Objectives:CD4+ T cells play key roles in regulating immune responses during pregnancy; therefore, we aimed to understand the CD4+ T-cell surface proteome and transcriptome during pregnancy. Methods:CD4+ T cells were analysed in blood and decidua from term pregnancies (> 37 weeks) and non-pregnant blood. > 350 surface proteins were screened via flow cytometry, and transcriptomes were analysed using single-cell RNA sequencing with > 130 CITE-seq barcoded antibodies. Results:Surface protein screening identified changes to ILT4/CD85d, CD9, IFN-γ receptor β-chain, CX3CR1 and CCR5 in the pregnant blood and decidual CD4+ T cells. CX3CR1 and CCR5 had the highest expression on the effector-memory T-cell (TEM) subset in the blood, with expression consistent across subsets in decidua. CD126/IL-6R was lower in pregnant blood and decidual CD4+ T cells, while scRNAseq identified enrichment in the IL-6R signalling pathway in naive CD4+ T cells in pregnant blood. Both sIL-6R and IL-6 concentrations were increased in plasma during pregnancy, suggesting perturbations to the IL-6/IL-6R signalling axis. Meanwhile, decidual CD4+ T cells had increased expression of transcription factor RUNX3 in the CD69+ tissue-resident-like subset. Conclusions:Our findings demonstrate altered molecular expression in CD4+ T cells during pregnancy. This provides important mechanistic insight of their adaptation and regulation during placental development, which may drive placental dysfunction or pregnancy complications, including preeclampsia, fetal growth restriction and stillbirth. These new data may inform future studies that focus on determining the significance of differentially expressed immune features in pregnancy to identify potential targets for immune modulation to treat pregnancy complications and infections.

OBJECTIVE:Eclampsia is associated with short- and long-term neurological deficits. Identifying which women may be at risk is important. Magnetic resonance imaging shows an incidence of 30%-40% of subclinical cerebral infarcts among women with eclampsia. A simple screening tool would be useful to identify at-risk women. The objective of this study was to explore clinical markers to identify women at highest risk for silent cerebral infarcts in women who have experienced eclampsia. DESIGN:This was a prospective observational study with cross-sectional MRI ascertainment conducted at Tygerberg Hospital, a tertiary referral centre in Cape Town, South Africa. Women were prospectively assessed for symptoms and signs known to be associated with eclampsia. Cerebral infarcts were identified using brain magnetic resonance imaging. Associations between clinical variables and the presence of cerebral infarcts were evaluated using logistic regression, with variables significant at the 20% level considered for inclusion in multivariable analyses using stepwise selection. RESULTS:A total of 49 women with eclampsia were included in the analysis, of whom 33% (n = 16) had cerebral infarcts detected on MRI. Highest systolic blood pressure and impaired hearing prior to the eclamptic seizure were the clinical variables most strongly associated with the presence of silent cerebral infarcts, with an area under the receiver operating characteristic curve of 0.72 (95% CI 0.56-0.88). At a risk threshold of 43%, sensitivity was 60% (95% CI 36%-80%) and specificity was 84% (95% CI 67%-93%). CONCLUSIONS:Higher systolic blood pressure and impaired hearing were the clinical features most strongly associated with silent cerebral infarcts in women with eclampsia. These findings highlight potentially useful clinical markers that, following external validation, may support triage decisions regarding neuroimaging and neurological follow up.

