Randomised placebo-controlled trial of antenatal corticosteroids for planned birth in twins (STOPPIT-3): study protocol.

INTRODUCTION: The aim of the STOPPIT-3 study is to determine the clinical and cost effectiveness of antenatal corticosteroids (ACS) prior to planned birth of twins in a multicentre placebo-controlled trial with internal pilot. METHODS AND ANALYSIS: This study will comprise a multicentre, double-blinded, randomised, placebo-controlled trial in at least 50 UK obstetric units. The target population is 1552 women with a twin pregnancy and a planned birth between 35 and 38+6 weeks' gestation recruited from antenatal clinics. Women will be randomised to Dexamethasone Phosphate (24 mg) or saline administered via two intramuscular injections 24 hours apart, 24-120 hours prior to scheduled birth. OUTCOMES: The primary outcome is need for respiratory support within 72 hours of birth. Secondary and safety outcomes will be included. Cognitive and language development at age 2 years will be assessed in a subset of participants using the Parent report of Children's Abilities-Revised questionnaire. We will also determine the cost effectiveness of the treatment with ACS compared with placebo. ETHICS AND DISSEMINATION: STOPPIT-3 has been funded and approved by the National Institute of Healthcare Research. It has been approved by the West Midlands Research Ethics Committee (22/WM/0018). The results will be disseminated via publication in peer-reviewed journals and conference presentation and will also be communicated to the public via links with charity partners and social media. TRIAL SPONSOR: The University of Edinburgh and Lothian Health Board ACCORD, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ. TRIAL REGISTRATION NUMBER: ISRCTN59959611.

Evaluating a multi-behavioural home-based intervention for reducing depressive symptoms in postnatal women : The food, move, sleep (FOMOS) for postnatal mental health randomised controlled trial protocol.

BACKGROUND: Postnatal depression (PND) is a leading cause of illness and death among women following childbirth. Physical inactivity, sedentary behaviour, poor sleep, and sub-optimal diet quality are behavioural risk factors for PND. A feasible, sustainable, and scalable intervention to improve healthy behaviours and reduce PND symptoms among women at postpartum is needed. This study aims to examine the effectiveness of a multi-behavioural home-based program Food, Move, Sleep (FOMOS) for Postnatal Mental Health designed to improve PND symptoms in women at postpartum. METHODS: This randomised clinical trial will recruit 220 Australian women (2-12 months postpartum) experiencing heightened PND symptoms (Edinburgh Postnatal Depression Scale score ≥ 10). Participants will be randomised to FOMOS or wait-list control receiving standard clinical care. FOMOS is a 6-month mobile health (mHealth) intervention targeting diet quality, physical activity, sedentary behaviour, sleep, and mental health. The intervention, informed by the Social Cognitive Theory and incorporating behaviour change techniques defined in the CALO-RE taxonomy and Cognitive Behavioural Treatment of Insomnia, provides exercise equipment, and educational/motivational material and social support via mHealth and social media. Data collection pre-intervention and at 3, 6 and 12 months will assess the primary outcome of PND symptoms and secondary outcomes (diet quality, physical activity, sitting time, sleep quality) using self-report and device measures. Process evaluation will explore acceptability, appropriateness, cost-effectiveness, feasibility, and sustainability via analytic tools, record keeping, interviews, and surveys. DISCUSSION: If effective, FOMOS could be a feasible and potentially scalable management strategy to support improvement of health behaviours and mental health for women with PND symptoms. TRIAL REGISTRATION: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12622001079730p.

Supporting multiple birth families: Perceptions and experiences of health visitors.

OBJECTIVE: To explore the current practice and perceptions of health visitors in supporting multiple birth families. DESIGN AND SAMPLE: Practicing health visitors across the United Kingdom were invited to complete a cross-sectional, descriptive, online survey. The questionnaire covered multiple birth caseload, education received about multiples and the experience of working with families. Two-hundred and ninety health visitors completed the questionnaire. Descriptive and inferential statistics were used for analysis of the quantitative components and thematic analysis for the qualitative data. RESULTS: Most health visitors had twins on their current workload. Most health visitors had not received any specific training or continuing professional development regarding the needs of multiple birth families. Supporting the families within the confines of reduced time and increased workload was challenging. Daily tasks of caring for multiples were the main areas that health visitors and parents wanted more information about. CONCLUSIONS: In the United Kingdom, health visitors are uniquely positioned to support multiple birth families, in particular during the more challenging early years. However, the findings of this study suggest that many health visitors are aware that the care and support that they are able to provide multiple birth families falls short of meeting their needs.

The Arabin pessary to prevent preterm birth in women with a twin pregnancy and a short cervix: the STOPPIT 2 RCT.

