Birmingham Women’s and Children’s NHS Foundation Trust

OBJECTIVE: To determine the clinical manifestations, risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane database, WHO COVID-19 database, China National Knowledge Infrastructure (CNKI), and Wanfang databases from 1 December 2019 to 6 October 2020, along with preprint servers, social media, and reference lists. STUDY SELECTION: Cohort studies reporting the rates, clinical manifestations (symptoms, laboratory and radiological findings), risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed covid-19. DATA EXTRACTION: At least two researchers independently extracted the data and assessed study quality. Random effects meta-analysis was performed, with estimates pooled as odds ratios and proportions with 95% confidence intervals. All analyses will be updated regularly. RESULTS: 192 studies were included. Overall, 10% (95% confidence interval 7% to 12%; 73 studies, 67 271 women) of pregnant and recently pregnant women attending or admitted to hospital for any reason were diagnosed as having suspected or confirmed covid-19. The most common clinical manifestations of covid-19 in pregnancy were fever (40%) and cough (41%). Compared with non-pregnant women of reproductive age, pregnant and recently pregnant women with covid-19 were less likely to have symptoms (odds ratio 0.28, 95% confidence interval 0.13 to 0.62; I2=42.9%) or report symptoms of fever (0.49, 0.38 to 0.63; I2=40.8%), dyspnoea (0.76, 0.67 to 0.85; I2=4.4%) and myalgia (0.53, 0.36 to 0.78; I2=59.4%). The odds of admission to an intensive care unit (odds ratio 2.13, 1.53 to 2.95; I2=71.2%), invasive ventilation (2.59, 2.28 to 2.94; I2=0%) and need for extra corporeal membrane oxygenation (2.02, 1.22 to 3.34; I2=0%) were higher in pregnant and recently pregnant than non-pregnant reproductive aged women. Overall, 339 pregnant women (0.02%, 59 studies, 41 664 women) with confirmed covid-19 died from any cause. Increased maternal age (odds ratio 1.83, 1.27 to 2.63; I2=43.4%), high body mass index (2.37, 1.83 to 3.07; I2=0%), any pre-existing maternal comorbidity (1.81, 1.49 to 2.20; I2=0%), chronic hypertension (2.0, 1.14 to 3.48; I2=0%), pre-existing diabetes (2.12, 1.62 to 2.78; I2=0%), and pre-eclampsia (4.21, 1.27 to 14.0; I2=0%) were associated with severe covid-19 in pregnancy. In pregnant women with covid-19, increased maternal age, high body mass index, non-white ethnicity, any pre-existing maternal comorbidity including chronic hypertension and diabetes, and pre-eclampsia were associated with serious complications such as admission to an intensive care unit, invasive ventilation and maternal death. Compared to pregnant women without covid-19, those with the disease had increased odds of maternal death (odds ratio 2.85, 1.08 to 7.52; I2=0%), of needing admission to the intensive care unit (18.58, 7.53 to 45.82; I2=0%), and of preterm birth (1.47, 1.14 to 1.91; I2=18.6%). The odds of admission to the neonatal intensive care unit (4.89, 1.87 to 12.81, I2=96.2%) were higher in babies born to mothers with covid-19 versus those without covid-19. CONCLUSION: Pregnant and recently pregnant women with covid-19 attending or admitted to the hospitals for any reason are less likely to manifest symptoms such as fever, dyspnoea, and myalgia, and are more likely to be admitted to the intensive care unit or needing invasive ventilation than non-pregnant women of reproductive age. Pre-existing comorbidities, non-white ethnicity, chronic hypertension, pre-existing diabetes, high maternal age, and high body mass index are risk factors for severe covid-19 in pregnancy. Pregnant women with covid-19 versus without covid-19 are more likely to deliver preterm and could have an increased risk of maternal death and of being admitted to the intensive care unit. Their babies are more likely to be admitted to the neonatal unit. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178076. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 1 of the original article published on 1 September 2020 (BMJ 2020;370:m3320), and previous updates can be found as data supplements (https://www.bmj.com/content/370/bmj.m3320/related#datasupp). When citing this paper please consider adding the update number and date of access for clarity.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

UK Biobank is a population-based cohort of half a million participants aged 40-69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world's largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future directions.

BACKGROUND: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). METHODS: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. FINDINGS: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). INTERPRETATION: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. FUNDING: UK Department of Health and Social Care and The Wellcome Trust.

