Biochemical tests of placental function versus ultrasound assessment of fetal size for stillbirth and small-for-gestational-age infants.

BACKGROUND: Stillbirth affects 2.6 million pregnancies worldwide each year. Whilst the majority of cases occur in low- and middle-income countries, stillbirth remains an important clinical issue for high-income countries (HICs) - with both the UK and the USA reporting rates above the mean for HICs. In HICs, the most frequently reported association with stillbirth is placental dysfunction. Placental dysfunction may be evident clinically as fetal growth restriction (FGR) and small-for-dates infants. It can be caused by placental abruption or hypertensive disorders of pregnancy and many other disorders and factorsPlacental abnormalities are noted in 11% to 65% of stillbirths. Identification of FGA is difficult in utero. Small-for-gestational age (SGA), as assessed after birth, is the most commonly used surrogate measure for this outcome. The degree of SGA is associated with the likelihood of FGR; 30% of infants with a birthweight < 10th centile are thought to be FGR, while 70% of infants with a birthweight < 3rd centile are thought to be FGR. Critically, SGA is the most significant antenatal risk factor for a stillborn infant. Correct identification of SGA infants is associated with a reduction in the perinatal mortality rate. However, currently used tests, such as measurement of symphysis-fundal height, have a low reported sensitivity and specificity for the identification of SGA infants. OBJECTIVES: The primary objective was to assess and compare the diagnostic accuracy of ultrasound assessment of fetal growth by estimated fetal weight (EFW) and placental biomarkers alone and in any combination used after 24 weeks of pregnancy in the identification of placental dysfunction as evidenced by either stillbirth, or birth of a SGA infant. Secondary objectives were to investigate the effect of clinical and methodological factors on test performance. SEARCH METHODS: We developed full search strategies with no language or date restrictions. The following sources were searched: MEDLINE, MEDLINE In Process and Embase via Ovid, Cochrane (Wiley) CENTRAL, Science Citation Index (Web of Science), CINAHL (EBSCO) with search strategies adapted for each database as required; ISRCTN Registry, UK Clinical Trials Gateway, WHO International Clinical Trials Portal and ClinicalTrials.gov for ongoing studies; specialist abstract and conference proceeding resources (British Library's ZETOC and Web of Science Conference Proceedings Citation Index). Search last conducted in Ocober 2016. SELECTION CRITERIA: We included studies of pregnant women of any age with a gestation of at least 24 weeks if relevant outcomes of pregnancy (live birth/stillbirth; SGA infant) were assessed. Studies were included irrespective of whether pregnant women were deemed to be low or high risk for complications or were of mixed populations (low and high risk). Pregnancies complicated by fetal abnormalities and multi-fetal pregnancies were excluded as they have a higher risk of stillbirth from non-placental causes. With regard to biochemical tests, we included assays performed using any technique and at any threshold used to determine test positivity. DATA COLLECTION AND ANALYSIS: We extracted the numbers of true positive, false positive, false negative, and true negative test results from each study. We assessed risk of bias and applicability using the QUADAS-2 tool. Meta-analyses were performed using the hierarchical summary ROC model to estimate and compare test accuracy. MAIN RESULTS: We included 91 studies that evaluated seven tests - blood tests for human placental lactogen (hPL), oestriol, placental growth factor (PlGF) and uric acid, ultrasound EFW and placental grading and urinary oestriol - in a total of 175,426 pregnant women, in which 15,471 pregnancies ended in the birth of a small baby and 740 pregnancies which ended in stillbirth. The quality of included studies was variable with most domains at low risk of bias although 59% of studies were deemed to be of unclear risk of bias for the reference standard domain. Fifty-three per cent of studies were of high concern for applicability due to inclusion of only high- or low-risk women.Using all available data for SGA (86 studies; 159,490 pregnancies involving 15,471 SGA infants), there was evidence of a difference in accuracy (P < 0.0001) between the seven tests for detecting pregnancies that are SGA at birth. Ultrasound EFW was the most accurate test for detecting SGA at birth with a diagnostic odds ratio (DOR) of 21.3 (95% CI 13.1 to 34.6); hPL was the most accurate biochemical test with a DOR of 4.78 (95% CI 3.21 to 7.13). In a hypothetical cohort of 1000 pregnant women, at the median specificity of 0.88 and median prevalence of 19%, EFW, hPL, oestriol, urinary oestriol, uric acid, PlGF and placental grading will miss 50 (95% CI 32 to 68), 116 (97 to 133), 124 (108 to 137), 127 (95 to 152), 139 (118 to 154), 144 (118 to 161), and 144 (122 to 161) SGA infants, respectively. For the detection of pregnancies ending in stillbirth (21 studies; 100,687 pregnancies involving 740 stillbirths), in an indirect comparison of the four biochemical tests, PlGF was the most accurate test with a DOR of 49.2 (95% CI 12.7 to 191). In a hypothetical cohort of 1000 pregnant women, at the median specificity of 0.78 and median prevalence of 1.7%, PlGF, hPL, urinary oestriol and uric acid will miss 2 (95% CI 0 to 4), 4 (2 to 8), 6 (6 to 7) and 8 (3 to 13) stillbirths, respectively. No studies assessed the accuracy of ultrasound EFW for detection of pregnancy ending in stillbirth. AUTHORS' CONCLUSIONS: Biochemical markers of placental dysfunction used alone have insufficient accuracy to identify pregnancies ending in SGA or stillbirth. Studies combining U and placental biomarkers are needed to determine whether this approach improves diagnostic accuracy over the use of ultrasound estimation of fetal size or biochemical markers of placental dysfunction used alone. Many of the studies included in this review were carried out between 1974 and 2016. Studies of placental substances were mostly carried out before 1991 and after 2013; earlier studies may not reflect developments in test technology.

