Time-varying effects are common in genetic control of gestational duration.

Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent-gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31 000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy 'clock'. We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new fetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm, periods and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant and should help design further experimental studies.

Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios.

Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25 000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (ROH) calling by maximizing the correlation between parental genetic relatedness and offspring ROHs. We then estimate the effect of maternal, paternal and fetal autozygosity and that of autozygosity mapping (common segments and gene burden test) on the timing of spontaneous onset of delivery. The correlation between offspring ROH using a variety of parameters and parental genetic relatedness ranged between -0.2 and 0.6, revealing the importance of the minimum number of genetic variants included in an ROH and the use of genetic distance. The optimized compared to predefined parameters showed a ≃45% higher correlation between parental genetic relatedness and offspring ROH. We found no evidence of an effect of maternal, paternal nor fetal overall autozygosity on spontaneous delivery timing. Yet, through autozygosity mapping, we identified three maternal loci TBC1D1, SIGLECs and EDN1 gene regions reducing the median time-to-spontaneous onset of delivery by ≃2-5% (P-value < 2.3 × 10-6). We also found suggestive evidence of a fetal locus at 3q22.2, near the RYK gene region (P-value = 2.0 × 10-6). Autozygosity mapping may provide new insights on the genetic determinants of delivery timing beyond traditional genome-wide association studies, but particular and rigorous attention should be given to ROH calling parameter selection.

The fetal cerebroplacental ratio in pregnancies complicated by hypertensive disorders of pregnancy.

BACKGROUND: Hypertensive disorder in pregnancy is common and the optimal ultrasound surveillance of the fetus in this setting is unclear. AIM: The aim of this study is to assess the relationship between the fetal cerebroplacental ratio (CPR) and perinatal outcomes in pregnancies complicated by maternal hypertension. MATERIALS AND METHODS: A retrospective cohort study was performed over ten years at a single centre. All women who had an ultrasound scan between 34 and 37 weeks gestation with a non-anomalous singleton pregnancy were included. The hypertensive cohorts were compared to a non-hypertensive cohort. Each cohort was divided into low CPR for gestational age, or normal/high CPR and these were correlated with intrapartum and perinatal outcomes. RESULTS: A low CPR in a hypertensive pregnancy is associated with an increased risk of induction of labour, emergency caesarean section and poor perinatal outcome. This significance persists when adjusted for gestational age and birth weight. The diagnosis of pre-eclampsia combined with a low CPR markedly increases the risk of poor perinatal outcome, with 52.6% (P < 0.001) of fetuses in this group having either neonatal intensive care unit admission, respiratory distress, low Apgar score, or acidosis. The odds ratio of a fetus with low CPR in a woman with pre-eclampsia having a poor composite outcome is 4.09 (95% CI: 1.85-9.06). CONCLUSION: There is an association between low CPR and the perinatal outcomes of pregnancies complicated by a hypertensive disorder. This association appears to be stronger in pregnancies complicated by pre-eclampsia than in other types of hypertensive disorders.

Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial.

