BJOG-22-0382.R1: Implementing Effective Investigations for Cause of StillbirthElizabeth M McClure, PhDRobert L Goldenberg, MDRTI International, Durham, NCColumbia University, New York, NYStillbirth is one of the most common adverse pregnancy outcomes in low and middle-income countries (LMICs), with rates in the range of 40 to 50 per thousand births in some regions . International goals aim for no country to have a rate of >10 per thousand births by 2035 [Hug L, et al. Lancet. 2021;398(10302):772-85]. To achieve this, a better understanding of stillbirth causes often requiring additional investigations is critical. For several reasons, including low prioritization, inadequate resources, and hesitancy by families and providers, investigations on stillbirth causes in LMICs have been limited to date.Bedwell et al used a grounded theory approach to explore the views of women, partners, families, health workers and community leaders in Malawi, Tanzania, and Zambia regarding investigations to determine the cause(s) of stillbirth [Bedwell et al, BJOG (in press)]. While most would like more information regarding the stillbirth, the authors noted cultural and religious obstacles to performing the investigations, including preferences for quick burial, reluctance to disfigure the deceased fetus, concerns about blame, as well as costs.One test to inform cause of stillbirths is minimally invasive tissue sampling (MITS), using needle biopsies to obtain internal organ tissue for histological evaluation and microbial analyses. For a study on causes of stillbirth in Pakistan and India, we explored the acceptability of MITS among parents, relatives, religious leaders, and government officials [Feroz A, et al. Reprod Health.2019;16(1):53]. The perceived benefits included knowing the cause of death, and both personal and societal benefits in preventing subsequent stillbirths. Concerns regarded rapid burial and reluctance to disfigure the stillborn. In Pakistan, with some caveats, religious leaders approved, and, when MITS was undertaken, in both Pakistan and India, approximately 50% of the parents consented for the MITS procedure.Because obstacles to testing in general and to MITS specifically relate to time, cost, and disfigurement, we have considered which examinations feasible in LMICs provide the most information at minimal cost. Page et al., in a similar exercise in a US study, noted that the most useful test was placental histology (65%) followed by full autopsy (42%) [Page JM, Obstet Gynecol 2017;129(4):699-706.]. No other tests were useful for >12% of cases. Similar studies have rarely been performed in LMICs. The prevalence of the causes relates to the frequency of tests’ usefulness. In high-income countries where birth asphyxia and infection have been reduced, congenital and genetic anomalies have assumed a larger proportion of stillbirths, and testing for those conditions using karyotyping and other genetic tests become proportionately more important. However, in many LMICs, birth asphyxia remains the major cause of stillbirth and genetic issues play a smaller proportional role.To develop the most effective methodology to determine cause of stillbirth, the prevalent conditions, and the tests’ usefulness to diagnose those conditions should be considered together. Importantly, the community and other stakeholder’s perceived benefits and obstacles to various tests as described in the Bedwell, et al must be considered to ultimately be successful in implementing the necessary investigations.For LMICs, given that asphyxia and infection appear to be major causes of stillbirth, tests to diagnose these conditions will likely be important to implement, including the obstetric history and histological placental evaluation for diagnosing asphyxia and infection. Of potential information gained from MITS, histology of the fetal lung, and bacteriological assessment of the fetal blood and brain/CSF may be the most useful. Thus, by considering the prevalence of the causes of stillbirth, the usefulness of tests to diagnose the prevalent conditions, and importantly addressing the community’s sense of benefit and obstacles, an effective approach to stillbirth cause of death investigation can be developed.Declaration of Interest: The authors declare no conflicts of interest.
