Search

The development of vaccines has been one of the major interventions in global health. Since they were first developed over two centuries ago, vaccines have played a prominent role in reducing morbidity and mortality from infectious diseases, including in pregnant women. The development of the coronavirus disease 2019 (COVID-19) vaccines has brought with it the possibility of reducing the high morbidity and mortality caused by this virus. This article focuses on the use of vaccines in pregnancy and discusses the benefits of maternal immunisation, recommended vaccines in pregnancy, the factors affecting uptake of vaccines, and COVID-19 vaccination in pregnancy.

Background Socioeconomic deprivation is associated with health inequality. Previous studies have described associations between primary care prescribing rates and deprivation for individual drugs or drug classes. We explore the correlation between socioeconomic deprivation and the rate of prescribing of individual pharmaceutical drugs, and drug classes, in primary care in England, to identify prescribing inequalities that would require further investigation. Methods In this cross-sectional study, national primary care prescribing data, by primary care practice, were retrieved for the calendar year 2019 in England. Socioeconomic deprivation was quantified using the Index of Multiple Deprivation (IMD) score. Correlations were calculated using Spearman's rank correlation coefficient (ρ), adjusting for practice list size and demographics, with a Bonferroni-corrected p value threshold of 5×10−5. Results We included 1.05 billion prescription items dispensed from 6896 England practices. 142/206 (69%) drug classes and 505/774 (65%) drugs were significantly correlated with IMD score (p0.4). Only one was moderately negatively correlated with IMD score (ρ Conclusion We identify novel associations of prescribing with deprivation. Further work is required to identify the underlying reasons for these associations so that appropriate interventions can be formulated to address drivers of inequality.

We read with interest the excellent editorial ‘Postnatal care: new NICE guideline for the “Cinderella service”’.1 GPs’ involvement in the care of women in the perinatal period has never been so important as currently, during the COVID-19 pandemic. Pregnant women affected by COVID-19 are at higher risk of developing serious complications,2 especially women of Black, Asian, and minority ethnic backgrounds, and those with underlying medical conditions.3 MBRRACE-UK reported that the maternal mortality rate due to COVID-19 …

BackgroundIn March 2018, NHS England published guidance for clinical commissioning groups (CCGs) to encourage implementation of policy to reduce primary care prescriptions of over-the-counter medications, including simple analgesia.AimTo investigate the impact of guidance publication on prescribing rates of simple analgesia (oral paracetamol, oral ibuprofen, and topical non-steroidal anti-inflammatory drugs) in primary care; CCG guidance implementation intentions; and whether the guidance has created health inequality based on socioeconomic status.Design and settingInterrupted time series analysis of primary care prescribing data in England.MethodPractice-level prescribing data from January 2015 to March 2019 were obtained from NHS Digital. Interrupted time series analyses were used to assess the association of guidance publication with prescribing rates. The association between practice-level prescribing rates and Index of Multiple Deprivation scores before and after publication was quantified using multivariable Poisson regression. Freedom of information requests were submitted to all CCGs.ResultsThere was a statistically significant 4.4% reduction in prescribing of simple analgesia following guidance publication (adjusted incidence rate ratio 0.96, 95% CI = 0.92 to 0.99, P = 0.027), adjusting for underlying time trend and seasonality. There was considerable diversity across CCGs in whether or how they chose to implement the guidance. Practice-level prescribing rates were greater in more deprived areas.ConclusionGuidance publication was associated with a small reduction in the prescribing rates of simple analgesia across England, without evidence of creating additional health inequality. Careful implementation by CCGs would be required to optimise cost saving to the NHS.

Objectives\ud Vitamin D is commonly prescribed in primary care for the prevention and treatment of deficiency and for maintenance after treatment (although supplementation for maintenance and prevention can be bought over-the-counter). There is wide variation in the costs to the NHS in England of oral preparations of vitamin D, even for a single-specific dose and route.1 It is possible that the availability of multiple options for the same intended medicine, the costs of which are unlikely to be known by the prescriber, could result in an inadvertent excess spend. We aimed to estimate the annual cost-saving if only the cheapest vitamin D preparations were prescribed.\ud \ud Design\ud Primary care prescribing data for 2018 were downloaded from NHS Digital (https://digital.nhs.uk).2 Monthly datasets include the number of items, quantity and cost of each drug prescribed and dispensed. Private prescriptions are not recorded. All prescription items relating to the vitamin D preparations colecalciferol and ergocalciferol, regardless of dose, route or manufacturer, were extracted. Data for each specific preparation were aggregated across all practices and all months to give the annual number of items and their cost across England. All liquid and injectable preparations were assumed to be appropriately prescribed and therefore excluded from the analysis. Combined preparations – such as calcium/vitamin D, calcium/alendronate and multivitamins – were also excluded. For each defined dose range of vitamin D, the lowest cost preparation was identified, and the potential cost-savings if only these preparations were prescribed was calculated.\ud \ud Setting\ud Primary care in England.\ud \ud Participants\ud All patients registered with a general practitioner in England in 2018.\ud \ud Main Outcome Measure\ud The difference between actual and potential spend on vitamin D prescriptions, if only the lowest priced preparation were available.\ud \ud Results\ud In 2018, over 4 million vitamin D items were prescribed in primary care, at a cost of over £21 million. If only the cheapest options were prescribed for non-liquid preparations across all dose ranges, and assuming all prescriptions were appropriate, it would have resulted in an approximate £15 million (>70%) cost-saving to the NHS. Maintenance doses of vitamin D (designated as 800 to 2000 international units per day as per NICE guidelines3) accounted for more than half of the spend (∼£12 million). It was noted that all the cheapest options available are suitable for vegetarians.\ud \ud Conclusion\ud The prescribing of more expensive vitamin D preparations in primary care may have significant financial consequences, although our results relate to a single year of prescribing within NHS primary care. Since choice of preparation may intentionally be based on factors other than cost (e.g. dietary requirements, bioavailability, what was initially prescribed by a hospital), work is needed nationally to rationalise available prescribing options. If national guidance were produced, the difficulties of implementation within individual Clinical Commissioning Groups might limit economic benefit. National efficient procurement strategies are an alternative approach, but require careful consideration of legislative frameworks (such as the Public Contract Regulations 20154) with safeguards to prevent horizontal cooperation between suppliers.

