Preterm prelabour rupture of membranes before 23 weeks' gestation: prospective observational study.

Objective: To describe perinatal and maternal outcomes of preterm prelabour rupture of membranes (PPROM) before 23 weeks' gestation in a national cohort. Design: Prospective observational study. Setting: National population based cohort study with the UK Obstetric Surveillance System (UKOSS), a research infrastructure of all 194 obstetric units in the UK, 1 September 2019 to 28 February 2021. Participants: 326 women with singleton and 38 with multiple pregnancies with PPROM between 16+0 and 22+6 weeks+days' gestation. Main outcome measures: Perinatal outcomes of live birth, survival to discharge from hospital, and severe morbidity, defined as intraventricular haemorrhage grade 3 or 4, or requiring supplemental oxygen at 36 weeks' postmenstrual age, or both. Maternal outcomes were surgery for removal of the placenta, sepsis, admission to an intensive treatment unit, and death. Clinical data included rates of termination of pregnancy for medical reasons. Results: Perinatal outcomes were calculated with all terminations of pregnancy for medical reasons excluded, and a worst-best range was calculated assuming that all terminations for medical reasons and those with missing data would have died (minimum value) or all would be liveborn (maximum value). For singleton pregnancies, the live birth rate was 44% (98/223), range 30-62% (98/326-201/326), perinatal survival to discharge from hospital was 26% (54/207), range 17-53% (54/326-173/326), and 18% (38/207), range 12-48% (38/326-157/326) of babies survived without severe morbidity. The rate of maternal sepsis was 12% (39/326) in singleton and 29% (11/38) in multiple pregnancies (P=0.004). Surgery for removal of the placenta was needed in 20% (65/326) and 16% (6/38) of singleton and twin pregnancies, respectively. Five women became severely unwell with sepsis; two died and another three required care in the intensive treatment unit. Conclusions: In this study, 26% of women who had very early PPROM with expectant management had babies that survived to discharge from hospital. Morbidity and mortality rates were high for both mothers and neonates. Maternal sepsis is a considerable risk that needs more research. These data should be used in counselling families with PPROM before 23 weeks' gestation, and currently available guidelines should be updated accordingly.

Consortium for the Study of Pregnancy Treatments (Co-OPT): An international birth cohort to study the effects of antenatal corticosteroids.

BACKGROUND: Antenatal corticosteroids (ACS) are widely prescribed to improve outcomes following preterm birth. Significant knowledge gaps surround their safety, long-term effects, optimal timing and dosage. Almost half of women given ACS give birth outside the "therapeutic window" and have not delivered over 7 days later. Overtreatment with ACS is a concern, as evidence accumulates of risks of unnecessary ACS exposure. METHODS: The Consortium for the Study of Pregnancy Treatments (Co-OPT) was established to address research questions surrounding safety of medications in pregnancy. We created an international birth cohort containing information on ACS exposure and pregnancy and neonatal outcomes by combining data from four national/provincial birth registers and one hospital database, and follow-up through linked population-level data from death registers and electronic health records. RESULTS AND DISCUSSION: The Co-OPT ACS cohort contains 2.28 million pregnancies and babies, born in Finland, Iceland, Israel, Canada and Scotland, between 1990 and 2019. Births from 22 to 45 weeks' gestation were included; 92.9% were at term (≥ 37 completed weeks). 3.6% of babies were exposed to ACS (67.0% and 77.9% of singleton and multiple births before 34 weeks, respectively). Rates of ACS exposure increased across the study period. Of all ACS-exposed babies, 26.8% were born at term. Longitudinal childhood data were available for 1.64 million live births. Follow-up includes diagnoses of a range of physical and mental disorders from the Finnish Hospital Register, diagnoses of mental, behavioural, and neurodevelopmental disorders from the Icelandic Patient Registers, and preschool reviews from the Scottish Child Health Surveillance Programme. The Co-OPT ACS cohort is the largest international birth cohort to date with data on ACS exposure and maternal, perinatal and childhood outcomes. Its large scale will enable assessment of important rare outcomes such as perinatal mortality, and comprehensive evaluation of the short- and long-term safety and efficacy of ACS.

Amnioinfusion versus Usual Care in Women with Prelabor Rupture of Membranes in Midtrimester: A Systematic Review and Meta-Analysis of Short- and Long-Term Outcomes.