The effect of antenatal depressive and anxious symptoms on the rate of physiological birthsA comment on the recently published article by Hulsbosch et al:Association between high levels of comorbid anxiety and depressive symptoms and decreased likelihood of birth without intervention: A longitudinal prospective cohort study
Background: Cervical cancer affects 3,197 women in the UK, and 604000 women worldwide annually, with peak incidence seen between 30-34 years of age. For many, fertility-sparing surgery is an appealing option where possible. However, absence of large-scale data, along with a notable variation in reported outcomes in relevant studies may undermine future efforts for consistent evidence synthesis. Objectives: To systematically review the reported outcomes measured in studies that include women who underwent fertility-sparing surgery for cervical cancer and identify whether variation exists. Search Strategy: We searched MEDLINE, EMBASE, and CENTRAL from inception to February 2019. Selection Criteria: Randomised controlled trials, cohort and observational studies, and case studies of more than 10 participants from January 1990 to date. Data Collection and Analysis: Study characteristics and all reported treatment outcomes. Main results: 104 studies with a sum of 9535 participants were identified. Most studies reported on oncological outcomes (97/104), followed by fertility and pregnancy (86/104), post-operative complications (74/104), intra-operative complications (72/104), and quality of life (5). There were huge variation and heterogeneity in reported outcomes, with only 12% being good quality and 87% being of poor quality. Conclusions: There is significant heterogeneity in the reported outcomes. An agreed Core Outcome Set (COS) is necessary for future studies to effectively harmonise reported outcomes that are measurable and relevant to patients, clinicians, and researchers. This systematic review sets the groundwork for the development of a COS for fertility sparing surgery in cervical cancer. Funding: British Medical Association’s Strutt and Harper Grant.
Objective To test equivalence of two doses of intravenous iron (ferric carboxymaltose) in pregnancy. Design Parallel, two-arm equivalence randomised controlled trial with an equivalence margin of 5%. Setting Single centre in Australia. Population 278 pregnant women with iron deficiency. Methods Participants received either 500 mg (n=152) or 1000mg (n=126) of intravenous ferric carboxymaltose in the second or third trimester. Main outcome measures The proportion of participants requiring additional intravenous iron (500mg) to achieve and maintain ferritin >30ug/L (diagnostic threshold for iron deficiency) at 4 weeks post-infusion, and at 6 weeks, and 3-, 6- and 12-months postpartum. Secondary endpoints included repeat infusion rate, iron status, birth, and safety outcomes. Results The two doses were not equivalent within a 5% margin at any timepoint. At 4 weeks post infusion, 26/73 (36%) participants required a repeat infusion in the 500 mg group compared with 5/67 (8%) in the 1000 mg group (difference in proportions, 0.283 95% confidence interval (0.177, 0.389)). Overall, participants in the 500 mg arm received twice the repeat infusion rate (0.81 (SD= 0.824 vs 0.40 (SD= 0.69), rate ratio 2.05, 95% CI (1.45, 2.91)). Conclusions Administration of 1000mg ferric carboxymaltose in pregnancy maintains iron stores and reduces the need for repeat infusions. A 500 mg dose requires ongoing monitoring to ensure adequate iron stores are reached and sustained.
Background A core outcome set could address inconsistent outcome reporting and improve evidence for stillbirth care research, which has been identified as an important research priority. Objectives To identify outcomes and outcome measurement instruments reported by studies evaluating interventions after the diagnosis of a stillbirth. Search strategy Amed, BNI, CINAHL, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase, MEDLINE, PsycINFO, and WHO ICTRP from 1998 to August 2021. Selection criteria Randomised and non-randomised comparative or non-comparative studies reporting a stillbirth care intervention. Data collection and analysis Interventions, outcomes reported, definitions and outcome measurement tools were extracted. Main results 40 randomised and 200 non-randomised studies were included. 58 different interventions were reported, labour and birth care (52 studies), hospital bereavement care (28 studies), clinical investigations (116 studies), care in a multiple pregnancy (2 studies), psychosocial support (28 studies) and care in a subsequent pregnancy (14 studies). 391 unique outcomes were reported and organised into 14 outcome domains: labour and birth; postpartum; delivery of care; investigations; multiple pregnancy; mental health; emotional functioning; grief and bereavement; social functioning; relationship; whole person; subsequent pregnancy; subsequent children and siblings and economic. 242 outcome measurement instruments were used, with 0-22 tools per outcome. Conclusions Heterogeneity in outcome reporting, outcome definition and measurement tools in care after stillbirth exists. Considerable research gaps on specific intervention types in stillbirth care were identified. A core outcome set is needed to standardise outcome collection and reporting for stillbirth care research.
