Over 5 million babies have been born as a result of IVF procedures. Worldwide, over 1 million cycles of IVF are performed annually. The IVF procedure involves ovarian stimulation with the purpose of developing multiple follicles and maximising the potential oocyte yield. As a consequence of high oestradiol levels produced during treatment and the use of GnRH agonists or antagonists, a luteal phase deficiency results. This phenomenon is associated with reduced implantation potential and suboptimal conditions for maintenance of early pregnancy. Luteal support in the form of progesterone or HCG has been demonstrated to improve pregnancy rates after IVF. A number of luteal support protocols have been investigated with progesterone the most commonly used drug. The optimum duration of luteal support has yet to be defined. With no agreement in clinical practice evident, the reported use of progesterone ranges from withdrawing luteal support at confirmation of biochemical pregnancy to continuation beyond 12 weeks gestation. Whilst luteal support is considered a very important aspect of IVF treatment, there is very little evidence to support an optimum duration of use. The DOLS trial is a prospective randomised double blind placebo controlled trial investigating the effect of additional luteal support beyond confirmation of pregnancy test after assisted conception. Four hundred and sixty seven patients were randomised after confirmation of biochemical pregnancy to receive a further 8 weeks of vaginal progesterone or 8 weeks of placebo. Summary results were to include a primary outcome defined as viable pregnancy at 12 weeks gestation, whilst secondary outcomes were to report on live birth rates, pregnancy associated complications, neonatal outcomes, effect on first trimester serum screening and effect on uterine artery Doppler velocity. The DOLS trial reported no difference in pregnancy outcome at 12 weeks gestation, with 167/228 (73.3%) women randomised to the extended luteal support treatment arm having a confirmed viable intrauterine pregnancy compared with 167/233 (71.7%) women randomised to the placebo arm of the trial; adjusted risk ratio 0.97 (95%CI 0.87 to 1.09). Similarly live birth rates were not different between the treatment groups; 71.1% versus 70.4% respectively. No effect of extending luteal support beyond positive pregnancy test was observed in reference to complications of pregnancy, neonatal outcome, uterine artery Doppler velocity or antenatal screening outcome. In conclusion, we have confirmed that continuing luteal support using progesterone beyond confirmation of biochemical pregnancy offers no benefit in terms of pregnancy outcomes. However the extended use of progesterone until 12 weeks gestation does not confer harm. We suggest that all clinics worldwide should consider offering luteal support no further than positive pregnancy test, at which point it can be safely withdrawn without compromising live birth rates and reducing treatment burden.