INTRODUCTION: Midtrimester prelabor rupture of membranes (PROM) between 16 and 24 weeks of gestational age is a major obstetric complication with high rates of perinatal morbidity and mortality. Amnioinfusion has been proposed in women with midtrimester PROM to target oligohydramnios and subsequently enhance pulmonary development and perinatal outcomes. MATERIAL AND METHODS: The purpose of this study was to perform a systematic review and meta-analysis including all randomized clinical trials investigating amnioinfusion versus no intervention in women with PROM between 16+0 and 24+0 weeks of gestational age. Databases Central, Embase, Medline, ClinicalTrials.gov and references of identified articles were searched from inception of database to December 2021. The primary outcome was perinatal mortality. Secondary outcomes included neonatal, maternal, and long-term developmental outcomes as defined in the core outcome set for preterm birth studies. Summary measures were reported as pooled relative risk (RR) or mean difference with corresponding 95% confidence interval (CI). RESULTS: Two studies (112 patients, 56 in the amnioinfusion group and 56 in the no intervention group) were included in this review. Pooled perinatal mortality was 66.1% (37/56) in the amnioinfusion group compared with 71.4% (40/56) in no intervention group (RR 0.92, 95% CI: 0.72-1.19). Other neonatal and maternal core outcomes were similar in both groups, although due to the relatively small number of events and wide CIs, there is a possibility that amnioinfusion can be associated with clinically important benefits and harms. Long-term healthy survival was seen in 35.7% (10/28) of children assessed for follow-up and treated with amnioinfusion versus 28.6% (8/28) after no intervention (RR 1.30, 95% CI: 0.47-3.60, "best case scenario"). CONCLUSIONS: Based on these findings, the benefits of amnioinfusion for midtrimester PROM <24 weeks of gestational age are unproven, and the potential harms remain undetermined.

Plasma long-chain omega-3 fatty acid status and risk of recurrent early spontaneous preterm birth: a prospective observational study.

INTRODUCTION: A 2018 Cochrane review found that omega-3 supplementation in pregnancy was associated with a risk reduction of early preterm birth of 0.58; prompting calls for universal supplementation. Recent analysis suggests the benefit may be confined to women with a low baseline omega-3 fatty acid status. However, the contemporary omega-3 fatty acid status of pregnant women in the UK is largely unknown. This is particularly pertinent for women with a previous preterm birth, in whom a small relative risk reduction would have a larger reduction of absolute risk. This study aimed to assess the omega-3 fatty acid status of a UK pregnant population and determine the association between the long-chain omega-3 fatty acids and recurrent spontaneous early preterm birth. MATERIAL AND METHODS: A total of 283 high-risk women with previous early preterm birth were recruited to the prospective observational study in Liverpool, UK. Additionally, 96 pregnant women with previous term births and birth ≥39+0  weeks in the index pregnancy provided a low-risk population sample. Within the high-risk group we assessed the odds ratio of recurrent early preterm birth compared with birth at ≥37+0  weeks of gestation according to plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) at 15-22 weeks of gestation. RESULTS: Our participants had low EPA+DHA; 62% (143/229) of women with previous preterm birth and 69% (68/96) of the population sample had levels within the lowest two quintiles of a previously published pregnancy cohort. We found no association between long-chain omega-3 status and recurrent early preterm birth (n = 51). The crude odds ratio of a recurrent event was 0.91 (95% CI 0.38-2.15, p = 0.83) for women in the lowest, compared with the highest three quintiles of EPA+DHA. CONCLUSIONS: In the majority of our participants, levels of long-chain omega-3 were low; within the range that may benefit from supplementation. However, levels showed no association with risk of recurrent early spontaneous preterm birth. This could be because our population levels were too low to show benefit in being omega-3 "replete"; or else omega-3 levels may be of lesser importance in recurrent early preterm birth.

Associations between consumption of coffee and caffeinated soft drinks and late stillbirth-Findings from the Midland and North of England stillbirth case-control study.

OBJECTIVE: The consumption of caffeinated drinks and soft drinks is widespread in society, including by pregnant women. Data regarding the association of caffeine intake and stillbirth are varied. We aimed to investigate the degree of consumption of caffeinated drinks or soft drinks in the last four weeks of pregnancy in women who experienced a late stillbirth compared to women with ongoing live pregnancies at similar gestation. Influences on maternal caffeine intake and soft drink consumption during pregnancy were also investigated. STUDY DESIGN: A case-control study undertaken in 41 maternity units in the United Kingdom. Cases were women who had a singleton non-anomalous stillbirth ≥28 weeks' gestation (n = 290) and controls were women with an ongoing pregnancy at the time of interview (n = 729). Data were collected using an interviewer-administered questionnaire which included questions regarding consumption of a variety of caffeinated drinks and soft drinks in the last four weeks of pregnancy as well as other behaviours (e.g. cigarette smoking). RESULTS: Multivariable analysis adjusting for co-existing demographic and behavioural factors found the consumption of instant coffee, energy drinks and cola were associated with increased risk of stillbirth. There was an independent association between caffeine intake and late stillbirth (adjusted Odds Ratio 1.27, 95 % Confidence Interval (95 %CI) 1.14, 1.43 for each 100 mg increment/day). 15 % of cases and 8% of controls consumed more than the World Health Organisation (WHO) recommendation (>300 mg of caffeine/day; aOR 2.30, 95 % CI 1.40, 4.24). The population attributable risk for stillbirth associated with >300 mg of caffeine/day was 7.4 %. The majority of respondents reduced caffeine consumption in pregnancy. Midwives and internet resources were the most frequently used sources of information which influenced maternal behaviour with regard to soft drinks and caffeine, and this did not differ between cases and controls. CONCLUSIONS: Women should be informed that consumption of caffeine during pregnancy is associated with increased risk of stillbirth, particularly at levels greater than recommended by the WHO (>300 mg/day). Recommendations from midwives and internet-based resources are likely to be the most effective means to influence maternal behaviour.