Objective: To explore the views of female genital mutilation (FGM) survivors, men, and healthcare professionals (HCPs) on the timing of deinfibulation surgery and NHS service provision. Design: Qualitative study informed by the sound of silence framework. Setting: Survivors and men were recruited from three FGM prevalent areas of England. HCPs and stakeholders were from across the UK. Sample: 44 survivors, 13 men and 44 HCPs. 10 participants at two community workshops and 30 stakeholders at a national workshop. Methods: Hybrid framework analysis of 101 interviews and three workshops. Results: There was no consensus across groups on the optimal timing of deinfibulation for survivors who wished to be deinfibulated. Within group, survivors expressed a preference for deinfibulation pre-pregnancy and HCPs antenatal deinfibulation. There was no consensus for men. Participants reported that deinfibulation should take place in a hospital setting and be undertaken by a suitable HCP. Decision making around deinfibulation was complex but for those who underwent surgery it helped to mitigate FGM impacts. Whilst there were examples of good practice, in general, FGM service provision was sub-optimal. Conclusion: Deinfibulation services need to be widely advertised. Information should highlight that the procedure can be carried out at different time points, according to preference, and in a hospital by suitable HCPs. Future services should ideally be developed with survivors, to ensure that they are clinically and culturally appropriate. Guidelines would benefit from being updated to reflect the needs of survivors and to ensure consistency in provision. Study registration number ISRCTN 14710507
Objectives: To evaluate risks of preterm birth and severe maternal morbidity (SMM) in female adolescent and young adult cancer survivors; assess maternal comorbidity as a potential mechanism; determine whether associations differ by use of assisted reproductive technology (ART). Design: Retrospective cohort Setting: Privately insured females in the U.S. Sample: Female with live births from 2000 to 2019 within OptumLabs®, a U.S. administrative health claims dataset Methods: Log-binomial regression models estimated relative risks of preterm birth and SMM by cancer status and tested for effect modification. Causal mediation analysis based on a counterfactual approach evaluated the proportions explained by maternal comorbidity. Main Outcome Measures: SMM, preterm birth Results: Among 46,064 cancer survivors, 2,440 singleton births, 214 multiple births, and 2,590 linked newborns occurred after cancer. In singleton births, preterm birth incidence was 14.8% in cancer survivors versus 12.4% in females without cancer (aRR 1.19, 95%CI 1.06-1.34); SMM incidence was 3.9% in cancer survivors versus 2.4% in females without cancer (aRR 1.44, 95%CI 1.13-1.83). Cancer survivors had more maternal comorbidities before and during pregnancy; 26% of the association between cancer and preterm birth and 30% of the association between cancer and SMM was mediated by maternal comorbidities. Associations between cancer and outcomes did not differ between ART and non-ART births. Conclusion: Preterm birth and SMM risks were modestly increased after cancer. Significant proportions of elevated risks may be due to increased comorbidities. Prevention and treatment of comorbidities provides an opportunity to improve perinatal outcomes among cancer survivors.
Clinician bias on the low resource workfloorThis is a mini commentary on R Goldenberg et al.,In this study in two LMIC settings in Asia, expert panels who looked at cause of death of premature neonates, with significantly more information available, found far more birth asphyxia and less Respiratory Distress Syndrome than the discharging NICU physicians did. Some NICU physicians attributed respiratory distress in the premature neonate to RDS by default, especially if there was no other information to contradict this belief. Especially in the Pakistan setting, birth asphyxia did not seem to be on the mind of the physician.What could be possible explanations?The maternal population, illiteracy rates, low rates of NICU admission and high death rates in the Pakistan setting suggest an impoverished background population and very restrained resources.In such setting one could easily imagine diagnostic means and treatment options are limited. If there is also lack of staff, reduced availability of beds, and work overload (ref: authors correspondence), priorities have to be made who to admit and who to treat. Life expectancy and quality of life may play a role in triaging.Physicians who work in labourward settings without CTGs may recognize the viewpoint that obstetric management only be guided by the maternal condition. On several SubSaharan African labourwards I experienced that decisions were not (solely) to be based on the supposed fetal condition. To perform ‘an unnecessary caesarean section’, or on the other hand to try and salvage the life of a baby who then turns out to be brain damaged after a poor start, was not seen as good obstetric care. A premature baby with apparent severe birth asphyxia might consequently not be transferred to the NICU. A baby who is admitted may not carry the diagnosis birth asphyxia since, as the authors point out this may imply mismanagement. It could even go further: if potential fetal compromise is not relevant in the obstetric management, it may also not be picked up. The obstetric physician could in such situation easily develop a blind spot for birth asphyxia.Another cause of clinician bias in such low resource settings could be underestimation of the gestation, making RDS a more likely diagnosis. If gestational scans are not available, and last menstrual periods are unreliable (associated with illiteracy) gestational age is more often estimated by fundal height at presentation in labourward, or by the birthweight of the baby. Underestimation could be the case in Pakistan where 65% of babies were thought to be less than 32 weeks, only 12,5 % of the neonates were thought to be growth restricted which is associated with birth asphyxia, but nearly 63 % suffered with birth asphyxia according to the panel.These are several hypotheses how physicians in a low resource setting could form biases in their clinical thinking, which, when not corrected by other information, could lead to incorrect diagnoses and mismanagement. This correcting information could come from diagnostic tools, such as PCR tests Xchest, etc,. However, sufficient time and systems in place for proper handovers, e.g. between the obstetrician and pediatrician, an open mind and awareness of pitfalls, audit and reflection on one’s management, and training to stay up to date are just as important. Hopefully expert panel studies such as these, could stimulate awareness and be a motor to improved Obstetric and Pediatric Care in LMIC settings.
