The effect of maternal position on placental blood flow and fetoplacental oxygenation in late gestation fetal growth restriction: a magnetic resonance imaging study.

Fetal growth restriction (FGR) and maternal supine going-to-sleep position are both risk factors for late stillbirth. This study aimed to use magnetic resonance imaging (MRI) to quantify the effect of maternal supine position on maternal-placental and fetoplacental blood flow, placental oxygen transfer and fetal oxygenation in FGR and healthy pregnancies. Twelve women with FGR and 27 women with healthy pregnancies at 34-38 weeks' gestation underwent MRI in both left lateral and supine positions. Phase-contrast MRI and a functional MRI technique (DECIDE) were used to measure blood flow in the maternal internal iliac arteries (IIAs) and umbilical vein (UV), placental oxygen transfer (placental flux), fetal oxygen saturation (FO2 ), and fetal oxygen delivery (delivery flux). The presence of FGR, compared to healthy pregnancies, was associated with a 7.8% lower FO2 (P = 0.02), reduced placental flux, and reduced delivery flux. Maternal supine positioning caused a 3.8% reduction in FO2 (P = 0.001), and significant reductions in total IIA flow, placental flux, UV flow and delivery flux compared to maternal left lateral position. The effect of maternal supine position on fetal oxygen delivery was independent of FGR pregnancy, meaning that supine positioning has an additive effect of reducing fetal oxygenation further in women with FGR, compared to women with appropriately grown for age pregnancies. Meanwhile, the effect of maternal supine positioning on placental oxygen transfer was not independent of the effect of FGR. Therefore, growth-restricted fetuses, which are chronically hypoxaemic, experience a relatively greater decline in oxygen transfer when mothers lie supine in late gestation compared to appropriately growing fetuses. KEY POINTS: Fetal growth restriction (FGR) is the most common risk factor associated with stillbirth, and early recognition and timely delivery is vital to reduce this risk. Maternal supine going-to-sleep position is found to increase the risk of late stillbirth but when combined with having a FGR pregnancy, maternal supine position leads to 15 times greater odds of stillbirth compared to supine sleeping with appropriately grown for age (AGA) pregnancies. Using MRI, this study quantifies the chronic hypoxaemia experienced by growth-restricted fetuses due to 13.5% lower placental oxygen transfer and 26% lower fetal oxygen delivery compared to AGA fetuses. With maternal supine positioning, there is a 23% reduction in maternal-placental blood flow and a further 14% reduction in fetal oxygen delivery for both FGR and AGA pregnancies, but this effect is proportionally greater for growth-restricted fetuses. This knowledge emphasises the importance of avoiding supine positioning in late pregnancy, particularly for vulnerable FGR pregnancies.

Circadian patterns of heart rate variability in fetal sheep after hypoxia-ischaemia: A biomarker of evolving brain injury.

Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and severe neurodevelopmental disability in survivors, including cerebral palsy, although there are no reliable biomarkers to detect at risk fetuses that may have suffered a transient period of severe HI. We investigated time and frequency domain measures of fetal heart rate variability (FHRV) for 3 weeks after HI in preterm fetal sheep at 0.7 gestation (equivalent to preterm humans) until 0.8 gestation (equivalent to term humans). We have previously shown that this is associated with delayed development of severe white and grey matter injury, including cystic white matter injury (WMI) resembling that observed in human preterm infants. HI was associated with suppression of time and frequency domain measures of FHRV and reduced their circadian rhythmicity during the first 3 days of recovery. By contrast, circadian rhythms of multiple measures of FHRV were exaggerated over the final 2 weeks of recovery, mediated by a greater reduction in FHRV during the morning nadir, but no change in the evening peak. These data suggest that the time of day at which FHRV measurements are taken affects their diagnostic utility. We further propose that circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury. KEY POINTS: Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and probably for disability in survivors, although there are no reliable biomarkers for antenatal brain injury. In preterm fetal sheep, acute HI that is known to lead to delayed development of severe white and grey matter injury over 3 weeks, was associated with early suppression of multiple time and frequency domain measures of fetal heart rate variability (FHRV) and loss of their circadian rhythms during the first 3 days after HI. Over the final 2 weeks of recovery after HI, exaggerated circadian rhythms of frequency domain FHRV measures were observed. The morning nadirs were lower with no change in the evening peak of FHRV. Circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury.

Fetal defenses against intrapartum head compression-implications for intrapartum decelerations and hypoxic-ischemic injury.

