Inherited susceptibility to miscarriage: a nested case-control study of 31,565 women from an intergenerational cohort.

BACKGROUND: Miscarriage can be a devastating outcome for couples, and most miscarriages are unexplained. Many adverse obstetric outcomes (such as preeclampsia, preterm birth, and growth restriction) are thought to be inherited. It is possible that these conditions could share similar pathophysiologic mechanisms (such as endothelial dysfunction) with miscarriage. Therefore, it was hypothesized that there could be a susceptibility to miscarriage transmitted from mother to daughter. OBJECTIVE: This study aimed to investigate the association between a maternal history of miscarriage and the risk of miscarriage in daughters. STUDY DESIGN: A case-control study nested within an intergenerational cohort was conducted. Mother-daughter pairs were identified from the intergenerational cohort within the Aberdeen Maternity and Neonatal Databank, United Kingdom. A mother's history of miscarriage was the exposure. The primary outcome was miscarriage in daughters. There were 31,565 mother-daughter pairs who were eligible for inclusion. A population average model that used generalized estimating equations with robust standard errors was used to estimate the odds of a mother's history of miscarriage in daughters with a miscarriage compared with daughters with only livebirths. This method accounted for clustering of daughters within mothers, and multiadjusted analyses were performed to include confounders at the daughter's pregnancy level. RESULTS: Daughters who miscarried had 11% greater odds of being born to mothers with a history of miscarriage (adjusted odds ratio, 1.11; 95% confidence interval, 1.01-1.22). Daughters with recurrent miscarriage (≥2) were also more likely to be born to a mother with a history of miscarriage (adjusted odds ratio, 1.25; 95% confidence interval, 1.04-1.49). CONCLUSION: There may be an inherited predisposition to miscarriage transmitted from mother to daughter. Future research should investigate genetic or familial environmental factors that may predispose women to miscarriage.

Inherited predisposition to stillbirth: an intergenerational analysis of 26,788 mother-daughter pairs.

BACKGROUND: Previous evidence suggests that placental dysfunction, which includes preeclampsia, is inherited from mother to daughter, but heritability of stillbirth has never been investigated. OBJECTIVE: The purpose of this study was to investigate whether there is an inherited predisposition to stillbirth that is transmitted from mother to daughter. STUDY DESIGN: We carried out a nested case-control study within the intergenerational cohort held in the Aberdeen Maternity and Neonatal Databank. All mothers who had at least 1 daughter in Aberdeen, United Kingdom, between 1949 and 2000 were included. Mother-daughter pairs were linked with the use of the Scottish Community Health Index number. The main exposure was the mother's history of stillbirth. The primary outcome was stillbirth in any of the daughter's pregnancies. A population average model that used generalized estimating equations with robust standard errors was used to estimate odds of a mother's history of stillbirth in daughters with a stillbirth compared with daughters with only livebirths. This method accounted for clustering of daughters within mothers, and multi-adjusted analyses were performed to include confounders at the daughter's pregnancy level. RESULTS: Among the daughters, 384 had a history of ≥1 stillbirths (cases); 26,404 only ever had livebirths (control subjects). We found no statistically significant association between mothers' history of stillbirth (adjusted odds ratio, 0.63; 95% confidence interval, 0.24-1.63) or miscarriage (adjusted odds ratio, 1.01; 95% confidence interval, 0.71-1.42) and stillbirth in daughters. CONCLUSION: This is the first study to investigate an inherited predisposition to stillbirth. There was no evidence of an inherited predisposition to stillbirth transmitted from mother to daughter.

Development and piloting of a food-based intervention to increase vitamin E intake in pregnant women in a randomized controlled trial.