An evaluation of the benefits and harms of antenatal corticosteroid treatment for women at risk of imminent preterm birth or prior to elective Caesarean-section: Study protocol for an individual participant data meta-analysis.

Background: Antenatal corticosteroid treatment (ACT) has been widely accepted as a safe, beneficial treatment which improves outcomes following preterm birth. It has been shown to reduce respiratory distress syndrome and neonatal mortality and is commonly used in threatened or planned preterm delivery, as well as prior to elective Caesarean-section at term. There are some concerns however, that in some cases, ACT is used in patients where clinical benefit has not been established, or may potentially increase harm. Many women who receive ACT do not deliver preterm and the long-term consequences of ACT treatment are unclear. This study aims to evaluate the benefits and harms of ACT using latest trial evidence to allow refinement of current practice. Methods: This study will compare ACT with placebo or non-treatment. Inclusion criteria are: Randomised Controlled Trials (RCT) comparing ACT vs. no ACT (with or without placebo) in all settings. Exclusion criteria are: non-randomised or quasi-randomised studies and studies comparing single vs. multiple courses of ACT. Main outcomes are to evaluate, for women at risk of preterm birth or undergoing planned Caesarean- section, the benefits and harms of ACT, on maternal, fetal, newborn, and long-term offspring health outcomes. The individual participant data (IPD) of identified RCTs will be collected and consecutively synthesised using meta-analysis with both a one-stage model where all IPD is analysed together and a two-stage model where treatment effect estimates are calculated for each trial individually first and thereafter pooled in a meta-analysis. Sub-group analysis will be performed to identify heterogeneous effects of ACT across predefined risk groups. Discussion: Co-opt is the Consortium for the Study of Pregnancy Treatments and aims to complete a robust evaluation of the benefits and harms of ACT. This IPD meta-analysis will contribute to this by allowing detailed interrogation of existing trial datasets. PROSPERO registration: CRD42020167312 (03/02/2020).

Cervical pessary for short cervix in high risk pregnant women: 5 years experience in a single centre.

Purpose: To describe single center clinical experience with cervical pessary used for high-risk pregnant women who also had short cervix. We have focused on the techniques to optimize efficacy and minimize the risk of complications and side effects related to pessary insertion, removal, and pregnancy management.Methods: This is an audit from specialist preterm birth prevention clinic in Liverpool Women's Hospital, United Kingdom for the period between January 2013 and December 2017. We also conducted postal survey in November 2015 to evaluate women's experience with vaginal pessary.Results: Out of 235 women who were treated for short cervix, 129 (55%) had cervical pessary as a first line treatment. Overall, 50% of treated women reached term. 17 women (13%) needed additional treatment, 9 women had pessary reinserted (7%), and 53 (41%) had pessary removed before 36 weeks, mainly due to ruptured membranes. Significant vaginal discharge and pelvic discomfort were reported by 14 and 7% women, respectively. 89% of treated women would recommend the pessary treatment to others.Conclusions: Whilst the cervical pessary continues to be evaluated in clinical trials, our experience suggests that pessary is quite easy to insert and remove and is well tolerated by the women.

Inequalities and stillbirth in the UK: a meta-narrative review.