Persistent inaccuracies in completion of medical certificates of stillbirth: A cross-sectional study.

BACKGROUND: The UK Medical Certificate of Stillbirth (MCS) records information relevant to the cause of stillbirth of infants ≥24 weeks' gestation. A cross-sectional audit demonstrated widespread inaccuracies in MCS completion in 2009 in North West England. A repeat study was conducted to assess whether practice had improved following introduction of a regional care pathway. METHODS: 266 MCS issued in 14 North West England obstetric units during 2015 were studied retrospectively. Cause of death was assigned following review of information available at the time of MCS completion. This was compared to that documented on the MCS, and to data from 2009. RESULTS: Twenty-three certificates were excluded (20 inadequate data, 3 late miscarriages). 118/243 (49%) MCS contained major errors. Agreement between the MCS and adjudicated cause of stillbirth was fair (Kappa 0.31; 95% CI 0.24, 0.38) and unchanged from 2009 (0.29). In 2015, excluding 34 terminations of pregnancy, the proportion of MCSs documenting "unexplained" stillbirths (113/211; 54%) was reduced compared to 2009 (158/213; 74%); causality could be assigned after case note review in 78% cases. Recognition of fetal growth restriction (FGR) as a cause of stillbirth improved (2015: 30/211; 14% vs 2009: 1/213; 0.5%), although 71% cases were missed. 47% MCSs following termination of pregnancy documented an iatrogenic primary cause of death. CONCLUSIONS: Completion of MCSs remains inaccurate, particularly in recognition of FGR as a cause of stillbirth. Detailed case note review before issuing the MCS could dramatically improve the usefulness of included information; evaluation of practitioner education programmes/internal feedback systems are recommended.

Ultrasound for fetal assessment in early pregnancy.

BACKGROUND: Diagnostic ultrasound is a sophisticated electronic technology, which utilises pulses of high-frequency sound to produce an image. Diagnostic ultrasound examination may be employed in a variety of specific circumstances during pregnancy such as after clinical complications, or where there are concerns about fetal growth. Because adverse outcomes may also occur in pregnancies without clear risk factors, assumptions have been made that routine ultrasound in all pregnancies will prove beneficial by enabling earlier detection and improved management of pregnancy complications. Routine screening may be planned for early pregnancy, late gestation, or both. The focus of this review is routine early pregnancy ultrasound. OBJECTIVES: To assess whether routine early pregnancy ultrasound for fetal assessment (i.e. its use as a screening technique) influences the diagnosis of fetal malformations, multiple pregnancies, the rate of clinical interventions, and the incidence of adverse fetal outcome when compared with the selective use of early pregnancy ultrasound (for specific indications). SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 March 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Published, unpublished, and ongoing randomised controlled trials that compared outcomes in women who experienced routine versus selective early pregnancy ultrasound (i.e. less than 24 weeks' gestation). We have included quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We used the Review Manager software to enter and analyse data. MAIN RESULTS: Routine/revealed ultrasound versus selective ultrasound/concealed: 11 trials including 37,505 women. Ultrasound for fetal assessment in early pregnancy reduces the failure to detect multiple pregnancy by 24 weeks' gestation (risk ratio (RR) 0.07, 95% confidence interval (CI) 0.03 to 0.17; participants = 295; studies = 7), moderate quality of evidence). Routine scans improve the detection of major fetal abnormality before 24 weeks' gestation (RR 3.46, 95% CI 1.67 to 7.14; participants = 387; studies = 2,moderate quality of evidence). Routine scan is associated with a reduction in inductions of labour for 'post term' pregnancy (RR 0.59, 95% CI 0.42 to 0.83; participants = 25,516; studies = 8), but the evidence related to this outcome is of low quality, because most of the pooled effect was provided by studies with design limitation with presence of heterogeneity (I² = 68%). Ultrasound for fetal assessment in early pregnancy does not impact on perinatal death (defined as stillbirth after trial entry, or death of a liveborn infant up to 28 days of age) (RR 0.89, 95% CI 0.70 to 1.12; participants = 35,735; studies = 10, low quality evidence). Routine scans do not seem to be associated with reductions in adverse outcomes for babies or in health service use by mothers and babies. Long-term follow-up of children exposed to scan in utero does not indicate that scans have a detrimental effect on children's physical or cognitive development.The review includes several large, well-designed trials but lack of blinding was a problem common to all studies and this may have an effect on some outcomes. The quality of evidence was assessed for all review primary outcomes and was judged as moderate or low. Downgrading of evidence was based on including studies with design limitations, imprecision of results and presence of heterogeneity. AUTHORS' CONCLUSIONS: Early ultrasound improves the early detection of multiple pregnancies and improved gestational dating may result in fewer inductions for post maturity. Caution needs to be exercised in interpreting the results of aspects of this review in view of the fact that there is considerable variability in both the timing and the number of scans women received.

