Prediction of preterm birth in growth-restricted and appropriate-for-gestational-age infants using maternal PlGF and the sFlt-1/PlGF ratio-A prospective study.

OBJECTIVE: To assess the utility of placental growth factor (PlGF) levels and the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). DESIGN: Prospective, observational cohort study. SETTING: Tertiary maternity hospital in Australia. POPULATION: There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32+0 weeks) and 109 (30.0%) late FGR (≥32+0 weeks). METHODS: Maternal serum PlGF and sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt-1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt-1/PlGF ratio to the time of birth or censoring. MAIN OUTCOME MEASURES: The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained. RESULTS: The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt-1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt-1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt-1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt-1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48-175.46). CONCLUSIONS: Low maternal PlGF levels and elevated sFlt-1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies.

Prediction of preterm birth in women with fetal growth restriction - Is the weekly change in sFlt-1/PlGF ratio or PlGF levels useful?

INTRODUCTION: To assess the rate of change in soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio and PlGF levels per week compared to a single sFlt-1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction. MATERIAL AND METHODS: A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt-1/PlGF ratio, change in PlGF levels per week or sFlt-1/PlGF ratio per week. Cox-proportional hazard models and Harrell's C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth. RESULTS: The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt-1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell's C: 0.85-0.76). The rate of increase per week of the sFlt-1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39-10.99, p = 0.01, Harrell's C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25-1.67, p = 0.37, Harrell's C: 0.68). CONCLUSIONS: Both a high sFlt-1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt-1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt-1/PlGF ratio or low PlGF level.

The impact of the COVID-19 pandemic on antenatal care provision and associated mental health, obstetric and neonatal outcomes.

OBJECTIVES: The COVID-19 pandemic imposed many challenges on pregnant women, including rapid changes to antenatal care aimed at reducing the societal spread of the virus. This study aimed to assess how the pandemic affected perinatal mental health and other pregnancy and neonatal outcomes in a tertiary unit in Queensland, Australia. METHODS: This was a retrospective cohort study of pregnant women booked for care between March 2019 - June 2019 and March 2020 - June 2020. A total of 1984 women were included with no confirmed cases of COVID-19. The primary outcome of this study was adverse maternal mental health defined as an Edinburgh Postnatal Depression Scale score of ≥13 or an affirmative response to 'EPDS Question 10'. Secondary outcomes were preterm birth <37 weeks and <32 weeks, mode of birth, low birth weight, malpresentation in labour, hypertensive disease, anaemia, iron/vitamin B12 deficiency, stillbirth and a composite of neonatal morbidity and mortality. RESULTS: There were no differences in the primary perinatal mental health outcomes. The rates of composite adverse neonatal outcomes (27 vs. 34 %, p<0.001) during the pandemic were higher; however, there was no difference in perinatal mortality (p=1.0), preterm birth (p=0.44) or mode of delivery (p=0.38). CONCLUSIONS: Although there were no adverse consequences on maternal mental health during the pandemic, there was a concerning increase in neonatal morbidity potentially due to the altered model of maternity care implemented in the early COVID-19 pandemic.

Dietary supplements, guideline alignment and biochemical nutrient status in pregnancy: Findings from the Queensland Family Cohort pilot study.

In high-income nations, multiple micronutrient (MMN) supplementation during pregnancy is a common practice. We aimed to describe maternal characteristics associated with supplement use and daily dose of supplemental nutrients consumed in pregnancy, and whether guideline alignment and nutrient status are related to supplement use. The Queensland Family Cohort is a prospective, Australian observational longitudinal study. Maternal characteristics, nutrient intake from food and supplements, and biochemical nutrient status were assessed in the second trimester (n = 127). Supplement use was reported by 89% of participants, of whom 91% reported taking an MMN supplement. Participants who received private obstetric care, had private health insurance and had greater alignment to meat/vegetarian alternatives recommendations were more likely to report MMN supplement use. Private obstetric care and general practitioner shared care were associated with higher daily dose of supplemental nutrients consumed compared with midwifery group practice. There was high reliance on supplements to meet nutrient reference values for folate, iodine and iron, but only plasma folate concentrations were higher in MMN supplement versus nonsupplement users. Exceeding the upper level of intake for folic acid and iron was more likely among combined MMN and individual supplement/s users, and associated with higher plasma concentrations of the respective nutrients. Given the low alignment with food group recommendations and potential risks associated with high MMN supplement use, whole food diets should be emphasized. This study confirms the need to define effective strategies for optimizing nutrient intake in pregnancy, especially among those most vulnerable where MMN supplement use may be appropriate.

Circulating biomarkers associated with placental dysfunction and their utility for predicting fetal growth restriction.