OBJECTIVE: To review what is known about the relationship between stillbirth and inequalities from different disciplinary perspectives to inform stillbirth prevention strategies. DESIGN: Systematic review using the meta-narrative method. SETTING: Studies undertaken in the UK. DATA SOURCES: Scoping phase: experts in field, exploratory electronic searches and handsearching. Systematic searches phase: Nine databases with no geographical or date restrictions. Non-English language studies were excluded. STUDY SELECTION: Any investigation of stillbirth and inequalities with a UK component. DATA EXTRACTION AND SYNTHESIS: Three authors extracted data and assessed study quality. Data were summarised, tabulated and presented graphically before synthesis of the unfolding storyline by research tradition; and then of the commonalities, differences and interplays between narratives into resultant summary meta-themes. RESULTS: Fifty-four sources from nine distinctive research traditions were included. The evidence of associations between social inequalities and stillbirth spanned 70 years. Across research traditions, there was recurrent evidence of the social gradient remaining constant or increasing, fuelling repeated calls for action (meta-theme 1: something must be done). There was less evidence of an effective response to these calls. Data pertaining to socioeconomic, area and ethnic disparities were routinely collected, but not consistently recorded, monitored or reported in relation to stillbirth (meta-theme 2: problems of precision). Many studies stressed the interplay of socioeconomic status, deprivation or ethnicity with aggregated factors including heritable, structural, environmental and lifestyle factors (meta-theme 3: moving from associations towards intersectionality and intervention(s)). No intervention studies were identified. CONCLUSION: Research investigating inequalities and stillbirth in the UK is underdeveloped. This is despite repeated evidence of an association between stillbirth risk and poverty, and stillbirth risk, poverty and ethnicity. A specific research forum is required to lead the development of research and policy in this area, which can harness the multiple relevant research perspectives and address the intersections between different policy areas. PROSPERO REGISTRATION NUMBER: CRD42017079228.

Women's experiences of being invited to participate in a case-control study of stillbirth - findings from the Midlands and North of England Stillbirth Study.

BACKGROUND: The Midlands and North of England Stillbirth Study (MiNESS) was a case-control study of women who had a stillbirth or who had an ongoing pregnancy. During the set up phase questions were raised about whether interviewing women within six weeks of a stillbirth and recruiting women who were still pregnant into a "stillbirth" study was acceptable. This led to the research questions "whether it is appropriate to ask women who have recently experienced a stillbirth to participate in research?" and "whether it is appropriate to ask pregnant women to participate in a research project looking at factors associated with stillbirth." This nested study aimed to describe the opinions of women approached to participate in MiNESS to explore their views and experiences of a research project focussed on stillbirth. METHODS: Semi- structured interviews were conducted at a single study site involved in MiNESS. Purposive sampling was used to obtain a sample of women who were approached following a stillbirth (case n = 6) and those who were approached during pregnancy who gave birth to a live born baby (control n = 6). These two groups of women were divided equally according to whether they participated in the main MiNESS questionnaire study and those who declined to do so (n = 3 in each group). Interview data were transcribed and analysed using thematic analysis to identify the most important factors in determining whether women participated in MiNESS. RESULTS: The following themes emerged from the analysis: participants' understanding of research; approach by researcher; wanting to help; stillbirth taboo. These themes are explored individually in the manuscript. Participants reported positive views about research and previous participation in research studies. Respondents valued an initial approach from a member of staff already known to them. The taboo around stillbirth was a barrier to participation for some women with ongoing pregnancies. CONCLUSIONS: Experiences and views regarding research differed between participants and non-participants in the MiNESS study. Participants reported a greater understanding of the importance and implications of clinical research. When designing future studies, the timing of approach, clarity of information and the person approaching potential participants should be considered to optimise recruitment. TRIAL REGISTRATION: NCT02025530 date registered: 01/01/2014.

Alterations in maternally perceived fetal movement and their association with late stillbirth: findings from the Midland and North of England stillbirth case-control study.

OBJECTIVE: To report perception of fetal movements in women who experienced a stillbirth compared with controls at a similar gestation with a live birth. DESIGN: Case-control study. SETTING: 41 maternity units in the UK. PARTICIPANTS: Cases were women who had a late stillbirth ≥28 weeks gestation (n=291) and controls were women with an ongoing pregnancy at the time of the interview (n=733). Controls were frequency matched to cases by obstetric unit and gestational age. METHODS: Data were collected using an interviewer-administered questionnaire which included questions on maternal perception of fetal movement (frequency, strength, increased and decreased movements and hiccups) in the 2 weeks before the interview/stillbirth. Five fetal movement patterns were identified incorporating the changes in strength and frequency in the last 2 weeks by combining groups of similar pattern and risk. Multivariable analysis adjusted for known confounders. PRIMARY OUTCOME MEASURE: Association of maternally perceived fetal movements in relation to late stillbirth. RESULTS: In multivariable analyses, women who reported increased strength of movements in the last 2 weeks had decreased risk of late stillbirth compared with those whose movements were unchanged (adjusted OR (aOR) 0.18, 95% CI 0.13 to 0.26). Women with decreased frequency (without increase in strength) of fetal movements were at increased risk (aOR 4.51, 95% CI 2.38 to 8.55). Daily perception of fetal hiccups was protective (aOR 0.31, 95% CI 0.17 to 0.56). CONCLUSIONS: Increased strength of fetal movements and fetal hiccups is associated with decreased risk of stillbirth. Alterations in frequency of fetal movements are important in identifying pregnancies at increased risk of stillbirth, with the greatest risk in women noting a reduction in fetal activity. Clinical guidance should be updated to reflect that increase in strength and frequency of fetal movements is associated with the lowest risk of stillbirth, and that decreased fetal movements are associated with stillbirth. TRIAL REGISTRATION NUMBER: NCT02025530.

