Aims: To study the effect of pre-existing maternal cardiac disease on cardiovascular function during pregnancy, and on obstetric and fetal/neonatal outcomes, and to investigate maternal risk factors for adverse events. Methods: Retrospective case note review. Results: Four hundred and eighty-nine pregnancies in 326 women were studied. Most pregnancies (50%) occurred in women with congenital heart disease. There were 4 maternal deaths, 6 stillbirths and 5 neonatal deaths. Cardiovascular events occurred in 7.4% of pregnancies, while obstetric and perinatal complications occurred in 34% and 30% of pregnancies respectively. Conclusions: Pregnancy in women with pre-existing heart disease continues to be associated with high rates of maternal and neonatal mortality and morbidity. This work highlights the importance of effective prepregnancy counselling and meticulous surveillance during pregnancy, delivery and the puerperium by an experienced multidisciplinary team. Additionally there is an urgent need for well-designed randomisedcontrolled trials to determine best practice.

Gestational diabetes and maternal obesity are associated with impaired maternal glycaemic control and increased risk of delivering a macrosomic fetus. Macrosomic as well as growth restricted neonates have an increased risk of metabolic syndrome and cardiovascular disease in adult life which may be mediated through an altered intra-uterine environment. The placenta acts as a mediator between the mother and the fetus and handles placental nutrient exchange and transfer. Insulin-like growth factors 1 and 2 (IGF1 and IGF2) are hormones similar to insulin and are known for their growth promoting function in the body. They are also present in the placenta and play an important role in regulating placental and fetal growth. Animal and human studies have shown that IGF1 and IGF2 deletions are associated with growth restriction. The IGFs are bound to their binding proteins called insulin-like growth factor binding proteins (IGFBPs) which modulate their bioavailability and can therefore modulate fetal growth. The IGFs and IGFBPs are associated with glucose regulation but their role in gestational diabetes is unclear. We hypothesized that the placental gene expression of IGF system related genes is altered in pregnancies complicated by fetal growth disorders (pregnancies with small or large fetuses) and in those women who had gestational diabetes mellitus (GDM) or increased body mass index (BMI > 30). Epigenetics is the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence. DNA methylation is an epigenetic mechanism which involves addition of methyl group to a cytosine base in the DNA forming a methylated cytosine-phosphate-guanine (CpG) dinucleotide which is known to silence gene expression. This can potentially alter the expression of IGFs and their binding proteins. We have also hypothesized that a relationship existed between DNA methylation and gene expression of components of the IGF axis in the placenta. The placental IGF1 expression was found to be reduced in women with small for gestational age (SGA) neonates. The expression of IGFBPs was upregulated in SGA neonates and downregulated in large for gestational age (LGA) neonates. The placental IGF1 gene promoter was found to be hypermethylated while the promoters of the binding proteins were hypomethylated in the placentas of SGA neonates. The umbilical cord levels of IGF1 and the binding proteins in SGA and LGA neonates showed a similar trend to the placental gene expression changes. We have also analysed the placental gene expression and umbilical levels of imprinted gene GRB10 which has been investigated in mice studies and is known to cause growth restriction. We found increased placental expression of GRB10 and hypomethylation of its promoter in SGA neonates. The placental expression of IGF1, IGFBP1 and IGFBP2 was found to be decreased in women with GDM on diet and on metformin but not in those on insulin. The IGF1, IGFBP1 and IGFBP2 promoters were noted to be hypermethylated but only in women on diet treatment and not on metformin on insulin. The umbilical levels of IGF1 and IGFBP1 but not IGFBP2, were increased in GDM thus showing an inverse trend to the placental gene expression changes. In conclusion our results suggest that in SGA neonates, changes in CpG methylation contribute to the changes in gene expression of components of the IGF axis and GRB10 in fetal growth disorders. Differential methylation of the IGF1 gene, its binding proteins and GRB10 is likely to play a role in the pathogenesis of SGA neonates. Our results also suggest that GDM is associated with gene expression and epigenetic alterations in the IGF1, IGFBP1 and IGFBP2 genes, which could be part of the wider metabolic complexities associated with GDM.

