TRPV3 expression and vasodilator function in isolated uterine radial arteries from non-pregnant and pregnant rats.

This study investigated the expression and function of transient receptor potential vanilloid type-3 ion channels (TRPV3) in uterine radial arteries isolated from non-pregnant and twenty-day pregnant rats. Immunohistochemistry (IHC) suggested TRPV3 is primarily localized to the smooth muscle in arteries from both non-pregnant and pregnant rats. IHC using C' targeted antibody, and qPCR of TRPV3 mRNA, suggested pregnancy increased arterial TRPV3 expression. The TRPV3 activator carvacrol caused endothelium-independent dilation of phenylephrine-constricted radial arteries, with no difference between vessels from non-pregnant and pregnant animals. Carvacrol-induced dilation was reduced by the TRPV3-blockers isopentenyl pyrophosphate and ruthenium red, but not by the TRPA1 or TRPV4 inhibitors HC-030031 or HC-067047, respectively. In radial arteries from non-pregnant rats only, inhibition of NOS and sGC, or PKG, enhanced carvacrol-mediated vasodilation. Carvacrol-induced dilation of arteries from both non-pregnant and pregnant rats was prevented by the IKCa blocker TRAM-34. TRPV3 caused an endothelium-independent, IKCa-mediated dilation of the uterine radial artery. NO-PKG-mediated modulation of TRPV3 activity is lost in pregnancy, but this did not alter the response to carvacrol.

Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia.

Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator-activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.

Intrapartum fetal scalp lactate sampling for fetal assessment in the presence of a non-reassuring fetal heart rate trace.

BACKGROUND: Fetal scalp blood sampling for lactate estimation may be considered following identification of an abnormal or non-reassuring fetal heart rate pattern. The smaller volume of blood required for this test, compared with the more traditional pH estimation, may improve sampling rates. The appropriate use of this practice mandates systematic review of its safety and clinical effectiveness prior to widespread introduction. OBJECTIVES: To evaluate the effectiveness and risks of fetal scalp lactate sampling in the assessment of fetal well-being during labour, compared with no testing or alternative testing. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2015). SELECTION CRITERIA: All published and unpublished randomised and quasi-randomised trials that compared fetal scalp lactate testing with no testing or alternative testing to evaluate fetal status in the presence of a non-reassuring cardiotocograph during labour. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures of the Cochrane Pregnancy and Childbirth Group. Two review authors independently assessed the studies. MAIN RESULTS: The search identified two completed randomised controlled trials (RCTs) and two ongoing trials. The two published RCTs considered outcomes for 3348 mother-baby pairs allocated to either lactate or pH estimation of fetal blood samples when clinically indicated in labour. Overall, the published RCTs were of low or unclear risk of bias. There was a high risk of performance bias, because it would not have been feasible to blind clinicians or participants.No statistically significant between-group differences were found for neonatal encephalopathy (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.32 to 3.09, one study, 2992 infants) or death. No studies reported neonatal seizures. We had planned to report death with other morbidities, for example, neonatal encephalopathy; however, the data were not available in a format suitable for this, therefore death due to congenital abnormality was considered alone. The three reported neonatal deaths occurred in babies with diaphragmatic hernias (n = 2) or congenital cardiac fibrosis (n = 1). All three babies had been randomised to the pH group and were not acidaemic at birth.There were no statistically significant differences for any of the pre-specified secondary fetal/neonatal/infant outcomes for which data were available. This included low Apgar score at five minutes (RR 1.13, 95% CI 0.76 to 1.68, two studies, 3319 infants) and admission to neonatal intensive care units (RR 1.02, 95% CI 0.83 to 1.25, one study, 2992 infants), or metabolic acidaemia (RR 0.91, 95% CI 0.60 to 1.36, one study, 2675 infants) considered within the studies, either overall or where data were available for those where fetal blood sampling had occurred within 60 minutes of delivery.Similar proportions of fetuses underwent additional tests to further evaluate well-being during labour, including scalp pH if in the lactate group or scalp lactate if in the pH group (RR 0.22, 95% CI 0.04 to 1.30, two studies, 3333 infants;Tau² 1.00, I² = 58%). Fetal blood sampling attempts for lactate and pH estimation were successful in 98.7% and 79.4% of procedures respectively in the one study that reported this outcome.There were no significant between-group differences in mode of birth or operative birth for non-reassuring fetal status, either for all women, or within the group where the fetal blood sample had been taken within 60 minutes of delivery (for example, caesarean section for all enrolled, RR 1.09, 95% CI 0.97 to 1.22, two studies, 3319 women; operative delivery for non-reassuring fetal status for all enrolled RR 1.02, 95% CI 0.93 to 1.11, one study, 2992 women).Neither study reported on adverse effects of fetal scalp lacerations or maternal anxiety. AUTHORS' CONCLUSIONS: When further testing to assess fetal well-being in labour is indicated, fetal scalp blood lactate estimation is more likely to be successfully undertaken than pH estimation. Further studies may consider subgroup analysis by gestational age, the stage of labour and sampling within a prolonged second stage of labour. Additionally, we await the findings from the ongoing studies that compare allocation to no fetal blood sample with sampling for lactate and address longer-term neonatal outcomes, maternal satisfaction with intrapartum fetal monitoring and an economic analysis.