BACKGROUND: Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. OBJECTIVE: STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. DESIGN: STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group - the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. SETTING: Antenatal clinics in the UK and elsewhere in Europe. PARTICIPANTS: Women with twin pregnancy at < 21 weeks' gestation with known chorionicity and gestation established by scan at ≤ 16 weeks' gestation. INTERVENTIONS: Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18+ 0-20+ 6 weeks' gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. MAIN OUTCOME MEASURES: Obstetric - all births before 34+ 0 weeks' gestation following the spontaneous onset of labour; and neonatal - composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. RESULTS: A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal 'easy' or 'fairly easy' in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. LIMITATIONS: There was the possibility of a type II error around smaller than anticipated benefit. CONCLUSIONS: In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of < 0.4. FUTURE WORK: Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 44. See the NIHR Journals Library website for further project information.

Women who are pregnant with twins have a much higher risk of going into labour early and having an early (preterm) birth than women who are pregnant with only one baby. For this reason, babies who are twins are much more likely to die or to have serious health complications in the first months of life. Although we know that women with twin pregnancy are at risk, there are no treatments that are recommended to prevent early births. Some studies have suggested that the Arabin pessary can help. The Arabin pessary is a silicone ring that fits around the cervix (neck of the womb). The pessary can be put in place in a clinic without any need for an anaesthetic. Some studies have suggested that the Arabin pessary helps and others have suggested that it does not. It appears to be most helpful when the cervix (neck of the womb) is already shortening. Shortening of the neck of the womb is a sign that early birth is even more likely. We asked women with twin pregnancy to take part in STOPPIT 2. Women who agreed had an ultrasound scan of the neck of the womb, which measured its length. Those with a short cervix were randomised to be offered the Arabin pessary (in addition to standard care) or standard care alone. This allocation was carried out 'at random' by a computer. We followed women up until the end of their pregnancy and collected information on the babies' health after birth. We found that the Arabin pessary did not reduce the risk of an early birth; nor did it reduce the risk of health complications for the baby. We conclude that the Arabin pessary should not be used for this purpose.

Evaluation of the Arabin cervical pessary for prevention of preterm birth in women with a twin pregnancy and short cervix (STOPPIT-2): An open-label randomised trial and updated meta-analysis.

BACKGROUND: Preterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix. METHODS AND FINDINGS: We conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses. CONCLUSIONS: These results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out. TRIAL REGISTRATION: ISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181.

Conducting Clinical Trials in Twin Populations: A Review of Design, Analysis, Recruitment and Ethical Issues for Twin-Only Trials.

Although twins often participate in medical research, few clinical trials are conducted entirely in twin populations. The purpose of this review is to demonstrate the substantial benefits and address the key challenges of conducting clinical trials in twin populations, or 'twin-only trials'. We consider the unique design, analysis, recruitment and ethical issues that arise in such trials. In particular, we describe the different approaches available for randomizing twin pairs, highlight the similarity or correlation that exists between outcomes of twins, and discuss the impact of this correlation on sample size calculations and statistical analysis methods for estimating treatment effects. We also consider the role of both monozygotic and dizygotic twins for studying variation in outcomes, the factors that may affect recruitment of twins, and the ethics of conducting trials entirely in twin populations. The advantages and disadvantages of conducting twin-only trials are also discussed. Finally, we recommend that twin-only trials should be considered more often.

The impact of cross-border IVF on maternal and neonatal outcomes in multiple pregnancies: Experience from a UK fetal medicine service.

OBJECTIVES: To determine whether women seeking NHS care for IVF multiple pregnancies were more likely to have sought IVF treatment overseas and whether this was associated with different maternal and neonatal outcomes. STUDY DESIGN: A single large tertiary centre, for perinatal care in northwest London. Sixty-five women were referred to our fetal medicine centre, between 2012-2016, with IVF conceived multiple pregnancies. INCLUSION CRITERIA: In Vitro fertilisation and conception of twins/ triplets/quadruplets. EXCLUSION CRITERIA: Intra-uterine insemination, ovulation induction, Clomid-conception and singleton pregnancies. The primary outcome measure was the Country where IVF treatment was performed. The secondary outcomes measures included the specifics of IVF treatment (e.g. number of embryos transferred), subsequent pregnancy outcomes (e.g. live-births and prematurity) and neonatal outcomes (e.g. length and cost of care). RESULTS AND CONCLUSION: Thirty-eight women had IVF overseas; they were older and had more pre-existing medical conditions. Eleven pregnancies used donor embryos, of which ten were from overseas treatment. 75% of women treated overseas conceived a triplet or higher order pregnancy compared to fewer than 10% of women who conceived in the UK. Almost half of all women treated overseas had more than two embryos transferred. Overseas IVF pregnancies had poorer obstetric and neonatal outcomes: 24% of live born babies died in the neonatal period compared to 0% in the UK group. The average neonatal costs per baby born from overseas IVF were £20, 600: two-and-a-half times higher than for those whose mothers conceived in the UK. Higher order multiple pregnancies are greatly over-represented by those undergoing IVF in overseas clinics. These are associated with poorer obstetric and neonatal outcomes. Perhaps paradoxically, improving NHS provision of fertility services might improve outcomes for the mother and babies while reducing the long-term burden to both fertility patients and the NHS.