BACKGROUND AND OBJECTIVE: Sildenafil citrate is a vasodilator used in erectile dysfunction and pulmonary hypertension. We tested whether it reduces emergency operative births for fetal compromise and improves fetal or uteroplacental perfusion in labor in a phase 2 double-blind randomized controlled trial. STUDY DESIGN: Women at term in early labor or undergoing scheduled induction of labor at Mater Mother's Hospital, Brisbane, Australia, were randomly allocated 50 mg of sildenafil citrate orally 8 hourly up to 150 mg or placebo. Intrapartum fetal monitoring followed Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines. Primary outcomes were (1) emergency operative birth (by cesarean delivery or instrumental vaginal birth) for intrapartum fetal compromise and (2) mean indices of fetal and uteroplacental perfusion using Doppler ultrasound. Analysis was by intention-to-treat. TRIAL REGISTRATION NUMBER: ANZCTRN12615000319572 RESULTS: Between September 2015 and January 2019, 300 women were randomized equally to sildenafil citrate or placebo. Sildenafil citrate reduced the risk of emergency operative birth by 51% (18% vs 36.7%; relative risk, 0.49, 95% confidence interval, 0.33-0.73, P=.0004, number needed to treat = 5 [3-11]). There was no difference in indices of fetal and uteroplacental perfusion, but these were ascertained in only 71 women. Sildenafil citrate reduced the risk of meconium-stained liquor or pathologic fetal heart rate patterns by 43% (25.3% vs 44.7%; relative risk, 0.57, 95% confidence interval, 0.41-0.79, P=.0005), but its effects on fetal scalp sampling rates (2.0% vs 6.7%; relative risk, 0.30, 95% confidence interval, 0.08-1.07, P=.06) and adverse neonatal outcome (20.7% vs 21.3%; relative risk, 0.97, 95% confidence interval, 0.62-1.50, P=.89) were inconclusive. Only 3.6% of maternal levels of sildenafil citrate or its metabolite were detected in cord blood. No differences in maternal adverse events were seen. CONCLUSION: Sildenafil citrate reduced operative birth for intrapartum fetal compromise, but much larger phase 3 trials of its effects on mother and child are needed before it can be routinely recommended.

An Epworth Sleep Score ≥11 is associated with emergency operative birth and poor neonatal composite outcome at term.

BACKGROUND: During pregnancy, the Epworth Sleepiness Scale can be used as a surrogate marker for maternal sleep-disordered breathing, a condition that is becoming increasingly prevalent in obstetric populations and is associated with a multitude of pregnancy complications. AIMS: The aim of this observational study was to investigate the relationship between the Epworth Sleepiness Scale score and indication and mode of delivery during pregnancy. MATERIALS AND METHODS: The Epworth Sleepiness Scale was completed by 178 women at Mater Mothers' Hospital, Brisbane, Australia. RESULTS: Women with a score ≥11 were less likely to achieve a spontaneous vaginal delivery (aOR 0.43, 95% CI 0.21-0.88, P = 0.02), and were more likely to have an instrumental (aOR 2.81, 95% CI 1.30-6.08, P = 0.01) or any operative birth (instrumental and caesarean section aOR 2.32, 95% CI 1.14-4.71, P = 0.02). These women were also more likely to have an operative birth for intrapartum fetal compromise (aOR 2.62, 95% CI 1.21-5.69, P = 0.015), as well as an infant with poor neonatal outcomes (aOR 2.77, 95% CI 1.09-7.03, P = 0.03). CONCLUSIONS: These results show that symptoms of sleep-disordered breathing are associated with emergency operative birth, particularly when the indication for operative birth was intrapartum fetal compromise.

Epidural use in labour is not associated with an increased risk of maternal or neonatal morbidity when the second stage is prolonged.

BACKGROUND: Epidural analgesia increases length of labour and risk of operative delivery (caesarean or instrumental). AIM: This study aimed to assess the impact of epidural anaesthesia on maternal and neonatal adverse outcomes when the second stage of labour was prolonged. METHODS: A retrospective cohort study of women delivering at term at the Mater Mother's Hospital, Brisbane between 2008 and 2017. Intrapartum, maternal and neonatal outcomes were assessed and dichotomised according to the presence of prolonged second stage of labour and further by epidural use. Prolonged second stage of labour was defined as: nulliparous women ≥3 h (with epidural) and ≥2 h (without); multiparous women ≥2 h (with epidural) and ≥1 h (without). RESULTS: There were 48 352 women who met the inclusion criteria - 43 676 without and 4676 with prolonged second stage of labour. The overall epidural rate was 35.9%. Women with epidural had significantly lower odds of achieving a spontaneous vaginal birth and higher odds of an operative birth regardless of length of second stage. While rates of several adverse maternal and neonatal outcomes were higher when the second stage was prolonged, after adjusting for clinically relevant confounders, epidural use was not associated with increased odds of the majority of these adverse outcomes. Indeed, epidural use was associated with a significant reduction in the odds of obstetric anal sphincter injuries and reduced odds of neonatal acidosis in women with prolonged second stage. CONCLUSION: While epidural increases the risk of operative birth, this is not associated with an increase in adverse maternal or neonatal outcomes.