Use of biochemical tests of placental function for improving pregnancy outcome.

BACKGROUND: The placenta has an essential role in determining the outcome of pregnancy. Consequently, biochemical measurement of placentally-derived factors has been suggested as a means to improve fetal and maternal outcome of pregnancy. OBJECTIVES: To assess whether clinicians' knowledge of the results of biochemical tests of placental function is associated with improvement in fetal or maternal outcome of pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised, cluster-randomised or quasi-randomised controlled trials assessing the merits of the use of biochemical tests of placental function to improve pregnancy outcome.Studies were eligible if they compared women who had placental function tests and the results were available to their clinicians with women who either did not have the tests, or the tests were done but the results were not available to the clinicians. The placental function tests were any biochemical test of placental function carried out using the woman's maternal biofluid, either alone or in combination with other placental function test/s. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data and assessed trial quality. Authors of published trials were contacted for further information. MAIN RESULTS: Three trials were included, two quasi-randomised controlled trials and one randomised controlled trial. One trial was deemed to be at low risk of bias while the other two were at high risk of bias. Different biochemical analytes were measured - oestrogen was measured in one trial and the other two measured human placental lactogen (hPL). One trial did not contribute outcome data, therefore, the results of this review are based on two trials with 740 participants.There was no evidence of a difference in the incidence of death of a baby (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.36 to 2.13, two trials, 740 participants (very low quality evidence)) or the frequency of a small-for-gestational-age infant (RR 0.44, 95% CI 0.16 to 1.19, one trial, 118 participants (low quality evidence)).In terms of this review's secondary outcomes, there was no evidence of a clear difference between women who had biochemical tests of placental function compared with standard antenatal care for the incidence of stillbirth (RR 0.56, 95% CI 0.16 to 1.88, two trials, 740 participants (very low quality evidence)) or neonatal death (RR 1.62, 95% CI 0.39 to 6.74, two trials, 740 participants, very low quality evidence)) although the directions of any potential effect were in opposing directions. There was no evidence of a difference between groups in elective delivery (RR 0.98, 95% CI 0.84 to 1.14, two trials, 740 participants (low quality evidence)), caesarean section (one trial, RR 0.48, 95% CI 0.15 to 1.52, one trial, 118 participants (low quality evidence)), change in anxiety score (mean difference -2.40, 95% CI -4.78 to -0.02, one trial, 118 participants), admissions to neonatal intensive care (RR 0.32, 95% CI 0.03 to 3.01, one trial, 118 participants), and preterm birth before 37 weeks' gestation (RR 2.90, 95% CI 0.12 to 69.81, one trial, 118 participants). One trial (118 participants) reported that there were no cases of serious neonatal morbidity. Maternal death was not reported.A number of this review's secondary outcomes relating to the baby were not reported in the included studies, namely: umbilical artery pH < 7.0, neonatal intensive care for more than seven days, very preterm birth (< 32 weeks' gestation), need for ventilation, organ failure, fetal abnormality, neurodevelopment in childhood (cerebral palsy, neurodevelopmental delay). Similarly, a number of this review's maternal secondary outcomes were not reported in the included studies (admission to intensive care, high dependency unit admission, hospital admission for > seven days, pre-eclampsia, eclampsia, and women's perception of care). AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of biochemical tests of placental function to reduce perinatal mortality or increase identification of small-for-gestational-age infants. However, we were only able to include data from two studies that measured oestrogens and hPL. The quality of the evidence was low or very low.Two of the trials were performed in the 1970s on women with a variety of antenatal complications and this evidence cannot be generalised to women at low-risk of complications or groups of women with specific pregnancy complications (e.g. fetal growth restriction). Furthermore, outcomes described in the 1970s may not reflect what would be expected at present. For example, neonatal mortality rates have fallen substantially, such that an infant delivered at 28 weeks would have a greater chance of survival were those studies repeated; this may affect the primary outcome of the meta-analysis.With data from just two studies (740 women), this review is underpowered to detect a difference in the incidence of death of a baby or the frequency of a small-for-gestational-age infant as these have a background incidence of approximately 0.75% and 10% of pregnancies respectively. Similarly, this review is underpowered to detect differences between serious and/or rare adverse events such as severe neonatal morbidity. Two of the three included studies were quasi-randomised, with significant risk of bias from group allocation. Additionally, there may be performance bias as in one of the two studies contributing data, participants receiving standard care did not have venepuncture, so clinicians treating participants could identify which arm of the study they were in. Future studies should consider more robust randomisation methods and concealment of group allocation and should be adequately powered to detect differences in rare adverse events.The studies identified in this review examined two different analytes: oestrogens and hPL. There are many other placental products that could be employed as surrogates of placental function, including: placental growth factor (PlGF), human chorionic gonadotrophin (hCG), plasma protein A (PAPP-A), placental protein 13 (PP-13), pregnancy-specific glycoproteins and progesterone metabolites and further studies should be encouraged to investigate these other placental products. Future randomised controlled trials should test analytes identified as having the best predictive reliability for placental dysfunction leading to small-for-gestational-age infants and perinatal mortality.

