Placental growth factor; potential for its use in twin pregnancy and evaluation of its benefit in singletons with suspected preterm pre-eclampsia

Abstract

Hypertensive Disorders of Pregnancy are common and may result in increased maternal and neonatal morbidity and mortality. Twin pregnancies confer an increased risk of development of a hypertensive disorder of pregnancy. Placental growth factor is an angiogenic protein highly expressed during pregnancy. The pro-angiogenic/anti-angiogenic synergism of PlGF and its receptors is critical for successful placentation in early pregnancy. Circulating maternal levels of placental growth factor correlate well with placental function. Women presenting with suspected pre-eclampsia are currently triaged based on hypertension and dipstick proteinuria. Numerous studies advocate a role for placental growth factor testing as a useful adjunct in the management of women presenting with preterm pre-eclampsia. Several automated immunoassay platforms to quantify placental growth factor are currently available. Comparative studies of these immunoassays are limited. Current reference values and clinical cut-offs for PlGF were constructed from singleton pregnancy cohorts. Given the larger placental volume present in a twin pregnancy, separate reference ranges are likely required. Pregnant women are seldom included in randomised controlled trials and their attitudes and experiences of this are not often investigated. Gathering feedback of their experience is paramount for future trial design to facilitate participation. In this thesis, I reviewed nine years of clinical data in twin pregnancies from a single maternity unit to understand the impact of hypertensive disorders on maternal and neonatal outcomes. I examined cross sectional values from uncomplicated twin pregnancies to assess the potential for using PlGF in this population. I compared the PlGF results obtained from an ELISA to an automated immunoassay, to determine if clinical cut-offs developed for one platform were transferrable to another. I conducted a national multi-site randomised control trial; PARROT Ireland, to evaluate the impact of incorporation of PlGF testing into routine clinical care. Lastly, through one on one interviews with trial participants, I investigated the barriers and facilitators to pregnant women taking part in clinical research. The data from these studies revealed that maternal age >40 years, nulliparity, conception through use of a donor oocyte, and presence of obstetric cholestasis are all important risk factors for the development of a hypertensive disorder in a twin pregnancy. The incidence of iatrogenic late prematurity and neonatal hypoglycaemia are increased when a hypertensive disorder complicates a twin pregnancy. PlGF levels in twin pregnancy differ significantly between those women with a pregnancy that will later be complicated by preeclampsia and those that will not. The difference is present many weeks before clinical signs or symptoms are present, indicating that PlGF has potential to aid diagnosis of pre-eclampsia in twin pregnancies. A dichorionic twin pregnancy specific reference range for PlGF has been developed, which may be utilised for further interventional research on PlGF in twins. The findings also indicate that PlGF biomarker levels vary significantly between different immunoassay platforms, highlighting the importance of developing validated clinical cut-offs for any automated immunoassay before they can be clinically applied. The result of the interim analysis from the PARROT Ireland trial is of no significant reduction in either maternal or neonatal morbidity with the integration of point of care PlGF based testing. These are interim results only however and the final results may differ. Should the final trial results demonstrate a positive impact on maternal morbidity, without a negative impact on neonatal morbidity, it would indicate that PlGF testing should be incorporated into routine clinical investigations for women presenting with suspected pre-eclampsia before 37 weeks’ gestation. The final study of the thesis highlights that pregnant women are interested and willing to participate in research. Identifying the correct timepoint and location to approach women, as well as the manner and language used to communicate with them, are key elements in ensuring their participation. The findings from this thesis, though supportive of the current literature in relation to the potential of PlGF, highlight that there is more research required.