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In the Autumn of 1947, the Writer of this thesis, in search of a suitable subject for study, prepared, with the aid of Individual case-papers, Midwive's Registers and Report Books, a detailed Annual Report of the work done during the year 1946 at the Lucy Baldwin Maternity Hospital, Stourport-on-Severn, Worcestershire, the Writer having been on the Medical Staff of this hospital since 1932. This report is included in the Appendix at pages 40-65. This hospital has no resident medical officer. Consideration of the 1946 report, and, hearing in mind the increasing use of Pethidine hydrochloride in current obstetrical practice, it was decided to study the action of this drug, already in somewhat tentative use at this hospital since 1944, as it became more fully used during the year 1948. As a control, the hospital results over the ten years period 1938-47 were prepared in a similar manner to the 1946 report, this being considered the only practicable control series obtainable. At the same time, during the trial year of 1948 it was decided to intensify the instruction of patients in "Relaxation" already in use at this hospital for some years, and to study the action of Trichlorethylene as an analgesic for self-administration in later labour. Supervision of Trichlorethylene administration limited the number of cases to 100 in hospital and 15 in private domiciliary practice.

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Human Cytomegalovirus (CMV) is a common herpesvirus found in 60% of the population. Normally, it poses no risk, however it can have consequences for unborn babies. This is of concern when donor sperm is used in assisted conception, as CMV is present in semen. The risk of transmission from a positive donor is unclear, as it is not known if sperm can act as a vector for transmission. Additionally, this raises questions about whether CMV might affect sperm function. The hypothesis for this study is that CMV will interact with human sperm and alter sperm function and that sperm will act as a vector for viral transmission. A survey was conducted to examine how fertility clinics were screening for CMV in sperm donors. This survey found that the majority of UK clinics are screening for CMV in sperm donors in the manner recommended by current guidelines but that the requirement to screen for CMV is causing problems in clinics with regards to sperm donor supply. Fortunately, this thesis has shown that sperm washing by density gradient centrifugation is mostly effective at removing CMV from semen samples infected in vitro, with CMV (AD169) grown in the laboratory, and in naturally infected samples. This presents a possible approach for alleviating some of the problems relating to CMV infection in sperm donors in UK fertility clinics. However, co-incubation with CMV has no effect on any of the sperm function parameters tested in this thesis, including, motility, viability, acrosome reaction, tyrosine phosphorylation and levels of DNA damage. In conclusion, this thesis has highlighted problems with the current approach to screening and managing CMV infection in sperm donors but has provided evidence to show that there could be a simple solution to the problem. No effect on sperm function was observed, but this does not rule out a direct interaction between CMV and sperm. Overall, this thesis shows that fertility clinics should be concerned about CMV infection in sperm donors, but that simple steps could be taken to alleviate the current problems clinics are experiencing.

Although the underlying aetiology of pre-eclampsia remains an enigma, it is only recently that oxidative stress and membrane transport abnormalities associated with sodium have been implicated. These represent two factors that may constitute the pre eclamptic phenotype proving important in the pathogenesis of the disease. White cell Na+/H+ exchanger activity was increased in pre-eclamptic pregnancy with respect to normotensive pregnant controls and persisted into the post-partum period. This was not due to increased expression of a 97kDa NHE-1 protein but possibly genetically determined due to the persistence of the phenotype in transformed lymphoblasts. Cells isolated from pre-eclamptic women exhibited an intracellular acidosis that again, persisted into the post-partum period. The mechanism(s) responsible were unclear but may have been associated with inhibition of the Na+K+ATPase by a digoxin-like factor. Neutrophil NADPH oxidase mediated reactive oxygen species production was measured using a chemiluminescent technique. These results were affected by the intracellular acidosis consequently measurements were performed in Epstein-Barr virus immortalized lymphoblasts. Upregulated NADPH oxidase activity was identified in pre-eclamptic and post-partum pre-eclamptic cells with tyrosine kinase signal transduction pathways being implicated in their control. Enhanced activity may have been influenced by a genetically determined phenotype resulting in an increased sensitivity of the enzyme. Collectively, this data adds to our understanding of pre-eclampsia and provides phenotypic characterisation of the Na+/H+ exchanger and NADPH oxidase enzyme. These membrane functions may have implications as markers for predisposition to disease or in therapeutic intervention.