Prenatal reflex DNA screening for trisomies 21, 18, and 13.

PURPOSE: The purpose of the study was to determine the screening performance of prenatal reflex DNA screening for trisomies 21 (T21), 18 (T18), and 13 (T13) as part of a routine service at five hospitals. METHODS: Women who accepted screening had a first-trimester combined test (pregnancy-associated plasma protein A, free ß-human chorionic gonadotropin, nuchal translucency interpreted with maternal age). Those with a risk of having an affected pregnancy ≥1 in 800 were reflexed to a DNA sequencing test using stored plasma from the original blood sample, thereby avoiding the need to recall them. RESULTS: Of 22,812 women screened (including 106 with affected pregnancies), 2,480 (10.9%) were reflexed to DNA testing; 101/106 were detected (69/73 T21, 24/25 T18, and 8/8 T13), a 95% detection rate (95% confidence interval 89-98%) with four false positives (0.02%, 95% confidence interval 0.00-0.05%). The odds of being affected given a positive result were 25:1. Of the 105 screen-positive pregnancies, 91 (87%) had an invasive diagnostic test. Reflex DNA screening avoided up to 530 invasive diagnostic tests compared with using the combined test. CONCLUSION: Reflex DNA screening was successfully implemented in routine care, achieving a high detection rate, low false-positive rate, and, consequently, greater safety with fewer invasive diagnostic tests than other methods of screening.

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.

BACKGROUND: Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. While researching the effects of the steroid dexamethasone on premature parturition in fetal sheep in 1969, Liggins found that there was some inflation of the lungs of lambs born at gestations at which the lungs would be expected to be airless. Liggins and Howie published the first randomised controlled trial in humans in 1972 and many others followed. OBJECTIVES: To assess the effects of administering a course of corticosteroids to the mother prior to anticipated preterm birth on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (17 February 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following spontaneous labour), regardless of other co-morbidity, for inclusion in this review. Most women in this review received a single course of steroids; however, nine of the included trials allowed for women to have weekly repeats. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: This update includes 30 studies (7774 women and 8158 infants). Most studies are of low or unclear risk for most bias domains. An assessment of high risk usually meant a trial had potential for performance bias due to lack of blinding. Two trials had low risks of bias for all risk of bias domains.Treatment with antenatal corticosteroids (compared with placebo or no treatment) is associated with a reduction in the most serious adverse outcomes related to prematurity, including: perinatal death (average risk ratio (RR) 0.72, 95% confidence interval (CI) 0.58 to 0.89; participants = 6729; studies = 15; Tau² = 0.05, I² = 34%; moderate-quality); neonatal death (RR 0.69, 95% CI 0.59 to 0.81; participants = 7188; studies = 22), RDS (average RR 0.66, 95% CI 0.56 to 0.77; participants = 7764; studies = 28; Tau² = 0.06, I² = 48%; moderate-quality); moderate/severe RDS (average RR 0.59, 95% CI 0.38 to 0.91; participants = 1686; studies = 6; Tau² = 0.14, I² = 52%); intraventricular haemorrhage (IVH) (average RR 0.55, 95% CI 0.40 to 0.76; participants = 6093; studies = 16; Tau² = 0.10, I² = 33%; moderate-quality), necrotising enterocolitis (RR 0.50, 95% CI 0.32 to 0.78; participants = 4702; studies = 10); need for mechanical ventilation (RR 0.68, 95% CI 0.56 to 0.84; participants = 1368; studies = 9); and systemic infections in the first 48 hours of life (RR 0.60, 95% CI 0.41 to 0.88; participants = 1753; studies = 8).There was no obvious benefit for: chronic lung disease (average RR 0.86, 95% CI 0.42 to 1.79; participants = 818; studies = 6; Tau² = 0.38 I² = 65%); mean birthweight (g) (MD -18.47, 95% CI -40.83 to 3.90; participants = 6182; studies = 16; moderate-quality); death in childhood (RR 0.68, 95% CI 0.36 to 1.27; participants = 1010; studies = 4); neurodevelopment delay in childhood (RR 0.64, 95% CI 0.14 to 2.98; participants = 82; studies = 1); or death into adulthood (RR 1.00, 95% CI 0.56 to 1.81; participants = 988; studies = 1).Treatment with antenatal corticosteroids does not increase the risk of chorioamnionitis (RR 0.83, 95% CI 0.66 to 1.06; participants = 5546; studies = 15; moderate-quality evidence) or endometritis (RR 1.20, 95% CI 0.87 to 1.63; participants = 4030; studies = 10; Tau² = 0.11, I² = 28%; moderate-quality). No increased risk in maternal death was observed. However, the data on maternal death is based on data from a single trial with two deaths; four other trials reporting maternal death had zero events (participants = 3392; studies = 5; moderate-quality).There is no definitive evidence to suggest that antenatal corticosteroids work differently in any pre-specified subgroups (singleton versus multiple pregnancy; membrane status; presence of hypertension) or for different study protocols (type of corticosteroid; single course or weekly repeats).GRADE outcomes were downgraded to moderate-quality. Downgrading decisions (for perinatal death, RDS, IVH, and mean birthweight) were due to limitations in study design or concerns regarding precision (chorioamnionitis, endometritis). Maternal death was downgraded for imprecision due to few events. AUTHORS' CONCLUSIONS: Evidence from this update supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. A single course of antenatal corticosteroids could be considered routine for preterm delivery. It is important to note that most of the evidence comes from high income countries and hospital settings; therefore, the results may not be applicable to low-resource settings with high rates of infections.There is little need for further trials of a single course of antenatal corticosteroids versus placebo in singleton pregnancies in higher income countries and hospital settings. However, data are sparse in lower income settings. There are also few data regarding risks and benefits of antenatal corticosteroids in multiple pregnancies and other high-risk obstetric groups. Further information is also required concerning the optimal dose-to-delivery interval, and the optimal corticosteroid to use.We encourage authors of previous studies to provide further information, which may answer any remaining questions about the use of antenatal corticosteroids in such pregnancies without the need for further randomised controlled trials. Individual patient data meta-analysis from published trials is likely to answer some of the evidence gaps. Follow-up studies into childhood and adulthood, particularly in the late preterm gestation and repeat courses groups, are needed. We have not examined the possible harmful effects of antenatal corticosteroids in low-resource settings in this review. It would be particularly relevant to explore this finding in adequately powered prospective trials.