Pregnancy-induced remodelling and enhanced endothelium-derived hyperpolarization-type vasodilator activity in rat uterine radial artery: transient receptor potential vanilloid type 4 channels, caveolae and myoendothelial gap junctions.

In pregnancy, the vasculature of the uterus undergoes rapid remodelling to increase blood flow and maintain perfusion to the fetus. The present study determines the distribution and density of caveolae, transient receptor potential vanilloid type 4 channels (TRPV4) and myoendothelial gap junctions, and the relative contribution of related endothelium-dependent vasodilator components in uterine radial arteries of control virgin non-pregnant and 20-day late-pregnant rats. The hypothesis examined is that specific components of endothelium-dependent vasodilator mechanisms are altered in pregnancy-related uterine radial artery remodelling. Conventional and serial section electron microscopy were used to determine the morphological characteristics of uterine radial arteries from control and pregnant rats. TRPV4 distribution and expression was examined using conventional confocal immunohistochemistry, and the contribution of endothelial TRPV4, nitric oxide (NO) and endothelium-derived hyperpolarization (EDH)-type activity determined using pressure myography with pharmacological intervention. Data show outward hypertrophic remodelling occurs in uterine radial arteries in pregnancy. Further, caveolae density in radial artery endothelium and smooth muscle from pregnant rats was significantly increased by ~94% and ~31%, respectively, compared with control, whereas caveolae density did not differ in endothelium compared with smooth muscle from control. Caveolae density was significantly higher by ~59% on the abluminal compared with the luminal surface of the endothelium in uterine radial artery of pregnant rats but did not differ at those surfaces in control. TRPV4 was present in endothelium and smooth muscle, but not associated with internal elastic lamina hole sites in radial arteries. TRPV4 fluorescence intensity was significantly increased in the endothelium and smooth muscle of radial artery of pregnant compared with control rats by ~2.6- and 5.5-fold, respectively. The TRPV4 signal was significantly higher in the endothelium compared with the smooth muscle in radial artery of both control and pregnant rats, by ~5.7- and 2.7-fold, respectively. Myoendothelial gap junction density was significantly decreased by ~37% in radial artery from pregnant compared with control rats. Pressure myography with pharmacological intervention showed that NO contributes ~80% and ~30%, and the EDH-type component ~20% and ~70% of the total endothelium-dependent vasodilator response in radial arteries of control and pregnant rats, respectively. TRPV4 plays a functional role in radial arteries, with a greater contribution in those from pregnant rats. The correlative association of increased TRPV4 and caveolae density and role of EDH-type activity in uterine radial artery of pregnant rats is suggestive of their causal relationship. The decreased myoendothelial gap junction density and lack of TRPV4 density at such sites is consistent with their having an integral, albeit complex, interactive role in uterine vascular signalling and remodelling in pregnancy.

Accuracy of sonographic prediction of birth weight.

Many clinicians use ultrasound estimates of fetal weight to assess fetal growth. This study assessed the accuracy of the Hadlock IV equation, the equation used at the Royal Hospital for Women, Randwick, NSW, in estimating birth weight. The accuracy of the Hadlock IV equation was assessed based on systematic and random error as well as absolute error. 709 women who underwent ultrasound examination within 8 weeks of delivery between January 2009-May 2011 were included. 305 women underwent ultrasound less than 2 weeks before delivery. The systematic, random and absolute errors of the Hadlock IV equation were -0.47, 27.45 and 8.52%, respectively. This study demonstrates that clinicians may rely on ultrasound estimates of fetal weight performed by well-trained staff in a tertiary institution within 2 weeks of delivery. The accuracy diminishes as the interval between testing and delivery increases. Absolute errors tended to increase with increasing birth weight for all ultrasound-delivery intervals.