BACKGROUND: Alterations in waveforms in the uterine artery are associated with the development of pre-eclampsia and intrauterine growth restriction. We investigated the predictive accuracy of all uterine artery Doppler indices for both conditions in the first and second trimesters. METHODS: We identified relevant studies through searches of MEDLINE, EMBASE, the Cochrane Library and Medion databases (all records to April 2006) and by checking bibliographies of identified studies and consulting with experts. Four of us independently selected studies, extracted data and assessed study validity. We performed a bivariable meta-analysis of sensitivity and specificity and calculated likelihood ratios. RESULTS: We identified 74 studies of pre-eclampsia (total 79,547 patients) and 61 studies of intrauterine growth restriction (total 41 131 patients). Uterine artery Doppler ultrasonography provided a more accurate prediction when performed in the second trimester than in the first-trimester. Most Doppler indices had poor predictive characteristics, but this varied with patient risk and outcome severity. An increased pulsatility index with notching was the best predictor of pre-eclampsia (positive likelihood ratio 21.0 among high-risk patients and 7.5 among low-risk patients). It was also the best predictor of overall (positive likelihood ratio 9.1) and severe (positive likelihood ratio 14.6) intrauterine growth restriction among low-risk patients. INTERPRETATION: Abnormal uterine artery waveforms are a better predictor of pre-eclampsia than of intrauterine growth restriction. A pulsatility index, alone or combined with notching, is the most predictive Doppler index. These indices should be used in clinical practice. Future research should also concentrate on combining uterine artery Doppler ultrasonography with other tests.

The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages sound clinical practice, and high-quality teaching and research related to diagnostic imaging in women's healthcare. The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements as educational recommendations that provide healthcare practitioners with a consensus-based approach, from experts, for diagnostic imaging. They are intended to reflect what is considered by ISUOG to be the best practice at the time at which they are issued. Although ISUOG has made every effort to ensure that Guidelines are accurate when issued, neither the Society nor any of its employees or members accepts any liability for the consequences of any inaccurate or misleading data, opinions or statements issued by the CSC. The ISUOG CSC documents are not intended to establish a legal standard of care because interpretation of the evidence that underpins the Guidelines may be influenced by individual circumstances, local protocol and available resources. Approved Guidelines can be distributed freely with the permission of ISUOG ([email protected]). The incidence of multiple pregnancy is rising, mainly due to delayed childbirth and advanced maternal age at conception and the resultant widespread use of assisted reproduction techniques1. The twin birth rate increased by just under 70% between 1980 (19 per 1000 live births) and 2006 (32 per 1000 live births)2. Twin pregnancy is associated with a high risk of perinatal mortality and morbidity3-6. In 2009, the associated stillbirth rate was 12 per 1000 twin births and 31 per 1000 triplet and higher-order multiple births, compared with five per 1000 singleton births7, 8. Preterm birth prior to 37 weeks' gestation occurs in up to 60% of multiple pregnancies, contributing to the increased risk of neonatal mortality (65% of neonatal deaths among multiple births are preterm, compared with 43% of neonatal deaths in singletons) and long-term morbidity9-12. Of course, such complications rise with a reduction in gestational age at birth. In addition, compared with singletons, twins are at increased risk of iatrogenic preterm delivery due to the greater incidence of maternal and fetal complications. The risk is significantly higher in monochorionic compared with dichorionic pregnancy3-6. Ultrasound assessment of fetal biometry, anatomy, Doppler velocimetry and amniotic fluid volume is used to identify and monitor twin pregnancies at risk of adverse outcomes such as twin-to-twin transfusion syndrome (TTTS) and fetal growth restriction (FGR). As in singletons, impaired fetal growth can be assessed in twins by comparing biometry and Doppler velocimetry parameters against standards for uncomplicated pregnancy. This guidance will address the role of ultrasound in the care of uncomplicated twin pregnancy and those complicated by TTTS, selective FGR (sFGR), twin anemia–polycythemia sequence (TAPS), twin reversed arterial perfusion (TRAP) sequence, conjoined twins and single intrauterine death (IUD). The document provides guidance on the methods used to determine gestational age and chorionicity, screening for chromosomal and structural abnormalities, and screening for TTTS, TAPS, growth abnormalities and preterm birth. The management of higher-order multiple pregnancy will be covered in a separate document. The Cochrane Library and Cochrane Register of Controlled Trials were searched for relevant randomized controlled trials, systematic reviews and meta-analyses and a search of MEDLINE from 1966 to 2014 was carried out. The date of the last search was 15 November 2014. In addition, relevant conference proceedings and abstracts were searched. Databases were searched using the relevant MeSH terms including all sub-headings. This was combined with a keyword search using ‘twin’, ‘multiple’, ‘pregnancy’, ‘ultrasound’, ‘twin-to-twin transfusion syndrome’, ‘fetal growth