BACKGROUND:Poor fetal growth is a major cause of perinatal morbidity and mortality and predisposes individuals to chronic diseases in adulthood. Antiseizure medication use in pregnancy has been linked with poor fetal growth, but this association has received little attention and its multifaceted aspects remain unclear. We investigated the risk of poor fetal growth in infants exposed prenatally to antiseizure monotherapy versus polytherapy, across different antiseizure monotherapies, and across common antiseizure medication combinations. METHODS:This prospective, observational, longitudinal cohort study was based on singleton livebirths of women (aged 14-55 years at conception) with epilepsy on antiseizure medication and enrolled at any point in pregnancy into the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) between June 20, 1999, and Nov 15, 2023. Follow-up data were acquired after each trimester and at delivery. Multivariable models were used to assess the association of antiseizure medication exposures with different fetal growth indicators: birthweight centile (primary outcome); small for gestational age (SGA; birthweight <10th centile for gestational age); severe SGA (birthweight <3rd centile); and low birthweight (<2500 g). Models were adjusted for a wide range of clinical and demographic factors that could influence the association between antiseizure medication exposure and poor fetal growth. FINDINGS:The primary outcome analysis included 15 893 offspring prenatally exposed to antiseizure medications (12 911 exposed to monotherapy and 2982 to polytherapy). The other analyses were limited to one offspring per mother and included 13 728 offspring (11 142 exposed to monotherapy and 2586 to polytherapy). Compared with offspring exposed to monotherapy, those exposed to polytherapy had a lower birthweight centile (adjusted unstandardised model coefficient [b] -2·74 [95% CI -4·22 to -1·26]) and an approximately 50% higher risk of SGA (adjusted odds ratio [OR] 1·48 [95% CI 1·29 to 1·70]), severe SGA (1·49 [1·22 to 1·83]), and low birthweight (1·50 [1·15 to 1·95]). Birthweight centile decreased with increasing number of concomitant antiseizure medications (adjusted b -14·18 [95% CI -24·07 to -4·29] with four antiseizure medications [n=48] relative to monotherapy). Among monotherapies, birthweight centile was lower (in decreasing order) with topiramate (adjusted b -11·93 [95% CI -16·72 to -7·15], n=248), phenobarbital (-8·08 [-11·89 to -4·26], n=431), oxcarbazepine (-5·10 [-8·24 to -1·96], n=557), carbamazepine (-3·15 [-5·01 to -1·28], n= 2797), valproic acid (-2·54 [-4·50 to -0·58], n=1829), and levetiracetam (-2·51 [-4·38 to -0·63], n=1809) compared with lamotrigine (n=4672). Offspring exposed to carbamazepine and levetiracetam in combination (n=173) had a lower birthweight centile (adjusted b -6·27 [95% CI -12·03 to -0·50]) than those exposed to lamotrigine monotherapy. No differences in birthweight centile were found between offspring exposed to lamotrigine monotherapy and those exposed to lamotrigine in combination with either levetiracetam (adjusted b 0·19 [95% CI -2·67 to 3·06], n=470) or valproic acid (0·11 [-3·59 to 3·82], n=258). INTERPRETATION:In addition to congenital malformations and neurodevelopmental effects, poor fetal growth should be regarded as an important adverse outcome of prenatal antiseizure medication exposure. Risk varies across individual antiseizure monotherapies and specific antiseizure combinations and increases with the number of concomitant antiseizure medications. These findings have important implications for preconception counselling and management, including risk prediction and individualised treatment selection. FUNDING:Brain Australia, Neurological Foundation of New Zealand, Norman Beischer Medical Research Foundation, Weary Dunlop Medical Research Foundation.

Background Hypertensive disorders of pregnancy are among the leading causes of maternal and neonatal morbidity and mortality worldwide. Labetalol and nifedipine are two of the most common oral antihypertensives used to manage these conditions; however, it is not clear whether one medication may offer greater benefit to mothers and babies than the other. The aim of this study was to compare the risks of adverse maternal and neonatal outcomes for oral labetalol versus nifedipine among women with hypertension in pregnancy. Methods This was a target trial emulation using linked data, including pregnancy episodes between January 1, 2009 and December 31, 2020 in Victoria, Australia. We included pregnant women with a hypertensive disorder (chronic hypertension, gestational hypertension, or preeclampsia) and prescribed oral labetalol or nifedipine between 11+0- and 36+6- weeks’ gestation. Our co-primary outcomes were: 1) a composite of maternal mortality or serious morbidity; and 2) a composite of neonatal mortality or serious morbidity. All outcomes were assessed from first prescription until 28 days postpartum. Analyses used a doubly robust inverse probability-weighted regression adjustment (IPWRA) model and are reported as adjusted risk ratios (aRR) and risk differences (aRD) with 95% confidence intervals (95% CI). Analyses were based on intention-to-treat approach. Findings 7416 pregnancies were eligible for inclusion. Of these, 6745 (91.0%) pregnancies received labetalol as a first-line treatment and 671 (9.0%) received nifedipine. After adjusting for confounding factors, nifedipine was associated with a 33% increased risk of the composite maternal outcome (6.6% versus 9.4%; aRR 1.33, 95% CI 1.07, 1.64), and no difference in the risk of the composite neonatal outcome (43.0% versus 46.1%; aRR 0.97, 95% CI 0.89, 1.06). This was largely driven by increased rates of eclampsia (1.6% versus 3.0%), haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (3.0% versus 4.3%), and renal failure (1.0% versus 1.5%) in the nifedipine group. Among secondary outcomes, nifedipine use was associated with an increased risk of iatrogenic preterm birth and need for additional antihypertensives. Interpretation Among women with hypertension in pregnancy, nifedipine was associated with an increased risk of poor maternal outcomes and iatrogenic preterm birth when compared with labetalol. Labetalol may have a better safety profile as a first-line therapy for pregnant women with hypertension. Future clinical trials are required to validate these findings. Funding This work was supported by a Trevor B Kilvington Bequest, awarded by the University of Melbourne.