Uterine contractions during labor and engagement of the fetus in the birth canal can compress the fetal head. Its impact on the fetus is unclear and still controversial. In this integrative physiological review, we highlight evidence that decelerations are uncommonly associated with fetal head compression. Next, the fetus has an impressive ability to adapt to increased intracranial pressure through activation of the intracranial baroreflex, such that fetal cerebral perfusion is well-maintained during labor, except in the setting of prolonged systemic hypoxemia leading to secondary cardiovascular compromise. Thus, when it occurs, fetal head compression is not necessarily benign but does not seem to be a common contributor to intrapartum decelerations. Finally, the intracranial baroreflex and the peripheral chemoreflex (the response to acute hypoxemia) have overlapping efferent effects. We propose the hypothesis that these reflexes may work synergistically to promote fetal adaptation to labor.

Speech Outcomes of a National Cohort of Children with Orofacial Cleft at 5 and 10 Years of age.

OBJECTIVE: To assess speech outcomes at five and ten years of age in a nationwide study of children with orofacial cleft. DESIGN: Prospective study. PARTICIPANTS: Children born with orofacial cleft and having primary surgery in New Zealand. Speech samples were available for 151 five-year-old, and 163 ten-year-old children. MAIN OUTCOME MEASURES: Intelligibility, Acceptability, Velopharyngeal function, Hypernasality, Hyponasality, severity of airflow evaluated by perceptual speech assessment (using the standardised Rhinocleft assessment), and overall assessment of requirement for clinical intervention. RESULTS: A large proportion of five-year-old children had speech that was considered to be not completely intelligible, was not acceptable, and had inadequate velopharyngeal function. The noted deficiencies led to a clinical judgement that further speech and/or surgical intervention was required in 85% with cleft lip and palate, 65% with cleft palate and 26% with cleft lip. The proportion of children with poor speech outcomes in the ten-year-old children was lower, though of clinical importance, further intervention required for 25% with CLP, 15% with CP and 3% with CL. The number of sound production errors in both age groups followed the same pattern with fewest in those with CL and most in those with CLP. CONCLUSIONS: A significant proportion of children with orofacial cleft were found to have poor speech outcomes requiring further treatment. The outcomes are poor compared to centres reported in the UK and Scandinavia. New Zealand requires a review of the current services for individuals born with cleft to improve speech outcomes and interdisciplinary care.

The effects of maternal position, in late gestation pregnancy, on placental blood flow and oxygenation: an MRI study.

KEY POINTS: Maternal supine sleep position in late pregnancy is associated with an increased risk of stillbirth. Maternal supine position in late pregnancy reduces maternal cardiac output and uterine blood flow. Using MRI, this study shows that compared to the left lateral position, maternal supine position in late pregnancy is associated with reduced utero-placental blood flow and oxygen transfer across the placenta with an average 6.2% reduction in oxygen delivery to the fetus and an average 11% reduction in fetal umbilical venous blood flow. ABSTRACT: Maternal sleep position in late gestation is associated with an increased risk of stillbirth, though the pathophysiological reasons for this are unclear. Studies using magnetic resonance imaging (MRI) have shown that compared with lateral positions, lying supine causes a reduction in cardiac output, reduced abdominal aortic blood flow and reduced vena caval flow which is only partially compensated for by increased flow in the azygos venous system. Using functional MRI techniques, including an acquisition termed diffusion-relaxation combined imaging of the placenta (DECIDE), which combines diffusion weighted imaging and T2 relaxometry, blood flow and oxygen transfer were estimated in the maternal, fetal and placental compartments when subjects were scanned both supine and in left lateral positions. In late gestation pregnancy, lying supine caused a 23.7% (P < 0.0001) reduction in total internal iliac arterial blood flow to the uterus. In addition, lying in the supine position caused a 6.2% (P = 0.038) reduction in oxygen movement across the placenta. The reductions in oxygen transfer to the fetus, termed delivery flux, of 11.2% (P = 0.0597) and in fetal oxygen saturation of 4.4% (P = 0.0793) did not reach statistical significance. It is concluded that even in healthy late gestation pregnancy, maternal position significantly affects oxygen transfer across the placenta and may in part provide an explanation for late stillbirth in vulnerable fetuses.

A Nationwide Survey of Oral Health Related Quality of Life of Children With Orofacial Cleft in New Zealand.