Maternal obesity is associated with adverse pregnancy outcomes, especially the development of gestational diabetes mellitus (GDM), with associated risks for mother and infant. Improved understanding of glucose intolerance in obese women and better prediction and prevention of GDM is key to improving the health of mother and her child. This thesis reports two related projects. The first explored mechanisms of insulin resistance and prediction of GDM in obese pregnant women participating in the pilot study for the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a lifestyle intervention RCT. The second investigated the potential of a dietary intervention to improve glycaemic profiles in this high-risk group. Following an 8 week dietary and physical activity intervention, a panel of biomarkers associated with obesity and insulin resistance were measured in 117 women in the pilot trial. At 27+0-28+6 weeks’ no difference was observed between the intervention and control arms but at 34+0-35+6 weeks’, significant reductions in plasma visfatin, cholesterol and LDL cholesterol were observed. Analysis by GDM status, confirmed greater concentrations of fructosamine, AST and insulin and lower plasma leptin and adiponectin in women who developed GDM. An algorithm based on clinical factors alone (age, parity, ethnicity and blood pressure at 15+0-18+6 weeks’ gestation) showed predictive potential which increased significantly with the addition of plasma adiponectin measured at 15+0-18+6 weeks. In obese pregnant women without GDM (n=16,) the effect of a slow-digesting low glycaemic index (SD-LGI) supplement drink was evaluated at 24+0-28+6 weeks’ gestation. Linear regression analysis with mixed modelling (LMM) showed a significant reduction in glycaemia over the 24 hour period following consumption of the test compared to the control supplement and habitual diet. Fasting and nocturnal glucose concentrations were also significantly improved. In summary biomarkers associated with insulin resistance were identified as potential targets for lifestyle interventions aimed at reducing GDM in obese women. A prediction model for GDM identified those at greatest risk and pending validation in the UPBEAT RCT may have the potential for translation into clinical care. Extending the role of interventions further, multiple improvements in parameters of glycaemic control were demonstrated using a SD-LGI nutritional supplement.

This thesis investigates whether human papillomaviruses are transmitted from mothers to their infants. Cervical/vaginal swabs were taken from 69 pregnant women. Buccal and genital samples were taken from their infants (all delivered vaginally) at 24 h (n=70; one set of twins), six weeks (n-49) and six months (n=19). All samples were examined for HPV-6, -11, -16, -18, -31 and -33 us polymerase chain reaction (PCR). Thirty seven (54%) women had detectable detectable in sixteen (23%) infants at 24 h and seven (14%) at six weeks; a perinatal transmission rate of 23% (6/37) and persistence of 14% (7/37). All infants tested at six months were HPV negative. At 24h, HPV-6 was demonstrated in 9 mother-infant pairs, HPV-18 in 1 mother-infant pair, HPV-11 in 1 mother-infant pair, dual infection with HPV type 16 and 18 in 3 mother-infant pairs. Two infants with HPV-18 were delivered to mothers in HPV-16/18. At 6 weeks, 5 infants remained HOV-16 positive, one infant HPV-18 positive, whilst one infant who was HPV 16/18 positive was now HPV-16 positive. To examine whether HPVs were acquired in utero or intrapartum, genital swabs were collected from 33 women who had amniotic fluid collected either at caesarean section (n=29) or at amniocentesis (n=4). Analysis of these samples demonstrated genital HPV in 10 (10%) of the women and none of the amniotic fluid samples. To demonstrate persistence and source of infectivity at 2 years, the same group sequenced a 521 bp segment of the upstream regulatory (URR) of HPV-16 DNA isolated from 13 maternal samples, samples taken from their infants. In conclusion, HPVs can be transmitted perinatally. HPV DNA persisted up to 2 years of age. In addition women with a high genital HPV load were more likely to transmit the virus.