Postpartum haemorrhage (PPH) is the most common cause of maternal mortality leading to an estimated 86, 000 deaths/year. The most common cause of PPH is failure of the uterus to contract properly (uterine atony). Several measures have been introduced to prevent and treat atonic PPH, but in spite of active management of the third stage of labour (AMTSL), maternal deaths from PPH still occur. PPH can kill rapidly within two hours or less. PPH has long been recognised as a dangerous complication for mothers. In order to optimise the prevention and treatment of PPH, different approaches have been introduced and modified over the last century. We reviewed the regimes used in the management of the third stage of labour between 1917 and 2011 as described in the successive editions of the ‘Ten Teachers’ books. Throughout the Ten Teachers series, uterotonic drugs have always been taught as being the best initial measure to manage PPH. However, the importance of bimanual uterine compression (BMC) has increased gradually, moving from third to first treatment option over the editions (Aflaifel and Weeks, 2012a). The components of the AMTSL package for PPH prophylaxis have recently been extensively examined in clinical trials. Its effectiveness in reducing blood loss is now known to be almost all due to the uterotonics (Aflaifel and Weeks, 2012b). However, clinical trials evaluating the efficacy of uterotonics in treating PPH are comparatively rare. Where present they usually compare two uterotonics with an absence of control group, as it is unethical to leave a bleeding woman untreated. A recent innovation is to model the likely outcomes in the absence of uterotonic therapy through histograms. This also allows an assessment of the efficiency of treatment by measuring the number of women who stop bleeding shortly after administering treatments. This model has never previously been applied to databases in which uterotonics were used for prophylaxis. In a secondary analysis of 4 large randomised trials, small secondary histogram peaks (primarily attributed to a treatment effect) were still present even if uterotonic therapy had not been used. Furthermore, the study revealed that women were commonly treated at low levels of blood loss (< 500 mls). It was also seen that, of those diagnosed with PPH (≥ 500 mls), most stopped bleeding at blood losses of around 700 mls even if they did not receive any uterotonic therapy. This should warn against ascribing all the effect to uterotonic therapy. As well as stopping spontaneously, other physical therapies may also have been used concurrently and may have had an effect. The evidence from the histogram study suggested that use of additional uterotonic is not a good surrogate for PPH in the research context. Chapter 4 reports on evaluations of the outcomes that are used by researchers in PPH trials. In the 121 studies evaluated, there was a huge diversity in choosing the outcomes (PPH prevention). The most common was ‘Incidence of PPH ≥ 500 mls’, which was mentioned in 21% (25/121) of trials. The study interestingly showed that use of additional uterotonic was used for sample size calculation in 6% (7/121) of studies as a surrogate for PPH. The above findings emphasise the importance of physical measures in the early treatment of PPH. BMC is thought to help in treating PPH, although there are no clinical trials on its effectiveness. A survey was therefore conducted amongst obstetric care providers in the UK to look at the frequency of BMC use in clinical practice and the attitudes towards its use. The survey found that, although clinicians find BMC effective, it is rarely used as the procedure is considered to be too tiring and too invasive. If, however, BMC could be performed in a less invasive manner, then it could act as an effective low-cost treatment for those PPHs arising from atony. The thesis concludes with an investigation into a new low cost intervention that might contribute to the early physical management of PPH. The ‘PPH Butterfly’ is a new device that is designed to make uterine compression simpler, less tiring and less invasive. It was compared to the standard BMC in a mannequin model. The main objective was to compare the efficacy of the PPH Butterfly to standard BMC in producing sustained uterine compression. The study revealed that the PPH Butterfly is simple to use on a mannequin model, even among obstetric care providers with little experience. It produces an equivalent amount of pressure to BMC, but neither method produced sustained compression over the 5 minutes of use. It also demonstrates the feasibility of using a mannequin model for teaching and performing BMC.

Background: Postnatal Depression (PND) is experienced by around 13% of women, who suffer a range of disabling symptoms that can have a negative effect on the mother and infant relationship, with significant consequences in terms of the child's later mental health. Research has shown that providing support to mothers experiencing PND can help reduce their depressive symptoms and improve their coping strategies. This study aimed to evaluate the impact of telephone peer-support for women experiencing PND. Methods/Design: A pilot RCT was conducted in which women who screened positive for postnatal depression using the Edinburgh Postnatal Depression Scale (EPDS > =10) were randomised to receive telephone-based support from peers who had recovered from PND, or standard care. Primary outcome measures included depressive symptomatology measured post-intervention and at six-months using the EPDS, and parent-infant interaction using the CARE-Index. Secondary outcome measures included anxiety and depression, dyadic adjustment, parenting stress, and self-efficacy. Maternal perceptions of the telephone peer-support were being assessed using semi-structured interviews. Quantitative and qualitative data was also collected from the peer-supporters to assess the impact on them of delivering the intervention. Results: Participants: twenty-eight participants were recruited to the study, and there was a fifty-percent dropout rate (intervention group n=6, control group n=8). While there were no differences in EPDS scores between the two groups at post-intervention, the intervention group continued to improve at six-month follow-up, whereas the control group showed signs of relapse. The intervention had no impact on mother-infant interaction. In-depth interview data show that women valued the support that was provided. Peer-Supporters: nineteen peer-supporters were recruited, of whom five left before supporting a participant, and eight left after supporting only one participant. The quantitative results showed a significant non-clinical increase in anxiety at post intervention. The qualitative results indicated that the peer-supporters found the majority of calls challenging, and that delivering the intervention had had a deleterious impact on some peer-supporters. Conclusion: While these findings suggest a positive impact of telephone-based peer-support, further research into ways of improving mother-infant interaction are urgently required. Research is also required into providing effective support for the peer supporters.