Enhanced contractility in pregnancy is associated with augmented TRPC3, L-type, and T-type voltage-dependent calcium channel function in rat uterine radial artery.

In pregnancy, α-adrenoceptor-mediated vasoconstriction is augmented in uterine radial arteries and is accompanied by underlying changes in smooth muscle (SM) Ca(2+) activity. This study aims to determine the Ca(2+) entry channels associated with altered vasoconstriction in pregnancy, with the hypothesis that augmented vasoconstriction involves transient receptor potential canonical type-3 (TRPC3) and L- and T-type voltage-dependent Ca(2+) channels. Immunohistochemistry showed TRPC3, L-type Cav1.2 (as the α1C subunit), T-type Cav3.1 (α1G), and Cav3.2 (α1H) localization to the uterine radial artery SM. Fluorescence intensity of TRPC3, Cav1.2, and Cav3.2 was increased, and Cav3.1 decreased in radial artery SM from pregnant rats. Western blot analysis confirmed increased TRPC3 protein expression in the radial artery from pregnant rats. Pressure myography incorporating pharmacological intervention to examine the role of these channels in uterine radial arteries showed an attenuation of phenylephrine (PE)-induced constriction with Pyr3 {1-[4-[(2,3,3-trichloro-1-oxo-2-propen-1-yl)amino]phenyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid}-mediated TRPC3 inhibition or with nifedipine-mediated L-type channel block alone in vessels from pregnant rats; both effects of which were diminished in radial arteries from nonpregnant rats. Combined TRPC3 and L-type inhibition attenuated PE-induced constriction in radial arteries, and the residual vasoconstriction was reduced and abolished with T-type channel block with NNC 55-0396 in arteries from nonpregnant and pregnant rats, respectively. With SM Ca(2+) stores depleted and in the presence of PE, nifedipine, and NNC 55-0396, blockade of TRPC3 reversed PE-induced constriction. These data suggest that TRPC3 channels act synergistically with L- and T-type channels to modulate radial artery vasoconstriction, with the mechanism being augmented in pregnancy.

Vibroacoustic stimulation for fetal assessment in labour in the presence of a nonreassuring fetal heart rate trace.

BACKGROUND: Fetal vibroacoustic stimulation (VAS) is a simple, non-invasive technique where a device is placed on the maternal abdomen over the region of the fetal head and sound is emitted at a predetermined level for several seconds. It is hypothesised that the resultant startle reflex in the fetus and subsequent fetal heart rate (FHR) acceleration or transient tachycardia following VAS provide reassurance of fetal well-being. This technique has been proposed as a tool to assess fetal well-being in the presence of a nonreassuring cardiotocographic (CTG) trace during the first and second stages of labour. OBJECTIVES: To evaluate the clinical effectiveness and safety of VAS in the assessment of fetal well-being during labour, compared with mock or no stimulation for women with a singleton pregnancy exhibiting a nonreassuring FHR pattern. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 September 2012) and reference lists of all retrieved articles. We sought unpublished trials and abstracts submitted to major international congresses and contacted expert informants. SELECTION CRITERIA: All published and unpublished randomised trials that compared maternal and fetal/neonatal/infant outcomes when VAS was used to evaluate fetal status in the presence of a nonreassuring CTG trace during labour, compared with mock or no stimulation. DATA COLLECTION AND ANALYSIS: Two review authors independently sought to assess for inclusion all the potential studies we identified as a result of the search strategy. We planned to resolve any disagreement through discussion or, if required, to consult a third person. Where there was uncertainty about a particular study, we attempted to contact study authors for additional information. However, these attempts were unsuccessful. MAIN RESULTS: The search strategies yielded six studies for consideration of inclusion. However, none of these studies fulfilled the requirements for inclusion in this review. AUTHORS' CONCLUSIONS: There are currently no randomised controlled trials that address the safety and efficacy of VAS used to assess fetal well-being in labour in the presence of a nonreassuring CTG trace. Although VAS has been proposed as a simple, non-invasive tool for assessment of fetal well-being, there is insufficient evidence from randomised trials on which to base recommendations for use of VAS in the evaluation of fetal well-being in labour in the presence of a nonreassuring CTG trace.

