Interventions for Infection and Inflammation-Induced Preterm Birth: a Preclinical Systematic Review

Spontaneous preterm births (< 37 weeks gestation) are frequently associated with infection. Current treatment options are limited but new therapeutic interventions are being developed in animal models. In this PROSPERO-registered preclinical systematic review, we aimed to summarise promising interventions for infection/inflammation-induced preterm birth. Following PRISMA guidance, we searched PubMed, EMBASE, and Web of Science using the themes: "animal models", "preterm birth", "inflammation", and "therapeutics". We included original quantitative, peer-reviewed, and controlled studies applying prenatal interventions to prevent infection/inflammation-induced preterm birth in animal models. We employed two risk of bias tools. Of 4020 identified studies, 23 studies (24 interventions) met our inclusion criteria. All studies used mouse models. Preterm birth was most commonly induced by lipopolysaccharide (18 studies) or Escherichia coli (4 studies). Models varied according to infectious agent serotype, dose, and route of delivery. Gestational length was significantly prolonged in 20/24 interventions (83%) and markers of maternal inflammation were reduced in 20/23 interventions (87%). Interventions targeting interleukin-1, interleukin-6, and toll-like receptors show particular therapeutic potential. However, due to the heterogeneity of the methodology of the included studies, meta-analysis was impossible. All studies were assigned an unclear risk of bias using the SYRCLE risk of bias tool. Interventions targeting inflammation demonstrate therapeutic potential for the prevention of preterm birth. However, better standardisation of preterm birth models, including the dose, serotype, timing of administration and pathogenicity of infectious agent, and outcome reporting is urgently required to improve the reproducibility of preclinical studies, allow meaningful comparison of intervention efficacy, and aid clinical translation

Implementation of Open Fetal Surgery for Spina Bifida in the UK

Spina bifida is a congenital neurological condition with lifelong physical and mental effects. Open fetal repair of the spinal lesion has been shown to improve hindbrain herniation, ventriculoperitoneal shunting rates, independent mobility and bladder outcomes for the child and, despite an increased risk of prematurity, does not seem to increase the risk of neurodevelopmental impairment. // We proposed to set up a fetal surgery centre in London, as a joint venture between UCLH and GOSH in collaboration with UZ Leuven, Belgium. Implementation of this treatment option for patients from the UK and Republic of Ireland has been the subject of my two year project. // I performed an initial review of existing global centres to establish what was already available, which techniques were being used and to confirm that a centre was required in the UK. I also conducted a systematic review into maternal outcomes of this and other fetal surgery, as this appeared to be a neglected area. This demonstrated the maternal morbidity associated with fetal surgery; the risk of severe complications was found to be approximately 4.5% for open fetal and 1.7% for fetoscopic surgery. // I have, with the help of many other people, set up this new clinical service and have developed local pathways and protocols to facilitate this. I have performed a cost-analysis study to evaluate the cost implications of this surgery; this showed that surgery itself is roughly equal to, if not slightly cheaper than, than the standard postnatal surgery at the point of operation. Prematurity (if it occurs) will bring the cost up, but the expected reduced healthcare utilisation of these children over their lifetime should bring the cost down. // Acceptability is an important consideration when introducing a new and potentially controversial technique. I surveyed healthcare workers throughout the UK and found there was general support for the concept of fetal surgery, but concern about long-term outcomes, which we have been mindful of in our planning. // We began seeing patients in January 2018 and to date we have evaluated 27 patients at UCLH and operated on 13 of them, either in London or Leuven. Eight of these patients have delivered and initial outcomes have been good, with no major maternal or fetal/neonatal morbidity. We will be following outcomes very closely to monitor for long-term data and complications. I have assessed patient experience and acceptability with all women we have seen, and this has been extremely positive. // Now this service is established, future work should include monitoring long-term patient outcomes, developing techniques for earlier detection of spina bifida (which we have attempted to do in our department, and is described in chapter 5.1) and evaluating emerging evidence regarding less-invasive methods of surgery

A study to assess knowledge and acceptability of foetal surgery for spina bifida amongst healthcare professionals in the UK