The UK Secretary of State for Health and Social Care’s announcement that all consultations should henceforth be remote by default1 recurred like a discordant leitmotif in the recent Royal College of General Practitioners’ virtual conference, A Fresh Approach to General Practice .2 Speakers and audience members alike acknowledged that remote consulting has some real strengths, but recoiled from the idea of remote as the norm from which the traditional face-to-face consultation would deviate. Most published research on remote consultations is either marginal to general practice (for example, trials of video appointments for hospital outpatients with chronic stable conditions)3 or lacking in granularity (for example, predominantly quantitative studies of telephone-first ‘demand management’).4 One detailed study of remote general practice consultations concluded that ‘efficiency’ gains, such as shorter consultations, may occur at the expense of other aspects of consultation quality, including information richness, shared decision making, and safety netting,5 though another interpretation of this non-randomised study is that more patients with complex problems book face-to-face. A randomised trial of telephone triage in general practice found an overall reduction in efficiency because of double-handling of problems.6 Studies of e-consultations7 and workload modelling8 came to similar conclusions. Clinicians …

Postnatal care has always been the ‘Cinderella’ of maternity services, both in primary and secondary care.1,2 One illustration of this is that until the most recent GP contract there was no requirement for a GP practice to provide a maternal postnatal check. Prior to the COVID-19 pandemic the provision of services to postnatal women showed wide variation across the country.1 With a paucity of more recent research to establish what best postnatal care looks like, it is difficult to provide evidence-based practice. In 2014 the annual Chief Medical Officer for England’s report came to the conclusion that postnatal care in England was ‘not fit for purpose’ .2 Since then community postnatal services, such as health visitor provision, have seen funding cut and services have become increasingly fragmented.3 The Royal College of General Practitioners (RCGP) issued a statement in 2017 recognising that GP training is not adequate when it comes to the provision of maternity care in the community, while also acknowledging that GPs are best placed to coordinate joined-up care across services.4 Successive confidential inquires into maternal deaths have also repeatedly highlighted the need for joined-up care to prevent women ‘falling through the cracks’ .5 COVID-19 has disproportionately affected people from black, Asian, and ethnic minority (BAME) backgrounds, as well as those in the most deprived …

The GP home visit has long been regarded as an integral element of NHS general practice that is needed to support both proactive and reactive care to patients in the community.1,2 There are increasing numbers of people living with multimorbidity and frailty, many of whom have complex healthcare needs and limited levels of social support. Now with the new challenges around providing care at home due to the COVID-19 pandemic, it could be argued that home visits or virtual consultations with patients in their homes are set to become a more essential element of general practice, including in the provision of acute care out of hours. Consulting with patients in their homes provides unique opportunities to develop insights into how illness affects their lives. However, with workloads in NHS primary care rising, and increasing pressures on the GP workforce, the place of home visits in core general practice provision is facing increasing challenge. The requirements of the current GP General Medical Services (GMS) contract in relation to home visiting are broad.3 The contract is not prescriptive about who should visit or where the visit should take place, and states that the decision to visit is dependent on the opinion and agreement of the GP contractor. In November 2019, the Local Medical Committee (LMC) conference debated the current contractual requirements and a motion was narrowly passed to instruct the General Practitioners Committee (GPC) (the negotiating arm of the British Medical …

Jakes and colleagues’ paper on the maternal six week postnatal check is timely but anachronistic.1 Although not stated, this is aimed at general practitioners. A letter to the Guardian from four royal colleges2 and the Royal College of Obstetricians and Gynaecologists’ publication Better for Women also emphasise the need to improve care at this check.3 This is against a background of lack of …

BackgroundPolycystic ovary syndrome (PCOS) is a common lifelong metabolic condition with serious associated comorbidities. Evidence points to a delay in diagnosis and inconsistency in the information provided to women with PCOS.AimTo capture women’s experiences of how PCOS is diagnosed and managed in UK general practice.Design and settingThis was a mixed-methods study with an online questionnaire survey and semi-structured telephone interviews with a subset of responders.MethodAn online survey to elicit women’s experiences of general practice PCOS care was promoted by charities and BBC Radio Leicester. The survey was accessible online between January 2018 and November 2018. A subset of responders undertook a semi-structured telephone interview to provide more in-depth data.ResultsA total of 323 women completed the survey (average age 35.4 years) and semi-structured interviews were conducted with 11 women. There were five key themes identified through the survey responses. Participants described a variable lag time from presentation to PCOS diagnosis, with a median of 6–12 months. Many had experienced mental health problems associated with their PCOS symptoms, but had not discussed these with the GP. Many were unable to recall any discussion about associated comorbidities with the GP. Some differences were identified between the experiences of women from white British backgrounds and those from other ethnic backgrounds.ConclusionFrom the experiences of the women in this study, it appears that PCOS in general practice is not viewed as a long-term condition with an increased risk of comorbidities including mental health problems. Further research should explore GPs’ awareness of comorbidities and the differences in PCOS care experienced by women from different ethnic backgrounds.