restriction’, ‘twin anemia polycythemia sequence’, ‘twin reversed arterial perfusion’, ‘acardiac twin’, ‘monochorionic monoamniotic’, ‘conjoined’, ‘demise’. The National Library for Health and the National Guidelines Clearing House were also searched for relevant guidelines and reviews. Gray (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections and clinical trial registries. The search was limited to the English language. When possible, recommendations are based on, and explicitly linked to, the evidence that supports them, while areas lacking evidence are annotated as ‘good practice points’. Details of the grades of recommendations and levels of evidence used in these Guidelines are given in Appendix 1. Other studies have recommended the use of the smaller CRL or the mean CRL, which takes into account both fetuses13-15. The disadvantage of using the smaller CRL is the potential of the operator believing that the larger twin is large-for-gestational age, and therefore being falsely reassured that the smaller twin is still growing appropriately. The most common practice is to use the larger CRL. If the woman presents after 14 weeks' gestation, the larger head circumference should be used1. Twin pregnancies conceived via in-vitro fertilization should be dated using the oocyte retrieval date or the embryonic age from fertilization (EVIDENCE LEVEL: 2+). Every attempt should be made to determine the chorionicity of a twin pregnancy. Chorionicity should be determined between 11 + 0 and 13 + 6 weeks of gestation using the membrane thickness at the site of insertion of the amniotic membrane into the placenta, identifying the T-sign or lambda sign (Figure 1), and the number of placental masses visualized using ultrasound1. It is important to examine the dividing membrane carefully; in dichorionic diamniotic twin pregnancy, the twins are separated by a thick layer of fused chorionic membranes with two thin amniotic layers, one on each side, giving the appearance of a ‘full lambda’, compared with only two thin amniotic layers separating the two fetuses in monochorionic diamniotic (MCDA) twin pregnancy (the T-sign). In women presenting for the first time after 14 weeks of gestation, chorionicity is best determined using the same ultrasound signs, in particular by counting the membrane layers, and noting discordant fetal sex. The reliability of the number of placental masses is questionable, as dichorionic placentae are commonly adjacent to each other, appearing as a single mass, and 3% of monochorionic twin pregnancies have two placental masses on ultrasound, the presence of which does not preclude the presence of vascular anastomoses16. It is likely that using a combination of ultrasound features, rather than a single one, would be more accurate1. If it is not possible to determine chorionicity by transabdominal ultrasound imaging, this should be attempted using transvaginal sonography. If it is still not possible to determine chorionicity, a second opinion should be sought from a tertiary referral center. If the center is uncertain about the chorionicity, it is safer to classify the pregnancy as monochorionic1 (EVIDENCE LEVEL: 3). At the time at which chorionicity is determined, amnionicity (i.e. whether or not the twins share the same amniotic sac) should be determined and documented. In case of doubt, absence of the intertwin membrane is best confirmed by transvaginal scan. Another useful finding is demonstration of cord entanglement, which is almost universal in MCMA twin pregnancy, using color and pulsed-wave Doppler ultrasound. Using pulsed-wave Doppler, two distinct arterial waveform patterns with different heart rates are seen within the same sampling gate (EVIDENCE LEVEL: 4). All MCMA twin pregnancies should be referred to a tertiary center with expertise in their management1. It is recommended that an ultrasound image demonstrating the chorionicity is stored electronically and that a hard copy is added to the medical records. As determination of chorionicity is most accurate at 11–14 weeks' gestation when the amnion and chorion have not yet fused, the first-trimester scan in twin pregnancy is paramount (EVIDENCE LEVEL: 4). It is important to follow a reliable, consistent strategy for antenatal twin labeling. Options include: labeling according to their site, either left and right, or upper and lower; or mapping in the first trimester according to the insertion of their cords relative to the placental edges and membrane insertion. In some healthcare settings, Twin A is the fetus on the right side, while Twin B is the one on the left. This information should be documented clearly in the woman's notes in order to ensure consistent labeling during follow-up scans17. It is advisable to describe each twin using as many features as possible so as to enable others to identify them accurately; e.g. ‘Twin A (female) is on the maternal right with a posterior placenta and marginal cord insertion’. For pregnancies with discordance, the labeling should be accompanied by a description such as ‘Twin A, potential recipient’. It is important to acknowledge that labeling is less accurate in MCMA twin pregnancy, particularly in the first trimester. It should be borne in mind that the twins labeled as ‘Twin A’ and ‘Twin B’ during antenatal ultrasound scans may not necessarily be delivered in that order, in particular if the mode of delivery is Cesarean section18. It is important to alert parents and healthcare professionals attending the delivery to this fact, particularly in pregnancies in which the twins are discordant for structural abnormalities that are not obvious by external examination, e.g. congenital diaphragmatic hernia or cardiac defects. In such