RNA sequencing (RNA-Seq) is increasingly used alongside exome and genome sequencing to identify causal variants underlying rare Mendelian disorders. We present short-read RNA-Seq data from 5,412 individuals with a diverse range of rare disorders recruited to Genomics England's 100,000 Genomes Project. We show that the proportion of genes from gene panels applied to different disorders which are well captured (transcripts per million (TPM) ≥ 5) from blood RNA varies widely, highlighting differences in applicability across disorder types. Using OUTRIDER and FRASER2 to identify gene expression and splicing outliers respectively, we identify at least one outlier event in a disorder relevant gene in 20% of the cohort. To prioritise likely diagnostic candidates, we apply multiple strategies including focussing on outlier events in known haploinsufficient genes (n=78), integrating outliers with structural variant calls (n=19), and using strategies integrating phenotypic presentation (Exomiser, n=39). We present a series of candidate diagnoses involving diverse variant types and disease mechanisms, demonstrating the broad utility of RNA-Seq in identifying and prioritising diagnostic candidates in individuals with a variety of different rare conditions and no known genetic diagnosis. Our findings demonstrate that blood-based RNA-Seq can deliver clinically relevant findings across a broad range of rare disorders.

BackgroundMagnesium sulphate halves the risk of eclampsia. There is no consensus on who to give magnesium sulphate prophylaxis because clinical tools are poor at identifying those at risk. Known prodromal symptoms such as headache, visual disturbance, or epigastric pain have modest associations with eclampsia. We set out to identify new prodromal symptoms of eclampsia.Methods and findingsThis case-control study prospectively recruited participants in South Africa and Pakistan who had eclampsia, preeclampsia, or normotensive pregnancies. We asked whether they experienced 20 neurological symptoms, within 7 days of the seizure for those who had eclampsia. The primary analysis was the likelihood of symptoms occurring before eclampsia, compared to being present with preeclampsia. 341 participants were recruited with eclampsia, 1,355 with preeclampsia and 389 with normotensive pregnancies. When comparing symptoms among those who had eclampsia versus preeclampsia, the odds ratios (OR) were 2.56 (95% confidence interval (CI) [1.81,3.62]; p < 0.001) for headache, 5.73 (95% CI [4.44,7.39]; p < 0.001) for visual disturbances and 2.25 (95% CI [1.76,2.89]; p < 0.001) for epigastric pain. We identified 10 symptoms with odds ratios over 10 for eclampsia. Odds ratios were 42.03 (95% CI [23.66,74.68]; p < 0.001) for twitching/jerking limbs (30.5% eclampsia versus 1% preeclampsia); 36.00 (95% CI [18.34,70.65]; p < 0.001) for affected hearing (21.1% versus 0.7%)' 33.60 (95% CI [21.39,52.78]; p < 0.001) for affected mind state (38.7% versus 1.8%); 33.12 (95% CI [19.46, 54.37]; p < 0.001) for impaired speech; 23.71 (95% CI [16.49,34.10]; p < 0.001) for feelings of doom; 26.59 (95% CI [7.82,90.41]; p < 0.001) for severe vertigo; 20.52 (95% CI [14.22,29.63]; p < 0.001) for confusion; 18.16 (95% CI [10.76,30.66]; p < 0.001) for jitters; 15.18 (95% CI [11.34,20.33]; p < 0.001) for difficulty concentrating; and 10.49 (95% CI [6.76,16.27]; p < 0.001) for weakness/paralysis. These symptoms were rare among normotensive pregnancies. Only 2.4% of women with eclampsia did not experience any prodromal symptoms. This study is limited by the fact that we asked about prodromal symptoms after the seizure happened, and the potential for recall bias.ConclusionsTen prodromal symptoms exhibit far stronger associations with eclampsia than headache, visual disturbances, or epigastric pain. Eclampsia is uncommon without any prodromal symptoms. It may be useful to screen these symptoms among women with preeclampsia as part of clinical history taking to guide management. They could help direct magnesium sulphate prophylaxis to those with a higher risk of eclampsia.