The Midland and North of England Stillbirth Study (MiNESS).

BACKGROUND: The United Kingdom has one of the highest rates of stillbirth in Europe, resulting in approximately 4,000 stillbirths every year. Potentially modifiable risk factors for late stillbirths are maternal age, obesity and smoking, but the population attributable risk associated with these risk factors is small.Recently the Auckland Stillbirth Study reported that maternal sleep position was associated with late stillbirth. Women who did not sleep on their left side on the night before the death of the baby had double the risk compared with sleeping on other positions. The population attributable risk was 37%. This novel observation needs to be replicated or refuted. METHODS/DESIGN: Case control study of late singleton stillbirths without congenital abnormality. Controls are women with an ongoing singleton pregnancy, who are randomly selected from participating maternity units booking list of pregnant women, they are allocated a gestation for interview based on the distribution of gestations of stillbirths from the previous 4 years for the unit. The number of controls selected is proportional to the number of stillbirths that occurred at the hospital over the previous 4 years. DATA COLLECTION: Interviewer administered questionnaire and data extracted from medical records. SAMPLE SIZE: 415 cases and 830 controls. This takes into account a 30% non-participation rate, and will detect an OR of 1.5 with a significance level of 0.05 and power of 80% for variables with a prevalence of 57%, such as non-left sleeping position. STATISTICAL ANALYSIS: Mantel-Haenszel odds ratios and unconditional logistic regression to adjust for potential confounders. DISCUSSION: The hypotheses to be tested here are important, biologically plausible and amenable to a public health intervention. Although this case-control study cannot prove causation, there is a striking parallel with research relating to sudden infant death syndrome, where case-control studies identified prone sleeping position as a major modifiable risk factor. Subsequently mothers were advised to sleep babies prone ("Back to Sleep" campaign), which resulted in a dramatic drop in SIDS. This study will provide robust evidence to help determine whether such a public health intervention should be considered. TRIAL REGISTRATION NUMBER: NCT02025530.

Amnioinfusion in preterm premature rupture of membranes (AMIPROM): a randomised controlled trial of amnioinfusion versus expectant management in very early preterm premature rupture of membranes--a pilot study.