cases, an ultrasound scan should be performed just prior to delivery and also before instigating any specific neonatal intervention. In uncomplicated dichorionic twin pregnancy, ultrasound imaging should be performed in the first trimester, again at around 20 weeks' gestation (second-trimester anomaly scan), and every 4 weeks thereafter (unless a complication is detected which might require more frequent scans) (Figure 2)1. In uncomplicated monochorionic twins, an ultrasound scan should be performed in the first trimester. There should then be scans every 2 weeks from 16 weeks onwards, as timely detection of TTTS and TAPS has been shown to improve perinatal outcome (Figure 3)19, 20 (EVIDENCE LEVEL: 4). At each ultrasound assessment, the following should be assessed: fetal biometry, amniotic fluid volume and umbilical artery Doppler (from 20 weeks' gestation) for both twins. Discordance in estimated fetal weight (EFW) should be calculated and documented at each scan from 20 weeks. In monochorionic twin pregnancy, middle cerebral artery (MCA) peak systolic velocity (PSV) should be recorded from 20 weeks, in order to screen for TAPS. In MCDA twins, the amniotic fluid volume (deepest vertical pocket) should be assessed and documented at each ultrasound scan to screen for TTTS. Cervical length assessment is performed ideally at the same visit as the anomaly scan in the second trimester, in order to identify women at risk of extreme preterm birth (EVIDENCE LEVEL: 2+, 2++). In twin pregnancy, screening for trisomy 21 can be performed in the first trimester using the combined test, which includes maternal age, NT measurement and serum β-hCG and PAPP-A levels. An alternative is the combination of maternal age and the NT recorded between 11 + 0 and 13 + 6 weeks of gestation1. In case of a vanished twin, if there is still a measurable fetal pole, β-hCG and PAPP-A measurements are biased and NT alone should be used for risk estimation. The risk of trisomy 21 in monochorionic twin pregnancy is calculated per pregnancy based on the average risk of both fetuses (because the twins share the same karyotype), whereas in dichorionic twin pregnancy the risk is calculated per fetus (as around 90% are dizygotic so have different karyotypes). The DR for Down syndrome may be lower in twin compared with singleton pregnancy1. However, a recent meta-analysis reported similar performance (89% for singletons, 86% for dichorionic twins and 87% for monochorionic twins, at a false-positive rate (FPR) of 5%)22 (EVIDENCE LEVEL: 2++). The likelihood of being offered invasive testing on the basis of a combined screening result is greater in twin compared with singleton pregnancy1. Moreover, invasive testing carries greater risks in twins23-25. A meta-analysis showed that the overall pregnancy loss rate following chorionic villus sampling (CVS) in twin pregnancy was 3.8%, and following amniocentesis was 3.1%23. Other research has reported lower loss rates: 2% following CVS and 1.5–2% following amniocentesis26. The risk was found to be similar for transabdominal and transcervical approaches, use of a single-needle or double-needle system, and single or double uterine entry23 (EVIDENCE LEVEL: 2++). Screening and diagnostic testing for trisomy is more complex in twin compared with singleton pregnancy. It is important, therefore, that counseling prior to testing is provided by healthcare professionals with expertise in this area1. It is important to inform women and their partners in advance of the potentially complex decisions that they will need to make on the basis of the results of combined screening, bearing in mind the increased risk of invasive testing in twins, the possible discordance between dichorionic twins for fetal aneuploidy, and the risks of selective fetal reduction1 (EVIDENCE LEVEL: 2+). Cell-free DNA (cfDNA) analysis of maternal blood for risk assessment for fetal trisomy 21 is used increasingly in clinical practice. It has the potential to overcome many of these complex issues, because it has a much higher DR and lower FPR than does the combined test27. In a recent meta-analysis, the weighted pooled DR for trisomy 21 in singleton pregnancy was 99% for a FPR of 0.1%28. The corresponding values in twin pregnancy were 94.4% and 0%. However, so far, the reported number of trisomy-21 cases in twin pregnancy diagnosed using cfDNA testing is far smaller than that in singleton pregnancy (EVIDENCE LEVEL: 2++). Invasive testing for chromosomal or genetic analysis of twins should be carried out by a fetal medicine expert. CVS is preferred in dichorionic twin pregnancy because it can be performed earlier than can amniocentesis. Earlier diagnosis of any aneuploidy is particularly important in twin pregnancy, given the lower risk of selective termination in the first compared with the second trimester (7% risk of loss of the entire pregnancy, and 14% risk of delivery before 32 weeks)29. It is important to map carefully the position of the twins within the uterus. During amniocentesis in monochorionic twins, if monochorionicity has been confirmed before 14 weeks' gestation and the fetuses appear concordant for growth and anatomy, it is acceptable to sample only one amniotic sac. Otherwise, both amniotic sacs should be sampled because of the possibility of rare discordant chromosomal anomalies in monochorionic pregnancy. CVS in monochorionic pregnancy will sample only the single placenta so will miss these rare discordant chromosomal anomalies. Discordance for most of the common human aneuploidies (trisomies 13, 18 and 21, Turner syndrome and triploidy) has been reported in monochorionic twin pairs30. In the event of heterokaryotypic monochorionic pregnancy, selective reduction