Objective Focus groups were conducted with individuals involved in prenatal diagnosis to determine their opinions relating to WES in fetuses with structural anomalies. Method Five representatives of patient groups/charities (PRGs) and eight clinical professionals (CPs) participated. Three focus groups occurred (the two groups separately and then combined). Framework analysis was performed to elicit themes. A thematic coding frame was identified based on emerging themes. Results Seven main themes (consent, analysis, interpretation/reinterpretation of results, prenatal issues, uncertainty, incidental findings, and information access) with sub-themes emerged. The main themes were raised by both groups, apart from ‘analysis’ which was raised by CPs only. Some subthemes were raised by PRGs and CPs (with different perspectives). Others were raised either by PRGs or CPs, showing differences in patient/clinician agendas. Conclusions Prenatal consent for WES is not a ‘perfect’ process but consent takers should be fully educated regarding the test. PRGs highlighted issues involving access to results feeling that women want to know all information. PRGs also felt that patients want re-interpretation of results over time whilst CPs felt that interpretation should be performed at the point of testing only.

Polycystic ovarian syndrome (PCOS) is a multisystem condition that can blight the course of a woman’s life. The condition is common and for many is associated with considerable distress. We argue the importance of diagnosis in what is currently an under-recognised condition. Diagnosis of PCOS requires two of the three Rotterdam criteria to be present.1 Introducing the criteria led to an increase in PCOS prevalence from 6% to 10% in screened women of childbearing age.2 However, this is unlikely to be a true reflection of the prevalence among women who choose to consult their GP. A recent retrospective cohort study of over 2 million women in the UK reported that the prevalence of women of reproductive age with PCOS was just 1.34%, rising to 2.27% if probable cases were included.3 The authors suggested that there is significant under-diagnosis occurring, with only about 50% of women with at least two of the three criteria having a recorded diagnosis of …

Objective To explore parental experiences of whole exome sequencing (WES) for prenatal diagnosis and ascertain what influenced their decision-making to undergo testing. Method Twelve women comprised a purposeful sample in a series of semistructured interviews. All had received a fetal anomaly diagnosis on ultrasound. A topic guide was used, and transcripts were thematically analyzed to elicit key themes. Results Five main themes (parental experiences of prenatal WES, need for information, consent/reasons for prenatal WES, sources of support for prenatal WES, and return of WES findings to families) emerged, some with multiple subthemes. Conclusions Parents desired as much information as possible and appreciated information being repeated and provided in various formats. Many struggled with clinical uncertainty relating to the cause and prognosis following a fetal anomaly diagnosis and found it difficult to balance the risks of invasive testing against their need for more definitive information. Parents trusted their clinicians and valued their support with decisions in pregnancy. Testing was sometimes pursued to reassure parents that their baby was "normal" rather than to confirm an underlying genetic problem. Parents were motivated to undergo WES for personal and altruistic reasons but disliked waiting times for results and were uncertain about what findings might be returned.

Prenatal diagnostic testing is a rapidly advancing field. An accurate diagnosis of structural anomalies and additional abnormalities in fetuses with structural anomalies is important to allow "triage" and designation of prognosis. This will allow parents to make an informed decision relating to the pregnancy. This review outlines the current tests used in prenatal diagnosis, focusing particularly on "new technologies" such as exome sequencing. We demonstrate the utility of exome sequencing above that of conventional karyotyping and Chromosomal Microarray (CMA) alone by outlining a recent proof of concept study investigating 30 parent-fetus trios where the fetus is known to have a structural anomaly. This may allow the identification of pathological gene anomalies and consequently improved prognostic profiling, as well as excluding anomalies and distinguishing between de novo and inherited mutations, in order to estimate the recurrence risk in future pregnancies. The potential ethical dilemmas surrounding exome sequencing are also considered, and the future of prenatal genetic diagnosis is discussed.

BackgroundPolycystic ovarian syndrome (PCOS) affects up to one in five women, with the diagnosis and management mostly occurring in general practice. The condition can affect many parts of a woman’s physical and mental health. Recent evidence shows that women often experience a delay in diagnosis and that there is a high rate of underdiagnosis.AimTo research patients’ perspectives as to how PCOS is managed in general practice, whether it is being viewed as a ‘multisystem’ condition rather than just one of fertility, and how the long-term effects of the syndrome are being addressed.MethodA questionnaire was designed to investigate women’s experience of how PCOS is being diagnosed, treated, and managed in general practice, including consideration of its longer-term potential consequences. Women were signposted to the questionnaire through websites/social media of four charities/patient support networks and BBC Radio Leicester.ResultsIn total 333 women completed the questionnaire. Only 12% of women recalled having been told by a GP about the risk of developing diabetes and none recalled being told about endometrial hyperplasia. Although 74% felt PCOS had impacted on their mental health only 39% had discussed this with their GP. In 116 cases (35%) women did not recall their weight being addressed despite having a body mass index of ≥25.ConclusionPCOS appears not to be viewed as a chronic metabolic condition, with women not able to recall being told of their higher risks for comorbid conditions. Concurrent mental health problems are often not being addressed.