The burden of adverse obstetric and perinatal outcomes from maternal smoking in an Australian cohort.

BACKGROUND: Maternal smoking is associated with a number of adverse outcomes with a dose-dependent increase in risk. The aim of this study was to evaluate the obstetric and perinatal outcomes in women who smoked during pregnancy. METHODS: This was a retrospective cohort study of women who smoked during pregnancy and birthed at a major perinatal centre in Australia between January 2000 and April 2017. The study cohort was compared to a cohort of women who did not smoke in pregnancy. Smoking status was ascertained on history and included all types of smoking. Demographic characteristics and obstetric, intrapartum and perinatal outcomes were compared between the two groups. RESULTS: The study cohort included 20 477 (14.6%) women who smoked during pregnancy and 119 396 controls. Women who smoked tended to be younger, of higher body mass index (BMI), Caucasian and Indigenous ethnicity. Smokers were less likely to be nulliparous, but more likely to be hypertensive and have a lower socioeconomic status compared to non-smokers. Women who smoked were more likely to have a caesarean section for non-reassuring fetal status (adjusted odds ratio (aOR) 1.16, 95%CI 1.07-1.26, P < 0.001). The infants of women who smoked were more likely to be born preterm, have a lower median birth weight and birth weights <10th (aOR 1.76, 95%CI 1.66-1.86, P < 0.001) and <5th centile (aOR 2.00, 95%CI 1.86-2.16, P < 0.001). Neonatal outcomes in the smoking cohort were worse with an increase in neonatal intensive care unit admission (aOR 1.34, 95%CI 1.27-1.43, P < 0.001), severe acidosis (aOR 1.41, 95%CI 1.27-1.43, P < 0.001) and a composite of severe neonatal outcomes (18.0% vs 12.0%, aOR 1.35, 95%CI 1.28-1.43, P < 0.001). CONCLUSION: Women who smoke in pregnancy have worse obstetric and perinatal outcomes compared to controls and should be managed as high risk.

Prolonged second stage of labour increases maternal morbidity but not neonatal morbidity.

BACKGROUND: Prolonged second stage of labour is known to be associated with higher caesarean section rates. However, the association between prolonged second stage of labour (PSSL) and adverse neonatal outcomes remains contradictory. The aim of this study was to assess the association between prolonged second stage of labour and obstetric and neonatal outcomes. METHODS: This was a retrospective cohort study of women with term, singleton pregnancies at the Mater Mother's Hospital, Brisbane. Intrapartum, maternal and neonatal outcomes were assessed and stratified according to prolonged second stage of labour. RESULTS: Of 48 352 women, 9.7% had PSSL. Women with PSSL were more likely to be nulliparous and have received oxytocin for augmentation of their labour (P < 0.001), less likely to have an epidural or have undergone induction of labour (P < 0.001). Women with PSSL were less likely to achieve a spontaneous vaginal delivery (adjusted odds ratio (aOR) 0.13, 95%CI 0.12-0.14, P < 0.001), more likely to undergo an instrumental delivery (aOR 3.93, 95%CI 3.62-4.25, P < 0.001) or emergency caesarean section (aOR 9.08, 95%CI 8.00-10.29, P < 0.001). PSSL was associated with shoulder dystocia (aOR 1.61, 95%CI 1.42-1.81, P < 0.001), and postpartum haemorrhage (aOR 1.37, 95%CI 1.16-1.60, P < 0.001). Univariate analysis demonstrated prolonged second stage of labour was associated with low five-minute Apgar score, acidosis and neonatal intensive care admission. However, after adjusting for potential confounders only five-minute Apgar scores ≤3 remained significantly increased (aOR 2.36, 95% CI 1.36-4.09, P = 0.002). CONCLUSION: PSSL is associated with increased operative birth and maternal morbidity.