BACKGROUND: Fetal survival is severely compromised when the amniotic membrane ruptures between 16 and 24 weeks of pregnancy. Reduced amniotic fluid levels are associated with poor lung development, whereas adequate levels lead to better perinatal outcomes. Restoring amniotic fluid by means of ultrasound-guided amnioinfusion (AI) may be of benefit in improving perinatal and long-term outcomes in children of pregnancies with this condition. OBJECTIVE: The AI in preterm premature rupture of membranes (AMIPROM) pilot study was conducted to assess the feasibility of recruitment, the methods for conduct and the retention through to long-term follow-up of participants with very early rupture of amniotic membranes (between 16 and 24 weeks of pregnancy). It was also performed to assess outcomes and collect data to inform a larger, more definitive, clinical trial. DESIGN: A prospective, non-blinded randomised controlled trial. A computer-generated random sequence using a 1 : 1 ratio was used. Randomisation was stratified for pregnancies in which the amniotic membrane ruptured between 16(+0) and 19(+6) weeks' gestation and 20(+0) and 24(+0) weeks' gestation. The randomisation sequence was generated in blocks of four. Telephone randomisation and intention-to-treat analysis were used. SETTING: Four UK hospital-based fetal medicine units - Liverpool Women's NHS Trust, St. Mary's Hospital, Manchester, Birmingham Women's NHS Foundation Trust and Wirral University Hospitals Trust. PARTICIPANTS: Women with confirmed preterm prelabour rupture of membranes between 16(+0) and 24(+0) weeks' gestation. Women with multiple pregnancies, resultant fetal abnormalities or obstetric indication for immediate delivery were excluded. INTERVENTIONS: Participants were randomly allocated to either serial weekly transabdominal AI or expectant management (Exp) until 37 weeks of pregnancy, if the deepest pool of amniotic fluid was < 2 cm. MAIN OUTCOME MEASURE: Short-term maternal, pregnancy and neonatal outcomes and long-term outcomes for the child were studied. Long-term respiratory morbidity was assessed using validated respiratory questionnaires at 6, 12 and 18 months of age and infant lung function was assessed at approximately 12 months of age. Neurodevelopment was assessed using Bayley's Scale of Infant Development II at a corrected age of 2 years. RESULTS: Fifty-eight women were randomised and two were excluded from the analysis owing to termination of pregnancy for lethal anomaly, leaving 56 participants (28 serial AI, 28 Exp) recruited between 2002 and 2009, with annual recruitment rates varying between 2 and 14. Recruitment to the study improved significantly from 2007 with National Institute for Health Research (NIHR) funding. There was no significant difference in perinatal mortality [19/28 vs. 19/28; relative risk (RR) 1.0; 95% confidence interval (CI) 0.70 to 1.43], maternal morbidity or neonatal morbidity. The overall chance of surviving without long-term respiratory or neurodevelopmental disability is 4/56 (7.1%): 4/28 (14.3%) in the AI arm and 0/28 in the expectant arm (0%) (RR 9.0; 95% CI 0.51 to 159.70). CONCLUSIONS: This pilot study found no major differences in maternal, perinatal or pregnancy outcomes. The study was not designed to show a difference between the arms and the number of survivors was too small to draw any conclusions about long-term outcomes. It does signal, however, that a larger, definitive, study to evaluate AI for improvement in healthy survival is indicated. The results suggest that, with appropriate funding, such a study is feasible. A larger, definitive, study with full health economic analysis and patient perspective assessment is required to show whether AI can improve the healthy survivor rate.

Interventions for the treatment of twin-twin transfusion syndrome.