Single-twin demise can pose substantial risks for the surviving co-twin, including increased risk of fetal loss, preterm delivery, neurovascular injury, and end-organ damage. In this chapter, we summarise recently published research on the causes of single twin demise, the pathophysiology of injury to the surviving co-twin, and the evidence for current management strategies. The gestation at which single intrauterine fetal demise occurs, and the chorionicity of the multiple pregnancies, are the two most important factors when considering the risks to the surviving twin. Management should include fortnightly ultrasound scans for growth, umbilical artery Doppler studies, and liquor volume. In monochorionic twins, more complex Doppler assessment with middle cerebral artery Doppler velocimetry and a magnetic resonance imaging of the survivor's brain at least 3 weeks after single intrauterine fetal demise occurs should be carried out to look for evidence of neurological morbidity. With no other obstetric complications, dichorionic pregnancies can be delivered at term. Monochorionic pregnancies are more difficult to manage, and are often delivered between 34 and 36 weeks.

The genetic etiology of non-aneuploid fetal structural abnormalities is typically investigated by karyotyping and array-based detection of microscopically detectable rearrangements, and submicroscopic copy-number variants (CNVs), which collectively yield a pathogenic finding in up to 10% of cases. We propose that exome sequencing may substantially increase the identification of underlying etiologies. We performed exome sequencing on a cohort of 30 non-aneuploid fetuses and neonates (along with their parents) with diverse structural abnormalities first identified by prenatal ultrasound. We identified candidate pathogenic variants with a range of inheritance models, and evaluated these in the context of detailed phenotypic information. We identified 35 de novo single-nucleotide variants (SNVs), small indels, deletions or duplications, of which three (accounting for 10% of the cohort) are highly likely to be causative. These are de novo missense variants in FGFR3 and COL2A1, and a de novo 16.8 kb deletion that includes most of OFD1. In five further cases (17%) we identified de novo or inherited recessive or X-linked variants in plausible candidate genes, which require additional validation to determine pathogenicity. Our diagnostic yield of 10% is comparable to, and supplementary to, the diagnostic yield of existing microarray testing for large chromosomal rearrangements and targeted CNV detection. The de novo nature of these events could enable couples to be counseled as to their low recurrence risk. This study outlines the way for a substantial improvement in the diagnostic yield of prenatal genetic abnormalities through the application of next-generation sequencing.

Background Most maternal deaths are preventable with emergency obstetric care; therefore, ensuring access is essential. There is little focused information on emergency transport of pregnant women. Objectives The literature on emergency transport of pregnant women in low- and middle-income countries (LMICs) was systematically reviewed and synthesized to explore current practices, barriers, and facilitators for transport utilization. Search strategy MEDLINE, EMBASE, BNI, Cochrane Library, CINAHL, African Index Medicus, ASSIA, QUALIDATA, RHL, and Science Citation Index (inception to April 2012) were searched without language restriction. Selection criteria: Studies using qualitative methodology and reporting on emergency transportation in LMICs were included. Data collection and analysis Thematic framework and synthesis through examination and translation of common elements were used to analyze and synthesize the data. Main results Twenty-nine articles were included. Eight major themes were identified: time for transport; transport options; geography; local support; autonomy; culture; finance; and ergonomics. Key issues were transport availability; transport speed; terrain; meteorology; support; dependence for decision making; cultural issues; cost; and lack of safe, comfortable positioning during transport. Conclusion Themes should be appreciated within local contexts to illuminate barriers and facilitators. Potential solutions include motorcycle ambulance programs, collaboration with taxi services, community education, subsidies, and vehicle maintenance.

Objectives Chromosomal microarray analysis (CMA) is utilized in prenatal diagnosis to detect chromosomal abnormalities not visible by conventional karyotyping. A prospective cohort of women undergoing fetal CMA and karyotyping following abnormal prenatal ultrasound findings is presented in the context of a systematic review and meta-analysis of the literature describing detection rates by CMA and karyotyping. Methods We performed a prospective cohort study of 243 women undergoing CMA alongside karyotyping when a structural abnormality was detected on prenatal ultrasound. A systematic review of the literature was also performed. MEDLINE (1970–Dec 2012), EMBASE (1980–Dec 2012) and CINAHL (1982–June 2012) databases were searched electronically. Selected studies included > 10 cases and prenatal CMA in addition to karyotyping. The search yielded 560 citations. Full papers were retrieved for 86, and 25 primary studies were included in the systematic review. Results Our cohort study found an excess detection rate of abnormalities by CMA of 4.1% over conventional karyotyping when the clinical indication for testing was an abnormal fetal ultrasound finding; this was lower than the detection rate of 10% (95% CI, 8–13%) by meta-analysis. The rate of detection for variants of unknown significance (VOUS) was 2.1% (95% CI, 1.3–3.3%) when the indication for CMA was an abnormal scan finding. The VOUS detection rate was lower (1.4%; 95% CI, 0.5–3.7%) when any indication for prenatal CMA was meta-analyzed. Conclusion We present evidence for a higher detection rate by CMA than by karyotyping not just in the case of abnormal ultrasound findings but also in cases of other indications for invasive testing. It is likely that CMA will replace karyotyping in high-risk pregnancies. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Key content The results of prenatal fetal chromosomal analysis may inform long term prognosis. Recent advances in chromosome microarray (CMA) are enabling genome-wide evaluation of submicroscopic chromosomal changes. Such technological advances promise increased sensitivity and specificity. They also potentially pose challenges of interpretation and clinical management. Learning objectives To systematically review the current literature and explain the benefit and pitfalls of CMAs and their relevance to the practising obstetrician in the NHS. Comment on the future of CMA and its cost effectiveness. Ethical issues Difficulties of informed consent with genome-wide prenatal testing. Difficulties surround results of unknown significance.