Open randomised trial of the (Arabin) pessary to prevent preterm birth in twin pregnancy with health economics and acceptability: STOPPIT-2-a study protocol.

INTRODUCTION: The STOPPIT-2 study aims to determine the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix, about which there is current uncertainty. STOPPIT-2 will resolve uncertainty around effectiveness for women with a twin pregnancy and a cervical length of 35 mm or less, define adverse effects, ascertain acceptability and estimate National Health Service costs and savings. METHODS: STOPPIT-2 is a pragmatic multicentre open-label randomised controlled trial. Consenting women with twin pregnancy will have an transvaginal ultrasound scan of their cervical length performed between 18+0 and 20+6 weeks' gestation by an accredited practitioner: women with a cervical length of ≤35 mm will be eligible for inclusion in the treatment phase of the study. The intervention by the insertion of the Arabin cervical pessary will be compared with standard treatment (no pessary).The primary outcomes are (obstetric) spontaneous onset of labour for the mother leading to delivery before 34 weeks' gestation and (neonatal) a composite of specific adverse outcomes or death occurring up to the end of the first 4 weeks after the estimated date of delivery to either or both babies.We plan to recruit 500 women in the treatment phase of the study. Assuming a treatment effect of 0.6, and background rates of 35% and 18%, respectively, for each of the primary outcomes, our study has 85% power to detect a difference between the intervention and the control groups. ANALYSIS: Data will be analysed on the intention-to-treat principle. ETHICS: STOPPIT-2 was approved by the South East Scotland Ethics Committee 02 on 29 August 2014, reference number 14/SS/1031 IRAS ID 159610. DISSEMINATION: Peer reviewed journals, presentations at national and international scientific meetings. TRIAL REGISTRATION NUMBER: ISRCTN98835694 and NCT02235181.

Appropriate maternal weight gain in singleton and twin pregnancies: what is the evidence?

A review of the literature on maternal weight gain in singleton and twin pregnancies has identified two main messages. Firstly, that very little robust evidence exists on which to base advice to mothers about appropriate weight gain during pregnancy. Evidence that does exist has tended to be observational, or based on under-powered intervention studies and unable to provide definitive conclusions. Secondly, that although specific weight gains have been recommended by the Institute of Medicine (IOM) in the USA, many women who gained weight outside these guidelines apparently achieved successful pregnancy and birth outcomes, in part because there were numerous confounders. Crucially, resources need to be invested to address women's concerns with weight management, so that they can receive the necessary support from midwives and others who care for them. Currently, women tend to receive little advice on weight gain during pregnancy and it is vital they are made aware of the increased risks associated with obesity, and that opportunities to minimise complications should be available and accessible prior to and during pregnancy. Overall, these findings highlight the difficulties in drawing up recommendations for individual women, whether expecting twins or singletons, on the basis of studies of populations, and the distinct difference between the USA and the UK in how weight gain is rationalised.

Toward developing a training pathway for fertility nurses: report of the 2010 training and educational survey.

Fertility nursing and its role extension has increasingly been referred to as 'specialist' or 'advanced nursing practice'. Nevertheless, Government initiatives have prompted a review of 'Advanced Nursing Practice' and the Nursing & Midwifery Council (NMC) has taken steps to address the disparity of roles, job titles, training and competence of nurse practitioners, concluding that advanced nursing practice should be subject to revalidation in the same way as professional registration. Fertility nurses form an integral part of the multidisciplinary team. Yet no formal or nationally recognised framework or training pathway exists. In this paper, we present the findings of a recent online survey of training and educational needs of fertility nurses; its aim being to work toward developing a national training pathway. Our findings identify the relationship between fertility nurse competencies, advanced nursing practice and medical sub-specialist training, at the same time, highlighting the difference in accessibility, funding and levels of training, as well as assessment and expertise within clinical practice. We conclude that it is essential to protect role extension through regonised Higher Educational Institution (HEI) accreditation, by appropriate, role-focussed training. Notwithstanding a national review, the diverse list of job titles also needs to be addressed adequately to encompass and respect role extension.

The effect of intrauterine growth on verbal IQ scores in childhood: a study of monozygotic twins.