OBJECTIVES: To describe (1) oral health related quality of life (OHRQoL) for children with orofacial cleft (OFC) in New Zealand and (2) assess any differences in OHRQoL by sex, ethnicity, and cleft phenotype using the 16 item (and 8 item subset) of the Child Perception Questionnaire (CPQ) and Parent version (P-CPQ). DESIGN AND SETTING: Prospective cross-sectional nationwide study. METHODS AND MATERIALS: Children with OFC and their parents completed the 16-item CPQ or the Parent CPQ, respectively, when attending cleft clinic appointments between January 2015 and December 2017. RESULTS: Overall, 174 children (mean age 10.4 ± 1.2 years) and their parents (n = 181) completed the CPQ or P-CPQ. In multivariable analysis, neither the CPQ nor P-CPQ 16-item or 8-item subset showed significant differences in OHRQoL total score with cleft phenotype. Children with cleft lip and palate (CLP) had higher (worse) well-being scores than those with cleft palate alone (CP) on the P-CPQ. Pacific Island children had consistently higher scores across both CPQ and P-CPQ, total and subscales. CONCLUSIONS: Significant differences in OHRQoL among children with OFC were found for the well-being domain for children with CLP as reported by P-CPQ, but the symptom domain and total score showed no differences. Poorer scores were reported for children of Pacific Island descent using both questionnaires. The study findings indicate that children with OFC in New Zealand are a group who experience worse OHRQoL when referenced to normative non-OFC data. Further investigations are required to establish greater insight into specific factors influencing OHRQoL.

Behavioral Outcomes in Children With an Orofacial Cleft in a National Study in New Zealand.

OBJECTIVE: To determine whether children with an orofacial cleft have higher levels of behavioral problems than the general population and whether this differs by cleft phenotype. DESIGN: A cohort of children with cleft lip and/or palate (CL/P) born in New Zealand from January 1, 2000. SETTING: Cleft clinics in New Zealand participating in a larger outcomes study between 2014 and 2017. PARTICIPANTS: Children (N = 378) aged 5 to 12 years of age and their parents. MAIN OUTCOMES: The Strengths and Difficulties Questionnaire (SDQ) and Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales 4.0 and Family Impact Module 2.0. RESULTS: Compared to standardized norms, children with a cleft had higher than expected (defined as 20%) levels of abnormal/borderline SDQ scores for conduct problems (27.4%, P = .0003) and peer relationship problems (31.6%, P < .0001) but lower than expected levels of problems with pro-social skills (6.3%, P < .0001). There were no significant differences by age-group and or cleft phenotype other than an increased risk of hyperactivity in children with CP compared to children with CL. Total difficulties SDQ scores had moderate correlations with the PedsQL. CONCLUSIONS: While over 90% of children with CL/P had normal prosocial skills, they may not be easily accepted by their peers which may result in behavioral problems. These concerns were moderately related to lower quality of life. Support for establishment and maintenance of peer relationships is important to address externalizing and peer difficulties in children with CL/P. Community knowledge and understanding of CL/P needs to continue to be promoted.

Quality of Life Using General Population Validated Questionnaires in Children With Cleft Lip and/or Palate in New Zealand.

OBJECTIVE: To determine the level of quality of life (QoL) in children with cleft lip and/or palate (CL/P) and whether this differs by cleft phenotype. DESIGN: A cohort of children with CL/P born in New Zealand. SETTING: A nationwide study of children born with CL/P and having primary surgery in New Zealand. PARTICIPANTS: Children with CL/P and their families (n = 397) who attended a cleft clinic between October 1, 2014, and September 30, 2017, and agreed to complete questionnaires on QoL. MAIN OUTCOMES: Primary outcomes were QoL from the PedsQL 4.0 core generic questionnaires and the PedsQL 2.0 Family impact scale. RESULTS: Children with CL/P in New Zealand generally have a high QoL as assessed by the PedsQL. The impact of cleft phenotype had limited effects on the child, however there were significant impacts on parents and families. We found that the family impact scale differed by cleft phenotype with those with CL having the highest QoL and those with cleft palate the lowest, and this was consistent across QoL subscales. Quality of life improved as a whole by age, particularly in physical and cognitive functioning, as well as in the ability to undertake family activities. CONCLUSIONS: Children with CL/P have generally good levels of QoL in New Zealand, however cleft phenotype impacts on the level, with the lowest levels in those with cleft palate. Psychological support of children with cleft and their families should be an integral part of cleft care.

Nasolabial outcomes in a nationwide study of orofacial cleft in New Zealand.