What you need to know A 30 year old, 35 week pregnant, nulliparous woman visits her general practitioner because of itching but no rash. Fundal height measurements and fetal movements are normal. The GP arranges an urgent antenatal clinic review, where liver function tests (LFTs), including bile acids, are reported as normal. At a midwife appointment two weeks later, she still has intense itching. Repeat tests show raised total bile acids (100 µmol/L; reference range 0-14) and aspartate aminotransferase (150 U/L; 5-35). Intrahepatic cholestasis of pregnancy is diagnosed and she is offered induction of labour that day. Intrahepatic cholestasis of pregnancy, also called “obstetric cholestasis,” is a multifactorial condition of pregnancy characterised by pruritus in the absence of a skin …

G-band chromosomal karyotyping of fetal cells obtained by invasive prenatal testing has been used since the 1960s to identify structural chromosomal anomalies. Prenatal testing is usually performed in response to parental request, increased risk of fetal chromosomal abnormality associated with advanced maternal age, a high-risk screening test and/or the presence of a congenital malformation identified by ultrasonography. The results of karyotyping may inform the long-term prognosis (e.g. aneuploidy being associated with a poor outcome or microscopic chromosomal anomalies predicting global neurodevelopmental morbidity). Relatively recent advances in microarray technology are now enabling high-resolution genome-wide evaluation for DNA copy number abnormalities (e.g. deletions or duplications). While such technological advances promise increased sensitivity and specificity they can also pose difficult challenges of interpretation and clinical management. This review aims to give interested clinicians without an extensive prior knowledge of microarray technology, an overview of its use in prenatal diagnosis, the literature to date, advantages, potential pitfalls and experience from our own tertiary center.

Genetics (the functioning and composition of a single gene) and genomics (all genes and their inter-relationships identifying their combined influence on the growth and development of the organism)1 are developing at a rapid rate. The impact this will have on general practice is uncertain. However, the recent publication of Dame Sally Davies’s 2016 Chief Medical Officer’s (CMO) report Generation Genome outlines how genomic medicine can be utilised and developed to become available to more patients within the NHS and the delivery of the genomic dream.2 GPs may progressively be expected to consider genomics in their diagnosis and treatment decision making, and patients are likely to increasingly seek from GPs explanation for tests they have had in secondary care or from direct-to-consumer testing that they obtained privately. A recent editorial in the BJGP looked at the clinical areas where GPs are most likely to come across genomics in practice and asked what is needed from general practice in order for it to become ‘genomics ready’.3 This article looks at some of the barriers and inequalities to accessing genomic medicine, and considers how genomics might be incorporated into general practice. Dame Sally Davies’s report describes the ‘tendency in some parts of the NHS to think of genomics as a thing far in the future or even worse, a potential burden rather than a boon’ . While acknowledging where this view comes from, she highlights that in the long term it will affect equality and access to genomic care.2 Though a third of all referrals to genetic services are currently made by GPs, there is wide variation in the extent to which this occurs, with some GPs never referring.4 Such variation reflects differences in access, knowledge, and confidence within primary care. From the …

Objective Array comparative genomic hybridization (CGH) is transforming clinical cytogenetics with its ability to interrogate the human genome at increasingly high resolution. The aim of this study was to determine whether array CGH testing in the prenatal population provides diagnostic information over conventional karyotyping. Methods MEDLINE (1970 to December 2009), EMBASE (1980 to December 2009) and CINAHL (1982 to December 2009) databases were searched electronically. Studies were selected if array CGH was used on prenatal samples or if array CGH was used on postnatal samples following termination of pregnancy for structural abnormalities that were detected on an ultrasound scan. Of the 135 potential articles, 10 were included in this systematic review and eight were included in the meta-analysis. The pooled rate of extra information detected by array CGH when the prenatal karyotype was normal was meta-analyzed using a random-effects model. The pooled rate of receiving an array CGH result of unknown significance was also meta-analyzed. Results Array CGH detected 3.6% (95% CI, 1.5–8.5) additional genomic imbalances when conventional karyo-typing was ‘normal’, regardless of referral indication. This increased to 5.2% (95% CI, 1.9–13.9) more than karyotyping when the referral indication was a structural malformation on ultrasound. Conclusions There appears to be an increased detection rate of chromosomal imbalances, compared with conventional karyotyping, when array CGH techniques are employed in the prenatal population. However, some are copy number imbalances that are not clinically significant. This carries implications for prenatal counseling and maternal anxiety. Copyright © 2010 ISUOG. Published by John Wiley & Sons, Ltd.

Placental chorioangioma is a relatively rare condition that often results in serious prenatal complications and adverse pregnancy outcome. We report a case of a large chorioangioma that was prenatally diagnosed at 23 weeks with polyhydramnios and fetal anemia. With prenatal monitoring, transplacental therapy with a COX-2 inhibitor and intrauterine transfusion, the pregnancy resulted in the live birth at 30 weeks. Due to the paucity of evidence relating to the management protocols in cases of placental chorioangiomas, we have conducted a systematic review of the literature.All reported cases in the English language were captured using the electronic databases. Bibliographies of relevant articles were manually searched.Sixty-four articles were included reporting 112 cases of placental chorioangioma. In 79, there was no prenatal treatment and in 33 there was in-utero treatment. A systematic comparison of antenatal complications and pregnancy outcomes was performed. No strong conclusion could be made due to the low number and quality of the reported cases.Placenta chorioangioma represents a challenge with its potentially serious complications adversely affecting pregnancy outcome. An international registry of pregnancies with this rare complication and documentation of pregnancy outcomes will improve the evidence base for prospective management.