by umbilical cord occlusion can be offered from 16 weeks onwards, with a survival rate of more than 80% for the healthy twin31, 32. When monochorionic twins are discordant for an abnormality, prior to invasive testing a discussion should take place regarding the complexity of selective termination, should it become necessary32 (EVIDENCE LEVEL: 3). Although some studies have reported an association between first-trimester intertwin discordance in NT or CRL, or reversed a-wave in the ductus venosus (DV), and the development of TTTS, their predictive value is poor17, 33-35. NT discordance of ≥ 20% had a sensitivity of 52–64% and a specificity of 78–80%, a positive predictive value of 50% and a negative predictive value of 86% for the development of TTTS36, 37. Discordance in NT of ≥ 20% is found in around 25% of monochorionic twins and the risk of early IUD or development of severe TTTS in this group is more than 30%37. The risk of complications is less than 10% if the NT discordance is < 20%37. An abnormal DV will pick up only 38% of all pregnancies that subsequently develop TTTS, and, of those predicted to be at high risk, only 30% will ultimately develop TTTS35. Similarly, although intertwin discordance in CRL at 11–13 weeks' gestation is significantly associated with the risk of pregnancy loss (area under the receiver–operating characteristics curve (AUC), 0.5), birth-weight discordance (AUC, 0.6), sFGR (AUC, 0.6) and preterm delivery prior to 34 weeks' gestation (AUC, 0.5), again the predictive value is poor (pooled predictive risk of 52%)38, 39. Nevertheless, the management of twin pregnancy with CRL discordance ≥ 10% or NT discordance ≥ 20% should be discussed with a fetal medicine expert and in these pregnancies there should be detailed ultrasound assessment and testing for karyotype abnormalities. The risk of fetal abnormalities was found to be 25% in pregnancies with CRL discordance ≥ 10%, compared with 4% in pregnancies with CRL discordance < 10%40. However, CRL discordance at 7 + 0 to 9 + 6 weeks' gestation is a predictor of the risk of single fetal demise in the first trimester (DR of 74% for a FPR of 5%)41 (EVIDENCE LEVEL: 2++). At the first-trimester scan (between 11 + 0 and 13 + 6 weeks' gestation) the fetuses should be assessed for the presence of any major anomalies42. Routine second-trimester ultrasound screening for anomalies in twins should be performed by an experienced operator at around 20 (18–22) weeks' gestation1, 43. This scan may be more difficult than usual because of the presence of a second fetus, and it is important to allow adequate time (i.e. in the order of 45 min). The risk of fetal anomaly is greater in twin compared with singleton pregnancy44. The rate per fetus in dizygotic twins is probably the same as that in singletons, whereas it is two-to-three times higher in monozygotic twins. In around 1 in 25 dichorionic, 1 in 15 MCDA and 1 in 6 monoamniotic twin pregnancies, there is a major congenital anomaly that typically affects only one twin45, 46. screening for anomalies should be considered in monochorionic twin pregnancy, bearing in mind that and cardiac abnormalities might become more obvious in the trimester. associated with twins abnormalities, cardiac and anomalies. screening cardiac assessment should be performed according to ISUOG including and and It is important to make the woman of the of ultrasound screening, which according to the of The of screening for fetal anomaly in the second trimester giving parents the to for the birth of a with a potential them the of termination, to a center for the and, intrauterine (EVIDENCE LEVEL: 3). to two of twin pregnancies will have an anomaly only one fetus, to the between management and selective termination of the in monozygotic twins, for a structural anomaly is found in than 20% of pregnancies should be referred to a fetal medicine center for management1. In monochorionic twins discordant for a structural abnormality, discordant aneuploidy is rare not In these expert ultrasound assessment in a tertiary with invasive fetal chromosomal or genetic testing if and a discussion of the likely for both the and the twin, are For that are and a high risk of intrauterine management is preferred in dichorionic twins, whereas in monochorionic twin pregnancy this would to the healthy against the adverse of demise of the The of selective termination in twin pregnancy the risk of preterm birth. This is particularly relevant in twin pregnancies discordant for in which selective termination in the second trimester is associated with a higher risk of and preterm compared with that in the first trimester (7% risk of loss of the entire pregnancy, and 14% risk of delivery before 32 weeks)29. When the diagnosis is made in the second trimester, women might for a selective termination in the trimester, if the when the is associated with a risk of preterm birth rather than fetal loss of the The and of each should be considered loss of a fetal medicine to the in the event of preterm and risk of complications associated with the specific (EVIDENCE LEVEL: 2++). in dichorionic twin pregnancy is performed by or of or When selective termination of one twin of a monochorionic is the of is not an because of the risk to the healthy cord or of the twin is This to demise of the twin while the healthy twin against of its blood volume into the twin following its The survival rate of the is 80% and the risk of of the membranes and preterm birth prior to 32 weeks is The risk of adverse in the may also be increased compared with that in uncomplicated (EVIDENCE LEVEL: 2++). and iatrogenic preterm births are more common in twin than in singleton than of twins are before 37 weeks of gestation and