Evaluation of the quality of guidelines for the management of reduced fetal movements in UK maternity units.

BACKGROUND: The development of evidence-based guidelines is a key step in ensuring that maternity care is of a universally high standard. To influence patient care national and international guidelines need to be interpreted and implemented locally. In 2011, the Royal College of Obstetricians and Gynaecologists published guidelines for the management of reduced fetal movements (RFM), which can be an important symptom of fetal compromise. Following dissemination it was anticipated that this guidance would be implemented in UK maternity units. This study aimed to assess the quality of local guidelines for the management of RFM in comparison to published national standards. METHODS: Cross-sectional survey of maternity unit guidelines for RFM. The guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Tool and scored by two independent investigators. Two national guidelines were used as standards to evaluate unit guidelines. RESULTS: Responses were received from 98 units (42%); 12 units had no guideline. National guidelines scored highly using the AGREE II tool but there was wide variation in the quality of individual maternity unit guidelines, which were frequently of low quality. No guidelines incorporated all the recommendations from the national guideline. Maternity unit guidelines performed well for clarity and presentation but had low scores for stakeholder involvement, rigour of development and applicability. CONCLUSIONS: In contrast to national evidence based guidance the quality of maternity unit guidelines for RFM is variable and frequently of low quality. To increase quality, guidelines need to include up to date evidence and audit standards which could be taken directly from national evidence-based guidance. Barriers to local implementation and resource implications need to be taken into consideration. Training may also improve the implementation of the guideline. Research is needed to inform strategies to realize the benefits of clinical guidance in practice.

Assessing the association between oral hygiene and preterm birth by quantitative light-induced fluorescence.

The aim of this study was to investigate the purported link between oral hygiene and preterm birth by using image analysis tools to quantify dental plaque biofilm. Volunteers (n = 91) attending an antenatal clinic were identified as those considered to be "at high risk" of preterm delivery (i.e., a previous history of idiopathic preterm delivery, case group) or those who were not considered to be at risk (control group). The women had images of their anterior teeth captured using quantitative light-induced fluorescence (QLF). These images were analysed to calculate the amount of red fluorescent plaque (ΔR%) and percentage of plaque coverage. QLF showed little difference in ΔR% between the two groups, 65.00% case versus 68.70% control, whereas there was 19.29% difference with regard to the mean plaque coverage, 25.50% case versus 20.58% control. A logistic regression model showed a significant association between plaque coverage and case/control status (P = 0.031), controlling for other potential predictor variables, namely, smoking status, maternal age, and body mass index (BMI).

A randomised controlled trial comparing standard or intensive management of reduced fetal movements after 36 weeks gestation--a feasibility study.

BACKGROUND: Women presenting with reduced fetal movements (RFM) in the third trimester are at increased risk of stillbirth or fetal growth restriction. These outcomes after RFM are related to smaller fetal size on ultrasound scan, oligohydramnios and lower human placental lactogen (hPL) in maternal serum. We performed this study to address whether a randomised controlled trial (RCT) of the management of RFM was feasible with regard to: i) maternal recruitment and retention ii) patient acceptability, iii) adherence to protocol. Additionally, we aimed to confirm the prevalence of poor perinatal outcomes defined as: stillbirth, birthweight <10th centile, umbilical arterial pH <7.1 or unexpected admission to the neonatal intensive care unit. METHODS: Women with RFM ≥36 weeks gestation were invited to participate in a RCT comparing standard management (ultrasound scan if indicated, induction of labour (IOL) based on consultant decision) with intensive management (ultrasound scan, maternal serum hPL, IOL if either result was abnormal). Anxiety was assessed by state-trait anxiety index (STAI) before and after investigations for RFM. Rates of protocol compliance and IOL for RFM were calculated. Participant views were assessed by questionnaires. RESULTS: 137 women were approached, 120 (88%) participated, 60 in each group, 2 women in the standard group did not complete the study. 20% of participants had a poor perinatal outcome. All women in the intensive group had ultrasound assessment of fetal size and liquor volume vs. 97% in the standard group. 50% of the intensive group had IOL for abnormal scan or low hPL after RFM vs. 26% of controls (p < 0.01). STAI reduced for all women after investigations, but this reduction was greater in the standard group (p = 0.02). Participants had positive views about their involvement in the study. CONCLUSION: An RCT of management of RFM is feasible with a low rate of attrition. Investigations decrease maternal anxiety. Participants in the intensive group were more likely to have IOL for RFM. Further work is required to determine the likely level of intervention in the standard care arm in multiple centres, to develop additional placental biomarkers and to confirm that the composite outcome is valid. TRIAL REGISTRATION: ISRCTN07944306.

Effect of encouraging awareness of reduced fetal movement and subsequent clinical management on pregnancy outcome: a systematic review and meta-analysis.