Deficits in respiratory control have been implicated in the aetiology of sudden infant death syndrome (SIDS). Victims of SIDS show signs consistent with chronic hypoxia prior to death and have abnormalities in both the brainstem and carotid body. Epidemiological studies have shown that maternal smoking is a major independent risk factor for SIDS. Pre and postnatal nicotine exposure may lead to changes in the brainstem and carotid body. This could result in respiratory control deficits which may be involved in SIDS. The aim of the current work was to investigate the independent effect of maternal smoking on respiratory responses to changes in inspired oxygen in infants. Smoking is associated with other factors which may affect respiratory control, so a matched study design was implemented. Mother/infant pairs were matched for social class, maternal age and parity, gestational age, birthweight, infant gender and feeding intention. Infants were seen overnight at approximately 10 weeks of age for tests of respiratory control using the alternating breath test. Ventilation was measured using respiratory inductance plethysmography and inspired and end-tidal oxygen levels by mass spectrometry. Fifty-nine infants were studied and data on 40 of these (17 smoking group) was included in the analysis. The respiratory responses were similar in both groups for all respiratory parameters, and there were no significant differences. The mean end-tidal oxygen level when 40% O2 was delivered was significantly higher in the smoking group even though the measured inspired oxygen levels were similar in the two groups. These unexpected findings seemed to be related to the ongoing nature of the response. In conclusion, there does not appear to be an independent effect of maternal smoking on respiratory control in infants, and the differences in end-tidal oxygen levels may represent differences in alveolar ventilation during the alternating breath test.

Background: Research in humans demonstrates a link between an adverse environment during development and unfavourable health outcomes in adulthood. Animal research used to understand this phenomenon reveals that exposure to prenatal stress and to glucocorticoids may programme offspring hypothalamic-pituitary-adrenal (HPA) axis, which is in turn hypothesised to mediate disease risk. Extension of these findings in human research is at a less advanced stage, although synthesis of a number of lines of evidence suggests that similar HPA axis programming exists. Glucocorticoids are hypothesised as the final mediator in the pathway from adverse antenatal environment to programming effects, including altered offspring HPA axis activity, although molecular mechanisms underlying this hypothesis are yet to be elucidated. Depression in pregnancy is a paradigm by which mechanisms for developmental programming may be further studied. Methodology: A prospective longitudinal observational study of 82 pregnant women from the second trimester of pregnancy, and their offspring to 1 year postnatal is described. A cases group with DSM-IV major depressive disorder (MDD) was compared with a non-depressed control group. Maternal mood, antenatal HPA axis, obstetric outcomes and infant basal HPA axis activity and cortisol response to pain stress were assessed. Results: Compared with the control group, women with MDD in pregnancy had overactivity of the HPA axis in the third trimester of pregnancy, a shorter length of gestation, infants with larger cortisol response to pain stress at 8 weeks and 1 year postnatal and higher evening cortisol at 1 year of age. Furthermore, associations were found between antenatal depression, maternal antenatal HPA axis and infant HPA axis. The findings were independent of socio-demographic and obstetric factors and maternal postnatal mood. Conclusions: The associations between maternal antenatal depression and altered maternal and infant HPA axis activity suggest programming effects and add to the important literature on developmental programming in humans. Furthermore, the findings have clinical relevance in the fields of obstetrics, psychiatry and paediatrics.

Preterm labour is the most important cause of perinatal mortality. Our ability to prevent preterm labour has been hindered by poor understanding of the factors that initiate human parturition. cAMP is a second messenger which plays significant role in respiratory, cardiovascular, and reproductive systems. The role of cAMP-signalling pathway in the maintenance of pregnancy has been investigated. My results suggest that during pregnancy, high cAMP levels repress OTR via PKA-dependent pathway and this repression may contribute to myometrial quiescence. My results also suggest that as pregnancy advances, the activity of cAMP/PKA pathway declines and, in contrast, the levels of Epac1, rise. This pattern may be associated with an increase in OTR expression, which may contribute to uterine contractions. The ability of cAMP to repress inflammation in human myometrial cells was explored. My results show that cAMP repress the expression of inflammation related genes and pro-inflammatory cytokines. These results suggest that high cAMP/PKA tone in pregnancy may exert an anti-inflammatory effect and a reduction of cAMP/PKA tone may contribute to the pro-inflammatory effects of labour. AKIP1 has been identified to act as a molecular switch, determining cAMP/PKA action towards NFκB activity in various cell types. To date, no study was done to investigate the role played by AKIP1 in myometrial cells. My results suggest that in myometrial cells, low AKIP1 levels, helps to promote the anti-inflammatory effects of cAMP/PKA. The ability of cAMP in enhancing myometrial response to progesterone was tested. The results suggest that cAMP enhanced progesterone responsive genes via PKA. Furthermore, the ability of progesterone to repress IL-1β-induced inflammation may be enhanced by cAMP. Knockdown studies using siRNA, suggest that cAMP acts via PKA to enhance the anti-inflammatory action of progesterone. Overall, these data support a novel role for cAMP which may help in the prevention of preterm labour.

No description available.

Background and Aim: Prenatal alcohol consumption can be associated with a range of adverse fetal effects, collectively known as Fetal Alcohol Spectrum Disorders. However, the ‘safe’ upper limit of prenatal drinking is unknown. Consequently, policy and practice in the UK is unclear. This lack of clarity is compounded by a failure to understand pregnant women’s decisions regarding alcohol consumption. This research aims to address this by exploring pregnant women’s own understanding of their choices regarding alcohol use. Methods: A systematic review of qualitative literature concerning women’s views about alcohol use in pregnancy and; in-depth interviews with pregnant women to develop an understanding of their alcohol related views and behaviour. Results and Discussion: Lupton’s concept of reproductive citizenship was utilised to illuminate the findings of both strands of work. There was a relative lack of importance of biomedical ‘expert’ discourses. Health professionals’ guidance was frequently unmentioned; professionals either didn’t discuss alcohol or delivered advice in a confusing manner. Within the interviews, narratives focussed upon accounts of ‘always knowing’ how pregnant women should drink. Thus, pregnant self-regulation is more complex than currently understood. Risk narratives were prevalent throughout, but were not communicated in biomedical terms. Rather, they illuminated the wider discourses of reproductive citizenship. The need to feel and be seen as a good mother was universal but how this was expressed varied according to drinking status. Good motherhood was a powerful yet malleable discourse, drinkers were still able to claim the identity of good mothers. Prenatal drinking was contextualised within the context of prior drinking in the interview data but not in the systematic review. The need to contextualise pregnancy focusses on the need to understand pregnancy as part of the life-course and calls into question the fetus-centric approach to public health messages regarding alcohol use in pregnancy.

Background: Vertical GBS transmission is the prerequisite for early-onset disease. Disease protection is associated with maternally-derived anti-GBS antibody. This study investigates the correlation between serotype-specific functional antibody in cord sera and maternal/infant GBS colonisation, as a surrogate marker of GBS colonisation and thus disease protection. Methods: 750 Gambian mother/infant pairs were followed to day 60-89 postpartum. Maternal/infant GBS colonisation was determined by culture and polymerase chain reaction. Cord and infant serum were collected for functional antibody concentrations, analysed by flow cytometry. Results: Maternal colonisation was 33.7%; serotype (ST) V was most prevalent. Functional antibody concentration was lower in colonised- than in non-colonised mother/infant pairs at birth (STIa (p<0.001), STII (p<0.001), STIII (p<0.001) and STV (p<0.001)). Mother-colonised/infant-non-colonised pairs had significantly lower functional antibody concentration than non-colonised mother/infant pairs against STIa (p=0.001), STII (p=0.001), STIII (p<0.001) but not STV (p=1.0). Persistently colonised infants had lower functional antibody concentration than non-colonised infants against STII (p=0.04) and STV (p=0.01). Reduced infant colonisation risk was associated with functional antibody concentration above the 75th centile against STIa (p<0.001), STII (p<0.001), STIII (p=0.01) and STV (p<0.001). A ST-dependent threshold was observed above which infants were non-colonised at birth. Conclusions: Higher concentrations of functional maternally-derived antibodies are associated with a decreased risk of GBS colonisation in infants up to day 60-89 of life. Enhancing maternally-derived antibody concentrations through vaccination may reduce infant colonisation and so reduce the risk of GBS disease.