Low maternal vitamin E intake during pregnancy is associated with childhood asthma and a trial is required to test whether increasing maternal vitamin E intake reduces childhood asthma. This study investigated whether such a trial is possible using food to increase vitamin E intake. Three soup varieties with enhanced vitamin E content (16-19 mg/can) from food ingredients were developed. Near identical retail versions (vitamin E 1-4 mg/can) acted as placebo. In a pilot double-blind randomized controlled trial, pregnant women were randomized 1:1 to enhanced or placebo soups (three tins/week) from 12 weeks gestation to delivery. Vitamin E intake was quantified at 12, 20, and 34 weeks gestation. Qualitative interviews were conducted. 59 women were randomized (29 enhanced, 30 placebo), 28 completed the trial, (15 enhanced, 13 placebo). In women completing the trial, vitamin E intake of the placebo group remained unchanged; 7.09 mg/d (95% CI 5.41-8.77) at 12 weeks, 6.41 mg/d (5.07-7.75) at 20 weeks, and 6.67 mg/d (5.38-7.96) at 34 weeks gestation; vitamin E intake of the enhanced group increased from 6.50 mg/d (5.21-7.79) at 12 weeks to 14.9 mg/d (13.3-16.4) at 20 weeks and 15.2 mg/d (12.9-17.5) at 34 weeks, P < 0.001. Qualitative interviewing provided clear guidance on improving adherence. Although 31 women withdrew at median 19 weeks gestation (interquartile range 16-25), the intervention was consumed by women for 80% of weeks between 12 and 34 weeks gestation and for 63% of weeks between 12 weeks gestation and delivery. In a pilot double-blind randomized controlled trial (RCT) it is possible to increase maternal vitamin E intake using food ingredients, a further food product is required to improve adherence.

Measurement of aortic augmentation index in pregnant women with raised blood pressure and subsequent outcomes: a preliminary prospective cohort study.

OBJECTIVE: Preeclampsia is associated with arterial dysfunction and augmentation index (AIX%) is an established indicator of arterial dysfunction. Our aim was to investigate the relationship of AIX% with time-to-delivery and other outcomes in women admitted to an antenatal triage unit. METHODS: We recruited 28 women with singleton pregnancies attending antenatal triage ward for assessment of hypertension. After 10 min rest, seated brachial blood pressure (Omron HEM-757) and AIX% (SphygmoCor applanation tonometry pulse wave analysis, PWA) were measured by a single investigator; other clinicians remained blinded to PWA results. Routine assessment included cardiotocography, urine analysis and blood tests. Subsequent outcomes were extracted from the obstetric records. RESULTS: Mean AIX% was 19.7% (SD 11.5; range -4% to +36%), maternal age 31 years, gestation 37 weeks, brachial BP 145/95, proteinuria 39%. Nine women had preeclampsia at assessment and six subsequently developed preeclampsia. Median time-to-delivery was 10 d (IQR 1.6-25 d) and was shorter for AIX% ≥ 20% (median 8.9 versus 19.8 d). AIX% was higher with preeclampsia (24.0%; SD 9.5) versus gestational hypertension (15.2%; SD 12.4); absolute difference 8.8% (95%CI 0.1-17.5; p = 0.05). A one-point higher AIX% (adjusted for age, urate and gestation) was associated with 0.3 d (95%CI -0.5 to 0.0; p = 0.06) reduced time-to-delivery. A higher AIX% was also associated with induction for preeclampsia, severe preeclampsia, peripartum-anti-hypertensives and discharge-on-anti-hypertensives. Area under the curve (AUC) for AIX% predicting preeclampsia was 0.80 (95%CI 0.59-1.00; p = 0.04). CONCLUSION: AIX% is associated with time-to-delivery and other outcomes in pregnancy.

Protease concentration in amniotic fluid at term and early childhood respiratory symptoms.

OBJECTIVE: Asthma is a common chronic disease associated with altered proteolytic activity. The present study tested the hypothesis that altered protease concentration in amniotic fluid (AF), an index of airway fluid at birth, precedes early cough and wheeze. METHODS: AF was collected and analysed for the following: matrix metalloproteinases (MMP) -2, -8 and -9, tissue inhibitor of metalloproteinases (TIMP) -1 and 2, plasminogen activator inhibitor (PAI)-1. Infant were followed up at ages 1, 2 and 3 years. RESULTS: Samples of AF were obtained in 92 infants. There were inconsistent and relatively small differences in some analytes between those individuals with and without symptoms at ages one and two years. PAI-1 concentrations were reduced in association with cough at age 1 year (p = 0.035). Reduced MMP-8:TIMP-2 ratio was associated with wheeze at age 2 years (p = 0.038). There were no associations between AF analytes and symptoms at 3 years of age. CONCLUSION: There is heterogeneity in concentrations of proteases and their inhibitors in airways at birth but in this exploratory study, there was no consistent evidence that protease concentration at birth was important to later respiratory symptoms.

Culture of airway epithelial cells from neonates sampled within 48-hours of birth.