of twin births before 37 and 32 weeks of gestation, these rates are and times the rates for singleton pregnancy, women found to have a at the second-trimester ultrasound scan are to be at increased risk of preterm However, the sensitivity of this finding is and the of the length used to increased risk of preterm birth is A length < 25 at weeks' gestation in twin pregnancy is a predictor of preterm birth before 34 weeks, not before 37 In a length 20 at weeks was the most accurate predictor of preterm birth before 32 and before 34 weeks (pooled and positive and negative likelihood were and and and and and A length 25 at weeks had a pooled positive likelihood of for the of preterm birth before The predictive of length for preterm birth was in (EVIDENCE LEVEL: 2++). Moreover, there is strategy to preterm birth in these or not the risk of preterm delivery in these However, might the risk of neonatal and research may management in this in due (EVIDENCE LEVEL: The assessment and management of FGR are among If both twins have an < the fetuses should be sFGR is a to twin pregnancies in which one fetus has an < and the intertwin discordance is The of and a of in the to discordant fetal A of for discordance in birth weight was found to adverse outcome not take into account the intertwin discordance use < in one the discordance most predictive of adverse outcome is likely to with gestational A discordance of 20% a for pregnancies at increased risk of adverse outcome of discordance is calculated by the following of larger twin weight of smaller of larger twin (EVIDENCE LEVEL: 2++). a diagnosis has been a should be This search should a detailed anomaly scan and screening for and may also be to chromosomal abnormalities as a of sFGR in monochorionic twin pregnancy occurs mainly due to of the placental and (EVIDENCE LEVEL: 3). using ultrasound is less accurate in twin than in singleton that a combination of and measurements best in both singleton and twin the used to monitor fetal growth in twin pregnancy are the same as those used for However, there is a reduction in fetal growth in twin compared with singleton pregnancy, particularly in the This is particularly in MCDA This that specific twin growth should be used for and growth in twin However, the use of specific twin growth is due to the that the growth in the trimester in most twin pregnancies might be by some of placental (EVIDENCE LEVEL: 2++). discordance between twins is significantly associated with the risk of perinatal The for the risk of perinatal loss in twins with an discordance ≥ 25% was found to be to the National for Health and discordance should be calculated and documented at every scan from 20 weeks If this discordance 25% or a referral should be made to a fetal medicine for assessment, increased fetal including fetal Doppler, and of delivery when (EVIDENCE LEVEL: 2++). The of sFGR on the of velocity in the umbilical artery (Figure In the umbilical artery Doppler waveform has positive In there is or reversed In there is a of The survival rate in sFGR is greater than 90% mortality rates of up to sFGR is associated with a high risk of IUD of the twin preterm delivery with associated risk of if the twin of either twin in up to and risk of in up to of cases prior to sFGR is associated with a risk of death of the fetus, which is in cases in which ultrasound features have been There is also a high to associated rate of in the larger (EVIDENCE LEVEL: 2++). In dichorionic twin pregnancy complicated by the of delivery should be determined based on a assessment and according to the of the by and neonatal As these twins have separate the pregnancy can be as in singleton pregnancy, for of umbilical and DV Doppler, and of pregnancies should be in with the relevant There is limited evidence to the management of monochorionic twins by Options include: management by early or cord occlusion of the twin order to the (EVIDENCE LEVEL: In monochorionic twin pregnancy complicated by fetal growth should be assessed at every 2 weeks, and fetal Doppler artery and at If the umbilical artery Doppler is assessment of the DV blood should be The in these pregnancies is to the pregnancy at is while at the same time single IUD with its associated consequences for the In dichorionic twin pregnancy complicated by follow-up be less as delivery is not recommended

Primary bone tumours are rare, accounting for < 0.2% of malignant neoplasms registered in the EUROCARE (European Cancer Registry based study on survival and care of cancer patients) database [1]. Different bone tumour subtypes have distinct patterns of incidence, and each has no more than 0.3 incident cases per 100 000 per year. Osteosarcoma (OS) and Ewing sarcoma (ES) have a relatively high incidence in the second decade of life, whereas chondrosarcoma (CS) is more common in older age [2–4].

These updated guidelines from the British Association for Psychopharmacology replace the original version published in 2011. They address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting was held in 2017, involving experts in schizophrenia and its treatment. They were asked to review key areas and consider the strength of the evidence on the risk-benefit balance of pharmacological interventions and the clinical implications, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. The guidelines cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. It is hoped that the practice recommendations presented will support clinical decision making for practitioners, serve as a source of information for patients and carers, and inform quality improvement.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm's potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause.