Term small-for-gestational-age infants from low-risk women are at significantly greater risk of adverse neonatal outcomes.

BACKGROUND: Small-for-gestational-age infants (birthweight <0th centile) are at increased risk of perinatal complications but are frequently not identified antenatally, particularly in low-risk women delivering at term (≥37 weeks gestation). This is compounded by the fact that late pregnancy ultrasound is not the norm in many jurisdictions for this cohort of women. We thus investigated the relationship between birthweight <10th centile and serious neonatal outcomes in low-risk women at term. OBJECTIVE(S): We aimed to determine whether there is a difference of obstetric and perinatal outcomes for small-for-gestational-age infants, subdivided into fifth to <10th centile and less than the fifth centile cohorts compared with an appropriate-for-gestational age (birthweight 10th-90th centile) group at term. STUDY DESIGN: This was a retrospective analysis of data from the Mater Mother's Hospital in Brisbane, Australia, for women who delivered between January 2000 and December 2015. Women with multiple pregnancy, diabetes mellitus, hypertension, preterm birth, major congenital anomalies, and large for gestational age infants (>90th centile for gestational age) were excluded. Small-for-gestational-age infants were subdivided into 2 cohorts: infants with birthweights from the fifth to <10th centile and those less than the fifth centile. Serious composite neonatal morbidity was defined as any of the following: Apgar score ≤3 at 5 minutes, respiratory distress syndrome, acidosis, admission into the neonatal intensive care unit, stillbirth, or neonatal death. Univariate and multivariate analyses were performed using generalized estimating equations to compare obstetric and perinatal outcomes for small-for-gestational-age infants compared with appropriate-for-gestational age controls. RESULTS: The final study comprised 95,900 infants. Five percent were between the fifth and <10th centiles for birthweight and 4.3% were less than the fifth centile. The rate of serious composite neonatal morbidity was 11.1% in the control group, 13.7% in the fifth and <10th centile, and 22.6% in the less than the fifth centile cohorts, respectively. Even after controlling for confounders, both the fifth to <10th centiles and less than the fifth centile cohorts were at significantly increased risk of serious composite neonatal morbidity compared with controls (odds ratio, 1.25, 95% confidence interval, 1.15-1.37, and odds ratio, 2.20, 95% confidence interval, 2.03-2.39, respectively). Infants with birthweights <10th centile were more likely to have severe acidosis at birth, 5 minute Apgar score ≤3 and to be admitted to the neonatal intensive care unit. The serious composite neonatal morbidity was higher in infants less than the fifth centile compared with those in the fifth to <10th centile cohort (odds ratio, 1.71, 95% confidence interval, 1.52-1.92). The odds of perinatal death (stillbirth and neonatal death) were significantly higher in both small-for-gestational age groups than controls. After stratification for gestational age at birth, the composite outcome remained significantly higher in both small-for-gestational-age cohorts and was highest in the less than the fifth centile group at 37+0 to 38+6 weeks (odds ratio, 3.32, 95% confidence interval, 2.87-3.85). The risk of perinatal death was highest for infants less than the fifth centile at 37+0 to 38+6 weeks (odds ratio, 5.50, 95% confidence interval, 2.33-12.98). CONCLUSION: Small-for-gestational-age infants from term, low-risk pregnancies are at significantly increased risk of mortality and morbidity when compared with appropriate-for-gestational age infants. Although this risk is increased at all gestational ages in infants less than the fifth centile for birthweight, it is highest at early-term gestation. Our findings highlight that early-term birth does not necessarily improve outcomes and emphasize the importance of identifying this cohort of infants.

Maternal demographic factors associated with emergency caesarean section for non-reassuring foetal status.