<p> The present study examines the relation between depression and trait anxiety symptoms and women&rsquo;s utterances during a routine ultrasound procedure in the second trimester of pregnancy. Participants included a diverse group of 70 women seeking prenatal care at an academic medical center in the Midwestern United States. The Depression Anxiety Stress Scales (DASS-21) depression subscale and the State Trait Anxiety Inventory (STAI), trait form were used to assess symptoms of depression and trait anxiety, respectively. Audio and video of participants&rsquo; faces during the ultrasound examination were used to assess the content, sentiment, and number of utterances. Results of regression analyses indicated that higher levels of depression symptoms were significantly related to a lower proportion of fetus-related utterances to total utterances. Higher levels of depression symptoms and trait anxiety were significantly related to a lower proportion of positive fetus-related utterances to total fetus-related utterances, after controlling for gestational age. Higher levels of depression symptoms were significantly related to a higher proportion of negative-fetus-related utterances to total fetus-related utterances, after controlling for education. These findings suggest that pregnant women who are experiencing symptoms of depression and anxiety may exhibit certain types and patterns of utterances during routine prenatal sonogram procedures. Thus, observation of pregnant women&rsquo;s naturalistic speech may provide helpful supplemental information to the traditional self-report measure in screening for symptoms of depression and anxiety.</p><p>

INTRODUCTION Preeclampsia, a hypertensive disorder of pregnancy, affects 3% to 7% of women throughout the world. Preeclampsia is a leading cause of maternal and infant mortality worldwide, occurring primarily in nulliparous women. Despite extensive research over the past decade, the underlying pathophysiological mechanisms of the disease are largely unknown. A recent hypothesis has suggested that when a pregnancy is complicated by preeclampsia, it is the result of an inability of the maternal cardiovascular system to fully adapt to the physiologic challenge of pregnancy. This may result when there is an underlying and predisposing prepregnancy maternal cardiovascular state that leads to the pathophysiologic consequences of preeclampsia when pregnancy is superimposed. Despite evidence for familial predisposition and presumed multifactorial genetic inheritance, preeclampsia generally occurs in first pregnancies and does not recur when the interpregnancy interval is short. One explanation for these observations is that pregnancy itself modifies the maternal cardiovascular system in ways that persist postpartum and reduce the risk for preeclampsia recurrence, at least for a limited period of time. It has been demonstrated that the maternal cardiovascular system is remodeled during pregnancy, and these changes extend postpartum. The long lasting reduction in mean arterial pressure postpartum that pregnancy induces, and the cardiovascular remodeling that accounts for this, may allow for easier adaptation to volume expansion in subsequent pregnancies, even when the first pregnancy was complicated by preeclampsia. As the maternal cardiovascular system returns, over time, to the baseline condition, this protective effect diminishes. With this knowledge, we hypothesize that the length of time between pregnancies is negatively correlated to the likelihood of recurrence of preeclampsia, and more narrowly that the length of time between pregnancies is inversely associated with mean arterial pressure differences comparing pregnancies across all trimesters. METHODS This study was a retrospective chart review of existing medical records. We reviewed medical records of women who had been diagnosed with preeclampsia at Fletcher Allen Health Care, during their first advanced pregnancy between 1995 and 2014, who went on to have a subsequent pregnancy within that time period. We aimed to identify factors that could affect the blood pressure and risk of preeclampsia in women who were previously diagnosed, including previous medical history and demographic variables. We collected blood pressures from each pregnancy, across each trimester, marking the recurrence of preeclampsia and other complications. Mean antepartum mean arterial blood pressure, pulse pressure, and systolic and diastolic blood pressures were calculated and compared between pregnancies examining differences as a function of interpregnancy interval. RESULTS One hundred and seventy two subjects were identified for review. Overall, there was evidence of a significant association of interpregnancy interval (IPI) and the difference in mean arterial pressure (MAP) between pregnancies (p=0.04). The mean MAP of pregnancy decreased significantly between first and second pregnancies when the interpregnancy interval was <24 months (p=0.0018) and 24-48 months (p=0.0003), but the change was non-significant at interpregnancy intervals of >48 months (p=0.55). The mean MAP during the third trimester, specifically, decreased significantly between first and second pregnancies across all subject groups (IPI <24 months: p<0.0001; IPI 24-48 months: p<0.0001; IPI >48 months: p=0.03). Preeclampsia recurred in 39 of the second pregnancies. The recurrence rate of preeclampsia did not vary significantly with interpregnancy interval (p=0.21). DISCUSSION/CONCLUSIONS The interval between preeclamptic pregnancies and subsequent pregnancies has an influence on the MAP of the second pregnancy. There is good evidence of a temporal influence, in that the shorter interpregnancy intervals resulted in a greater reduction in MAP when compared to the longer interpregnancy interval. We believe that with additional research on interpregnancy intervals >48 months, there could be more a conclusive association identified between the rate of recurrence of preeclampsia and the length of interpregnancy interval.