Neurodevelopmental disorders (NDDs) affect 2-4% of the population, are predominantly genetic and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive RNU2-2 syndrome is genetically, clinically and mechanistically distinct from the dominant RNU2-2 disorder. Within our cohort, the recessive RNU2-2 syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.

BACKGROUND:Cesarean deliveries are one of the most common obstetric interventions globally. It is important all risks are fully understood. OBJECTIVE:This study aimed to investigate the impact of first birth by cesarean delivery on subsequent reproductive outcomes. STUDY DESIGN:We conducted a retrospective cohort study of all women who gave birth to their first spontaneously conceived, singleton infant in Victoria, Australia from January 2005 to December 2015, with follow-up for second births until December 2017. The exposure was first birth by cesarean delivery, compared with vaginal birth. Primary outcomes included (1) a second live birth occurring within the study time frame and (2) conception via in vitro fertilization or other assisted reproductive technologies among those for whom a second birth was reported. Secondary outcomes included interpregnancy interval and miscarriage rates. Statistical analyses included Cox proportional hazards regression, Poisson regression, or quantile regression depending on the outcome. Outcomes were adjusted for maternal age (at both first and second pregnancy), Socio-Economic Indexes for Areas quintile at the time of pregnancy, preexisting hypertension, and preexisting diabetes. RESULTS:There were 298,241 women who met the inclusion criteria, of whom 184,061 (61.7%) had both their first and second birth during the 12-year study period. A total of 205,164 had a vaginal birth and 93,077 gave birth by cesarean delivery. Having a first birth by cesarean delivery was associated with an 11% reduction in the likelihood of having a second live birth (adjusted hazard ratio, 0.89; 95% confidence interval, 0.88-0.90). Among the cohort reporting a second live birth, there was a 28% increase in the use of in vitro fertilization for conception among those who had a prior cesarean delivery (adjusted risk ratio, 1.28; 95% confidence interval, 1.15-1.43) and a 28% increase in the probability of any assisted reproductive technology use (adjusted risk ratio, 1.28; 95% confidence interval, 1.18-1.40). No difference in miscarriage rates was observed (adjusted risk ratio, 1.01; 95% confidence interval, 0.98-1.03). CONCLUSION:First birth by cesarean delivery was associated with an 11% reduced likelihood of a second live birth within the 12-year study period and a 28% increase in the use of assisted reproductive technologies to achieve a second birth. Factors leading to a cesarean delivery may also be associated with subsequent reproductive outcomes and warrant further study.