OBJECTIVES: To (a) assess nasolabial outcomes across four main cleft subgroups, (b) assess agreement using a categorical and a continuous scoring measure and (c) compare outcomes to international studies. SETTINGS AND SAMPLE POPULATION: Analysis of 470 images of which 218 was unilateral cleft lip and palate (UCLP), 128 unilateral cleft lip (UCL), 90 bilateral cleft lip and palate (BCLP) and 34 bilateral cleft lip (BCL). Images were taken around five (n = 279) and eight-ten (n = 191) years of age. MATERIALS & METHODS: Cropped images were assessed using the Asher-McDade (AM) and a 100 mm visual analogue scale (VAS) by a panel of six raters. Scoring was undertaken for vermillion border and nasal form, symmetry and profile. Analysis was undertaken for each subscore, a total score with sensitivity analysis using a total score based on the subscores for each patient. AM intra- and inter-rater reliability was assessed using weighted kappa and for the VAS components reliability was assessed using Pearson correlation. RESULTS: The AM intra-rater reliability was moderate/substantial, whilst inter-rater reliability was fair. The VAS intra-rater correlations were high, and inter-rater correlations were moderate. Better outcomes were found with cleft lip (CL) vs cleft lip and palate (CLP). No differences were found for sex, ethnicity, age and cleft laterality (unilateral). The AM found no difference between unilateral or bilateral. The VAS found bilateral scored worse than unilateral for both CL and CLP. CONCLUSIONS: The nasolabial outcomes differ by cleft type. The correlation was relatively high for the VAS whilst the AM had relatively poor reliability.

An investigation of fetal behavioural states during maternal sleep in healthy late gestation pregnancy: an observational study.

KEY POINTS: Fetal behavioural state in healthy late gestation pregnancy is significantly affected by maternal position overnight. Maternal left lateral position is the one most frequently adopted at sleep onset. The maternal position at sleep onset is maintained the longest overnight. Fetal state 1F is more common in maternal supine positions overnight. Fetal state 4F is less common in maternal supine sleep positions. Fetal state and maternal sleep position are independently associated with fetal heart rate variability. Maternal sleep position significantly affects fetal heart rate and heart rate variability and affects circadian fetal heart rate patterns. ABSTRACT: Fetal behavioural states (FBS) are measures of fetal wellbeing. Maternal position affects FBS with supine position being associated with an increased likelihood of fetal quiescence consistent with the human fetus adapting to a lower oxygen consuming state. Several studies have now confirmed the association between sleep position and risk of late intrauterine death. We designed this study to observe the effects of maternal sleep positions overnight in healthy late gestation pregnancy. Twenty-nine healthy women had continuous fetal ECG recordings overnight. Two blinded observers assigned fetal states in 5 min blocks. Measures of fetal heart rate variability (FHRV) were calculated from ECG beat to beat data. Maternal position was determined from infrared video recording. Compared to state 2F (active sleep), 4F (active awake-high activity) occurred almost exclusively when the mother was in a left or right lateral position. State 1F (quiet sleep) was more common when the mother was supine [odds ratio (OR) 1.30, 95% confidence interval (CI) 1.11-1.52] and less common on the maternal right side with the left being the referent position (OR 0.81, 95% CI, 0.70-0.93). State 4F was more common between 21.00 and 01.00 h than between 01.00 and 07.00 h (OR 2.83, 95% CI 2.32-3.47). In each fetal state, maternal position had significant effects on fetal heart rate and measures of FHRV. In healthy late gestation pregnancy, maternal sleep position affects FBS and heart rate variability. These effects are probably fetal adaptations to positions which may produce a mild hypoxic stress.

Effect of maternal position on fetal behavioural state and heart rate variability in healthy late gestation pregnancy.

KEY POINTS: Fetal behavioural state in healthy late gestation pregnancy is affected by maternal position. Fetal state 1F is more likely to occur in maternal supine or right lateral positions. Fetal state 4F is less likely to occur when the woman lies supine or semi-recumbent. Fetal state change is more likely when the woman is supine or semi-recumbent. Fetal heart rate variability is affected by maternal position with variability reduced in supine and semi-recumbent positions. ABSTRACT: Fetal behavioural states (FBS) are measures of fetal wellbeing. In acute hypoxaemia, the human fetus adapts to a lower oxygen consuming state with changes in the cardiotocograph and reduced fetal activity. Recent studies of late gestation stillbirth described the importance of sleep position in the risk of intrauterine death. We designed this study to assess the effects of different maternal positions on FBS in healthy late gestation pregnancies under controlled conditions. Twenty-nine healthy women had continuous fetal ECG recordings under standardized conditions in four randomly allocated positions, left lateral, right lateral, supine and semi-recumbent. Two blinded observers, assigned fetal states in 5 min blocks. Measures of fetal heart rate variability were calculated from ECG beat to beat data. Compared to state 2F, state 4F was less likely to occur when women were semi-recumbent [odds ratio (OR) = 0.11, 95% confidence interval (95% CI) 0.02, 0.55], and supine (OR = 0.27, 95% CI 0.07, 1.10). State 1F was more likely on the right (OR = 2.36, 95% CI 1.11, 5.04) or supine (OR = 4.99, 95% CI 2.41, 10.43) compared to the left. State change was more likely when the mother was semi-recumbent (OR = 2.17, 95% CI 1.19, 3.95) or supine (OR = 2.67, 95% CI 1.46, 4.85). There was a significant association of maternal position to mean fetal heart rate. The measures of heart rate variability (SDNN and RMSSD) were reduced in both semi-recumbent and supine positions. In healthy late gestation pregnancy, maternal position affects FBS and heart rate variability. These effects are likely fetal adaptations to positions which may produce a mild hypoxic stress.

