Expert opinion: Stepwise ultrasound assessment of suspected placenta accreta spectrum using 2D, Doppler and 3D imaging.

Placenta Accreta Spectrum (PAS) describes a spectrum of conditions ranging from 'sticky' placenta to placenta accreta, increta and percreta-each describing progressively deeper invasion into the uterus. It is a major contributor to maternal and perinatal morbidity particularly where clinical facilities are not immediately available. Hence accurate diagnosis is important in determining timing and place of delivery, and logistical arrangements of the clinical team and specialties. Although many different ultrasound features have been described, their relationship to the final operative diagnosis remains variably described. Ultrasound manufactures have developed new imaging techniques particularly in relation to Doppler and 3D processing techniques. We describe a standardized imaging approach employing new ultrasound modalities matched to the attributes unique to invasive placenta. The '3V' system describes the stages of placental invasion: namely low-flow Doppler techniques to delineate the vascular anatomy of the placenta and delineating its interface with the myometrium, and 3D 'context preserving' post processing technologies defining the placental interface with maternal structures (vesicular invasion and visceral extension). Used together with well characterized 2D imaging signs, we describe pictorially by reference to clinical cases how this standardized methodology allows new insights into the ultrasound diagnosis of PAS.

Expectant management versus multifetal pregnancy reduction in dichorionic triamniotic (DCTA) triplets: Single centre experience.

OBJECTIVES: In trichorionic triplet pregnancies, multifetal pregnancy reduction (MFPR) reduces the risk of preterm birth, neonatal morbidity and mortality without increasing miscarriage. A similar benefit has been suggested in dichorionic triamniotic (DCTA) pregnancy, but multiple methods are currently used. This study investigates if the method of reduction used in DCTA triplet pregnancy influences the evidence of benefit from MFPR. METHODS: This is a retrospective cohort study of DCTA pregnancies between 2010 and 2019 who attended a single UK fetal medicine tertiary referral center. Cohorts were defined based on MFPR decision and method. The primary outcome was offspring survival until neonatal discharge. The secondary outcomes included miscarriage, preterm birth, livebirth, rates of small for gestational age (SGA) neonates, ans maternal morbidity. To evaluate the differences in neonatal survival until discharge we used Cox proportional regression to calculate hazard rates (HR) and 95% confidence intervals (CI). Differences in secondary outcomes were compared using univariate analysis. RESULTS: The study reports the outcomes for 83 DCTA pregnancies. MFPR to DCDA twins was chosen in 19 pregnancies (14 radiofrequency ablation, RFA; 5 intrafetal laser, IFL); in 9 pregnancies selective reduction to a singleton was performed by KCl injection. The rate of pregnancies in with ≥ 1 fetus born alive was not different between groups (p = 0.90). However, the number of expected neonates alive at discharge from hospital was highest in the RFA group (89%, HR 0.28, 95% CI 0.21-0.87, p = 0.02). Rates of premature delivery before 32 weeks (p = 0.02), low birth weight (p < 0.001) and birthweight < 10th percentile (p = 0.01) were all elevated in the expectant management group, compared to women who opted for reduction. There was no difference in miscarriage between groups. CONCLUSIONS: Our study suggests that MFPR by RFA, an established and widely available procedure, is of benefit in promoting neonatal survival until discharge in DCTA triplets.

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.

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.

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.

Developing and testing an algorithm for automatic segmentation of the fetal face from three-dimensional ultrasound images.

Fetal craniofacial abnormalities are challenging to detect and diagnose on prenatal ultrasound (US). Image segmentation and computer analysis of three-dimensional US volumes of the fetal face may provide an objective measure to quantify fetal facial features and identify abnormalities. We have developed and tested an atlas-based partially automated facial segmentation algorithm; however, the volumes require additional manual segmentation (MS), which is time and labour intensive and may preclude this method from clinical adoption. These manually refined segmentations can then be used as a reference (atlas) by the partially automated segmentation algorithm to improve algorithmic performance with the aim of eliminating the need for manual refinement and developing a fully automated system. This study assesses the inter- and intra-operator variability of MS and tests an optimized version of our automatic segmentation (AS) algorithm. The manual refinements of 15 fetal faces performed by three operators and repeated by one operator were assessed by Dice score, average symmetrical surface distance and volume difference. The performance of the partially automatic algorithm with difference size atlases was evaluated by Dice score and computational time. Assessment of the manual refinements showed low inter- and intra-operator variability demonstrating its suitability for optimizing the AS algorithm. The algorithm showed improved performance following an increase in the atlas size in turn reducing the need for manual refinement.