Parental care and control during childhood: associations with maternal perinatal mood disturbance and parenting stress.

This study examined the associations between perceived parental care and control in childhood and maternal anxiety, depression and parenting stress during the transition to parenthood. Eighty-eight women completed the Parental Bonding Instrument, self-report measures of anxiety and depression and a structured diagnostic interview (Mini-plus International Neuropsychiatric Interview) during the third trimester of pregnancy. The MINI-Plus and anxiety and depression measures were re-administered at 7 months postpartum. The Parenting Stress Index was also administered at this time. Significant associations were found between maternal 'affectionless control' and prenatal and postnatal symptom measures of anxiety and depression, p values <0.005. Compared to women who reported optimal parenting, women who recalled maternal 'affectionless control' were also six times more likely to be diagnosed with an anxiety disorder during pregnancy (OR = 6.1, 95% CI = 2.17-30.11) and seven times more likely to be diagnosed with postnatal major depression (OR = 6.8, 95% CI = 1.80-25.37). Paternal 'affectionless control' was associated with significantly higher scores on symptom measures of prenatal and postnatal anxiety, p values <0.005. This study suggests that assessing a woman's own parenting history is important in identifying and managing the risk of prenatal and postnatal affective disorders and parenting stress.

Intrapartum fetal scalp lactate sampling for fetal assessment in the presence of a non-reassuring fetal heart rate trace.

BACKGROUND: Fetal blood sampling for lactate estimation may be considered following identification of an abnormal or non-reassuring fetal heart rate pattern. The smaller volume of blood required for this test, compared with the more traditional pH estimation, may improve sampling rates. The appropriate use of this practice mandates systematic review of its safety and clinical effectiveness prior to widespread introduction. OBJECTIVES: To evaluate the effectiveness and risks of fetal scalp lactate sampling in the assessment of fetal well-being during labour, compared with no testing or alternative testing. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (November 2009). SELECTION CRITERIA: All published and unpublished randomised and quasi-randomised trials that compared fetal scalp lactate testing with no testing or alternative testing to evaluate fetal status in the presence of a non-reassuring cardiotocograph during labour. DATA COLLECTION AND ANALYSIS: Two review authors assessed the studies independently. MAIN RESULTS: The two identified randomised trials considered outcomes for 3348 mother-baby pairs allocated to either lactate or pH estimation of fetal blood samples in labour. There were no statistically significant differences for any fetal/neonatal/infant outcomes, including low Apgar score at five minutes, admission to neonatal intensive care units or neonatal encephalopathy, or for low umbilical arterial pH, base deficit or metabolic acidaemia. There was a statistically higher success rate for lactate compared with pH estimation (risk ratio 1.10, 95% confidence interval 1.08 to 1.12, n = 2992). There were no significant between-group differences in mode of birth or operative birth for non-reassuring fetal status. No studies reported outcomes of maternal satisfaction with fetal monitoring, anxiety, length of hospital stay or economic analysis. AUTHORS' CONCLUSIONS: When further testing to assess fetal well-being in labour is indicated, fetal scalp blood lactate estimation is more likely to be successfully undertaken than pH estimation. Action cut-off lactate values need to consider the lactate meter used. Further studies may consider sub-group analysis by gestational age, the stage of labour and sampling within a prolonged second stage of labour. Additionally, future studies may address longer-term neonatal outcomes, maternal satisfaction with intrapartum fetal monitoring and an economic analysis.

Do women's perceptions of care at the time of unexplained stillbirth influence their wishes for management in subsequent pregnancy? An Internet-based empirical study.

AIM: The aim of this study was to examine women's perceptions of their care at the time of unexplained stillbirth, and whether these appear to affect wishes for management in subsequent pregnancy. METHODS: An Internet-based survey was conducted of women after unexplained stillbirth, seeking information about their perceptions of management, and their wishes for care in a subsequent pregnancy. RESULTS: One hundred and five completed surveys were included in the study group. Only 18 respondents (17%) reported that the diagnosis was broken in an uncaring way. Twenty respondents (19%) felt 'rushed into making decisions'. Almost all respondents (95%) felt that they were given adequate time with the baby after delivery. Fifty-seven respondents (54%) consented to perinatal autopsy. Most women (93%) wanted additional testing in their next pregnancy, 81% wanted delivery before the due date, but only 26% wanted cesarean delivery next time. CONCLUSION: Women's perceptions of care at the time of an unexplained stillbirth did not appear to influence their wishes for management in the next pregnancy.