OBJECTIVES: This study aimed to determine maternal and obstetric factors associated with emergency caesarean section (CS) for non-reassuring foetal status (NRFS). MATERIALS AND METHODS: This was a retrospective analysis of term singleton births between January 2007 and December 2015 at the Mater Mother's Hospital in Brisbane. The study group comprised all cases of emergency CS for NRFS, and the control cohort comprised all other births meeting the inclusion criteria but excluding those in the study cohort. RESULTS: Over the study period, there were 74,177 births fulfilling the inclusion criteria. The overall rate of emergency CS for NRFS was 4.2% (3132/74,177). Multivariate analysis showed that being overweight and obese, Indian and "other" ethnicity, artificial reproductive techniques, smoking, induction of labour and gestation at 39-42 weeks were associated with an increased risk, whereas being underweight, female sex, hypertension and birth without labour conferred a lower risk. CONCLUSION: Many maternal and obstetric factors were associated with emergency CS for NRFS and influenced adverse perinatal outcomes. Recognition of these risk factors could help risk stratify women prior to labour.

Birth-weight centiles and the risk of serious adverse neonatal outcomes at term.

BACKGROUND: Birth-weight is an important determinant of perinatal outcome with low birth-weight being a particular risk factor for adverse consequences. AIM: To investigate the impact of neonatal sex, mode of birth and gestational age at birth according to birth-weight centile on serious adverse neonatal outcomes in singleton term pregnancies. MATERIALS AND METHODS: This was a retrospective cohort study of singleton term births at the Mater Mother's Hospital, Brisbane, Australia. Serious adverse neonatal outcome was defined as a composite of severe acidosis at birth (pH ≤7.0 and/or lactate ≥6 mmol/L and/or base excess ≤-12 mmol/L), Apgar <3 at 5 min, neonatal intensive-care unit admission and antepartum or neonatal death. The main exposure variable was birth-weight centile. RESULTS: Of the 69,210 babies in our study, the overall proportion of serious adverse neonatal outcomes was 9.1% (6327/69,210). Overall, neonates in the <3rd birth-weight centile category had the highest adjusted odds ratio (OR) for serious adverse neonatal outcomes [OR 3.53, 95% confidence interval (CI) 3.06-4.07], whilst those in the ≥97th centile group also had elevated odds (OR 1.51, 95% CI 1.30-1.75). Regardless of birth modality, smaller babies in the <3rd centile group had the highest adjusted OR and predicted probability for serious adverse neonatal outcomes. When stratified by sex, male babies consistently demonstrated a higher predicted probability of serious adverse neonatal outcomes across all birth-weight centiles. The adjusted odds, when stratified by gestational age at birth, were the highest from 37+0 to 38+6 weeks in the <3rd centile group (OR 5.97, 95% CI 4.60-7.75). CONCLUSIONS: Low and high birth-weights are risk factors for serious adverse neonatal outcomes. The adjusted OR appears to be greatest for babies in the <3rd birth-weight centile group, although an elevated risk was also found in babies within the ≥97th centile category.

Impact of shoulder dystocia, stratified by type of manoeuvre, on severe neonatal outcome and maternal morbidity.