OBJECTIVE: To evaluate the association between umbilical cord pH at birth and long term outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline (1966-August 2008), Embase (1980-August 2008), the Cochrane Library (2008 issue 8), and Medion, without language restrictions; reference lists of selected articles; and contact with authors. STUDY SELECTION: Studies in which cord pH at birth was compared with any neonatal or long term outcome. Cohort and case-control designs were included. RESULTS: 51 articles totalling 481 753 infants met the selection criteria. Studies varied in design, quality, outcome definition, and results. Meta-analysis carried out within predefined groups showed that low arterial cord pH was significantly associated with neonatal mortality (odds ratio 16.9, 95% confidence interval 9.7 to 29.5, I(2)=0%), hypoxic ischaemic encephalopathy (13.8, 6.6 to 28.9, I(2)=0%), intraventricular haemorrhage or periventricular leucomalacia (2.9, 2.1 to 4.1, I(2)=0%), and cerebral palsy (2.3, 1.3 to 4.2, I(2)=0%). CONCLUSIONS: Low arterial cord pH showed strong, consistent, and temporal associations with clinically important neonatal outcomes that are biologically plausible. These data can be used to inform clinical management and justify the use of arterial cord pH as an important outcome measure alongside neonatal morbidity and mortality in obstetric trials.

Advances in technology have allowed for the sensitive, specific, and simultaneous quantitative profiling of steroid precursors, bioactive steroids and inactive metabolites, facilitating comprehensive characterization of the serum and urine steroid metabolomes. The quantification of steroid panels is therefore gaining favor over quantification of single marker metabolites in the clinical and research laboratories. However, although the biochemical pathways for the biosynthesis and metabolism of steroid hormones are now well defined, a gulf still exists between this knowledge and its application to the measured steroid profiles. In this review, we present an overview of steroid hormone biosynthesis and metabolism by the liver and peripheral tissues, specifically highlighting the pathways linking and differentiating the serum and urine steroid metabolomes. A brief overview of the methodology used in steroid profiling is also provided.

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations - POLEmut, MMR deficiency - MMRd, p53 abnormal - p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as 'multiple-classifier' ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd-p53abn), 31 with POLEmut (POLEmut-p53abn), and 12 with all three aberrations (MMRd-POLEmut-p53abn). MMRd-p53abn ECs and POLEmut-p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd-p53abn ECs and 7/15 (46.7%) POLEmut-p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd-p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut-p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd-p53abn and POLEmut-p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd-p53abn EC as MMRd and POLEmut-p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.

Mammalian spermatozoa motility is a subject of growing importance because of rising human infertility and the possibility of improving animal breeding. We highlight opportunities for fluid and continuum dynamics to provide novel insights concerning the mechanics of these specialized cells, especially during their remarkable journey to the egg. The biological structure of the motile sperm appendage, the flagellum, is described and placed in the context of the mechanics underlying the migration of mammalian sperm through the numerous environments of the female reproductive tract. This process demands certain specific changes to flagellar movement and motility for which further mechanical insight would be valuable, although this requires improved modeling capabilities, particularly to increase our understanding of sperm progression in vivo. We summarize current theoretical studies, highlighting the synergistic combination of imaging and theory in exploring sperm motility, and discuss the challenges for future observational and theoretical studies in understanding the underlying mechanics.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.

Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96 y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0 y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.

Importance: Previous in vitro and postmortem research suggests that inflammation may lead to structural brain changes via activation of microglia and/or astrocytic dysfunction in a range of neuropsychiatric disorders. Objective: To investigate the relationship between inflammation and changes in brain structures in vivo and to explore a transcriptome-driven functional basis with relevance to mental illness. Design, Setting, and Participants: This study used multistage linked analyses, including mendelian randomization (MR), gene expression correlation, and connectivity analyses. A total of 20 688 participants in the UK Biobank, which includes clinical, genomic, and neuroimaging data, and 6 postmortem brains from neurotypical individuals in the Allen Human Brain Atlas (AHBA), including RNA microarray data. Data were extracted in February 2021 and analyzed between March and October 2021. Exposures: Genetic variants regulating levels and activity of circulating interleukin 1 (IL-1), IL-2, IL-6, C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were used as exposures in MR analyses. Main Outcomes and Measures: Brain imaging measures, including gray matter volume (GMV) and cortical thickness (CT), were used as outcomes. Associations were considered significant at a multiple testing-corrected threshold of P < 1.1 × 10-4. Differential gene expression in AHBA data was modeled in brain regions mapped to areas significant in MR analyses; genes were tested for biological and disease overrepresentation in annotation databases and for connectivity in protein-protein interaction networks. Results: Of 20 688 participants in the UK Biobank sample, 10 828 (52.3%) were female, and the mean (SD) age was 55.5 (7.5) years. In the UK Biobank sample, genetically predicted levels of IL-6 were associated with GMV in the middle temporal cortex (z score, 5.76; P = 8.39 × 10-9), inferior temporal (z score, 3.38; P = 7.20 × 10-5), fusiform (z score, 4.70; P = 2.60 × 10-7), and frontal (z score, -3.59; P = 3.30 × 10-5) cortex together with CT in the superior frontal region (z score, -5.11; P = 3.22 × 10-7). No significant associations were found for IL-1, IL-2, CRP, or BDNF after correction for multiple comparison. In the AHBA sample, 5 of 6 participants (83%) were male, and the mean (SD) age was 42.5 (13.4) years. Brain-wide coexpression analysis showed a highly interconnected network of genes preferentially expressed in the middle temporal gyrus (MTG), which further formed a highly connected protein-protein interaction network with IL-6 (enrichment test of expected vs observed network given the prevalence and degree of interactions in the STRING database: 43 nodes/30 edges observed vs 8 edges expected; mean node degree, 1.4; genome-wide significance, P = 4.54 × 10-9). MTG differentially expressed genes that were functionally enriched for biological processes in schizophrenia, autism spectrum disorder, and epilepsy. Conclusions and Relevance: In this study, genetically determined IL-6 was associated with brain structure and potentially affects areas implicated in developmental neuropsychiatric disorders, including schizophrenia and autism.