Uterine contractions during labor reduce placental perfusion, which limits fetal oxygenation. Intrapartum fetal hypoxia and acidemia occur when there is insufficient reperfusion time between contractions or when placental dysfunction restricts oxygen transfer. The risks of hypoxic-ischemic injury during labor include intrapartum stillbirth, neonatal death, and neonatal encephalopathy. Emergency cesarean or instrumental deliveries are often required when fetal acidemia is suspected, though these interventions carry increased maternal and neonatal risk. Despite widespread use of electronic fetal heart rate monitoring to detect fetal compromise, rates of cerebral palsy, perinatal mortality, and other neonatal well-being measures have not improved. This highlights the need for more effective strategies to prevent adverse perinatal outcomes related to hypoxic injury. Phosphodiesterase type 5 inhibitors may be used to improve uteroplacental perfusion and enhance vasoconstriction in uterine and spinal arteries. Sildenafil citrate, a PDE5 inhibitor, has been used for indications related to placental dysfunction, to treat maternal hypertension, or both. A previous phase II randomized clinical trial (RCT) found that oral sildenafil reduced operative birth for fetal distress by 51% compared with placebo, but was underpowered to assess perinatal outcomes. The aim of this study was to assess whether oral sildenafil citrate during labor improves perinatal outcomes related to intrapartum hypoxia.The iSEARCH trial was a placebo-controlled, double-blind RCT conducted at 14 Australian hospitals from September 2021 to June 2024. Included were adult women with singleton or dichorionic twin pregnancies attempting vaginal birth at term, either by spontaneous labor or induction of labor. Excluded were those with monochorionic twins, triplets, higher-order multifetal gestation, or severe hepatic or kidney impairment. Also excluded were those taking nitrate-containing medications or other PDE inhibitors. Study participants were randomized 1:1 to receive 50 mg sildenafil citrate or a placebo every 8 hours for a maximum of 3 doses. The primary outcome was a composite of 10 intrapartum or neonatal events, including intrapartum stillbirth, 28-day neonatal death, Apgar score <4 at 5 minutes, acidosis at birth, hypoxic ischemic encephalopathy, neonatal seizure, neonatal respiratory support, admission to the neonatal unit, persistent pulmonary hypertension of the newborn, or meconium aspiration syndrome. Secondary outcomes included the 10 individual primary outcomes and emergency cesarean delivery or instrumental vaginal birth for fetal distress.A total of 3257 women were included in the analysis, with 1626 in the sildenafil citrate group and 1631 receiving placebos. The primary composite outcome occurred in 5.1% of women in the intervention group and 5.2% in the placebo group [relative risk (RR), 1.02; 95% CI, 0.75-1.37]. No cases of infant death occurred. The sildenafil group had no effect on the individual secondary outcomes. There was also no effect on emergency operative birth for fetal distress (RR, 1.12; 95% CI, 0.98-1.29). In conclusion, no differences were observed in the incidence of adverse perinatal outcomes or emergency operative birth between women who received sildenafil citrate or placebo during labor.

BackgroundAboriginal and Torres Strait Islander people experience intergenerational trauma as a legacy of the impacts of colonisation. Replanting the Birthing Trees (RBT) aims to transform compounding cycles of intergenerational trauma and harm to positively reinforcing cycles of intergenerational nurturing and recovery for Aboriginal and Torres Strait Islander parents and babies. This paper describes the protocol for developmental evaluation of the culturally responsive, trauma-aware, healing-informed, continuity of care(r) model to support Aboriginal and Torres Strait Islander parents during the first 2000 days (pregnancy, birth and the first 5 years after birth).MethodsThe RBT project will be conducted in partnership with seven health services across Victoria (Royal Women’s Hospital and Mercy Hospital for Women) and Western Australia (WA) [Armadale Hospital, Western Australian Country Health Service (Northam, Narrogin, Moora and Merredin)], Australia. The RBT project consists of five workstreams: a resource repository including support framework; culturally validated sensitive enquiry tools; workforce development and training; continuity of care(r) toolkit; and strategies to support families to stay together from the start. The Consolidated Framework for Implementation Research (CFIR) informs implementation strategies. Acceptability, feasibility, costs and effectiveness will be evaluated using mixed methods analysis of qualitative and quantitative data, collected using key stakeholder interviews; parent and service provider discussion groups and interviews; cost audit; knowledge, attitude and practice surveys; pre- and post-implementation outcome data; interrupted time series analysis of routinely collected administrative linked data for primary and secondary outcomes; and co-design workshops. Competitive funding and human research ethics committee approval were assessed against Indigenous research excellence criteria with protocols to ensure the cultural and emotional safety of participants and communities.DiscussionParticipatory action research approaches are used to foster reflective cycles on data within the research process. Findings will be shared in project newsletters, plain language summaries, presentations and publications.