INTRODUCTION: Little is known about how neonatal airway epithelial cell phenotype impacts on respiratory disease in later life. This study aimed to establish a methodology to culture and characterise neonatal nasal epithelial cells sampled from healthy, non-sedated infants within 48 hours of delivery. METHODS: Nasal epithelial cells were sampled by brushing both nostrils with an interdental brush, grown to confluence and sub-cultured. Cultured cells were characterised morphologically by light and electron microscopy and by immunocytochemistry. As an exemplar pro-inflammatory chemokine, IL-8 concentrations were measured in supernatants from unstimulated monolayers and after exposure to IL-1ß/TNF-α or house dust mite extract. RESULTS: Primary cultures were successfully established in 135 (91%) of 149 neonatal samples seeded, with 79% (n  =  117) successfully cultured to passage 3. The epithelial lineage of the cells was confirmed by morphological analysis and immunostaining. Constitutive IL-8 secretion was observed and was upregulated by IL-1ß/TNF-α or house dust mite extract in a dose dependent manner. CONCLUSION: We describe a safe, minimally invasive method of culturing nasal epithelial cells from neonates suitable for functional cell analysis offering an opportunity to study "naïve" cells that may prove useful in elucidating the role of the epithelium in the early origins of asthma and/or allergic rhinitis.

Instrumental vaginal deliveries; are midwives safer practitioners? A retrospective cohort study.

OBJECTIVE: To compare obstetric morbidity of midwife-performed instrumental vaginal deliveries with those performed by doctors. DESIGN: Retrospective cohort study. SETTING: University Hospital, UK. POPULATION: Women undergoing an instrumental vaginal delivery of a singleton infant outside of the operating theater in Aberdeen Maternity Hospital, between June 2005 and June 2010. METHODS: Prospectively entered data were obtained from the hospital data management system. Obstetric outcomes of deliveries by midwives were compared with those performed by any doctor and, in a secondary analysis, with those by junior doctors (fewer than two years at 'registrar' level). Sociodemographic characteristics and clinical outcomes were compared using the chi-squared test, Mann-Whitney U-test and independent sample t-test. MAIN OUTCOME MEASURES: Third- or fourth-degree tears. RESULTS: Among 2540 women identified, 330 (13%) were delivered by midwives. Maternal and clinical characteristics were comparable in each group. Midwives were more likely to use ventouse as their instrument of choice. Women delivered by midwives were less likely to suffer a third- or fourth-degree tears than those delivered by doctors and junior doctors. This difference did not reach statistical significance once adjusted for instrument used: odds ratio 0.6 (95% confidence interval: 0.3-1.2) and odds ratio 0.6 (95% confidence interval: 0.3-1.1), respectively. CONCLUSIONS: Instrumental vaginal deliveries performed by trained midwives are associated with equivalent maternal morbidity to those performed by doctors once adjusted for midwives' preference for the ventouse. This study highlights the potential contribution of an advanced role for midwives in the labor ward.

Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis.

BACKGROUND: Women with twin pregnancy are at high risk for spontaneous preterm delivery. Progesterone seems to be effective in reducing preterm birth in selected high-risk singleton pregnancies, albeit with no significant reduction in perinatal mortality and little evidence of neonatal benefit. We investigated the use of progesterone for prevention of preterm birth in twin pregnancy. METHODS: In this double-blind, placebo-controlled trial, 500 women with twin pregnancy were recruited from nine UK National Health Service clinics specialising in the management of twin pregnancy. Women were randomised, by permuted blocks of randomly mixed sizes, either to daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24 weeks' gestation. All study personnel and participants were masked to treatment assignment for the duration of the study. The primary outcome was delivery or intrauterine death before 34 weeks' gestation. Analysis was by intention to treat. Additionally we undertook a meta-analysis of published and unpublished data to establish the efficacy of progesterone in prevention of early (<34 weeks' gestation) preterm birth or intrauterine death in women with twin pregnancy. This study is registered, number ISRCTN35782581. FINDINGS: Three participants in each group were lost to follow-up, leaving 247 analysed per group. The combined proportion of intrauterine death or delivery before 34 weeks of pregnancy was 24.7% (61/247) in the progesterone group and 19.4% (48/247) in the placebo group (odds ratio [OR] 1.36, 95% CI 0.89-2.09; p=0.16). The rate of adverse events did not differ between the two groups. The meta-analysis confirmed that progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51). INTERPRETATION: Progesterone, administered vaginally, does not prevent preterm birth in women with twin pregnancy. FUNDING: Chief Scientist Office of the Scottish Government Health Directorate.

Smoking cessation in pregnancy.