Background 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. Main results Twenty-six studies including 1921 patients were included, of which most 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 one day to 36 years postnatally. The most commonly assessed parameter was arterial blood pressure (18 studies), followed by echocardiography (8 studies), heart rate (5 studies), electrocardiogram (ECG, 3 studies) and cardiac magnetic resonance imaging (MRI, 1 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 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 due to the small number of studies, study heterogeneity and mixed quality. Given the emerging preclinical evidence of harm following ACS exposure, there is a need for further research to assess central cardiac function in human offspring exposed to ACS. Keywords: Antenatal corticosteroids, ACS, cardiovascular, offspring, blood pressure
Intrapartum stillbirths and early neonatal deaths remain stubbornly high in low income countries. Fetal monitoring in labour can reduce these poor outcomes, but limited progress is being achieved in these settings. Intermittent auscultation and continuous electronic fetal monitoring (CEFM) can both be employed to monitor a fetus during labour. There are challenges and limitations with both modalities. We used AI augmented fetal monitoring in a hospital in Malawi and demonstrated substantial reductions in both intrapartum stillbirths and early neonatal deaths with a small increase in the cesarean delivery rate. AI-CEFM should be studied further to achieve better perinatal outcomes.
BJOG mini commentary on study BJOG-21-1829TITLE: Putting patients at the centre of pain managementAlexandra Wojtaszewskaa, Arvind Vashishtb, Martin Hirschc,daWatford General Hospital, Watford, United KingdombInstitute for Women’s Health, University College London, London, United Kingdom.cThe John Radcliffe Hospital, Oxford University Hospitals, Oxford, United Kingdom.dOxford Endometriosis CaRe Centre, Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, United Kingdom.Conflict of interest : noneFinancial support received : none
Objective To investigate the clinical outcomes and toxicity in patients with locally advanced cervical cancer treated with supplementary applicator guided-intensity modulated radiation therapy (IMRT) based on conventional intracavitary brachytherapy (IC/IMRT). Population Large high risk clinical target volume (HR-CTV) volume (>40cc) at the time of brachytherapy cervical cancer patients were recruited. Methods This study is a retrospective analysis of 76 patients with locally advanced cervical cancer (FIGO IIB-IVA) treated with concurrent chemo-radiotherapy followed by IC/IMRT between June 2010 and October 2016. External radiotherapy (45 Gy in 25 fractions) with cisplatin chemotherapy treated before IC/IMRT. The prescription dose for HR-CTV and IR-CTV were 6 Gy and 5 Gy per fraction for 5 fractions respectively. Results: Mean HR-CTV was 65.8±23.6 cc at the time of brachytherapy. D90 for HR-CTV and IR-CTV were 88.7±3.6 Gy and 78.1±2.5 Gy. D2cc for bladder, rectum, sigmoid and small intestine were 71.8±3.8 Gy, 64.6±4.9 Gy, 63.9±5.3 Gy and 56.7±8.7 Gy respectively. Median follow-up was 85 months (47.9-124.2 months). Five-year local recurrence free survival rate, metastasis recurrence free survival rate, disease free survival rate and cancer special survival rate were 87.6%, 82.4%, 70.9% and 76.3%, respectively. The grade 1+2 gastrointestinal and urinary late toxicities were 15.8% and 21.1%, while grade 3 late toxicities were 3.9% and 5.2%, respectively. Neither acute nor late grade 4 gastrointestinal or urinary toxicities were seen. Conclusions: The combination of ICBT with an applicator-guided supplementary IMRT boost achieved an excellent local control and overall survival with low toxicity for bulky residual cervical tumor