OBJECTIVE:To investigate whether lithium exposure in pregnancy is associated with spontaneous preterm birth, congenital malformations and abnormal fetal growth. DESIGN:Statewide retrospective cohort study. SETTING:Victoria, Australia. POPULATION:867 454 births (2009-2020), including 234 (0.03%) exposed to lithium during pregnancy. METHODS:Inverse probability weighted regression adjustment to investigate the association between maternal lithium use and perinatal outcomes. MAIN OUTCOME MEASURES:Spontaneous preterm birth (< 37 weeks' gestation), large for gestational age (LGA) (birthweight > 90th percentile), macrosomia (birthweight > 4000 g), major congenital malformations, congenital cardiac malformations. RESULTS:Lithium use was associated a two-fold increased risk of spontaneous preterm birth compared with unexposed pregnancies (8.1% vs. 2.4%; adjusted relative risk [aRR] 2.18, 95% CI 1.45-3.30). Lithium was associated with an increased risk of an LGA infant (13.7% vs. 6.4%; aRR 1.94, 95% CI 1.36-2.76), and congenital cardiac malformations (3.0% vs. 0.8%; aRR 2.64, 95% CI 1.26-5.53). Lithium was not associated with an altered risk of major congenital malformations overall (aRR 1.51, 95% CI 0.92-2.50). Restricting the cohort to women with bipolar disorder or schizophrenia diagnoses, associations remained between lithium exposure and spontaneous preterm birth (aRR 1.88, 95% CI 1.06-3.32) and birth of an LGA infant (aRR 1.68, 95% CI 1.07-2.65). CONCLUSIONS:In our study, lithium exposure during pregnancy was associated with a two-fold increased risk of spontaneous preterm birth. Lithium use was also associated with an increased risk of cardiac malformations and having an LGA infant. These findings may be useful for shared decision-making around lithium use during pregnancy.

OBJECTIVE:The impact of diabetes in pregnancy on offspring neurodevelopment is unclear. We investigate whether exposure to diabetes in utero is associated with developmental vulnerability or educational delay during primary school. RESEARCH DESIGN AND METHODS:We used population-level pregnancy and birth data from 2009 to 2021 from Victoria, Australia, linked with standardized national assessments. Adjusting for a range of maternal and childhood covariates, we investigated whether diabetes in pregnancy was associated with an altered risk of developmental vulnerability compared with no diabetes in the first year of full-time school (ages 4-6 years), defined as below the tenth centile in two or more domains in the Australian Early Development Census (AEDC), and altered educational outcomes in grade 3 (ages 7-8 years), defined as the adjusted mean difference in overall z score in the National Assessment Program - Literacy and Numeracy test (NAPLAN). RESULTS:Our study comprised 177,898 children who had linked birth and AEDC data, and 115,231 with linked birth and NAPLAN data, including, respectively, 16,363 (9.2%) and 7,532 (6.5%) exposed to diabetes in pregnancy. Following adjusted analysis, diabetes in pregnancy was not associated with an altered risk of overall developmental vulnerability compared with no diabetes (adjusted relative risk 1.02 [95% CI 0.98, 1.07]). Diabetes was associated with a marginally higher overall NAPLAN z score, but below the prespecified threshold for clinical significance (adjusted mean difference 0.04 [95% CI 0.01, 0.07]). CONCLUSIONS:Diabetes in pregnancy was not associated with overall developmental vulnerability or a clinically meaningful difference in educational outcomes. This should provide reassurance for patients and their treating clinicians.

Linked article: This is a mini commentary on Kingdon et al., pp. 2024–2039 in this issue. To view this article, visit https://doi.org/10.1111/1471‐0528.18269 .