IMPORTANCE: Excessive gestational weight gain (GWG) is common and associated with adverse pregnancy outcomes. Antenatal lifestyle interventions limit GWG; yet benefits of different intervention types and specific maternal and neonatal outcomes are unclear. OBJECTIVE: To evaluate the association of different types of diet and physical activity-based antenatal lifestyle interventions with GWG and maternal and neonatal outcomes. DATA SOURCES: A 2-stage systematic literature search of MEDLINE, Embase, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, and Health Technology Assessment Database was conducted from February 1, 2017, to May 31, 2020. Search results from the present study were integrated with those from a previous systematic review from 1990 to February 2017. STUDY SELECTION: Randomized trials reporting GWG and maternal and neonatal outcomes. DATA EXTRACTION AND SYNTHESIS: Data were extracted for random-effects meta-analyses to calculate the summary effect estimates and 95% CIs. MAIN OUTCOMES AND MEASURES: Outcomes were clinically prioritized, with mean GWG as the primary outcome. Secondary outcomes included gestational diabetes, hypertensive disorders of pregnancy, cesarean section, preterm delivery, large or small for gestational age neonates, neonatal intensive care unit admission, or fetal death. RESULTS: A total of 117 randomized clinical trials of antenatal lifestyle interventions (involving 34 546 women) were included. Overall lifestyle intervention was associated with reduced GWG (-1.15 kg; 95% CI, -1.40 to -0.91), risk of gestational diabetes (odds ratio [OR], 0.79; 95% CI, 0.70-0.89), and total adverse maternal outcomes (OR, 0.89; 95% CI, 0.84-0.94) vs routine care. Compared with routine care, diet was associated with less GWG (-2.63 kg; 95% CI, -3.87 to -1.40) than physical activity (-1.04 kg; 95% CI, -1.33 to -0.74) or mixed interventions (eg, unstructured lifestyle support, written information with weight monitoring, or behavioral support alone) (-0.74 kg; 95% CI, -1.06 to -0.43). Diet was associated with reduced risk of gestational diabetes (OR, 0.61; 95% CI, 0.45-0.82), preterm delivery (OR, 0.43; 95% CI, 0.22-0.84), large for gestational age neonate (OR, 0.19; 95% CI, 0.08-0.47), neonatal intensive care admission (OR, 0.68; 95% CI, 0.48-0.95), and total adverse maternal (OR, 0.75; 95% CI, 0.61-0.92) and neonatal outcomes (OR, 0.44; 95% CI, 0.26-0.72). Physical activity was associated with reduced GWG and reduced risk of gestational diabetes (OR, 0.60; 95% CI, 0.47-0.75), hypertensive disorders (OR, 0.66; 95% CI, 0.48-0.90), cesarean section (OR, 0.85; 95% CI, 0.75-0.95), and total adverse maternal outcomes (OR, 0.78; 95% CI, 0.71-0.86). Diet with physical activity was associated with reduced GWG (-1.35 kg; 95% CI, -1.95 to -0.75) and reduced risk of gestational diabetes (OR, 0.72; 95% CI, 0.54-0.96) and total adverse maternal outcomes (OR, 0.81; 95% CI, 0.69-0.95). Mixed interventions were associated with reduced GWG only. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found level 1 evidence that antenatal structured diet and physical activity-based lifestyle interventions were associated with reduced GWG and lower risk of adverse maternal and neonatal outcomes. The findings support the implementation of such interventions in routine antenatal care and policy around the world.