Foetal surgery to repair open spina bifida before birth improves infant motor function and reduces ventriculoperitoneal shunt requirement. Alongside the development of the first UK foetal surgery service, we surveyed the knowledge and acceptability of this treatment to healthcare professionals in the UK and Ireland via an electronic questionnaire. Ninety-eight (98) responses were received: MFM clinicians (21), midwives (20), paediatric neurosurgeons (17), obstetricians (15), neonatologists (13), theatre nurses (11) and commissioners (1). Overall 70% of responders agreed with the concept that foetal surgery improved neonatal outcome in selected cases; although, only 41% of paediatric neurosurgeons agreed. A variety of concerns were expressed, the most common being the lack information regarding mid- to long-term effects on the child and mother.In offering this new service, it is important that we are cognisant of healthcare professional concerns and address them by applying internationally accepted criteria for foetal surgery, emphasising patient choice and collecting long-term data.Impact statementWhat is already known on this subject? Foetal surgery is a potentially controversial intervention, which is increasing in availability globally. Foetal surgery is now available in the UK on a charitable-funding basis. Prior to starting a UK foetal surgery service, we assessed the attitudes and knowledge of healthcare professionals in the UK towards this new surgery.What the results of this study add? Overall the majority of healthcare professionals agree with the concept that foetal surgery improves neonatal outcome in selected cases, but a variety of concerns exist, the most common being the lack of information regarding mid- to long-term effects on the child and mother. Other concerns included a lack of education, training and research; the specific risk of preterm birth following surgery; the evidence base for this procedure; effects on maternal choice and financial implications.What the implications are of these findings for clinical practice and/or further research? Those developing this new service should be mindful of the concerns expressed and address them by applying internationally accepted criteria for foetal surgery, emphasising patient choice and collecting long-term data.status: publishe

Long-term neuropathological and/or neurobehavioral effects of antenatal corticosteroid therapy in animal models: a systematic review

BACKGROUND: Antenatal corticosteroids (ACSs) are recommended to all women at risk for preterm delivery; currently, there is controversy about the subsequent long-term neurocognitive sequelae. This systematic review summarizes the long-term neurodevelopmental outcomes after ACS therapy in animal models. METHODS: An electronic search strategy incorporating MeSH and keywords was performed using all known literature databases and in accordance with PRISMA guidance (PROSPERO CRD42019119663). RESULTS: Of the 669 studies identified, eventually 64 were included. The majority of studies utilized dexamethasone at relative high dosages and primarily involved rodents. There was a high risk of bias, mostly due to lack of randomization, allocation concealment, and blinding. The main outcomes reported on was neuropathological, particularly glucocorticoid receptor expression and neuron densities, and neurobehavior. Overall there was an upregulation of glucocorticoid receptors with lower neuron densities and a dysregulation of the dopaminergic and serotonergic systems. This coincided with various adverse neurobehavioral outcomes. CONCLUSIONS: In animal models, ACSs consistently lead to deleterious long-term neurocognitive effects. This may be due to the specific agents, i.e., dexamethasone, or the repetitive/higher total dosing used. ACS administration varied significantly between studies and there was a high risk of bias. Future research should be standardized in well-characterized models.status: publishe

The effect of antenatal corticosteroid use on offspring cardiovascular function: A systematic review.

Funder: UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012621BACKGROUND: Antenatal corticosteroids (ACS) are recommended in threatened preterm labour to improve short-term neonatal outcome. Preclinical animal studies suggest detrimental effects of ACS exposure on offspring cardiac development; their effects in humans are unknown. OBJECTIVES: To systematically review the human clinical literature to determine the effects of ACS on offspring cardiovascular function. SEARCH STRATEGY: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in MEDLINE, EMBASE and Cochrane databases. SELECTION CRITERIA: Offspring who had been exposed to ACS during fetal life, in comparison with those not receiving steroids, those receiving a placebo or population data, were included. Studies not performed in humans or that did not assess cardiovascular function were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently screened the studies, extracted the data and assessed the quality of the studies. Results were combined descriptively and analysed using a standardised Excel form. MAIN RESULTS: Twenty-six studies including 1921 patients were included, most of which were cohort studies of mixed quality. The type of ACS exposure, gestational age at exposure, dose and number of administrations varied widely. Offspring cardiovascular outcomes were assessed from 1 day to 36 years postnatally. The most commonly assessed parameter was arterial blood pressure (18 studies), followed by echocardiography (eight studies), heart rate (five studies), electrocardiogram (ECG, three studies) and cardiac magnetic resonance imaging (MRI, one study). There were no clinically significant effects of ACS exposure on offspring blood pressure. However, there were insufficient studies assessing cardiac structure and function using echocardiography or cardiac MRI to be able to determine an effect. CONCLUSIONS: The administration of ACS is not associated with long-term effects on blood pressure in exposed human offspring. The effects on cardiac structure and other measures of cardiac function were unclear because of the small number, heterogeneity and mixed quality of the studies. Given the preclinical and human evidence of potential harm following ACS exposure, there is a need for further research to assess central cardiac function in human offspring exposed to ACS

Maternal complications following open and fetoscopic fetal surgery: A systematic review and meta-analysis