Introduction: To determine the cost-effectiveness of prenatal chromosomal microarray (CMA) when performed for structural anomalies on fetal ultrasound scan over conventional techniques. Method: A decision tree was populated using data from a prospective cohort of women undergoing testing when a fetal ultrasound scan showed a structural abnormality. Nine strategies of testing were modeled including combinations of the tests: QFPCR, G-band karyotyping, CMA and FISH for DiGeorge (22q) microdeletion. Results: When CMA costs GBP 405 and using a 1-Mb BAC array it would cost GBP 24,600 for every additional case detected by CMA over a combination of QFPCR, followed by G-band karyotype, followed lastly by FISH (for DiGeorge syndrome). If CMA is performed instead of conventional karyotyping alone it costs GBP 33,000 for every additional case detected. However, if the cost of CMA is reduced to GBP 360 than when CMA is performed instead of conventional karyotyping alone it would cost GBP 9,768 for every additional case detected. Discussion: The use of a prenatal BAC CMA is not currently cost-effective when compared to other testing strategies. However, as CMA costs decrease and resolution (and detection rates) increase it is likely to become the cost-effective option of the future.

Chromosomal Microarray Analysis (CMA) has a higher detection rate of pathogenic chromosome abnormalities over conventional (G-band) karyotyping. The optimum resolution of CMA in the prenatal setting remains debatable. Our objective was to determine if an increased detection rate was obtained by performing differing resolution of CMA on the same fetal samples and whether this resulted in an increase in variants of uncertain clinical significance (VOUS).Sixty-two fetal cases initially underwent a 1 Mb targeted BAC microarray within a clinical diagnostic setting in addition to conventional karyotyping. At the conclusion of pregnancy, a higher resolution 60 K oligonucleotide microarray was performed.The 1 Mb BAC analysis demonstrated a detection rate of pathogenic copy number variations (CNVs) in 4.1% (95% CI 2.1-7.6) of cases and a variation of unknown significance (VOUS) rate of 0.4% (95% CI 0.07-2.2) over conventional G-band karyotyping. The 60 K array had an additional pathogenic detection rate of 4.8% (95% CI 1.6-13.3) over the BAC array but also detected an additional 8% (95% CI 1.3-14.8) VOUS.As the CMA platform resolution increases detection rates increase but are associated with an increase in VOUS rates. Our findings support the need for further large scale studies to inform the national consensus on the resolution required and on reporting of VOUS in the antenatal setting.

Background Approximately 50% of spontaneous miscarriages are associated with chromosome abnormalities. Identification of these karyotypic abnormalities helps to estimate recurrence risks in future pregnancies. Chromosomal microarray analysis (CMA) is transforming clinical cytogenetic practice with its ability to examine the human genome at increasingly high resolution. Objectives The aim of this study was to determine whether CMA testing on the products of conception following miscarriage provides better diagnostic information compared with conventional karyotyping. Search strategy MEDLINE (from 1996 to December 2012), EMBASE (from 1974 to December 2012), and CINAHL (from 1996 to December 2012) databases were searched electronically. Selection criteria Studies were selected if CMA was used on products of conception following miscarriage, alongside conventional karyotyping. Data collection and analysis Nine papers were included in the systematic review and meta-analysis. All statistical analyses were performed using stata 11.0 (Stata Corp., College Station, TX, USA). Main results There was agreement between CMA and karyotyping in 86.0% of cases (95% CI 77.0–96.0%). CMA detected 13% (95% CI 8.0–21.0) additional chromosome abnormalities over conventional full karyotyping. In addition, traditional, full karyotyping detected 3% (95% CI 1.0–10.0%) additional abnormalities over CMA. The incidence of a variant of unknown significance (VOUS) being detected was 2% (95% CI 1.0–10.0%). Author's conclusions Compared with karyotyping, there appears to be an increased detection rate of chromosomal abnormalities when CMA is used to analyse the products of conception; however, some of these abnormalities are VOUS, and this information should be provided when counselling women following miscarriage and when taking consent for the analysis of miscarriage products by CMA.

Sarah Hillman describes how changing specialties has helped her to look to the future with enthusiasm

The objective was to gain insight into the experiences of women and their partners diagnosed with a fetal abnormality on prenatal ultrasound examination and receiving genetic testing including microarray. Twenty-five semi-structured interviews were performed with women +/− their partners after receiving the results of prenatal genetic testing. Framework analysis was performed to elicit themes and subthemes. Five main themes were recognized; diagnosis, genetic testing, family and support, reflections of the treatment received and emotions. Our results showed that women recall being told about QFPCR for trisomy 13, 18, and 21 but often no further testing. Women expected the conventional karyotype and microarray result would be normal following a normal QFPCR result. There were frequent misconceptions by couples regarding aspects of counseling/testing. Communication of variants of unknown (clinical) significance (VOUS) presents a particularly difficult challenge. Good clear communication by health care professionals is paramount. When counseling women and their partners for fetal chromosomal testing it should be reinforced that although the most common, trisomy 13, 18, and 21 only account for some of the chromosomal changes resulting in abnormal scan findings. Couples should have literature to take home summarizing scan anomalies and reinforcing information about genetic testing. © 2013 Wiley Periodicals, Inc.