Placental Nano-vesicles Target to Specific Organs and Modulate Vascular Tone In Vivo.

STUDY QUESTION: How do nano-vesicles extruded from normal first trimester human placentae affect maternal vascular function? SUMMARY ANSWER: Placental nano-vesicles affect the ability of systemic mesenteric arteries to undergo endothelium- and nitric oxide- (NO-) dependent vasodilation in vivo in pregnant mice. WHAT IS KNOWN ALREADY: Dramatic cardiovascular adaptations occur during human pregnancy, including a substantial decrease in total peripheral resistance in the first trimester. The human placenta constantly extrudes extracellular vesicles that can enter the maternal circulation and these vesicles may play an important role in feto-maternal communication. STUDY DESIGN, SIZE, DURATION: Human placental nano-vesicles were administered into CD1 mice via a tail vein and their localization and vascular effects at 30 min and 24 h post-injection were investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nano-vesicles from normal first trimester human placentae were collected and administered into pregnant (D12.5) or non-pregnant female mice. After either 30 min or 24 h of exposure, all major organs were dissected for imaging (n = 7 at each time point) while uterine and mesenteric arteries were dissected for wire myography (n = 6 at each time point). Additional in vitro studies using HMEC-1 endothelial cells were also conducted to investigate the kinetics of interaction between placental nano-vesicles and endothelial cells. MAIN RESULTS AND THE ROLE OF CHANCE: Nano-vesicles from first trimester human placentae localized to the lungs, liver and kidneys 24 h after injection into pregnant mice (n = 7). Exposure of pregnant mice to placental nano-vesicles for 30 min in vivo increased the vasodilatory response of mesenteric arteries to acetylcholine, while exposure for 24 h had the opposite effect (P < 0.05, n = 6). These responses were prevented by L-NAME, an NO synthase inhibitor. Placental nano-vesicles did not affect the function of uterine arteries or mesenteric arteries from non-pregnant mice. Placental nano-vesicles rapidly interacted with endothelial cells via a combination of phagocytosis, endocytosis and cell surface binding in vitro. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: As it is not ethical to administer labelled placental nano-vesicles to pregnant women, pregnant CD1 mice were used as a model of pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to report the localization of placental nano-vesicles and their vascular effects in vivo. This work provides new insight into how the dramatic maternal cardiovascular adaptations to pregnancy may occur and indicates that placental extracellular vesicles may be important mediators of feto-maternal communication in a healthy pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Faculty of Medical and Health Science (FMHS) School of Medicine PBRF research fund to L.W.C. M.T. is a recipient of a University of Auckland Health Research Doctoral Scholarship and the Freemasons Postgraduate Scholarship. No authors have any competing interests to disclose.

In vivo targets of human placental micro-vesicles vary with exposure time and pregnancy.

Throughout human gestation, the placenta extrudes vast quantities of extracellular vesicles (EVs) of different sizes into the maternal circulation. Although multinucleated macro-vesicles are known to become trapped in the maternal lungs and do not enter the peripheral circulation, the maternal organs and cells that smaller placental micro-vesicles interact with in vivo remain unknown. This study aimed to characterise the interaction between placental micro-vesicles and endothelial cells in vitro and to elucidate which organs placental micro-vesicles localise to in vivo Placental macro- and micro-vesicles were isolated from cultured human first trimester placental explants by sequential centrifugation and exposed to human microvascular endothelial cells for up to 72 h. In vivo, placental macro- and micro-vesicles were administered to both non-pregnant and pregnant CD1 mice, and after two or 30 min or 24 h, organs were imaged on an IVIS Kinetic Imager. Placental EVs rapidly interacted with endothelial cells via phagocytic and clathrin-mediated endocytic processes in vitro, with over 60% of maximal interaction being achieved by 30 min of exposure. In vivo, placental macro-vesicles were localised exclusively to the lungs regardless of time of exposure, whereas micro-vesicles were localised to the lungs, liver and kidneys, with different distribution patterns depending on the length of exposure and whether the mouse was pregnant or not. The fact that placental EVs can rapidly interact with endothelial cells and localise to different organs in vivo supports that different size fractions of placental EVs are likely to have different downstream effects on foeto-maternal communication.

Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.

BACKGROUND: Preeclampsia and small-for-gestational-age pregnancy are major causes of maternal and perinatal morbidity and mortality. Women with a previous pregnancy affected by these conditions are at an increased risk of recurrence in a future pregnancy. Past trials evaluating the effect of low-molecular-weight heparin for the prevention of recurrence of preeclampsia and small-for-gestational-age pregnancy have shown conflicting results with high levels of heterogeneity displayed when trials were compared. OBJECTIVE: We sought to assess the effectiveness of enoxaparin in addition to high-risk care for the prevention of preeclampsia and small-for-gestational-age pregnancy in women with a history of these conditions. STUDY DESIGN: This was an open-label randomized controlled trial in 5 tertiary care centers in 3 countries. Women with a viable singleton pregnancy were invited to participate between >6+0 and <16+0 weeks if deemed to be at high risk of preeclampsia and/or small for gestational age based on their obstetric history. Eligible participants were randomly assigned in a 1-to-1 ratio to standard high-risk care or standard high-risk care plus enoxaparin 40 mg (4000 IU) by subcutaneous injection daily from recruitment until 36+0 weeks or delivery, whichever occurred sooner. Standard high-risk care was defined as care coordinated by a high-risk antenatal clinic service, aspirin 100 mg daily until 36+0 weeks, and-for women with prior preeclampsia-calcium 1000-1500 mg daily until 36+0 weeks. In a subgroup of participants serum samples were taken at recruitment and at 20 and 30 weeks' gestation and later analyzed for soluble fms-like tyrosine kinase-1, soluble endoglin, endothelin-1, placental growth factor, and soluble vascular cell adhesion molecule 1. The primary outcome was a composite of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile. All data were analyzed on an intention-to-treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12609000699268). RESULTS: Between July 26, 2010, and Oct. 28, 2015, a total of 156 participants were enrolled and included in the analysis. In all, 149 participants were included in the outcome analysis (72 receiving standard high-risk care plus enoxaparin and 77 receiving standard high-risk care only). Seven women who miscarried <16 weeks' gestation were excluded. The majority of participants (151/156, 97%) received aspirin. The addition of enoxaparin had no effect on the rate of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile: enoxaparin 18/72 (25%) vs no enoxaparin 17/77 (22.1%) (odds ratio, 1.19; 95% confidence interval, 0.53-2.64). There was also no difference in any of the secondary outcome measures. Levels of soluble fms-like tyrosine kinase-1 and soluble endoglin increased among those who developed preeclampsia, but there was no difference in levels of these antiangiogenic factors (nor any of the other serum analytes measured) among those treated with enoxaparin compared to those receiving standard high-risk care only. CONCLUSION: The use of enoxaparin in addition to standard high-risk care does not reduce the risk of recurrence of preeclampsia and small-for-gestational-age infants in a subsequent pregnancy.

Early pregnancy probiotic supplementation with Lactobacillus rhamnosus HN001 may reduce the prevalence of gestational diabetes mellitus: a randomised controlled trial.

The study aims to assess whether supplementation with the probiotic Lactobacillus rhamnosus HN001 (HN001) can reduce the prevalence of gestational diabetes mellitus (GDM). A double-blind, randomised, placebo-controlled parallel trial was conducted in New Zealand (NZ) (Wellington and Auckland). Pregnant women with a personal or partner history of atopic disease were randomised at 14-16 weeks' gestation to receive HN001 (6×109 colony-forming units) (n 212) or placebo (n 211) daily. GDM at 24-30 weeks was assessed using the definition of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) (fasting plasma glucose ≥5·1 mmol/l, or 1 h post 75 g glucose level at ≥10 mmol/l or at 2 h ≥8·5 mmol/l) and NZ definition (fasting plasma glucose ≥5·5 mmol/l or 2 h post 75 g glucose at ≥9 mmol/l). All analyses were intention-to-treat. A total of 184 (87 %) women took HN001 and 189 (90 %) women took placebo. There was a trend towards lower relative rates (RR) of GDM (IADPSG definition) in the HN001 group, 0·59 (95 % CI 0·32, 1·08) (P=0·08). HN001 was associated with lower rates of GDM in women aged ≥35 years (RR 0·31; 95 % CI 0·12, 0·81, P=0·009) and women with a history of GDM (RR 0·00; 95 % CI 0·00, 0·66, P=0·004). These rates did not differ significantly from those of women without these characteristics. Using the NZ definition, GDM prevalence was significantly lower in the HN001 group, 2·1 % (95 % CI 0·6, 5·2), v. 6·5 % (95 % CI 3·5, 10·9) in the placebo group (P=0·03). HN001 supplementation from 14 to 16 weeks' gestation may reduce GDM prevalence, particularly among older women and those with previous GDM.