BACKGROUND: Twin-twin transfusion syndrome, a condition affecting monochorionic twin pregnancies, is associated with a high risk of perinatal mortality and morbidity. A number of treatments have been introduced to treat the condition but it is unclear which intervention improves maternal and fetal outcome. OBJECTIVES: The objective of this review was to evaluate the impact of treatment modalities in twin-twin transfusion syndrome. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013). SELECTION CRITERIA: Randomised and quasi-randomised studies of amnioreduction versus laser coagulation, septostomy versus laser coagulation or septostomy versus amnioreduction. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three studies (253 women and 506 babies) were included. All three trials were judged to be of moderate quality. One study compared amnioreduction with septostomy (71 women), whilst the other two studies compared amnioreduction with endoscopic laser coagulation (182 women). Not all trials provided outcome data that could be included in all meta-analyses. Amnioreduction compared with laser coagulation Although there was no difference in overall death between amnioreduction and laser coagulation (average risk ratio (RR) 0.87; 95% confidence interval (CI) 0.55 to 1.38 adjusted for clustering, two trials) or death of at least one infant per pregnancy (RR 0.91; 95% CI 0.75 to 1.09, two trials), or death of both infants per pregnancy (average RR 0.76; 95% 0.27 to 2.10, two trials), more babies were alive without neurological abnormality at the age of six years in the laser group than in the amnioreduction groups (RR 1.57; 95% CI 1.05 to 2.34 adjusted for clustering, one trial). There were no significant differences in the babies alive at six years with major neurological abnormality treated by laser coagulation or amnioreduction (RR 0.97; 95% CI 0.34 to 2.77 adjusted for clustering, one trial). Outcomes for death in this 2013 update are different from the previous 2008 update, where improvements in perinatal death and death of both infants per pregnancy were shown in the laser intervention arm. The NIHCD trial included in this update exerts an opposite direction of effects to the Eurofetus study, which was previously the only included laser study, hence the difference in outcome. Amnioreduction compared with septostomy There are no differences in overall death (RR 0.83; 95% CI 0.47 to 1.47, adjusted for clustering, one trial), death of at least one infant per pregnancy (RR 0.80; 95% CI 0.48 to 1.35, one trial), or death of both infants per pregnancy (RR 0.90; 95% CI 0.37 to 2.22, one trial) or gestational age at birth (RR 1.20; 95% CI -0.81 to 3.21, one trial) between amnioreduction and septostomy. AUTHORS' CONCLUSIONS: Endoscopic laser coagulation of anastomotic vessels should continue to be considered in the treatment of all stages of twin-twin transfusion syndrome to improve neurodevelopmental outcomes.Further research targeted towards assessing the effect of treatment on milder (Quintero stage 1 and 2) and more severe (Quintero stage 4) forms of twin-twin transfusion syndrome is required. Studies should aim to assess long-term outcomes of survivors.

Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy.

BACKGROUND: Cervical cerclage is a well-known surgical procedure carried out during pregnancy. It involves positioning of a suture (stitch) around the neck of the womb (cervix), aiming to give a mechanical support to the cervix and thereby reducing the risk of preterm birth. The effectiveness and safety of this procedure remains controversial. OBJECTIVES: To assess whether the use of cervical stitch in singleton pregnancy at high risk of pregnancy loss based on a woman's history and/or ultrasound finding of 'short cervix' and/or physical exam improves subsequent obstetric care and fetal outcome. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2011) and reference lists of identified studies. SELECTION CRITERIA: We included all randomised trials of cervical suturing in singleton pregnancies carried out when pregnancy was considered to be at sufficiently high risk of pregnancy loss for cerclage to be potentially indicated. We included any study that compared cerclage with either no treatment or any alternative intervention. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion. Two review authors independently assessed risk of bias and extracted data. Data were checked for accuracy. MAIN RESULTS: We included 12 trials (involving 3328 women). When cerclage was compared with no treatment, there was no statistically significant difference in perinatal deaths (8.4% versus 10.7%) (risk ratio (RR) 0.78; 95% confidence interval (CI) 0.61 to 1.00; eight trials, 2391 women) and neonatal morbidity (9.6% versus 10.2%) (RR 0.95; 95% CI 0.63 to 1.43; four trials, 818 women), despite significant reduction in preterm births (average RR 0.80; 95% CI 0.69 to 0.95; nine trials, 2898 women). Cervical cerclage was associated with the higher rate of maternal side effects (vaginal discharge and bleeding, pyrexia) (average RR 2.25; 95% CI 0.89 to 5.69; three trials, 953 women). Caesarean section rates were significantly higher after cervical cerclage (RR 1.19; 95% CI 1.01 to 1.40; 8 trials, 2817 women).There was no evidence of any important differences across all prespecified clinical subgroups (history-indicated, ultrasound-indicated)One study that compared cerclage with weekly intramuscular injections of 17 α-hydroxyprogesterone caproate in women with a short cervix detected by transvaginal ultrasound, failed to reveal any obvious differences in obstetric and neonatal outcomes between the two management strategies.Two studies compared the benefits of performing cerclage based on previous history with cerclage, only if the cervix was found to be short on transvaginal ultrasound. There was no significant difference in any of the primary and secondary outcomes. AUTHORS' CONCLUSIONS: Compared with no treatment, cervical cerclage reduces the incidence of preterm birth in women at risk of recurrent preterm birth without statistically significant reduction in perinatal mortality or neonatal morbidity and uncertain long-term impact on the baby. Ceasarean section is more likely in women who had cervical suture inserted during pregnancy.The decision on how best to minimise the risk of recurrent preterm birth in women at risk, either because of poor history of a short or dilated cervix, should be 'personalised', based on the clinical circumstances, the skill and expertise of the clinical team and, most importantly, woman's informed choice.