To perform a systematic review and meta-analysis of the effects on the surviving twin of single fetal death comparing monochorionic to dichorionic twins to report the rates of co-twin death, preterm delivery, and neurologic morbidity in the surviving fetus.MEDLINE (inception-December 2010), EMBASE (inception-December 2010), The Cochrane library (inception-December 2010), Web of Science (inception-December 2010), and British Nursing Index (inception-December 2010) were searched electronically.Selected studies had more than five cases of single fetal death with reports of co-twin death, neurologic morbidity, or both co-twin death and neurologic morbidity. They also must have defined the gestational age of single fetal death and chorionicity.The search yielded 1,386 citations. Full manuscripts were retrieved for 204 and 22 were included in the review and meta-analysis. Twenty manuscripts were used to calculate overall summary statistics for monochorionic and dichorionic twins showing rates of co-twin death after single fetal death (15% compared with 3%), rates of preterm delivery after single fetal death (68% compared with 54%), the rate of abnormal postnatal cranial imaging after single fetal death (34% compared with 16%), and the rate of neurodevelopmental impairment after single fetal death (26% compared with 2%). Odds ratios (ORs) were calculated from 16 manuscripts. There was no significant difference reported between preterm delivery of monochorionic or dichorionic twins (OR 1.1, 95% confidence interval [CI] 0.34-3.51, P=.9). After single fetal death, monochorionic twins had higher odds of an abnormal cranial imaging after delivery, this was not significant (OR 3.25, 95% CI 0.66-16.1, P=.12). After single fetal death, monochorionic twins were 4.81-times more likely to have neurodevelopmental morbidity (95% CI 1.39-16.6, P.05).Monochorionic twins are at significantly increased odds of co-twin demise and neurodevelopmental morbidity after single fetal death.

Multiple pregnancies, the majority of which are twins, are at substantially higher risk of fetal morbidity and mortality when compared with singleton pregnancies. Single fetal demise occurs in up to 6.2% of all twin pregnancies. It may cause considerable risk for the co-twin including increased risk of fetal loss, premature delivery, neurovascular injury and end-organ damage. In this review we seek to summarise the most contemporary literature on the aetiology of single twin demise, the pathophysiology of injury to the surviving twin and the evidence for current management strategies.

Background Fetoscopic laser coagulation (FLC) has been shown to improve survival and reduce neurological morbidity in twin to twin transfusion syndrome (TTTS). Varying techniques for ablation exist with “Solomonisation” being a selective laser coagulation of placental vessels (SLCPV) with the addition of a subsequent surface coagulation of the placenta between the ablated vessels. The hypothesis is that the Solomon technique reduces the recurrence of TTTS (TOPS) and twin anaemia-polycythaemia sequence (TAPS), both highly morbid complications. Methods Protocol according to PICOS criteria. Electronic searches of MEDLINE, Embase, Cinahl, Cochrane and grey literature. Inclusion criteria were a pregnancy undergoing FLC for TTTS, intervention sequential laser compared to Solomon technique. Primary outcomes were perinatal survival, incidence of recurrent TTTS and/or TAPS. Secondary outcomes included maternal and neonatal morbidity outcomes. Included studies could be randomised controlled trials (RCT) or observational. Quality assessment was performed using the appropriate assessment criteria (CASP, STROBE). Results are reported as odds ratios (OR) with 95% confidence intervals. Results There were 3 studies, one RCT and two observational, including 523 monochroionic twin pregnancies. Meta-analysis could not be performed for perinatal survival due to different outcome measures being used thus data from each of the studies will be presented. For recurrence of TTTS with Solomon technique there was a significant reduction, OR 0.30 (95% CI 0.11–0.81) p = 0.02. For TAPS there was also a significant reduction, OR 0.22 (95% CI 0.09–0.53) p = 0.001. Conclusion The Solomon technique significantly reduces the complications of FLC of TOPS and TAPS.

Background The genetic aetiology of non-aneuploid fetal structural abnormalities is typically investigated by karyotyping and array-based detection of microscopically detectable rearrangements, and submicroscopic copy number variants (CNVs), which collectively yield a pathogenic finding in up to 10% of cases. We propose that exome sequencing may substantially increase the identification of underlying aetiologies. Methods We performed exome sequencing on a cohort of 30 non-aneuploid fetuses and neonates (along with their parents) with diverse structural abnormalities first identified by prenatal ultrasound. We identified candidate pathogenic variants with a range of inheritance models, and evaluated these in the context of detailed phenotypic information. Findings We identified 35 de novo single nucleotide variants (SNVs), small indels, deletions or duplications, of which three (accounting for 10% of the cohort) are highly likely to be causative. These are de novo missense variants in FGFR3 and COL2A1, and a de novo 16·8 kb deletion that includes most of OFD1. In five further cases (17%) we identified de novo or inherited recessive or X-linked variants in plausible candidate genes, which require additional validation to determine pathogenicity. Interpretation Our diagnostic yield of 10% is comparable to, and supplementary to, the diagnostic yield of existing microarray testing for large chromosomal rearrangements and targeted CNV detection. The de novo nature of these events enables couples to be counselled as to their low recurrence risk. This study outlines the way for a substantial improvement in the diagnostic yield of prenatal genetic abnormalities through the application of next generation sequencing.

