Abstract
IntroductionSpontaneous preterm birth complicates around 7% of deliveries globally, with approximately 1.2% occurring prior to 32 weeks’ gestation (classified as very preterm birth). Preterm birth remains the leading cause of neonatal mortality and long-term morbidity worldwide, with outcome inversely correlated with gestational age at delivery. Between 1990 and 2023, neonatal disorders, of which preterm birth is the major cause, have been the leading contributor to disability associated life years across all diseases. While the aetiology of preterm birth is diverse, chorioamnionitis is a well-recognised association particularly at earlier gestations. Therefore, the implications of preterm birth for the fetal immune system are of interest, as are those for the adrenal glands which are also implicated in the stress response to inflammation and infection. While this has been studied in animal models, investigation in the human fetus has been largely limited to volumetric ultrasound of fetal organs, post-mortem assessment, and extrapolation from postnatal data. This thesis aims to use volumetric and advanced MRI techniques to determine the effect of preterm birth prior to 32 weeks’ gestation on the fetal immune and endocrine systems that are visible on imaging in vivo.
Methods
A control group of women with uncomplicated pregnancies and a cohort who were deemed to be at very high risk of preterm birth prior to 32 gestational weeks consented to undergo a fetal and placental MRI. This was undertaken at 3 Tesla and obtained T2 (volumetric) and T2* (functional) imaging of the fetus and placenta as well as placental diffusion data. Key organs related to fetal inflammatory processes, the thymus, spleen and adrenal glands, and the placenta, were included for analysis. Clinical outcome data were obtained for all participants, as was placental histopathology for those who subsequently delivered prior to 32 weeks. Any participant who developed any confounding obstetric pathology, and any woman recruited into the high-risk cohort who subsequently delivered after 32 weeks’ gestation was retrospectively excluded from the analysis. After assessing for statistical normality, linear regression was used to compare the two groups taking into account gestational age at time of scan.
Results
Fetuses who subsequently delivered prior to 32 weeks had lower thymic volume with a reduction in mean thymus tissue T2* values as compared to controls (p=0.021 and p<0.001 respectively). Splenic volume was increased when standardised for fetal body volume (p=0.027) and mean splenic T2* values were maintained between the two groups (p=0.755). Likewise, adrenal gland volume was increased when standardised for fetal body size (p=0.011). Placental T2* decreased in a model incorporating the whole placenta parenchyma (p<0.001), and also in both compartments of a bicompartmental model of diffusing and perfusing tissue (p=0.001 and p<0.001 respectively). Apparent diffusion coefficient and fractional anisotropy were statistically unchanged in the cohort who subsequently delivered preterm (p=0.760 and p=0.087 respectively for whole placental parenchyma), although trends across gestation did seem to vary as compared to the term born cohort.
Conclusion
T2*, a proxy marker for oxygenation, is reduced in the thymus of fetuses who subsequently deliver preterm. This is likely to reflect thymic involution that has been demonstrated in animal and human work prior to preterm birth. Unlike the thymus, alterations in organ growth prior to preterm birth has not been shown in the spleen, although histopathology has demonstrated microscopic alterations suggestive of functional changes, and animal models have proposed a prolonged splenic response to inflammation. The relative increase in size of the spleen and the maintenance of normal T2* values may reflect an increase in activity and preferential sparing or sustained metabolic activity of the spleen. The adrenal glands have previously been volumetrically assessed in the fetus prior to preterm birth and, although there is some contradictory evidence, an increase in size is the prevailing finding. The relatively increased gland size demonstrated in this thesis is in line with this and is likely to reflect increased cortisol production secondary to inflammation. Placental pathologies are common in women who subsequently deliver preterm, with chorioamnionitis the leading cause prior to 32 gestational weeks. The reduction in T2* across the whole placenta and within the perfusing and diffusing compartments may reflect the direct impact of leukocyte invasion and necrotic processes associated with this. While diffusion parameters were not significantly different, the alterations in trends across apparent diffusion coefficient and fractional anisotropy, both suggestive of increasing tissue complexity, may also point towards this.
Distinct immunologically-driven changes can be demonstrated in fetuses who subsequently deliver extremely and very preterm. These are likely to be the result of a pro-inflammatory environment associated with chorioamnionitis and funisitis. As well as highlighting early differences in the immune status of preterm born infants as compared to their term born counterparts, this may also provide some insight into the mechanisms of end-organ damage, such as that to the brain, seen in conjunction with preterm birth. These findings add credence to ongoing research into the use of fetal and placental MRI as a clinical tool for investigation of preterm pathologies.
| Date of Award | 1 Jul 2024 |
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| Original language | English |
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| Supervisor | Andrew Shennan (Supervisor), Lisa Story (Supervisor) & Natalie Suff (Supervisor) |