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.

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.

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.

The feasibility and accuracy of ultrasound assessment in the labor room.

Objective: Vaginal examination is widely used to assess the progress of labor; however, it is subjective and poorly reproducible. We aim to assess the feasibility and accuracy of transabdominal and transperineal ultrasound compared to vaginal examination in the assessment of labor and its progress. Methods: Women were recruited as they presented for assessment of labor to a tertiary inner city maternity service. Paired vaginal and ultrasound assessments were performed in 192 women at 24-42 weeks. Fetal head position was assessed by transabdominal ultrasound defined in relation to the occiput position transformed to a 12-hour clock face; fetal head station defined as head-perineum distance by transperineal ultrasound; cervical dilatation by anterior to posterior cervical rim measurement and caput succedaneum by skin-skull distance on transperineal ultrasound. Results: Fetal head position was recorded in 99.7% (298/299) of US and 51.5% (154/299) on vaginal examination (p < .0001 1 ). Bland-Altman analysis showed 95% limits of agreement, -5.31 to 4.84 clock hours. Head station was recorded in 96.3% (308/320) on vaginal examination (VE) and 95.9% (307/320) on US (p = .79 1 ). Head station and head perineum distance were negatively correlated (Spearman's r = -.57, p < .0001). 54.4% (178/327) of cervical dilatation measurements were determined using US and 100% on VE/speculum (p < .0001). Bland-Altman analysis showed 95% limits of agreement -2.51-2.16 cm. The presence of caput could be assessed in 98.4% (315/320) of US and was commented in 95.3% (305/320) of VEs, with agreement for the presence of caput of 76% (p < .05). Fetuses with caput greater than 10 mm had significantly lower head station (p < .0001). Conclusions: We describe comprehensive ultrasound assessments in the labor room that could be translated to the assessment of women in labor. Fetal head position is unreliably determined by vaginal examination and agrees poorly with US. Head perineum distance has a moderate correlation with fetal head station in relation to the ischial spines based on vaginal examination. Cervical dilatation is not reliably assessed by ultrasound except at dilatations of less than 4 cm. Caput is readily quantifiable by ultrasound and its presence is associated with lower fetal head station. Transabdominal and transperineal ultrasound is feasible in the labor room with an accuracy that is generally greater than vaginal examinations.

Maternal Serum B Cell activating factor in hypertensive and normotensive pregnancies.

OBJECTIVES: The objective of this study was the analysis of B-Cell Activating Factor (BAFF) levels in pregnancies affected by PE, and in pregnancies affected by fetal growth restriction without Hypertensive disorders and its possible correlation with pulse wave velocity and cardiac output. STUDY DESIGN: Prospective study of 69 women at 24-40 weeks gestation. Haemodynamic function was assessed in those with Pre-eclampsia (PE, n = 19), fetal growth restriction (FGR, n = 10) and healthy pregnancies (n = 40). Maternal venous BAFF levels at recruitment were measured using ELISA. We analysed the relationship between BAFF and cardiac output (CO), and BAFF and PWV (pulse wave velocity); the gold standard for assessing arterial stiffness. PWV was measured with an oscillometric device and CO using inert gas rebreathing technique. PWV and CO were converted to gestation adjusted indices (z scores). MAIN OUTCOME MEASURES: The association between BAFF levels in PE and FGR, and the relationship of BAFF with PWV and CO. RESULTS: BAFF was higher in PE (p = 0.03) but not in FGR (p = 0.83) when compared to healthy pregnancies. There was a positive correlation between BAFF levels and z score PWV (r = 0.25, p = 0.04), but not CO (r = -0.01, p = 0.91). BAFF levels did not change with gestational age. (r = 0.012, p = 0.925). CONCLUSIONS: These findings provide evidence of a possible contribution of BAFF to both maternal inflammation and arterial dysfunction associated with PE. Though no relationship was found with another disorder of placentation: normotensive FGR, this condition is not thought to be associated with maternal inflammation.

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.