Fetal growth restriction (FGR) leading to low birth weight (LBW) is a major cause of neonatal morbidity and mortality worldwide. Normal placental development involves a series of highly regulated processes involving a multitude of hormones, transcription factors, and cell lineages. Failure to achieve this leads to placental dysfunction and related placental diseases such as pre-clampsia and FGR. Early recognition of at-risk pregnancies is important because careful maternal and fetal surveillance can potentially prevent adverse maternal and perinatal outcomes by judicious pregnancy surveillance and careful timing of birth. Given the association between a variety of circulating maternal biomarkers, adverse pregnancy, and perinatal outcomes, screening tests based on these biomarkers, incorporating maternal characteristics, fetal biophysical or circulatory variables have been developed. However, their clinical utility has yet to be proven. Of the current biomarkers, placental growth factor and soluble fms-like tyrosine kinase 1 appear to have the most promise for placental dysfunction and predictive utility for FGR.

Risks of stillbirth, neonatal mortality, and severe neonatal morbidity by birthweight centiles associated with expectant management at term.

BACKGROUND: Determining the optimal time of birth at term is challenging given the ongoing risks of stillbirth with increasing gestation vs the risks of significant neonatal morbidity at early-term gestations. These risks are more pronounced in small infants. OBJECTIVE: This study aimed to evaluate the risks of stillbirth, neonatal mortality, and severe neonatal morbidity by comparing expectant management with delivery from 37+0 weeks of gestation. STUDY DESIGN: This was a retrospective cohort study evaluating women with singleton, nonanomalous pregnancies at 37+0 to 40+6 weeks' gestation in Queensland, Australia, delivered from 2000 to 2018. Rates of stillbirth, neonatal death, and severe neonatal morbidity were calculated for <3rd, 3rd to <10th, 10th to <25th, 25th to <90th, and ≥90th birthweight centiles. The composite risk of mortality with expectant management for an additional week in utero was compared with rates of neonatal mortality and severe neonatal morbidity. RESULTS: Of 948,895 singleton, term nonanomalous births, 813,077 occurred at 37+0 to 40+6 weeks' gestation. Rates of stillbirth increased with gestational age, with the highest rate observed in infants with birthweight below the third centile: 10.0 per 10,000 (95% confidence interval, 6.2-15.3) at 37+0 to 37+6 weeks, rising to 106.4 per 10,000 (95% confidence interval, 74.6-146.9) at 40+0 to 40+6 weeks' gestation. The rate of neonatal mortality was highest at 37+0 to 37+6 weeks for all birthweight centiles. The composite risk of expectant management rose sharply after 39+0 to 39+6 weeks, and was highest in infants with birthweight below the third centile (125.2/10,000; 95% confidence interval, 118.4-132.3) at 40+0 to 40+6 weeks' gestation. Balancing the risk of expectant management and delivery (neonatal mortality), the optimal timing of delivery for each birthweight centile was evaluated on the basis of relative risk differences. The rate of severe neonatal morbidity sharply decreased in the period between 37+0 to 37+6 and 38+0 to 38+6 weeks, particularly for infants with birthweight below the third centile. CONCLUSION: Our data suggest that the optimal time of birth is 37+0 to 37+6 weeks for infants with birthweight <3rd centile and 38+0 to 38+6 weeks' gestation for those with birthweight between the 3rd and 10th centile and >90th centile. For all other birthweight centiles, birth from 39+0 weeks is associated with the best outcomes. However, large numbers of planned births are required to prevent a single excess death. The healthcare costs and acceptability to women of potential universal policies of planned birth need to be carefully considered.

The social predictors of paternal antenatal mental health and their associations with maternal mental health in the Queensland Family Cohort prospective study.

Antenatal depression (AND) affects 1 in 10 fathers, potentially negatively impacting maternal mental health and well-being during and after the transition to parenthood. However, few studies have assessed the social predictors of paternal AND or their possible associations with maternal mental health. We analysed data from 180 couples participating in the Queensland Family Cohort longitudinal study. Both parents completed surveys measuring mental health, relationship quality, social support, and sleep quality at 24 weeks of pregnancy. Mothers also completed the same surveys 6 weeks' postpartum. Antenatal depression, stress, and anxiety were highest among fathers reporting lower social support and higher sleep impairment. Maternal AND, stress, and anxiety were higher among mothers reporting higher physical pain and poor sleep quality. Postnatally, mothers reporting lower social support also reported higher depression, anxiety, stress, and psycho-social well-being. While there were no significant associations between AND among fathers and maternal antenatal or postnatal depression, an exploratory analysis revealed that mothers whose partners reported lower antenatal social support also reported lower postnatal social support and higher postnatal depression. Our findings highlight the importance of including data among fathers to achieve a whole family approach to well-being during the transition to parenthood.

Predictive utility of the fetal cerebroplacental ratio for hypoxic ischaemic encephalopathy, severe neonatal morbidity and perinatal mortality in late-preterm and term infants.