BACKGROUND: Pregnant women who continue to smoke expose their developing fetus to a wide range of risks. Assisting these patients to stop smoking can be an important intervention for the health of the baby and the mother. The management of pregnant smokers can be challenging, due to the potential risks of pharmacotherapy. There are a number of options available to the clinician to aid smoking cessation in non pregnant women. These include nicotine replacement therapy (NRT), bupropion, varenicline, and a range of non-drug therapies. OBJECTIVE: To provide guidance to prescribers on the best way to manage smoking cessation in the pregnant patient, reviewing the risks and efficacy of the different approaches. METHODS: An extensive literature search was carried out to find original studies which examined issues surrounding the safety and efficacy of methods of smoking cessation in pregnancy. RESULTS/CONCLUSION: NRT is the agent of choice for smoking cessation in pregnancy as the safety of other therapies in pregnancy have not yet been proved.

B-Lynch sutures for major primary postpartum haemorrhage at caesarean section.

This was a retrospective observational study of 11 consecutive patients of major primary postpartum haemorrhage (PPH) who had the B-Lynch suture at the time of caesarean section, performed between 1 March 2001 and 31 March 2004 at a teaching hospital in Scotland. Case-note review was performed in 123 patients, who had major primary PPH to identify patients who had B-Lynch sutures at the time of caesarean section. The patient's age, parity, gestation of pregnancy at which the B-Lynch suture was performed, the indication for caesarean section and the cause of primary major PPH were recorded. The operative details, intraoperative and immediate postoperative complications and the need for subsequent hysterectomy were noted. The patients were followed-up with clinic visits at 6 weeks and any further hospital referral for late postoperative complications and whether subsequent successful pregnancy was achieved, were documented. The incidence of major PPH in our centre was 0.5% of the total deliveries, of which 11 cases had the B-Lynch suture applied at the time of caesarean section. The patients were aged between 25 and 38 years old (mean 31 years). Parity ranged from 0 to 1 and the gestational age at which the procedure was performed ranged from 34 to 41 weeks (mean 38 weeks). Ten operations (91%) were performed by senior registrars supervised by the consultant on call and one (9%) case was performed by a consultant on call. All cases had the B-Lynch sutures performed for major primary PPH caused by uterine atony at the time of caesarean section. The weight of the babies delivered ranged between 2,110 - 4,820 g (mean 3,500 g). The total blood loss at surgery ranged from 2,000 - 10,000 ml (mean 3,500 ml). Only three patients (28%) required hysterectomy. All the patients made a good postoperative recovery. The hospital stay ranged from 4 - 24 days (mean 8 days). The patient who remained in hospital for 24 days did so because her baby was admitted into the neonatal unit. All the patients were reviewed 6 weeks postnatally. There was no significant morbidity. A subsequent successful pregnancy has been achieved in one patient.

Oral misoprostol (100 microg) versus vaginal misoprostol (25 microg) in term labor induction: a randomized comparison.

OBJECTIVE: To compare the efficacy of vaginal misoprostol (25 microg) to oral misoprostol (100 microg) in labor induction at term. METHODS: One hundred and one women at term, with indications for labor induction and cervical Bishop's scores of less than 8, were randomly assigned to receive 100 microg of oral misoprostol or 25 microg vaginal misoprostol after random allocation. This could be repeated every 4 h to a maximum of five doses. The number delivering vaginally within 24 h of the induction was the main outcome measure. RESULTS: Of those who delivered vaginally (74.5% in the oral group vs. 72% in the vaginal group), significantly fewer women delivered within 24 h of induction in the oral group (42.1% vs. 72.2%, RR 0.6, 95% CI 0.4-0.9), with more women receiving more than one dose (45.7% vs. 16.7%, RR 2.7, 95% CI 1.2-6.0). More women in the oral group received oxytocin (68.6% vs. 44%, RR 1.6, 95% CI 1.1-2.2), and the induction to delivery interval was shorter in the vaginal group, although this was not statistically significant [28.9 h (SD 20.2) vs. 20.6 h (SD 16.1), mean difference - 8.3 h, 95% CI - 16.8 to 0.2]. There were no differences in the modes of delivery, uterine hyperstimulation rates or in the neonatal outcomes. CONCLUSION: Vaginal misoprostol in its currently recommended dose of 25 microg seems to be more efficacious than the 100 microg oral dose.

Sublingual compared with oral misoprostol in term labour induction: a randomised controlled trial.