Maternal prenatal anxiety, postnatal caregiving and infants' cortisol responses to the still-face procedure.

This study prospectively examined the separate and combined influences of maternal prenatal anxiety disorder and postnatal caregiving sensitivity on infants' salivary cortisol responses to the still-face procedure. Effects were assessed by measuring infant salivary cortisol upon arrival at the laboratory, and at 15-, 25-, and 40-min following the still-face procedure. Maternal symptoms of anxiety during the last 6 months of pregnancy were assessed using clinical diagnostic interview. Data analyses using linear mixed models were based on 88 women and their 7-month-old infants. Prenatal anxiety and maternal sensitivity emerged as independent, additive moderators of infant cortisol reactivity, F (3, 180) = 3.29, p = .02, F (3, 179) = 2.68, p = .05 respectively. Results were independent of maternal prenatal depression symptoms, and postnatal symptoms of anxiety and depression. Infants' stress-induced cortisol secretion patterns appear to relate not only to exposure to maternal prenatal anxiety, but also to maternal caregiving sensitivity, irrespective of prenatal psychological state.

Women's expectations of management in their next pregnancy after an unexplained stillbirth: an Internet-based empirical study.

BACKGROUND: Unexplained stillbirth is the largest contributor to perinatal death, accounting for one-third of stillbirths. There appears to be no increase in perinatal death rates in the pregnancies that follow an unexplained stillbirth. However, these pregnancies have increased rates of induced labour and elective caesarean section, as well as preterm birth, low birthweight, instrumental delivery, 'fetal distress' and postpartum haemorrhage. AIM: To study the wishes for future pregnancy management in women who have suffered an unexplained stillbirth. METHODS: An Internet-based survey of women after an unexplained stillbirth, seeking demographic information and reproductive history, details of management of the index stillbirth and information about their wishes for subsequent pregnancy management (antenatal surveillance, early delivery and caesarean delivery). RESULTS: Of the total respondents included in the study, 93% wanted 'testing' over and above normal pregnancy care in their next pregnancy. Of the respondents, 81% wanted early delivery and 26% wanted a Caesarean delivery, irrespective of obstetric indications. These wishes were not influenced by socio-demographic factors, management of the index stillbirth (with the exception of having had a Caesarean delivery) or advice received on management of the next pregnancy (with the exception of being advised to have an early or Caesarean delivery). CONCLUSIONS: The women surveyed wanted increased fetal surveillance and early delivery, but not necessarily elective caesarean section.

Prenatal stress, the hypothalamic-pituitary-adrenal axis, and fetal and infant neurobehaviour.

BACKGROUND: Although it has long been acknowledged that chronic HPA axis dysregulation impacts on adult neural function, little attention has been paid to the impact that disturbances of the maternal HPA axis may have on the developing fetal brain. AIM: This editorial examines the associations between prenatal stress, neuroendocrine functioning, and behavioural outcome in both animal and human offspring, with a particular focus on the relationship between prenatal stress and human fetal and infant neurobehaviour. STUDY DESIGN: Using electronic databases, a computerized search of published and unpublished data was undertaken. RESULTS: There is growing evidence that prenatal stress impacts on offspring neural function and behaviour in animal populations. That these findings may be applicable to human fetal neurobehaviour and infant development and outcome is gaining research attention, and the potential importance of the timing of pregnancy stress is being increasingly highlighted. CONCLUSIONS: There is a pressing need for more research into the role of maternal stress and anxiety during pregnancy on human fetal and infant outcomes. Future studies should prospectively pair physiological and psychological measures both pre- and postnatally if the HPA axis function of the mother and her infant is to be more fully understood.

Maternal trait anxiety, depression and life event stress in pregnancy: relationships with infant temperament.