AIMS: The aim of this study was to evaluate the association of a low cerebroplacental ratio (CPR) with hypoxic ischaemic encephalopathy (HIE), severe neonatal morbidity (SNM) and perinatal mortality (PNM). METHODS: This was a retrospective cohort study of late-preterm and term births at Mater Mothers' Hospital, Brisbane, between 2016 and 2020. Study outcomes were HIE, PNM and SNM (a composite of severe acidosis, Apgar score less than four at 5 min, severe respiratory distress or need for significant cardiopulmonary resuscitation at birth). Univariate and multivariable logistic regressions were used to determine if a low CPR was associated with HIE, SNM or PNM. RESULTS: A total of 51 870 births met the inclusion criteria. Of these, 216 (0.42%) were complicated by HIE, 10 224 (19.7%) had SNM and 251 (0.48%) had PNM. Rates of low CPR (<10th and <5th centile) were significantly higher in the SNM cohort (20.1 and 13.2%, respectively) and PNM cohort (21.1 and 15.1%, respectively) compared to the overall cohort. A low CPR was associated with significantly increased adjusted odds for SNM but not for HIE or PNM. The area under the receiver operating characteristic curve for CPR <10th centile was greatest for SNM (0.768) and lowest for HIE (0.595). Predictive margins of a low CPR for HIE, SNM and PNM were significant only for SNM at late-preterm gestations. CONCLUSIONS: A low CPR is associated with increased odds of SNM in infants born >34 weeks' gestation but not for HIE or PNM.

Male infants are at higher risk of neonatal mortality and severe morbidity.

BACKGROUND: While a male infant is usually born with a higher birthweight than his female counterpart, he is more at risk of variety of adverse perinatal outcomes. Indeed, throughout life, females exhibit a marked survival advantage compared to males. The aetiology for such pertinent sex disparity remains unclear and is likely multifactorial. AIMS: The aim of this study was to investigate obstetric and perinatal outcomes by infant sex from 28 weeks in a contemporary, large Australian birth cohort. MATERIALS AND METHODS: A 14-year retrospective cohort study of 130 133 births over 28 weeks gestation from a single tertiary centre. RESULTS: Male infants had overall higher rates of neonatal mortality (0.12% vs 0.06%, P < 0.001) and severe neonatal morbidity (12% vs 9.1%, P < 0.001) (adjusted odds ratio (aOR) 1.41, 95% CI 1.35-1.47). The odds of overall perinatal mortality (stillbirth and neonatal death) were higher for male infants (aOR 1.30, 95% CI 1.08-1.56). The difference in severe neonatal morbidity when stratified by gestational age at birth only remained significant from >35 weeks gestation. Regardless of infant sex, rates of neonatal mortality and morbidity were lowest at 39 weeks gestation. Rates of preterm birth and operative birth were also higher for male infants. CONCLUSIONS: Our study demonstrates significant disparities in clinical outcomes by infant sex with males at a disadvantage to female infants.

Perinatal antecedents of moderate and severe neonatal hypoxic ischaemic encephalopathy: An Australian birth cohort study.

BACKGROUND: Neonatal hypoxic ischaemic encephalopathy (HIE) is the most common cause of encephalopathy in the neonatal period and carries a high risk of mortality and long-term morbidity. AIM: The aim of this study was to investigate key antecedents of moderate and severe HIE in a large contemporary birth cohort. METHODS: A retrospective cohort study of births meeting criteria was conducted between 2016 and 2020 at the Mater Mothers' Hospital, Brisbane, Australia. This is a quaternary perinatal centre and Australia's largest maternity hospital. Univariate and multivariate Firth logistic regression were used to account for imbalanced frequency classes between non-HIE and HIE groups. Maternal variables and intrapartum factors were investigated for associations with neonatal moderate and severe HIE. RESULTS: Overall, 133 of 46 041 (0.29%) infants were diagnosed with HIE: 77 (0.17%) with mild HIE and 56 (0.12%) with moderate/severe HIE. Nulliparity, type 1 diabetes mellitus and maternal intensive care unit admission were associated with increased odds of moderate/severe HIE. Intrapartum risk factors included emergency caesarean birth, emergency caesarean for non-reassuring fetal status or failure to process, intrapartum haemorrhage and an intrapartum sentinel event (shoulder dystocia, cord prolapse, uterine rupture and placental abruption). Neonatal risk factors included male sex, late preterm gestation (35+0 -36+6  weeks), Apgar score less than four at 5 min, severe respiratory distress requiring ventilatory support and severe acidosis at birth. CONCLUSIONS: This cohort study identified a series of potentially modifiable maternal and obstetric risk factors for HIE. Risk factors for HIE do not appear to have changed significantly with evolution in modern obstetric care.