OBJECTIVE: Reduced fetal movement, defined as a decrease in the frequency or strength of fetal movements as perceived by the mother, is a common reason for presentation to maternity care. Observational studies have demonstrated an association between reduced fetal movement and stillbirth and fetal growth restriction related to placental insufficiency. However, individual intervention studies have described varying results. This systematic review and meta-analysis aimed to determine whether interventions aimed at encouraging awareness of reduced fetal movement and/or improving its subsequent clinical management reduce the frequency of stillbirth or other important secondary outcomes. DATA SOURCES: Searches were conducted in MEDLINE, Embase, CINAHL, The Cochrane Library, Web of Science, and Google Scholar. Guidelines, trial registries, and gray literature were also searched. Databases were searched from inception to January 20, 2022. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and controlled nonrandomized studies were eligible if they assessed interventions aimed at encouraging awareness of fetal movement or fetal movement counting and/or improving the subsequent clinical management of reduced fetal movement. Eligible populations were singleton pregnancies after 24 completed weeks of gestation. The primary review outcome was stillbirth; a number of secondary maternal and neonatal outcomes were specified in the review. METHODS: Risk of bias was assessed using the Cochrane Risk of Bias 2 and Risk of Bias in Non-Randomized Studies I tools for randomized controlled trials and nonrandomized studies, respectively. Variation caused by heterogeneity was assessed using I2. Data from studies employing similar interventions were combined using random effects meta-analysis. RESULTS: A total of 1609 citations were identified; 190 full-text articles were evaluated against the inclusion criteria, 18 studies (16 randomized controlled trials and 2 nonrandomized studies) were included. The evidence is uncertain about the effect of encouraging awareness of fetal movement on stillbirth when compared with standard care (2 studies, n=330,084) with a pooled adjusted odds ratio of 1.19 (95% confidence interval, 0.96-1.47). Interventions for encouraging awareness of fetal movement may be associated with a reduction in neonatal intensive care unit admissions and Apgar scores of <7 at 5 minutes of age and may not be associated with increases in cesarean deliveries or induction of labor. The evidence is uncertain about the effect of encouraging fetal movement counting on stillbirth when compared with standard care with a pooled odds ratio of 0.69 (95% confidence interval, 0.18-2.65) based on data from 3 randomized controlled trials (n=70,584). Counting fetal movements may increase maternal-fetal attachment and decrease anxiety when compared with standard care. When comparing combined interventions of fetal movement awareness and subsequent clinical management with standard care (1 study, n=393,857), the evidence is uncertain about the effect on stillbirth (adjusted odds ratio, 0.86; 95% confidence interval, 0.70-1.05). CONCLUSION: The effect of interventions for encouraging awareness of reduced fetal movement alone or in combination with subsequent clinical management on stillbirth is uncertain. Encouraging awareness of fetal movement may be associated with reduced adverse neonatal outcomes without an increase in interventions in labor. The meta-analysis was hampered by variations in interventions, outcome reporting, and definitions. Individual studies are frequently underpowered to detect a reduction in severe, rare outcomes and no studies were included from high-burden settings. Studies from such settings are needed to determine whether interventions can reduce stillbirth.

Do medical certificates of stillbirth provide accurate and useful information regarding the cause of death?

Stillbirth affects one in 200 pregnancies in the UK. Understanding the causes of stillbirth is essential to reducing perinatal mortality. Stillbirth certificates represent a potential source of data on perinatal mortality. We aimed to assess whether the information on stillbirth certificates used in the UK is accurate. A retrospective cross-sectional audit of stillbirth certificates issued in a geographical region of the UK in 2009 was undertaken. Data were recorded from the stillbirth certificate and health records. The cause of death was classified using the ReCoDe system. Two hundred and thirteen stillbirth certificates were issued for stillbirths (feticides for fetal anomaly were excluded). Agreement for the primary factor associated with the stillbirth was fair (Kappa = 0.286). This contrasts with the gestation of stillbirth, which was almost complete agreement (Kappa = 0.883). The majority of stillbirths (58.7%) were classified on the certificate as 'unknown cause'. A proportion of 9.4% of stillbirths were classified as congenital anomaly and 8.0% as placental abruption. Only 0.5% of stillbirth certificates cited fetal growth restriction as a relevant condition contributing to death. A total of 49.6% of 'unexplained' stillbirths were associated with fetal growth restriction on review. Errors were present in 77.9% of certificates, including missing co-morbidities (55.9%) and the wrong cause of death (40.4%). The cause(s) of death is (are) not recorded accurately on the UK medical certificate of stillbirth, and the majority of certificates contain one or more errors. Training is required to improve understanding of the causes of stillbirth and completion of medical certificates. Data recorded directly from medical certificate of stillbirths are not sufficiently reliable for descriptive studies of causation and epidemiology.

Specialised antenatal clinics for women with a pregnancy at high risk of preterm birth (excluding multiple pregnancy) to improve maternal and infant outcomes.