BackgroundHypertensive disorders of pregnancy may be associated with an increased risk of adverse neurodevelopmental outcomes for the child, though no recent comprehensive meta-analyses exist. The aim of this study was to conduct a systematic review and meta-analysis examining the association between hypertensive disorders of pregnancy and child neurodevelopmental disabilities, intelligence, and educational outcomes.Methods and findingsA search was conducted of MEDLINE, CINAHL, Web of Science, and PsycINFO databases from inception until 18 September 2024. Reference lists of included papers were also screened. Observational studies and secondary analyses of randomized trials reporting neurodevelopmental, cognitive, or educational outcomes for children born following hypertensive disorders of pregnancy against a reference population (unaffected pregnancies) were included. Two reviewers independently screened records, extracted data, and assessed quality of studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Studies reporting similar outcomes were pooled using a random-effects meta-analysis model. Outcomes included autism, attention-deficit/hyperactivity disorder, cerebral palsy, global developmental delay, intellectual disability, intelligence quotient, and educational attainment. Results were reported as odds ratios (OR) or mean difference (MD) with corresponding 95% confidence intervals (CI). After screening 13,419 records, 121 studies reporting outcomes of 29,649,667 offspring were included. We included 85 cohort studies, 30 case-control studies, four cross-sectional studies, and two secondary analyses of randomized trials. Compared with unaffected pregnancies, hypertensive disorders of pregnancy were associated with an increased unadjusted likelihood of autism spectrum disorder (OR 1.65 (95% CI [1.49,1.83]); p < 0.001; n = 26,727,500), attention-deficit/hyperactivity disorder (OR 1.27 (95% CI [1.21,1.33]); p < 0.001; n = 12,987,737), intellectual disability (OR 1.77 (95% CI [1.31,2.38]); p < 0.001; n = 10,718,504), global developmental delay (OR 1.77 (95% CI [1.21,2.59]); p < 0.001; n = 2,961,195), and reduced mean intelligence (MD -2.20 95% CI [-3.35,-1.06]); p < 0.001; n = 1,150,664). Associations between hypertension and autism spectrum disorder and global developmental delay were no longer significant after adjusting for gestational age and birthweight. Results for intelligence quotient remained significant when adjusting for birthweight, but not gestational age. Adjusted analyses for attention-deficit/hyperactivity disorder and intellectual disability could not be performed due to a lack of suitable studies. In sensitivity analyses, results were unchanged after exclusion of papers at high risk of bias. This study is limited by a lack of constituent papers which adjusted for confounding and mediating factors, a high amount of heterogeneity among included studies, and possible publication bias for some outcomes.ConclusionsHypertensive disorders of pregnancy are potentially associated with adverse neurodevelopmental and cognitive outcomes among affected offspring. While the mechanisms driving these associations are not clear, these results highlight a group of children that will benefit from early intervention and support to improve their neurodevelopmental outcomes.

BackgroundThere is no universally agreed upon obstetric growth standard for use during pregnancy. We aimed to design a simple novel growth standard, which incorporates key beneficial features identified in prior research.Methods and findingsWe developed the Fetal Region-specific Optimized Growth Standard (FROGS), then validated it following International Federation of Gynaecology and Obstetrics (FIGO) guidelines. FROGS follows the shape of the fetal (ultrasound-based) Hadlock curve. It is region-specific; allowing adjustment for the mean birthweight and standard deviation of babies born at term in the local population where it will be applied. It provides an exact centile for each gestational day (rather than rounding off by weeks) and is optionally adjustable for fetal sex. Further, FROGS provides an 'estimate range' for the estimated fetal weight centile, assuming a 10% ultrasound measurement error. Following development, we validated FROGS in a retrospective cohort study by comparing its ability to identify small babies with an increased risk of adverse perinatal outcomes to four charts in current use: (1) population birthweight chart (Australian Institute of Health and Welfare, AIHW chart); (2) Hadlock's 1991 fetal chart; (3) Mikolajczyk's global fetal and birthweight centile chart; and (4) INTERGROWTH-21st fetal growth standards. To do this, we identified infants classified as small for gestational age (<10th centile) by each chart. We then identified non-overlapping <10th centile populations, i.e., infants classified as small by one chart, but not another. We compared rates of stillbirth and adverse perinatal outcomes between the non-overlapping populations. All charts except INTERGROWTH classified similar proportions of infants as <10th centile (10.4% FROGS, 9.3% AIHW, 11.1% Hadlock, 10.9% global, 4.4% INTERGROWTH). Of the three charts that classified similar proportions as <10th centile, infants classified by FROGS were at the highest risk of adverse perinatal outcomes. The infants classified as <10th centile by only FROGS had significantly increased relative risk (RR) of stillbirth, compared to the infants classified as <10th centile by only AIHW (RR 13.1, 95% CI 6.5-26.5), only Hadlock (RR 2.1, 95% CI 1.28-3.56) or only the global chart (RR 1.54, 95% CI 1.00-2.37). The FROGS chart outperformed these three charts in identifying infants at risk of other adverse perinatal outcomes associated with being small for gestational age, such as neonatal intensive care admission, Apgar scores <7 at 5 min, and operative (instrumental) vaginal birth for suspected fetal compromise. The cohort of infants classified as small for gestational age by INTERGROWTH was, in size and risk, closer to the cohort classified as <3rd centile by FROGS (3.4% of infants <3rd). This study is limited in that it retrospectively assesses birthweight, which may have different implications to a prospective evaluation of estimated fetal weight.ConclusionsCompared to currently used charts, the Fetal Region-specific Optimized Growth Standard outperforms existing charts that classify a similar proportion of infants as small for gestational age in identifying small infants at increased risk of stillbirth and other serious perinatal outcomes. The FROGS centile algorithm is simple and transparent. It has the potential to be adapted to other local populations, or applied to clinical and research settings globally.