OBJECTIVE: Given the adverse neurobiological effects of suboptimal nutrition on the developing brain, it is of social and medical importance to determine if the global prevalence of poor intrauterine growth causes lasting cognitive deficits. We examined whether suboptimal intrauterine growth relates to impaired cognitive outcome by comparing birth weight and cognition in monozygotic twins and considered whether children within-pair differences in birth weight were related to within-pair differences in IQ scores. METHODS: A total of 71 monozygotic twin pairs (aged 7 years 11 months to 17 years 3 months) participated. The Wechsler Intelligence Scale for Children, Third Edition, was administered, and verbal IQ (VIQ) and performance IQ (PIQ) scores were calculated. Regression was used to relate within-pair differences in birth weight to within-pair differences in IQ scores. RESULTS: VIQ but not PIQ score was affected by prenatal growth restriction. The results suggest that the mean advantage for heavier twins relative to their lighter co-twins can be as much as half an SD in VIQ points. In pairs with minimal discordance, heavier twins had lower VIQ scores than their lighter co-twins. CONCLUSIONS: Our study results suggest that lower birth weight in monozygotic twins can also have a negative long-term impact on cognition both in infants who are small at birth and also those with birth weights across the spectrum. Studying monozygotic twins enabled us to examine the effect of reduced intrauterine growth on cognition independently of confounding factors, including parental IQ and education and infant gender, age, genetic characteristics, and gestation.

Attitudes towards single embryo transfer, twin and higher order pregnancies in patients undergoing infertility treatment: a review.

The problems associated with twin and higher order pregnancies have assumed major importance, with international debate about multiple pregnancy; the single biggest risk with in vitro fertilisation (IVF). We have critically reviewed published papers on female patients' and their partners' views of single embryo transfer (SET) and twin or higher level pregnancies to identify the requirements needed to improve the acceptability of SET. Twenty relevant papers were identified and included in the review. Although the majority of IVF patients and their partners, in the more recent studies, exhibited a desire for twins rather than singletons, closer examination of the evidence revealed that elective SET (eSET) could become increasingly acceptable. As success rates of IVF have improved and the risks and consequences of multiple pregnancies are well-documented, patients have accepted the transfer of two rather than three embryos as standard practice. However, more would accept eSET if success rates approached those of double embryo transfer (DET). This emphasises the importance of improving success rates of eSET so that more patients can achieve a singleton birth with one IVF cycle. If patients were offered only SET, it is likely that this would be acceptable as the normal expectation of pregnancy is one baby. Measures to improve the acceptability of SET include: using eSET, especially with younger patients; including partners when providing risk information; improving eSET success rates; improving outcomes with cryopreserved embryos; changing reimbursement/free cycles to favour eSET; using legal enforcement.

Preparation for parenting multiple birth children.

The experience of expecting and parenting multiples is decidedly different from that of a singleton pregnancy and parenthood. Multiple births are associated with substantial medical, health care, socio-emotional, developmental, educational and economic consequences for both families and society. This paper aims to advise health professionals on how best to help families prepare for and successfully respond to the demands of multiple pregnancy and the first 5 years of parenthood after the births of twins, triplets or more. Four inter-related principles of good practice are vital to the care of multiple birth families: the involvement of a range of disciplines, of the family and of the multiple birth community; the provision of specialised care; coordinated services; and the building of family competency including the capacity to make informed decisions. Preparation should include education on the special aspects of multiple pregnancy and parenting using multiples-focused resources, health promotion and risk modification strategies, infant care and feeding, child development and advice on securing help and support while ensuring family participation in all care decisions.

Twins and more--1. Some current thinking on multiple births.

The incidence of multiple births is rising in many countries including the U.K., mainly as a result of treatment for infertility. Parents of twins, triplets or more require specific information, advice and support at all stages of parenting from diagnosis of a multiple pregnancy onwards. Specialist midwives have an important role to play in this, as do voluntary organisations such as the Multiple Births Foundation. The first part of this two-part article provides an update of some current thinking on multiple births, including twin-twin transfusion syndrome. Part two will provide information about the needs of families with a multiple birth in the early years.

Twins and more--2. Practical aspects of parenting in the early years.

Caring for twin, triplets or more can be a daunting prospect for parents, however much the children are wanted and loved. Multiple birth babies are more likely to be born preterm and of low birth weight, adding to the practical, financial and emotional pressures of coping with two or more babies. Good preparation and advice before the babies are born, as described in Part 1 of this article (Journal of Family Health Care 2005; 15151: 143-146) is essential. After the birth, parents need continuing support and access to care from professionals who understand their different and special needs. Bereavement counselling and support may also be required, as the mortality rate is higher for multiple births. Part Two looks at the care commonly needed for multiple birth families during the first five years.