AIMS: To assess whether links exist between maternal trait anxiety (STAI), perceived life event (LE) stress and depression (Edinburgh scale) and infant temperament. STUDY DESIGN AND SUBJECTS: Women in the third trimester of pregnancy returned psychological self-report questionnaires; infant temperament was evaluated at 4 and 6 months by maternal and paternal report, while depression (concurrent Edinburgh scale) was also assessed at four and six months. As data were returned inconsistently at 4 and 6 months, we combined these two time points for simplicity of reporting and optimisation of numbers. RESULTS: Univariate logistic regressions on 970 subjects indicated that the pregnancy STAI (>40) scores were associated with 2.56- and 1.57-fold increases (maternal and paternal, respectively), in the odds of "difficult" infant temperament at 4 or 6 months. Concurrent Edinburgh scores (OR of 3.06 and 2.64 for maternal reports, respectively) were also predictive of infant temperament. Age, education, income, marital status, obstetric complications, infant gender and prematurity were not predictive of infant temperament. In stepwise multiple logistic regression analyses, the antenatal trait STAI (odds ratio 1.96) significantly predicted maternal reports of "difficult" temperament at 4 or 6 months independent of both antenatal and postnatal depression scores. There were similar trends for paternal reports of "difficult" temperament but these were not significant. Antenatal depression and perceived LE stress were not predictive of temperament. Finally, women (N=14) reporting domestic violence (DV) in pregnancy had highly significant increased Edinburgh and STAI scores. CONCLUSIONS: Maternal trait anxiety was predictive of "difficult" infant temperament, independent of "concurrent" depression and key sociodemographic and obstetric risk factors. These findings, while needing replication using objective measures of infant temperament, suggest that antenatal psychological interventions aimed at minimising anxiety may optimize infant temperament outcomes. There may be some benefit in shaping specific interventions to women reporting specific risk factors such as DV or past abuse.

Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality.

OBJECTIVE: To determine whether hormone replacement therapy (HRT) after treatment for breast cancer is associated with increased risk of recurrence and mortality. DESIGN: Retrospective observational study. PARTICIPANTS AND SETTING: Postmenopausal women diagnosed with breast cancer and treated by five Sydney doctors between 1964 and 1999. OUTCOME MEASURES: Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes and to death from primary tumour were compared between women who used HRT for menopausal symptoms after diagnosis and those who did not. Relative risks (RRs) were determined from Cox regression analyses, adjusted for patient and tumour characteristics. RESULTS: 1122 women were followed up for 0-36 years (median, 6.08 years); 154 were lost to follow-up. 286 women used HRT for menopausal symptoms for up to 26 years (median, 1.75 years). Compared with non-users, HRT users had reduced risk of cancer recurrence (adjusted relative risk [RR], 0.62; 95% CI, 0.43-0.87), all-cause mortality (RR, 0.34; 95% CI, 0.19-0.59) and death from primary tumour (RR, 0.40; 95% CI, 0.22-0.72). Continuous combined HRT was associated with a reduced risk of death from primary tumour (RR, 0.32; 95% CI, 0.12-0.88) and all-cause mortality (RR, 0.27; 95% CI, 0.10-0.73). CONCLUSION: HRT use for menopausal symptoms by women treated for primary invasive breast cancer is not associated with an increased risk of breast cancer recurrence or shortened life expectancy.

Functional data analysis with application to periodically stimulated foetal heart rate data. I: functional regression.

Functional regression is used to model longitudinal data where the number of measurements on the functional covariate is much greater than the number of subjects in the study. Thus, functional regression can be thought of as singular longitudinal analysis. We have modified existing functional regression techniques to the case of a functional covariate with a repeated stimulus. We applied this modified functional regression to periodically stimulated foetal heart rates. The heart rate tracings were used as a predictor of the child's psychomotor development at approximately 18 months of age. In the past, this type of data has been analysed using the partially subjective concept of habituation. By using the entire heart rate tracings through functional regression, we have the advantage that habituation does not need to be defined and all available information is used to predict later child development.

Functional data analysis with application to periodically stimulated foetal heart rate data. II: functional logistic regression.

We present a basis solution for the modelling of a binary response with a functional covariate plus any number of scalar covariates. This can be thought of as singular longitudinal data analysis as there are more measurements on the functional covariate than subjects in the study. The maximum likelihood parameter estimates are found using a basis expansion and a modified Fisher scoring algorithm. This technique has been extended to model a functional covariate with a repeated stimulus. We used periodically stimulated foetal heart rate tracings to predict the probability of a high risk birth outcome. It was found that these tracings could predict 94.1 per cent of the high risk pregnancies and without the stimulus, the heart rates were no more predictive than chance.