Proteomic characterization of macro-, micro- and nano-extracellular vesicles derived from the same first trimester placenta: relevance for feto-maternal communication.

STUDY QUESTION: What proteins are carried by extracellular vesicles (EVs) released from normal first trimester placentae? SUMMARY ANSWER: One thousand five hundred and eighty-five, 1656 and 1476 proteins were characterized in macro-, micro- and nano-vesicles, respectively, from first trimester placentae, with all EV fractions being enriched for proteins involved in vesicle transport and inflammation. WHAT IS KNOWN ALREADY: Placental EVs are being increasingly recognized as important mediators of both healthy and pathological pregnancies. However, current research has focused on detecting changes in specific proteins in particular fractions of vesicles during disease. This is the first study to investigate the full proteome of different-sized fractions of EVs from the same first trimester placenta and highlights the differences/similarities between the vesicle fractions. STUDY DESIGN, SIZE, DURATION: A well-established ex vivo placental explant culture model was used to generate macro-, micro- and nano-vesicles from 56 first trimester placentae. Vesicle fractions were collected by differential ultracentrifugation, quantified and characterized. PARTICIPANTS/MATERIALS, SETTING, METHODS: Placental macro-, micro- and nano-vesicles were characterized by microscopy, dynamic light scattering and nanoparticle tracking analysis. The proteome of each EV fraction was interrogated using liquid chromatography-coupled tandem mass spectrometry. Results were validated by semi-quantitative western blotting. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1585, 1656 and 1476 proteins were identified in macro-, micro- and nano-vesicles, respectively. One thousand one hundred and twenty-five proteins were shared between all three fractions while up to 223 proteins were unique to each fraction. Gene Ontology pathway analysis showed an enrichment of proteins involved in vesicle transport and inflammation in all three fractions of EVs. The expression levels of proteins involved in internalization of vesicles (annexin V, calreticulin, CD31, CD47), the complement pathway [C3, decay-accelerating factor (DAF), membrane cofactor protein (MCP), protectin] and minor histocompatibility antigens [ATP-dependent RNA helicase (DDX3), ribosomal protein S4 (RPS4)] were different between different-sized EVs. LIMITATIONS, REASONS FOR CAUTION: This study is largely hypothesis-generating in nature. It is important to validate these findings using EVs isolated from maternal plasma and the function of the different EV fractions would need further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the concept that various EV factions can interact with different maternal cells and have unique effects to mediate feto-maternal communication during early pregnancy. This study also provides a list of candidate proteins, which may inform the identification of robust markers that can be used to isolate placental vesicles from the maternal blood in the future. STUDY FUNDING/COMPETING INTERESTS: M.T. is a recipient of the University of Auckland Health Research Doctoral Scholarship and the Freemasons Postgraduate Scholarship. This project was supported by a School of Medicine Performance-based research fund (PBRF) grant awarded to L.W.C. No authors have any conflicts of interest to disclose.

A description of sleep behaviour in healthy late pregnancy, and the accuracy of self-reports.

BACKGROUND: The importance of maternal sleep and its contribution to maternal and fetal health during pregnancy is increasingly being recognised. However, the ability to accurately recall sleep practices during pregnancy has been questioned. The aim of this study is to test the accuracy of recall of normal sleep practices in late pregnancy. METHODS: Thirty healthy women between 35 and 38 weeks of gestation underwent level III respiratory polysomnography (PSG) with infrared digital video recordings in their own homes. Data regarding sleep positions, number of times getting out of bed during the night and respiratory measures were collected. A sleep questionnaire was administered the morning after the recorded sleep. Continuous data were assessed using Spearman's Rho and Bland-Altman. Cohen's Kappa was used to assess recall in the categorical variables. RESULTS: Two-thirds of participants went to sleep on their left side. There was good agreement in sleep onset position between video and questionnaire data (Kappa 0.52), however the there was poor agreement on position on wakening (Kappa 0.24). The number of times getting out of bed during the night was accurately recalled (Kappa 0.65). Twenty five out of 30 participants snored as recorded by PSG. Questionnaire data was inaccurate for this measure. Bland-Altman plots demonstrated acceptable agreement between video and questionnaire data for estimated sleep duration, but not the time taken to fall asleep (sleep latency). One participant had mild obstructive sleep apnoea and another probable high upper airways resistance. CONCLUSIONS: Sleep onset position, sleep duration and the number of times getting out of bed during the night were accurately recalled, but sleep latency and sleep position on waking were not. This study identifies the sleep variables that can be accurately obtained by questionnaire and those that cannot.

