the DV groups, 93% were free of neurological impairment vs 85% of surviving infants in the CTG-STV group (P = 0.049). All fetal deaths (n = 7) occurred in the groups with DV monitoring. Of the monitoring parameters obtained shortly before fetal death in these seven cases, an abnormal CTG was observed in only one case. Multivariable regression analysis of factors at study entry demonstrated that a later gestational age, higher estimated fetal weight-to-50th percentile ratio and lower umbilical artery pulsatility index (PI)/fetal middle cerebral artery-PI ratio were significantly associated with normal outcome. Allocation to DV monitoring had a smaller effect on outcome, but remained in the model (P < 0.1). Abnormal fetal arterial Doppler before delivery was significantly associated with adverse outcome in the CTG-STV group. In contrast, abnormal DV flow was the only monitoring parameter associated with adverse outcome in the DV groups, while fetal arterial Doppler, STV below the cut-off used in the CTG-STV group and recurrent decelerations in fetal heart rate were not. CONCLUSIONS: In accordance with the findings of the TRUFFLE study on monitoring and intervention management of very preterm FGR, we found that the proportion of infants surviving without neuroimpairment was not significantly different when the decision for delivery was based on changes in DV waveform vs reduced STV on CTG. The uneven distribution of fetal deaths towards the DV groups was probably a chance effect, and neurological outcome was better among surviving children in these groups. Before 32 weeks, delaying delivery until abnormalities in DV-PI or STV and/or recurrent decelerations in fetal heat rate occur, as defined by the study protocol, is likely to be safe and possibly benefits long-term outcome. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Short-term outcome of periviable small-for-gestational-age babies: is our counseling up to date?

OBJECTIVE: There are limited data for counseling on and management of periviable small-for-gestational-age (SGA) fetuses. We therefore aimed to investigate the short-term outcome of periviable SGA fetuses in relation to the likely underlying cause. METHODS: This was a retrospective study of data from three London tertiary fetal medicine centers obtained between 2000 and 2015. We included viable singleton pregnancies with a severely small fetus, defined as those with an abdominal circumference ≤ 3rd percentile, identified between 22 + 0 and 25 + 6 weeks' gestation. Data obtained included fetal biometry, presence of placental anomalies, uterine and fetal Doppler and neonatal outcome. We excluded cases with structural abnormalities, proven or suspected abnormal karyotype or genetic syndromes. Cases were classified according to the suspected underlying cause of the small fetal size into one of the following categories: uteroplacental insufficiency, evidence of placental damage with normal uterine artery Doppler, viral infection, or unclassied. RESULTS: There were 245 cases included in the study. Of these, at diagnosis of SGA, 201 (82%) were categorized as uteroplacental cause, 13 (5%) as suspected placental cause, one (0.4%) as suspected viral cause and 30 (12%) could not be assigned to any of these categories. Overall, 101 (41%) cases survived the neonatal period; 89 (36%) underwent in-utero fetal demise, 22 (9%) died neonatally and 33 (14%) pregnancies were terminated. The diagnosis-to-delivery interval was 8.1 weeks in those that survived and 4.5 weeks in those that died neonatally. CONCLUSIONS: Almost 90% of periviable SGA cases are associated with uteroplacental insufficiency or intraplacental damage. Survival is related to gestational age at delivery, with outcomes better than might be assumed at diagnosis and some pregnancies reaching term. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Hypertension in pregnancy: natural history and treatment options.

Hypertensive disorders of pregnancy affect approximately 5-10% of all maternities and are major contributors of maternal and neonatal morbidity and mortality worldwide. This group of disorders encompasses chronic hypertension, as well as conditions that arise de novo in pregnancy: gestational hypertension and pre-eclampsia. The latter group is thought to be part of the same continuum but with arbitrary division. Research into the aetiology of hypertension in pregnancy have largely been focused on pre-eclampsia, with a majority of studies exploring either pregnancy-associated factors such as placental-derived or immunologic responses to pregnancy tissue, or maternal constitutional factors such as cardiovascular health and endothelial dysfunction. The evidence base for the pathophysiology and progression of hypertensive disorders in pregnancy, particularly pre-eclampsia, is reviewed. Clinical algorithms and pharmacological agents for the management of hypertension in pregnancy are summarised, with a brief focus on post-partum considerations and long-term health implications. Novel therapeutic options for the management of pre-eclampsia are also explored.