BACKGROUND: Shoulder dystocia is an uncommon and unpredictable obstetric emergency. It is associated with significant neonatal, maternal and medico-legal consequences. AIM: To ascertain the impact shoulder dystocia has on severe neonatal and maternal outcomes specific to the type of manoeuvre. MATERIALS AND METHODS: This was a retrospective study of 48 021 term singleton vaginal deliveries the Mater Mothers' Hospital in Brisbane between 2007 and 2015. Maternal and neonatal outcomes were compared between deliveries complicated by shoulder dystocia and those uncomplicated. RESULTS: Deliveries complicated by shoulder dystocia are associated with low Apgar scores (≤3) at five minutes (odds ratio (OR) 5.25, 95% CI 3.23-8.56, P < 0.001), acidosis (OR 3.10, 95% CI 2.76-3.50, P < 0.001), postpartum haemorrhage (OR 2.28, 95% CI 1.90-2.75, P < 0.001) and perineal trauma (OR 1.92, 95% CI 1.54-2.39, P < 0.001). Compared to McRoberts' manoeuvre and suprapubic pressure alone, the odds of serious neonatal outcome are increased with internal rotational manoeuvres (OR 3.82, 95% CI 2.54-5.74, P < 0.001) and delivery of the posterior arm (OR 4.49, 95% CI 3.54-5.69, P < 0.001). The OR of maternal injury is 2.07 (95% CI 1.77-2.45, P < 0.001), 2.26 (95% CI 1.21-4.21, P < 0.001) and 2.29 (95% CI 1.58-3.32, P < 0.001) with McRoberts'/suprapubic pressure, internal rotation and posterior arm delivery, respectively. Brachial plexus injuries and fractures complicate 1.4 and 0.9% of deliveries, with the risk of injury increasing when greater than one manoeuvre is required. CONCLUSION: The risk of neonatal and maternal trauma is strongly associated with the number and types of manoeuvres. Given the associated implications, adequate antenatal counselling, simulation training and enhanced labour surveillance are essential.

Intrapartum intervention rates and perinatal outcomes following induction of labour compared to expectant management at term from an Australian perinatal centre.

BACKGROUND: Induction of labor (IOL) is a common obstetric intervention, yet its impact on intervention rates and perinatal outcomes is conflicting. AIMS: To evaluate the impact of IOL on intrapartum intervention rates and perinatal outcomes in women with singleton pregnancies at term. MATERIAL AND METHODS: This was a retrospective, cross-sectional study of term singleton deliveries at the Mater Mother's Hospital in Brisbane, Australia in 2007-2013. The IOL cohort was compared to an expectantly managed group. RESULTS: Of the final cohort (44 698 women), 64.4% had expectant management and 35.6% had IOL. Multivariate analyses showed that IOL was associated with lower odds of spontaneous vaginal delivery from ≥37 weeks gestation. The risk of emergency caesarean for non-reassuring fetal status was also higher in the IOL cohort at 40 and 41 weeks gestation. For women who were managed expectantly, the highest rate of spontaneous vaginal delivery and the lowest rate of emergency caesareans occurred at 39 weeks gestation. For women who underwent IOL, the nadir emergency caesarean rate and the highest spontaneous vaginal delivery rate was also at 39 weeks. Rates of neonatal intensive car unit admission were higher in the IOL group at 37 weeks (adjusted odds ratio (aOR) 3.11, 95% CI: 2.62-3.68) and 38 weeks (aOR 1.78, 95% CI: 1.55-2.04) and lower at >42 weeks (OR 0.35, 95% CI: 0.14-0.81) respectively. CONCLUSION: IOL compared to expectant management is associated with lower spontaneous vaginal delivery rates and increased risk of emergency caesarean for intrapartum fetal compromise with broadly comparable perinatal outcomes.

Demographic characteristics and pregnancy outcomes in adolescents - Experience from an Australian perinatal centre.

BACKGROUND: Adolescent pregnancy is defined as pregnancy in girls aged 10-19 years and can be associated with increased risks. AIM: To investigate obstetric and perinatal outcomes in a cohort of adolescent girls from a major Australian tertiary centre. MATERIALS AND METHODS: This was a nine-year retrospective cohort study of women who birthed at the Mater Mother's Hospital (MMH) in Brisbane, Australia between 1 January 2007 and 31 December 2015. The adolescent cohort was aged <19 years and the control group was aged 20-24 years. RESULTS: Over the study period the total study cohort comprised 8904 women. Of these, the adolescent cohort consisted of 1625 girls (18.2%) and the control group consisted of 7279 women (81.8%). Adolescents were more likely to be nulliparous, single, of Indigenous ethnicity or to have refugee status. They had higher rates of smoking, asthma, diabetes mellitus and thyroid disease. They were more likely to have an uncomplicated spontaneous vaginal delivery but were less likely to have an intact perineum and had higher rates of pre-term delivery and low birth weight babies. There were no differences in rates of postpartum haemorrhage. CONCLUSIONS: Teenage pregnancy results in poorer obstetric and perinatal outcomes. A focus on optimising maternal health care and providing culturally appropriate antenatal and intrapartum care is imperative to improving outcomes.