The reproductive lifetime of a woman is limited primarily by her age. The state of an oocyte represents the central determinant of the fate of an ovarian follicle as well as embryo development throughout maturation. Oocyte reserve and oocyte quality are two major determinants of the likelihood of achieving pregnancy for a woman. Assisted Reproductive Technology (ART) has provided a valuable alternative for women attempting to conceive at an older age, however even with ART the likelihood of a live birth also decreases with increased age. Mammalian oocytes undergo meiotic maturation in preparation for ovulation and fertilization. Throughout most of its lifetime the oocyte remains arrested in the dictyate stage of prophase of meiosis I (MI), also called the germinal vesicle (GV) stage, until the follicle receives a hormonal signal to progress through meiosis. Only a small fraction of the follicles present in the ovaries receive this signal, while the rest remain unresponsive. The DNA damage response (DDR) is activated in the presence of double stranded breaks (DSBs) in DNA and can induce various cellular responses including senescence or cell cycle arrest, and/or apoptosis, also known as programmed cell death. Telomeres mediate senescence in most cells. Telomeres consist of tandem DNA repeats and associated proteins, which cap and protect chromosome ends. Telomeres and their associated proteins form a loop at the ends of chromosomes, which buries them. This telomere complex is called shelterin. Shelterin prevents the ends of chromosomes from triggering a DNA damage response. However, with each round of DNA replication chromosomes lose small segments of their telomeres. Telomere attrition also can arise in non-dividing cells via the action of oxygen radicals. We hypothesize that germinal vesicle arrest, which occurs in some oocytes retrieved for ART that fail to progress through meiosis, is associated with telomere attrition and the associated cellular senescence pathway induced by DNA damage. Previous studies have identified higher levels of DNA damage foci in isolated GV arrested oocytes compared to those that progress through the meiotic cell cycle. Our studies confirm the presence of the DNA damage response (DDR) regulator, ATM, at higher levels in GV stage oocytes versus those that have matured to later stages. Immunostaining shows a near 50% increase in presence of ATM in arrested oocytes. Confirming the role of the DDR in cell cycle arrest during oocyte maturation could highlight a new target for strategies to improve ART technology and increase the likelihood of achieving pregnancy later in life.