BACKGROUND: Amongst the risk factors for preterm birth, previous preterm delivery is a strong predictor. Specialised clinics for women with a history of spontaneous preterm delivery have been advocated as a way of improving outcomes for women and their infants. OBJECTIVES: To assess using the best available evidence, the value of specialised antenatal clinics for women with a pregnancy at high risk of preterm delivery when compared with 'standard' antenatal clinics. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2011). SELECTION CRITERIA: All published, unpublished, and ongoing randomised controlled trials (including cluster-randomised trials) examining specialised compared with standard antenatal clinic care for women with a singleton pregnancy considered at high risk of preterm labour. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: We included three trials with 3400 women, all carried out in the USA. All focused on specialised clinics for women at high risk of preterm birth. Gestational age at delivery, preterm delivery, or both were primary outcomes in all studies. The interventions in the three trials differed.Overall there was very little data on our prespecified outcomes. For most outcomes a single study provided data, hence there was not the statistical power to detect any possible differences between groups. There was no clear evidence that specialised antenatal clinics reduce the number of preterm births. AUTHORS' CONCLUSIONS: Specialised antenatal clinics are now an accepted part of care in many settings, and carrying out further randomised trials may not be possible. Any future research in this area should include psychological outcomes and should focus on which aspects of service provision are preferred by women. Such research could underpin further service development in this area.

Young women's and midwives' perspectives on improving nutritional support in pregnancy: The babies, eating, and LifestyLe in adolescence (BELLA) study.

RATIONALE: Teenage pregnancy has a high risk of poor outcomes for both mother and baby. Teenage girls have the poorest diets of any population group in the UK, which compounds the risk of poor pregnancy outcomes. Pregnant teenagers trust advice from their midwives, but midwives feel they do not have time, confidence, or knowledge to discuss nutrition. OBJECTIVE: This study examined how the relationship between pregnant teenagers and their midwives could be utilised to deliver support to improve diet quality. METHOD: Qualitative interviews were conducted across three urban sites in the UK: Manchester, Doncaster, and Southampton with adolescent mothers and their midwives regarding diet and lifestyle, and what form of support would be helpful. In total, 106 young women and 20 midwives were interviewed. Most of the young mothers were 19 or younger (67%). Half had had their first child in the past year (52%) and 21% were pregnant during the study. Thematic analysis was used to identify ways to better support young mothers to eat well. RESULTS: Young women found it difficult to prioritise healthy eating; they often felt isolated and not in control of their own lives and wanted support from their midwife. Midwives felt that it was their role to support young mothers with diet in pregnancy but were anxious about initiating conversations and felt they lacked clear guidance. CONCLUSIONS: Pregnant teenagers and their midwives lack reliable resources and strategies for healthy eating support. An effective intervention to improve pregnant teenagers' diet quality must empower, inform, and motivate young mothers and their midwives, and enable connections between young mothers.

Adiposity and cardiovascular outcomes in three-year-old children of participants in UPBEAT, an RCT of a complex intervention in pregnant women with obesity.

BACKGROUND: Maternal obesity is associated with offspring cardiometabolic risk. UPBEAT was a randomised controlled trial of an antenatal diet and physical activity intervention in 1555 women with obesity. The intervention was associated with lower gestational weight gain, healthier diet and metabolic profile in pregnancy, and reduced infant adiposity at six months. OBJECTIVE: We have investigated whether the UPBEAT intervention influenced childhood cardiometabolic outcomes or was associated with sustained improvements in maternal lifestyle 3-years after delivery. METHODS: In UPBEAT mother-child dyads at the 3-year follow-up, we assessed childhood blood pressure, resting pulse rate, and adiposity (body mass index, skinfold thicknesses, body fat, waist and arm circumferences) and maternal diet, physical activity, and anthropometry. RESULTS: 514 three-year-old children attended the appointment (49% intervention, 51% standard care). There was no difference in the main outcome of interest, subscapular skinfold thickness, between the trial arms (-0.30 mm, 95% confidence interval: -0.92, 0.31). However, the intervention was associated with a lower resting pulse rate (-5 bpm [-8.41, -1.07]). There was also a non-significant lower odds of overweight/obesity (OR 0.73; 0.50, 1.08). Maternal dietary improvements observed in the UPBEAT trial, including glycaemic load and saturated fat were maintained 3-years postpartum. CONCLUSION: This study has demonstrated that an antenatal dietary and physical activity intervention in women with obesity is associated with lower offspring pulse rate and sustained improvement in maternal diet. Whilst larger than previous cohorts, there remains potential for bias from attrition and these findings require validation in future cohorts.

Ultrasound for fetal assessment in early pregnancy.

BACKGROUND: Diagnostic ultrasound is a sophisticated electronic technology, which utilises pulses of high frequency sound to produce an image. Diagnostic ultrasound examination may be employed in a variety of specific circumstances during pregnancy such as after clinical complications, or where there are concerns about fetal growth. Because adverse outcomes may also occur in pregnancies without clear risk factors, assumptions have been made that routine ultrasound in all pregnancies will prove beneficial by enabling earlier detection and improved management of pregnancy complications. Routine screening may be planned for early pregnancy, late gestation, or both. The focus of this review is routine early pregnancy ultrasound. OBJECTIVES: To assess whether routine early pregnancy ultrasound for fetal assessment (i.e. its use as a screening technique) influences the diagnosis of fetal malformations, multiple pregnancies, the rate of clinical interventions, and the incidence of adverse fetal outcome when compared with the selective use of early pregnancy ultrasound (for specific indications). SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (September 2009). SELECTION CRITERIA: Published, unpublished, and ongoing randomised controlled trials that compared outcomes in women who experienced routine versus selective early pregnancy ultrasound (i.e. less than 24 weeks' gestation). We have included quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data for each included study. We used the Review Manager software to enter and analyse data. MAIN RESULTS: Routine/revealed ultrasound versus selective ultrasound/concealed: 11 trials including 37505 women. Ultrasound for fetal assessment in early pregnancy reduces the failure to detect multiple pregnancy by 24 weeks' gestation (risk ratio (RR) 0.07, 95% confidence interval (CI) 0.03 to 0.17). Routine scan is associated with a reduction in inductions of labour for 'post term' pregnancy (RR 0.59, 95% CI 0.42 to 0.83). Routine scans do not seem to be associated with reductions in adverse outcomes for babies or in health service use by mothers and babies. Long-term follow up of children exposed to scan in utero does not indicate that scans have a detrimental effect on children's physical or cognitive development. AUTHORS' CONCLUSIONS: Early ultrasound improves the early detection of multiple pregnancies and improved gestational dating may result in fewer inductions for post maturity. Caution needs to be exercised in interpreting the results of aspects of this review in view of the fact that there is considerable variability in both the timing and the number of scans women received.