OBJECTIVE: To establish maternal complication rates for fetoscopic or open fetal surgery. METHODS: We conducted a systematic literature review for studies of fetoscopic or open fetal surgery performed since 1990, recording maternal complications during fetal surgery, the remainder of pregnancy, delivery, and after the index pregnancy. RESULTS: One hundred sixty-six studies were included, reporting outcomes for open fetal (n = 1193 patients) and fetoscopic surgery (n = 9403 patients). No maternal deaths were reported. The risk of any maternal complication in the index pregnancy was 20.9% (95%CI, 15.22-27.13) for open fetal and 6.2% (95%CI, 4.93-7.49) for fetoscopic surgery. For severe maternal complications (grades III to V Clavien-Dindo classification of surgical complications), the risk was 4.5% (95% CI 3.24-5.98) for open fetal and 1.7% (95% CI, 1.19-2.20) for fetoscopic surgery. In subsequent pregnancies, open fetal surgery increased the risk of preterm birth but not uterine dehiscence or rupture. Nearly one quarter of reviewed studies (n = 175, 23.3%) was excluded for failing to report the presence or absence of maternal complications. CONCLUSIONS: Maternal complications occur in 6.2% fetoscopic and 20.9% open fetal surgeries, with serious maternal complications in 1.7% fetoscopic and 4.5% open procedures. Reporting of maternal complications is variable. To properly quantify maternal risks, outcomes should be reported consistently across all fetal surgery studies.status: publishe

Incidence and patterns of abnormal corpus callosum in fetuses with isolated spina bifida aperta

OBJECTIVE: To determine the incidence and characterise corpus callosum (CC) abnormalities in fetuses with spina bifida aperta (SBA) between 18 and 26 weeks of gestation. METHODS: This was a retrospective study on fetuses with isolated SBA and who were assessed for fetal surgery. Digitally stored ultrasound images of the brain were reviewed for the presence/absence of the CC, and the length and diameter of its constituent parts (rostrum, genu, body and splenium). We used regression analysis to determine the relationship between CC abnormalities and gestational age, head circumference, ventricle size, lesion level and lesion type. RESULTS: Nearly three-quarters of fetuses with isolated SBA had an abnormal CC (71.7%, 76/106). Partial agenesis was most common in the splenium (18.9%, 20/ 106) and the rostrum (13.2%, 14/106). The most common abnormal pattern was of a short CC with normal diameter throughout. Of note, 20.8% (22/106) had a hypoplastic genu and 28.3% (30/106) had a thick body part. Larger lateral ventricle size was associated with partial agenesis of the CC (odds ratio [OR]: 0.14, p < 0.001) and inversely associated with a shorter CC (OR: 2.60, p < 0.01). CONCLUSION: An abnormal CC is common in fetuses with isolated SBA who are referred for fetal surgery

Evaluating the value of intrapartum fetal scalp blood sampling to predict adverse neonatal outcomes: A UK multicentre observational study.

ObjectiveTo evaluate the value of fetal scalp blood sampling (FBS) as an adjunct test to cardiotocography, to predict adverse neonatal outcomes.Study designA multicentre service evaluation observational study in forty-four maternity units in the UK. We collected data retrospectively on pregnant women with singleton pregnancy who received FBS in labour using a standardised data collection tool. The primary outcome was prediction of neonatal acidaemia diagnosed as umbilical cord arterial pH < 7.05, the secondary outcomes were the prediction of Apgar scores<7 at 1st and 5th minutes and admission to the neonatal intensive care unit (NICU). We evaluated the correlation between the last FBS blood gas before birth and the umbilical cord blood and adjusted for time intervals. We constructed 2 × 2 tables to calculate the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) and generated receiver operating curves to report on the Area Under the Curve (AUC).ResultsIn total, 1422 samples were included in the analysis; pH values showed no correlation (r = 0.001, p = 0.9) in samples obtained within an hour (n = 314), or within half an hour from birth (n = 115) (r=-0.003, p = 0.9). A suboptimal FBS pH value (<7.25) had a poor sensitivity (22%) and PPV (4.9%) to predict neonatal acidaemia with high specificity (87.3%) and NPV (97.4%). Similar performance was noted to predict Apgar scores <7 at 1st (sensitivity 14.5%, specificity 87.5%, PPV 23.4%, NPV 79.6%) and 5th minute (sensitivity 20.3%, specificity 87.4%, PPV 7.6%, NPV 95.6%), and admission to NICU (sensitivity 20.3%, specificity 87.5%, PPV 13.3%, NPV 92.1%). The AUC for FBS pH to predict neonatal acidaemia was 0.59 (95%CI 0.59–0.68, p = 0.3) with similar performance to predict Apgar scores<7 at 1st minute (AUC 0.55, 95%CI 0.51–0.59, p = 0.004), 5th minute (AUC 0.55, 95%CI 0.48–0.62, p = 0.13), and admission to NICU (AUC 0.58, 95%CI 0.52–0.64, p = 0.002).Forty-one neonates had acidaemia (2.8%, 41/1422) at birth. There was no significant correlation in pH values between the FBS and the umbilical cord blood in this subgroup adjusted for sampling time intervals (r = 0.03, p = 0.83).ConclusionsAs an adjunct tool to cardiotocography, FBS offered limited value to predict neonatal acidaemia, low Apgar Scores and admission to NICU