Intrapartum and neonatal outcomes in singleton pregnancies following conception by assisted reproduction techniques.

BACKGROUND: To characterise maternal demographics and ascertain whether clinically important differences exist in the intrapartum and neonatal outcomes associated with assisted reproductive technology (ART). MATERIALS AND METHODS: A retrospective study was undertaken between January 2007 and December 2013 of all singleton pregnancies conceived via ART at a major tertiary unit in Brisbane, Australia. Intrapartum outcomes were mode of delivery and indication for emergency caesarean. Neonatal outcomes investigated were gestation at delivery, birth weight, Apgar scores, acidosis at birth, respiratory distress, need for resuscitation, admission to neonatal intensive care and stillbirth. RESULTS: There were 4733 (7.4%) ART and 59 277 (92.6%) spontaneous conception pregnancies. Women who conceived using ART were less likely to have a spontaneous vaginal delivery (odds ratio (OR) 0.60, 95% CI 0.57-0.64) and were more likely to require operative or assisted birth: elective caesarean (adjusted OR (aOR) 1.31, 95% CI 1.22-1.40), emergency caesarean (aOR 1.19, 95% CI 1.09-1.28), or instrumental delivery (aOR 1.45, 95% CI 1.32-1.58). Neonates who were conceived using ART were less likely to be born at term (aOR 0.64, 95% CI 0.58-0.71) and have lower birth weights. No differences were observed in rates of respiratory distress, admission to the neonatal intensive care unit, or stillbirth between the ART and spontaneous conception cohorts. The odds of neonatal acidosis (OR 0.71, 95% CI0.63-0.81) were lower in the ART cohort. CONCLUSION: Although higher rates of operative deliveries were seen for women who conceive using ART, neonatal outcomes were generally no different between the two cohorts.

Cell line and patient-derived xenograft models reveal elevated CDCP1 as a target in high-grade serous ovarian cancer.

BACKGROUND: Development of targeted therapies for high-grade serous ovarian cancer (HGSC) remains challenging, as contributing molecular pathways are poorly defined or expressed heterogeneously. CUB-domain containing protein 1 (CDCP1) is a cell-surface protein elevated in lung, colorectal, pancreas, renal and clear cell ovarian cancer. METHODS: CUB-domain containing protein 1 was examined by immunohistochemistry in HGSC and fallopian tube. The impact of targeting CDCP1 on cell growth and migration in vitro, and intraperitoneal xenograft growth in mice was examined. Three patient-derived xenograft (PDX) mouse models were developed and characterised for CDCP1 expression. The effect of a monoclonal anti-CDCP1 antibody on PDX growth was examined. Src activation was assessed by western blot analysis. RESULTS: Elevated CDCP1 was observed in 77% of HGSC cases. Silencing of CDCP1 reduced migration and non-adherent cell growth in vitro and tumour burden in vivo. Expression of CDCP1 in patient samples was maintained in PDX models. Antibody blockade of CDCP1 significantly reduced growth of an HGSC PDX. The CDCP1-mediated activation of Src was observed in cultured cells and mouse xenografts. CONCLUSIONS: CUB-domain containing protein 1 is over-expressed by the majority of HGSCs. In vitro and mouse model data indicate that CDCP1 has a role in HGSC and that it can be targeted to inhibit progression of this cancer.

A randomised, double-blind controlled trial of intranasal midazolam for the palliation of dyspnoea in patients with life-limiting disease.