The design of a community lifestyle programme to improve the physical and psychological well-being of pregnant women with a BMI of 30 kg/m2 or more.

BACKGROUND: Obesity is a global public health issue. Having a BMI of 30 kg/m2 or more (classifying a person as obese) at the start of pregnancy is a significant risk factor for maternal and fetal morbidity. There is a dearth of evidence to inform suitable interventions to support pregnant women with a BMI of 30 kg/m2 or more. Here we describe a study protocol to test the feasibility of a variety of potential healthy lifestyle interventions for pregnant women with a BMI of 30 kg/m2 or more in a community based programme. METHODS/DESIGN: Four hundred women will be approached to attend a 10-week community lifestyle programme. The programme will be provided as a supplement to standard antenatal care. The programme is multi-faceted, aimed at equipping participants with the skills and knowledge needed to adopt healthy behaviours. The social (cognitive) learning theory will be used as a tool to encourage behaviour change, the behaviour change techniques are underpinned by five theoretical components; self-efficacy, outcome expectancies, goal setting, feedback and positive reinforcement.The main outcomes are pregnancy weight gain and caesarean section rate. Other important outcomes include clinical outcomes (e.g., birth weight) and psychological outcomes (e.g., well-being). Secondary outcomes include women's experience of pregnancy and health care services, amount of physical activity, food intake and the suitability of the intervention components.A prospective study using quantitative and qualitative methods will inform the feasibility of implementing the community lifestyle programme with pregnant women with a BMI of 30 kg/m2 or more. Mixed methods of data collection will be used, including diaries, focus groups/interviews, pedometers, validated and specifically designed questionnaires, a programme register, weight gain during pregnancy and perinatal outcome data. DISCUSSION: Findings from this current feasibility study will inform future interventions and NHS services and add to the evidence-base by providing information about the experiences of pregnant women with a BMI of 30 kg/m2 or more undertaking a community lifestyle programme. The study will lead on to a randomised control trial of a suitable intervention to improve the pregnancy outcomes of this target group.

Routine pre-pregnancy health promotion for improving pregnancy outcomes.

BACKGROUND: A number of potentially modifiable risk factors are known to be associated with poor pregnancy outcomes. These include smoking, drinking excess alcohol, and poor nutrition. Routine health promotion (encompassing education, advice and general health assessment) in the pre-pregnancy period has been proposed for improving pregnancy outcomes by encouraging behavioural change, or allowing early identification of risk factors. While results from observational studies have been encouraging, this review examines evidence from randomised controlled trials of preconception health promotion. OBJECTIVES: To assess the effectiveness of routine pre-pregnancy health promotion for improving pregnancy outcomes when compared with no pre-pregnancy care or usual care. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (February 2009). SELECTION CRITERIA: Randomised and quasi-randomised trials examining health promotion interventions which aim to identify and modify risk factors before pregnancy. The review focuses on all women of childbearing age rather than those in high-risk groups. We have excluded trials where interventions are aimed specifically at women with established medical, obstetric or genetic risks or already receiving treatment as part of programmes for high-risk groups. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and carried out data extraction. MAIN RESULTS: Four trials (2300 women) are included. The interventions ranged from brief advice through to education on health and lifestyle over several sessions. For most outcomes, data were only available from individual studies. Only one study followed up through pregnancy and there was no strong evidence of a difference between groups for preterm birth, congenital anomalies or weight for gestational age; only one finding (mean birthweight) reached statistical significance (mean difference -97.00, 95% confidence interval (CI) -168.05 to -25.95). This finding needs to be interpreted with caution as pregnancy outcome data were available for only half of the women randomised. There was some evidence that health promotion interventions were associated with positive maternal behavioural change including lower rates of binge drinking (risk ratio 1.24, 95% CI 1.06 to 1.44). Overall, there has been little research in this area and there is a lack of evidence on the effects of pre-pregnancy health promotion on pregnancy outcomes. AUTHORS' CONCLUSIONS: There is little evidence on the effects of pre-pregnancy health promotion and much more research is needed in this area. There is currently insufficient evidence to recommend the widespread implementation of routine pre-pregnancy health promotion for women of childbearing age, either in the general population or between pregnancies.

Relationships between Maternal Obesity and Maternal and Neonatal Iron Status.