BACKGROUND:Placental insufficiency underpins pregnancy complications, fetal growth restriction (FGR) and preeclampsia, yet predictive biomarkers are limited. Neuronal Cell Adhesion Molecule (NrCAM) may be a promising biomarker of placental dysfunction. This study investigated whether NrCAM can predict diseases of placental insufficiency. METHODS:Circulating NrCAM was measured across independent cohorts. Plasma NrCAM was assessed at 36 weeks' gestation in women who later delivered FGR infants (<3rd centile birthweight), or developed preeclampsia at term. Circulating NrCAM was also measured in international cohorts: a UK high-risk cohort of women presenting with reduced fetal movements and delivered an FGR infant; a high-risk cohort from South Africa diagnosed with preeclampsia or eclampsia. NrCAM was also assessed in pregnancies with preterm FGR or preeclampsia (<34 weeks gestation). The effect of hypoxia on NrCAM expression was measured in trophoblast stem cells, primary trophoblasts, and a murine FGR model. FINDINGS:Circulating NrCAM was reduced at 36 weeks' gestation in women who later delivered FGR infants (p = 4.75 x 10-6, AUC = 0.76, n = 26 FGR, n = 957 controls). In the UK cohort, reduced NrCAM levels were associated with FGR (p = 9.34 × 10-3, AUC = 0.72, n = 12 FGR, n = 235 control). In the South Africa cohort, circulating NrCAM was reduced with preeclampsia (p = 0.03, AUC = 0.70, n = 27 preeclampsia, n = 15 control). Placental NrCAM expression was lower in FGR (p = 0.0003, n = 23 FGR) and preeclampsia (p = 0.0003, n = 41 preeclampsia, n = 20 controls). Hypoxia reduced NrCAM expression in human trophoblast stem cells (p < 0.01) primary trophoblasts (p < 0.0001) and in a murine FGR model (p < 0.01, n = 9 per group). INTERPRETATION:Reductions in plasma and placental NrCAM are strongly associated with FGR and may be driven by hypoxia. FUNDING:This study was funded by a grant from National Health and Medical Research Council.

Alpha-fetoprotein (AFP) is a protein commonly used to screen for aneuploidy in pregnancy. This study measured circulating AFP in maternal plasma at 36 weeks' gestation preceding diagnosis of term preeclampsia or delivery of a small for gestational age infant (SGA; <10 % birthweight centile) in a case-cohort design (122 SGA; 23 preeclampsia; 182 controls). AFP was significantly reduced in SGA < 5th birthweight centile (n = 51; P = 0.002) but not changed preceding preeclampsia diagnosis. This suggests that AFP is reduced near term preceding SGA diagnosis and may have potential as a biomarker if combined with other candidate molecules.