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Importance: In Africa most P. falciparum malaria infections during pregnancy remain asymptomatic yet are associated with maternal anaemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy during the second and third trimester with Sulphadoxine-Pyrimethamine (IPTp-SP). However, SP efficacy is threatened by high-level parasite resistance. Thesis objectives: The objectives of this thesis were three fold: Efficacy and safety of ISTp-DP To evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with Dihydroartemisinin-piperaquine (ISTp-DP) as an alternative strategy to IPTp-SP in an area of high malaria transmission and SP resistance. Effect of asymptomatic malaria infections To investigate the effect of asymptomatic malaria infections, specifically evaluating the role of asymptomatic infections missed by a malaria rapid diagnostic test (mRDT) on pregnancy and birth outcomes. Diagnostic sensitivity of HRP2/pLDH RDT for active placental malaria To determine the sensitivity of an mRDT to detect active malaria infection sequestered in the placenta. Design, setting, and participants: This was an open-label two-arm individually randomised superiority trial in 3 sites with high SP resistance in Malawi. Between July 2011 and March 2013, 1873 HIV-seronegative women at 16-28 weeks of gestation were recruited (1155 primigravidae and secundigravidae [paucigravidae], 718 multigravidae). Interventions: IST and IPTp-SP were administered at 3 or 4 scheduled visits in the 2nd and 3rd trimester, 4 to 6 weeks apart. The IPTp-SP arm received SP at each visit. The ISTp-DP arm were screened for malaria at every visit and treated with DP if RDT-positive. Main outcomes and measures: Efficacy and safety The primary outcomes of interest to evaluate the efficacy and safety of ISTp-DP were gravidity dependent. Amongst paucigravidae these were any adverse live birth outcome (composite of small-for-gestation age, low birthweight or preterm birth) whilst amongst multigravidae, any P. falciparum infection at delivery was of primary interest. Analysis was by modified intention to treat. Effect of asymptomatic malaria infections Outcomes of interest in this analysis were composite adverse live birth outcome, individual adverse live birth outcomes (small for gestational age, preterm birth and low birthweight) and maternal anaemia. Analysis was restricted to only women in the IST arm fulfilling the modified intention to treat criteria. Diagnostic sensitivity of HRP2/pLDH RDT for active placental malaria The diagnostic sensitivity of mRDT on peripheral maternal venous blood at delivery for active placental malaria against placental histology as the gold standard was the primary outcome of interest. Analysis included women from both trial arms at delivery. Results: Efficacy and safety The prevalence of adverse birth outcome was similar in both arms: ISTp-DP=29.9%, IPTp-SP=28.8%, Risk-Difference: 1.08%, 95% confidence interval (CI): -3.25 to 5.41; Relative Risk (RR) =1.04 (0.90-1.20), p=0.625, (paucigravidae: RR=1.10 [0.92-1.31], p=0.282; multi-gravidae RR=0.92 [0.71-1.20], p=0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% vs 40.8%): Risk-Difference=7.85 (3.07-12.63); RR=1.19 (1.07-1.33), p=0.007 (paucigravidae: RR=1.16 [1.04-1.31], p=0.011; multi-gravidae: RR=1.29 [1.02-1.63], p=0.037). Foetal loss was more common with ISTp-DP (2.6% vs 1.3%; RR=2.06 [1.01-4.21], p=0.046) and highest among non DP-recipients (3.1%) in the ISTp-DP arm. Effect of asymptomatic malaria infections by RDT 46.2% of women had malaria infection by either RDT or PCR at their first antenatal visit. The prevalence of sub-RDT infection was consistently higher in multigravidae than paucigravidae throughout pregnancy. The risk for any placental malaria was higher with asymptomatic missed RDT parasitaemia than never having had any detected parasitaemia at study visits: 38.8% vs 20.4%; RR= 1.90; 95% CI 1.28, 2.82; p=0.002. This was consistent when stratified by gravidity. Missed infections were also associated with higher risk for composite any adverse live birth outcome (26.5% vs 12.8%; RR=2.06; 95%CI 1.23, 3.42; p=0.005) which was driven by the strong association with preterm birth: 19.1% vs 4.1%; RR=4.7; 95% CI 2, 11.1; p<0.001. Asymptomatic patent RDT infections were associated with increased risk for maternal anaemia, placental malaria, composite adverse live birth outcome, preterm birth and low birth weight. Diagnostic sensitivity of HRP2/pLDH RDT for active placental malaria Peripheral blood RDTs at delivery were 48% sensitive (95% C.I 39.6, 56.4%) to diagnose active placental malaria infection. This was lower than PCR (64% vs 48%; difference=16.4%; 95% CI 8.4, 24.5%; p < 0.001) but higher than LM (48% vs 16%; difference=31.5%; 95% CI 22.4, 40.6%; p < 0.001). The sensitivity of RDTs on placental blood to diagnose active placental infection was lower than in peripheral blood: 34% vs 48%; difference=-13.7%; 95% CI -21.1, -6.3%, p < 0.001. Peripheral blood RDT had a low diagnostic sensitivity at 70% (95% CI 47.1, 86.8%) in detecting an active placental infection density of above 100 parasites/500 RBCs, associated with an increased risk of low birth weight. Conclusion and relevance: Scheduled screening for malaria parasites with RDTs provided 3 to 4 times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in a setting of high SP resistance, being associated with higher foetal loss and more malaria at delivery. This may be attributable to the effect of asymptomatic parasitaemia that are left to persists in the peripheral blood without treatment due to low rate of detection of infection by RDTs through subsequent antenatal visits, and/or the low sensitivity to detect active infection sequestered in the placenta. As such, in areas with high SP resistance, ISTp-DP is not a viable option. There remains an urgent need to identify alternative drugs that can replace SP for antenatal malaria prevention.