Chromosomal microarray (CMA) technology is increasingly used to detect chromosomal anomalies in the prenatal setting. Although its increased detection rates over karyotyping has been proven the cost-effectiveness is yet to be established. A decision tree was built and populated using two data sets; that of the literature from 21 journal articles and 13755 fetal samples where there was a range of indications for testing and data from 17 cohorts where the indication for testing was abnormalities on fetal ultrasound scan, 4276 fetal samples are included. Costs included were those incurred by the West Midlands Genetics laboratory. Staff costs were taken from Unit costs of health and social care 2011. When the base case cost of CMA is £405 and there is a range of indications for performing testing, CMA will cost an extra £6800 per case detected over karyotyping. CMA will cost an extra £2600 over karyotyping per case detected when the indication is abnormal ultrasound scan. Threshold analysis shows that when the cost of CMA is reduced to £220 it becomes the cost-effective option. Cost effectiveness association curves show that for any referral indication when the willingness to pay is >£7500 and for abnormal scans when the WTP is >2830 the probability of CMA being cost effective is over 95%. CMA will become the cost effective option of the future as technology costs fall. At the present time for abnormal ultrasound scan CMA may be considered if the WTP per case detected is £2600 in addition to standard costs.

Background Chromosomal microarray testing (CMA) is utilised in prenatal diagnosis to detect chromosomal abnormalities not visible by full, conventional karyotyping. We present our prospective cohort of women undergoing fetal microarray and karyotyping for an abnormal prenatal ultrasound scan (USS). This cohort is presented in the context of a systematic review and meta-analysis of the literature (until December 2012) which defines overall detection rates by microarray over karyotyping. Systematic review methods: MEDLINE (1970–June 2012), EMBASE (1980–June 2012), Cinhal (1982–June 2012) were searched electronically. Selected studies had >5 cases and microarray testing was performed prenatally in addition to karyotyping. The search yielded 559 citations. Full manuscripts were retrieved for 85 and 24 primary studies were included in the systematic review. Cohort Methods A prospective cohort study of 243 women undergoing microarray testing alongside karyotyping when a structural abnormality was detected on prenatal USS. Results When clinical indication for testing was abnormal fetal USS our cohort study noted a 4.1% increase in detection rate; lower than the rate of 10.1% (95% CI 8.0–12.7%) by meta-analysis. When any clinical indication for prenatal microarray was meta-analysed the detection rate over karyotyping was 5.6% (95%CI 3.0–10.6%) and the variant of unknown significance (VOUS) rate was 1.4% (95%CI 0.5–3.7%). Conclusion Chromosomal microarray is useful prenatally particularly for an abnormal fetal USS. Prospective counselling should include the approximate VOUS rate (1.4% rising to 2.1% for abnormal USS). It is likely that microarray testing will replace karyotyping in high risk pregnancies (such as abnormal USS).

Background Array comparative genomic hybridisation (aCGH) technology has allowed examination of the human genome at previously unthinkable resolution. It has enabled the detection of microdeletions and microduplications too small to be noted on standard G-band Karyotype. Its use in the prenatal setting is appropriate due to its ability to analyse DNA from uncultured cells, its rapid turn-around of results and its ability for high throughput analysis. Its use has been approached with caution due to difficulties in interpreting copy number variance (CNVs) of unknown clinical significance which may give parents9 elevated anxiety. Methods We are prospectively recruiting a cohort of patients with structural anomalies found on ultrasound scan at FMC, Birmingham Women9s hospital, UK. Patients were offered and consented to a targeted array (BlueGnome constitutional array) analysis of the fetal genome in addition to a rapid QF-PCR and G-band karyotyping. Results Between November 2009 and October 2010, 102 cases were included; the major fetal anomalies being 28% cardiac, 22% central nervous system and 21% NT (>3.5 mm) anomalies. From the 102 cases, QF-PCR detected 19 trisomies on 81 samples to date (detection rate of 8.1%). In three (3.7%) of these samples the karyotypic anomaly was not detected by standard karyotyping. The % of pathological and benign CNVs are discussed. aCGH results were turned around 1.76 days quicker than karyotyping. Conclusions Our ongoing prospective study has demonstrated that focused array CGH is capable of detecting chromosomal differences over PCR and G-band techniques. The impact upon prenatal diagnosis and counselling will be discussed.

Background Array comparative genomic hybridisation (array CGH) is transforming clinical cytogenetics with its ability to interrogate the human genome at increasingly high resolution. Objective To determine whether array CGH testing in the prenatal population provides diagnostic information over conventional karyotyping. Search Strategy MEDLINE (1970 to December 2009), EMBASE (1980 to December 2009) and CINAHL (1982 to December 2009) were searched electronically. Selection criteria Studies were selected if array CGH was used on prenatal samples or where array CGH was used on postnatal samples following termination of pregnancy for structural abnormalities detected on an ultrasound scan. Of the 135 potential articles, 10 were included in this systematic review. Data Collection and Analysis Results from the chromosome analysis and array CGH analysis were extracted. The pooled rate of extra information detected by array CGH when the prenatal karyotype was normal and conversely the pooled rate of extra information from karyotyping when the array CGH was normal was calculated. Main Results Array CGH detected 3.6% (95% CI 1.5% to 8.5%) additional genomic abnormalities when conventional karyotyping was ‘normal’ regardless of referral indication. This increased to 5.2% (95% CI 1.9% to 13.9%) more than prenatal karyotyping when the referral indication was a structural malformation detected on ultrasound scan. Conclusion There appears to be an increased detection rate of chromosomal abnormalities when array CGH techniques are employed in the prenatal population over conventional karyotyping. However, some of these are copy number imbalances that are not clinically significant. This carries implications for prenatal counselling and maternal anxiety.