The Pathways project was undertaken to devise guidelines to facilitate rapid diagnosis of paediatric brain tumours. Methods: A systematic review and meta-analysis of published data on paediatric brain tumour presentation and analysis of the presentation of children newly diagnosed with a brain tumour at four oncology centres was undertaken. The results informed a professional consensus process. Results: 74 papers met the inclusion criteria for the meta-analysis. 56 symptoms and signs at diagnosis were identified. The most frequent symptoms and signs at diagnosis were: headache (33%), nausea and vomiting (32%), abnormalities of gait and coordination (27%), and papilloedema (13%). 139 patients were recruited to a multi-centre cohort study. Symptoms and signs at disease onset and at diagnosis and factors associated with a long and short symptom interval were determined. A shorter symptom interval was associated with nausea and vomiting and motor system abnormalities. A longer symptom interval was associated with head tilt, cranial nerve palsies, endocrine and growth abnormalities and reduced visual acuity. A multi-disciplinary workshop and Delphi consensus voting were used to translate the evidence into a clinical guideline comprising 76 statements advising on the identification and assessment of children who may have a brain tumour.

Obstetric anal sphincter injuries (OASIS) are serious complications of vaginal birth with a reported average worldwide incidence of 4%-6%. They are a recognised major risk factor for anal incontinence resulting in concern amongst women who sustain such injuries when considering the most suitable mode of birth in a subsequent pregnancy. This thesis contains three studies; a systematic review and meta-analysis of the published literature exploring the impact of a subsequent birth and it’s mode on bowel function and/or QoL for women with previous OASIS, a follow-up study on the long-term effects of OASIS on bowel function and QoL and finally a prospective cohort study of women with previous OASIS to assess the impact of subsequent birth and its mode on change in bowel function. The work in this thesis demonstrated an increase in incidence of bowel symptoms in women with previous OASIS over time and that short-term bowel symptoms were significantly associated with bowel symptoms and QoL. This thesis also showed that the mode of subsequent birth was not significantly associated with bowel symptoms or QoL and for women with previous OASIS who have normal bowel function and no anal sphincter disruption a subsequent vaginal birth is a suitable option.

Fetal position throughout labour exerts considerable influence on labour and delivery, with a mal-positioned fetus during active labour known to contribute towards fetal and maternal morbidity. In response there is a move towards promoting the Left Occipito-Anterior (LOA) position at labour onset as optimal. It is thought that the LOA position encourages anterior rotation thus reducing the likelihood of mal-rotation. A systematic review was undertaken which highlighted an absence of scientific evidence. A prospective cohort study was therefore conducted with 1250 nulliparous women who were scanned to accurately determine fetal position, specifically the LOA position at the onset of labour and the association with delivery mode and other birth outcomes was examined. The LOA position at the onset of labour was not associated with mode of delivery, nor were any of the other positions (p=0.39). Pain relief, labour duration, augmentation, and Apgar scores did not show any association with the LOA or other positions. The only association found was that women with a fetus in the posterior position were more likely to use pethidine (p=0.008). This study has shown that the LOA fetal position at labour onset was not associated with improved outcomes and therefore should not be promoted as optimum.

Background: Every year 287,000 women die from pregnancy related complications. Methods: Systematic reviews of interventions to reduce maternal mortality in developing countries with meta-analysis or meta-synthesis where appropriate. Results: Participatory learning and actions cycles with women’s groups significantly reduce maternal and neonatal mortality, training and supporting TBAs also reduces perinatal mortality. Clinical officers performing caesareans section do not seem to cause any more maternal or perinatal mortalities than doctors. Prophylactic antibiotics reduce infectious morbidity in surgical abortion, yet the effect on miscarriage surgery is unclear. Cell salvage in ectopic pregnancy and caesarean section appear to be a safe and effective alternative in the absence of homologous transfusion. Motivational interviews may have potential to improve contraceptive use short term. Symphysiotomy may be a safe alternative to caesarean section. The anti-shock garment may improve outcomes when used in addition to standard obstetric haemorrhage management. Potential solutions to emergency transport for pregnant women include motorcycle ambulance programmes, collaboration with local minibus taxis services, and community education and insurance schemes. Conclusion: Several interventions reviewed in this thesis can be utilised to aid reduction in maternal mortality, however the level of evidence available within each review varies, some allowing firm inferences with others more tentative.