PURPOSE: Anxiety is a major component of breathlessness and is often palliated with benzodiazepines. Midazolam is a short-acting water-soluble benzodiazepine with a rapid onset of action and short half-life. Intranasal midazolam had been shown to be of marked clinical benefit in an uncontrolled pilot study for the control of dyspnoea. A blinded randomised controlled study was therefore undertaken across four Australasian palliative care services. METHODS: All participants received six numbered study nasal spray (SNS) bottles, three of which contained midazolam and three placebo. They were instructed to use one SNS bottle on each day they were breathless, for 6 days within 2 weeks. Dyspnoea scores were recorded before and at set time intervals following the first use of each SNS bottle. RESULTS: Across all SNS bottles, the maximum change of 2.1 on an 11-point numerical rating scale was seen at 60 min. There was no difference in dyspnoea score between the two arms. Approximately 50 % of participants in each arm had a positive response (i.e. ≥2 point change in dyspnoea score from baseline). Anxiety scores at baseline were low. The most common adverse event was local nasal reactions. CONCLUSION: Intranasal midazolam had no clinical benefit over intranasal placebo for the control of dyspnoea. The low level of anxiety at baseline and dose of active drug delivered may have been important factors. Many participants found the SNS bottles to be a challenging mode of drug delivery. This study confirms the importance of placebo-controlled trials for defining best clinical practise.

A field study of household attack rates and the effectiveness of macrolide antibiotics in reducing household transmission of pertussis.

Bordetella pertussis (whooping cough) is an endemic, highly contagious bacterial respiratory infection, which is notifiable to Australian state and territory health departments. Between 2008 and 2011 there was a substantial outbreak in New South Wales with an initial increase in cases occurring in North Coast New South Wales from late 2007. During September and October 2011 the North Coast Public Health Unit conducted a household study of secondary attack rates to assess the effectiveness of pertussis vaccination as well as the timely use of antibiotics in preventing household transmission. At the time the study was commenced, notified cases included a large proportion of individuals with a documented history of vaccination against pertussis. We found lower attack rates amongst vaccinated compared with non-vaccinated subjects in all age groups, with the exception of the 5-11 years age group, who were also primarily responsible for the introduction of pertussis into the household. There was an increased risk of pertussis transmission from the household first primary case to contacts when antibiotic treatment was commenced later than 7 days after the onset of symptoms compared with within 7 days. This protective effect of timely antibiotic treatment in relation to transmission highlights the need to control for antibiotic treatment in field studies of pertussis. The benefits of timely diagnosis and use of antibiotics in preventing household transmission underscore the importance of early presentation and diagnosis of pertussis cases, particularly in households with susceptible occupants.

Time-varying effects are common in genetic control of gestational duration.

Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent - gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31,000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy "clock". We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new foetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm periods, and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant, and should help design further experimental studies.

Exploring the association of parity and its interaction with history of preterm delivery on gestational duration.

PURPOSE: Preterm delivery is a major cause of child mortality. While the relationship between parity and preterm delivery is known, its association with gestational duration and variability remains underexplored. Differences in variance may suggest interaction with other well-established risk factors. METHODS: With 1.1 million spontaneous deliveries (1990-2012) from the Swedish Medical Birth Register, we assessed while accounting for potential confounders the effects of parity on the mean and variance of gestational duration, and its possible interactions with history of preterm delivery. Pedigrees allowed to account for nonobserved, shared confounders using linear mixed models. RESULTS: Parity has a modest association with mean gestational duration, but a large effect on its variance. For example, the first pregnancy had the shortest mean gestational duration, 0.29 days shorter (95% CI: -0.33, -0.25) than the second, and the largest variance (σ2 = 135 days2). Accounting for shared unobserved confounders highlighted a group effect bias, likely linked to the mothers' total number of offspring. Parity interacts with other risk factors, including previous preterm delivery where the magnitude of its effect increases with parity (up to 4.6 days effect difference). CONCLUSIONS: Nonshared factors across a mother's pregnancies highlight parity's importance to gain insight into the mechanisms governing the timing of delivery.