OBJECTIVE: To compare the efficacy and patient acceptability of 50 microg of sublingual misoprostol with 100 microg of oral misoprostol in the induction of labour at term. DESIGN: Non-blinded randomised comparative trial. SETTING: Tertiary level UK Hospital. SAMPLE: Two hundred and fifty women at term with indications for labour induction. METHODS: Fifty micrograms of sublingual misoprostol or 100 microg of oral misoprostol was administered every four hours after random allocation, to a maximum of five doses. MAIN OUTCOME MEASURES: Number of patients delivering vaginally within 24 hours of the induction, mode of delivery, neonatal outcomes and patient acceptability. RESULTS: There was no significant difference in the number of women delivering vaginally within 24 hours of the induction in the sublingual group as compared with the oral group (62.8% vs 59%, RR 1.1, 95% CI 0.6-2.1), or in the mean induction to delivery time (21.8 vs 24.1 h, mean difference 2.3 h 95% CI -2.2 to +6.7). There was no difference in the uterine hyperstimulation rates (1.6% in both groups), operative delivery rates or neonatal outcomes. In the sublingual group, 92.6% found the induction acceptable with 15.8% finding the tablets with an unpleasant taste, while in the oral group it was 96.9% and 4%, respectively. More patients in the oral group thought that they would consider the same method of induction again as compared with the sublingual group (58.6% vs 40%, RR 1.4, 95% CI 1.04-1.9). CONCLUSION: Fifty micrograms of sublingual misoprostol every four hours has the same efficacy and safety profile as compared with 100 microg orally, but the oral route might be preferred by women.

A comparison of two dosage regimens of oral misoprostol for labor induction at term.

METHODS: 251 women with indications for labor induction at term were randomised to receive either 50 or 100 microgs of oral misoprostol, repeated every 4 h to a maximum of 5 doses. Parous women in the higher dose group received 50 microgs as their first dose, subsequent doses being 100 microgs. Women who failed to respond to the 5 doses of misoprostol had the option of having vaginal PGE2 gel. The primary outcome measure was the induction to delivery interval in those who delivered vaginally. Patient satisfaction was assessed by postnatal questionnaire. RESULTS: The induction to vaginal delivery interval, although shorter in the 100 microgs group was not statistically significant (26.8 versus 33.7 h, mean difference 6.9 h, 95% CI 0.4-13). There were, however, more failed inductions with misoprostol in the 50 microgs group (12.7% Vs 4.8%, RR 2.6, 95% CI 1.07-6.5). There were no differences in the modes of delivery, number of caesarean sections for fetal distress or in the neonatal outcomes in the two groups. Most patients, 83% and 92% in the 50 and 100 microgs, respectively, were satisfied with their inductions, and 64% of patients would prefer to have the inducing agent given orally if they were to have another induction. CONCLUSION: Oral misoprostol is effective in inducing labor and seems acceptable to patients. Both the 50 and 100 microgs dose regimens have a reasonable safety profile, but in view of the higher incidence of failed inductions with the 50 microgs dosage, the 100 microgs dose regimen may be the preferred dose regimen.

Sublingual misoprostol for the induction of labor at term.

OBJECTIVE: To evaluate the efficacy, safety, and patient acceptability of sublingual misoprostol compared with an equivalent dose administered orally for labor induction at term. STUDY DESIGN: One hundred women with medical or obstetric indications for induction of labor after 37 weeks of gestation and unfavorable cervices were randomized to receive 50 microg of misoprostol either orally or sublingually. The dose was repeated every 4 hours to a maximum of 5 doses if indicated. Previous cesarean delivery was a criteria for exclusion. Our primary outcome measure was the number of patients who went on to have a vaginal delivery within 24 hours of the induction. The need for oxytocin, mode of delivery, number of cesarean deliveries for fetal distress, uterine hyperstimulation rates, and neonatal outcomes were secondary outcome measures. Patient acceptability was assessed by questionnaires completed after delivery. RESULTS: Significantly more patients were delivered of infants within 24 hours (73.8% versus 45.7%; relative risk, 1.6; 95% confidence interval, 1.1 to 2.4) and the induction to delivery intervals were significantly shorter (20 hours versus 28.3 hours; mean difference, 8.3 hours; 95% confidence interval, 1.2 to 15.4) in the sublingual group compared with the oral group. There was 1 case of uterine hyperstimulation in the sublingual group. There were no significant differences in the mode of delivery, interventions for fetal distress, or neonatal outcomes in the 2 groups. The satisfaction rates were 82.5% and 85.7% in the oral and sublingual groups respectively, and 9.5% of patients thought that the sublingual tablets did not dissolve completely. CONCLUSION: There has been no previous report in the literature of misoprostol given sublingually for labor induction. Sublingual misoprostol seems to have better efficacy than oral misoprostol, seems to be acceptable to patients, and is an option to be considered to induce labor at term.