: Obesity in pregnancy may negatively influence maternal and infant iron status. The aim of this study was to examine the association of obesity with inflammatory and iron status in both mother and infant in two prospective studies in pregnancy: UPBEAT and SCOPE. Maternal blood samples from obese (n = 245, BMI ≥ 30 kg/m²) and normal weight (n = 245, BMI < 25 kg/m²) age matched pregnant women collected at approximately 15 weeks' gestation, and umbilical cord blood samples collected at delivery, were analysed for a range of inflammatory and iron status biomarkers. Concentrations of C- reactive protein and Interleukin-6 in obese women compared to normal weight women were indicative of an inflammatory response. Soluble transferrin receptor (sTfR) concentration [18.37 nmol/L (SD 5.65) vs 13.15 nmol/L (SD 2.33)] and the ratio of sTfR and serum ferritin [1.03 (SD 0.56) vs 0.69 (SD 0.23)] were significantly higher in obese women compared to normal weight women (P < 0.001). Women from ethnic minority groups (n = 64) had higher sTfR concentration compared with white women. There was no difference in maternal hepcidin between obese and normal weight women. Iron status determined by cord ferritin was not statistically different in neonates born to obese women compared with neonates born to normal weight women when adjusted for potential confounding variables. Obesity is negatively associated with markers of maternal iron status, with ethnic minority women having poorer iron statuses than white women.

Regulation of fibroblast growth factor-2 activity by human ovarian cancer tumor endothelium.

Fibroblast growth factor-2 (FGF-2) is a potent angiogenic cytokine that is dependent on heparan sulfate for its biological activity. We have investigated the relationship among heparan sulfate, FGF-2, and the signal-transducing receptors in human, advanced-stage, serous ovarian adenocarcinoma. Using a unique molecular probe, FR1c-Ap, which consisted of a soluble FGF receptor 1 isoform IIIc covalently linked to an alkaline phosphatase moiety, the distribution of heparan sulfate that had the ability to support the formation of a heparan sulfate/FGF-2/FGFR1 isoform IIIc alkaline phosphatase heparan sulfate construct complex was determined. This may be taken as a surrogate marker for the distribution of biologically active heparan sulfate and was distributed predominantly in endothelial cells and stroma but was absent from adenocarcinoma cells. In situ hybridization revealed the expression of FGFR1 mRNA in the endothelium and reverse transcription-PCR confirmed the presence of FGFR1 isoform IIIc but not isoform IIIb. The presence of FGF-2 around tumor endothelium was detected through immunohistochemistry. Double-staining techniques showed that heparan sulfate was found predominantly at the basal aspect of the endothelium and suggested that syndecan-3 might function as one of the proteoglycans involved in FGF-2 signaling in the endothelium. The data suggest that the entire extracellular signaling apparatus, consisting of FGF-2, biologically active heparan sulfate, and FGFRs capable of responding to FGF-2, is present in ovarian cancer endothelium, thereby highlighting the cytokine and its cognate receptor as potential targets for the antiangiogenic treatment of this disease.

Early Antenatal Prediction of Gestational Diabetes in Obese Women: Development of Prediction Tools for Targeted Intervention.

All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0-18+6 weeks' gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68-0.74). This increased to 0.77 (95%CI 0.73-0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74-0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most.

The feasibility phase of a community antenatal lifestyle programme [The Lifestyle Course (TLC)] for women with a body mass index (BMI)≥ 30 kg/m(2.).

INTRODUCTION: maternal obesity [body mass index (BMI)≥30kg/m(2)] is a cause for concern because of increasing rates and risk of associated complications. However, little is known about how to improve the health of women with a BMI≥30kg/m(2). OBJECTIVE AND METHODS: a 10-week antenatal lifestyle programme (The Lifestyle Course - TLC), underpinned by behaviour change theory, was developed in a programme of research which included a prospective, multicentred, feasibility phase (n=227). Participants had a BMI≥30kg/m(2) at the start of their pregnancy, planned to deliver in two areas of Greater Manchester and were aged 18 or over. The objectives were to (1) assess the feasibility of the intervention and (2) to pilot the trial processes and outcome measures. FINDINGS: (1) Trial intervention: only 22% of women in the feasibility phase had received gestational weight advice prior to the study. One or more TLC sessions were attended by 79% of women and 97% said they would recommend TLC to a friend due to the content suitability, perceived personal gains and extra care received. Changes to the TLC were suggested and implemented in the pilot phase. (2) Trial processes: recruitment rates (36%), retention rates (100%) and questionnaire completion rates up to one year (33%) were found. Daily general 'lifestyle' diaries and pedometers were not acceptable data collection tools (response rates of 32% and 16% respectively). However, specific food diaries were acceptable (response rates of 80-81%). The major challenge was the collection of maternal weight data at the follow-up points. CONCLUSIONS AND IMPLICATIONS: the antenatal intervention (TLC) designed for this programme of work appears to suit the needs of women with a BMI≥30kg/m(2). The need for an antenatal intervention is clear from this study and also highlights reflections on effective communication with pregnant women with a BMI≥30kg/m(2). Lessons learnt for designing a future trial include effective ways to communicate with pregnant women with a BMI≥30kg/m(2). TRIAL REGISTRATION: ISRCTN29860479.