Validation of thoracic impedance cardiography by echocardiography in healthy late pregnancy.

BACKGROUND: Assessment of stroke volume (SV) is often necessary in clinical and research settings. The clinically established method for SV assessment in pregnancy is echocardiography, but given its limitations, it is not always an appropriate measurement tool. Thoracic impedance cardiography (ICG) allows continuous, non-invasive SV assessment. However, SV determination relies on assumptions regarding the thoracic shape that may mean the algorithm is not valid in pregnancy. The available data regarding the validity of ICG against an established reference standard using modern SV algorithms are both limited and conflicting. We aimed to test the validity of ICG in a clinically realistic setting in late pregnancy using echocardiography. METHODS: Twenty-nine women in late pregnancy underwent standard echocardiography assessments with simultaneous ICG measurement. Agreement between devices was tested using Bland-Altman analysis. RESULTS: Bland-Altman analysis of the relationship between ICG and echocardiography demonstrated that the 95% limits of agreement exceeded acceptable or expected ranges. Measures of maternal and fetal anthropometry do not account for the lack of agreement. CONCLUSIONS: Absolute values of SV as determined by ICG are not valid in pregnancy. Further work is required to examine the ability of ICG to assess relative changes in maternal haemodynamics in late pregnancy.

Antiphospholipid antibodies internalised by human syncytiotrophoblast cause aberrant cell death and the release of necrotic trophoblast debris.

Antiphospholipid antibodies (aPL) are the strongest maternal risk factor for pre-eclampsia, a hypertensive disease of human pregnancy. Pre-eclampsia is triggered by a toxic factor released from the placenta that activates the maternal endothelium. Antiphospholipid antibodies cause the release of necrotic trophoblast debris from the placental syncytiotrophoblast and this debris can activate endothelial cells. In this study, we investigated how aPL affects syncytiotrophoblast death and production of necrotic trophoblast debris by examining the interaction between aPL and human first trimester placental explants. Human polyclonal and murine monoclonal aPL, but not control antibodies, were rapidly internalised by the syncytiotrophoblast. Inhibitors of endocytosis or the low-density lipoprotein receptor (LDLR) family, but not toll-like receptors, decreased the internalisation of aPL and prevented the release of necrotic trophoblast debris from the syncytiotrophoblast. Once internalised, aPL increased inner mitochondrial membrane leak and Cytochrome c release while depressing oxidative flux through Complex IV of the electron transport system in syncytiotrophoblast mitochondria. These data suggest that the human syncytiotrophoblast internalises aPL by antigen-dependent endocytosis involving LDLR family members. Once internalised by the syncytiotrophoblast, aPL affects the death-regulating mitochondria, causing extrusion of necrotic trophoblast debris which can activate maternal endothelial cells thereby contributing to the pathogenesis of pre-eclampsia.

A postal survey of maternal sleep in late pregnancy.

BACKGROUND: Sleep disturbances in late pregnancy are common. This study aimed to survey sleep problems in third trimester pregnant women and to compare sleep in the pre-pregnancy period with the third trimester. METHODS: Third-trimester women (n=650) were sent a postal survey containing questions relating to sleep experience, including perceived sleep quality, sleep difficulties, night waking, sleep environment, snoring, daytime tiredness and daytime napping. Time periods reported on were before pregnancy and in the last week. RESULTS: Respondents numbered 244 (38%). Before pregnancy, the mean reported duration of night-time sleep was 8.1 (SD 1.1) hours; in the last week this had decreased to 7.5 (SD 1.8) hours (p<.0001). Only 29% rated their sleep quality in the last week as very good or fairly good, compared with 82% rating their sleep this way before the pregnancy. The main reasons for sleeping difficulties were discomfort (67%) and pain (36%). Snoring increased significantly over the course of the pregnancy, with 37% reporting snoring often or every night in the last week. Those with a pre-pregnancy body mass index of greater than 25 were significantly more likely to snore (p=.01). Only 4% of women had an abnormal Epworth Sleepiness Scale score (i.e. >10) prior to pregnancy, whereas in the last week 33% scored in the abnormal range. Likewise, 5% had regularly napped during the daytime before pregnancy, compared with 41% in the last week. CONCLUSIONS: Sleep problems are common in women in late pregnancy, and increase markedly compared with before pregnancy.