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

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

An exploration of women's experience of taking part in a randomized controlled trial of a diagnostic test during pregnancy: A qualitative study

Objective: To explore pregnant women's views of participation in a clinical research trial while pregnant. Design: Prospective nested qualitative cohort study embedded within a national, multi‐site randomized controlled trial of a diagnostic test for preeclampsia: Placental Growth Factor. One‐to‐one in‐depth semi‐structured interviews were undertaken with 19 women who had recently participated in the trial at a single recruiting site. The interviews were conducted in private, recorded digitally and transcribed verbatim. Setting: Single tertiary maternity hospital currently recruiting eligible women onto an on‐going randomized controlled trial (NCT 02881073). Participants: Women who had participated in the PARROT Ireland randomized controlled trial during their recent pregnancy. Methods: Thematic analysis was utilized. Each line of the transcribed interviews was coded into a category by two researchers. The resultant categories were reviewed, and those with similarities were pooled allowing the development of themes. Main Outcome Measures: Women's opinions and experience of participation in a randomized controlled trial of an interventional diagnostic test during their pregnancy. Results: Four major themes were identified as follows: (a) Understanding of preeclampsia, (b) Motivators for clinical trial participation, (c) Barriers to decision making and (d) Influence of PARROT Ireland on pregnancy experience. Conclusions:Women are generally interested and positively inclined to participate in research during pregnancy. The potential of risk is an important consideration for eligible pregnant woman. Information and support by both researchers and clinicians are paramount in aiding women's understanding of a research trial

The maternal and perinatal implications of hypertensive disorders of pregnancy in a multiple pregnancy cohort

Introduction: Hypertensive Disorders of Pregnancy are common and may result in increased maternal and neonatal morbidity and mortality. Multiple pregnancies confer an increased risk of development of a hypertensive disorder of pregnancy. The purpose of this study was to examine a large cohort of women delivering a multiple pregnancy in a single large tertiary unit, and to evaluate the implications of hypertensive disorders of pregnancy on both maternal and perinatal outcomes. Material and methods: Retrospective study of all twin pregnancies delivered at Cork University Maternity Hospital, Ireland over a 9‐year period (2009–2017). The twin pregnancies were divided according to the presence or absence of hypertensive disorder of pregnancy and the two groups compared. Results: Maternal age >40 years, nulliparity, conception through use of a donor oocyte, and presence of obstetric cholestasis are all risk factors for the development of Hypertensive Disorders of Pregnancy in women with a multiple pregnancy. When a hypertensive disorder complicates a twin pregnancy, it increases the incidence of iatrogenic late prematurity & neonatal hypoglycaemia. Conclusions: This study is informative for clinicians caring for women with a multiple pregnancy with its relevant data on perinatal outcomes following a diagnosis of hypertensive disorder in pregnancy

Placental Growth Factor: A review of literature and future applications

Placental growth factor is an angiogenic protein, highly expressed during pregnancy, which correlates well with placental function. In this review, we highlight the origin, structure and function of Placental Growth Factor and its receptors. We discuss how their pro-angiogenic/anti-angiogenic synergism is critical for successful placentation and how their imbalance may be utilised as a diagnostic marker of disease or a potential therapeutic target for adverse pregnancy outcomes

Maternity ultrasound in the Republic of Ireland 2016: a review

Antenatal ultrasound, comprising of a dating ultrasound in the late first trimester followed by a fetal anomaly scan, is a recognised and necessary component of good antenatal care. We conducted a telephone survey of all 19 obstetric units to ascertain the status of maternity ultrasound provision in Ireland. Fetal anomaly ultrasound is offered universally to all women in 7/19 (37%) units, selectively to some women in 7/19 (37%) units and not offered at all in the remaining 5/19 (26%) units. Overall ≈ 41,700 (64%) women receive a fetal anomaly ultrasound nationally. Universal first trimester ultrasound, performed in a dedicated ultrasound department by a suitably qualified sonographer, is offered to 47% of women nationally. This study highlights the lack of development in Irish maternity ultrasound services over the last decade. Substantial investment by health care policy makers is urgently needed

A prospective study of placental growth factor in twin pregnancy and development of a dichorionic twin pregnancy specific reference range

Objective: To develop a dichorionic twin pregnancy specific reference range for placental growth factor (PlGF), and to compare gestation‐specific placental growth factor levels in twin pregnancies later complicated by pre‐eclampsia, hypertensive disorder of pregnancy or fetal growth restriction with control pregnancies. Design: Prospective observational study. Setting: Single large tertiary maternity unit in Ireland. Population or Sample: Women with a twin pregnancy. Methods: Consenting pregnant women, across a variety of gestations, had a single blood sample taken at one time‐point only during their pregnancy. The plasma was initially biobanked and PlGF was measured later in batches using the point of care Triage® PlGF test. Main outcome measures: Development of pre‐eclampsia, hypertensive disorder of pregnancy or fetal growth restriction. Results: Placental growth factor levels in uncomplicated dichorionic twin pregnancies were significantly lower in the women who later developed pre‐eclampsia than in the controls at all gestational intervals. In those that later developed any hypertensive disorder of pregnancy, median PlGF was lower only in those recruited before 24 weeks of gestation, whereas in infants with a customised birthweight below the third centile, PlGF was lower only in those sampled after 24 weeks of gestation. Conclusions: Placental growth factor levels in twin pregnancy differ significantly between those women with a pregnancy that will later be complicated by pre‐eclampsia and those that will not. This difference is present many weeks before clinical signs or symptoms of disease are present. Using cross‐sectional values from uncomplicated twin pregnancies, we have developed a dichorionic twin pregnancy specific reference range for PlGF

Emotional Dysregulation as a target in the treatment of co-existing substance use and borderline personality disorders: A pilot study

Background: Borderline Personality Disorder (BPD) and Substance Use Disorders (SUD) are frequently co-morbid and their co-occurrence exacerbates the symptomatology and associated harms for both disorders. However, few intervention studies have examined the delivery of an integrated intervention for BPD and SUD within alcohol and other drug (AOD) treatment settings. This single arm pilot study examined the clinical utility and outcomes of a 12-session emotion regulation intervention for clients with co-occurring SUD and BPD symptoms delivered in an outpatient AOD treatment setting. Method: Forty-five adult treatment-seekers (64.4% women, mean age 35.8 years [SD=10.4]) attending an outpatient AOD service, who exhibited three or more symptoms of BPD, engaged in a 12-session emotion regulation intervention. Clinical measures assessing alcohol and drug use, BPD symptoms, emotion dysregulation and acceptance, non-avoidance of thoughts and emotions, and psychological flexibility were collected at baseline, session six and session 12. Treatment engagement, satisfaction and rapport were also measured. Results: Fifty-one percent of participants completed the 12-session intervention. The results demonstrated that the number of drug using occasions in the past 28 days significantly reduced from baseline compared to session 12. Furthermore, a significant reduction was identified in BPD symptom severity, emotion dysregulation, and non-acceptance, experiential avoidance and psychological inflexibility from baseline to session 12. Conclusions: For those individuals who completed the 12-session emotion regulation intervention, there were significant reductions across a number of clinical outcomes. However, retention in treatment for this vulnerable client group remains a significant challenge in the AOD setting

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects