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
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.
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 compare the estimates of preterm birth (PTB; 22-36 weeks gestational age, GA) and stillbirth rates during COVID-19 pandemic in Italy with those recorded in the three previous years. Design. A population-based cohort study of liveborn and stillborn infants was conducted using data from Regional Health Systems and comparing the pandemic period (March 1st, 2020-March 31st, 2021, N= 362,129) to an historical period (January 2017- February 2020, N=1,117,172). The cohort covered 84.3% of the births in Italy. Methods. Logistic regressions were run in each Region and meta-analyses were performed centrally. We used an interrupted time series regression analysis to study the trend of preterm births from 2017 to 2021. Main Outcome Measures. The primary outcomes were PTB and stillbirths. Secondary outcomes were late PTB (32-36 weeks’ GA), very PTB (<32 weeks’ GA), and extreme PTB (<28 weeks’ GA), overall and stratified into singleton and multiples. Results. The pandemic period compared with the historical one was associated with a reduced risk for PTB (Odds Ratio: 0.90; 95% Confidence Interval, CI: 0.87, 0.93), late PTB (0.91; 0.87, 0.94), very PTB (0.87; 0.84, 0.91), and extreme PTB (0.88; 0.82, 0.94). In multiples, point estimates were not very different, but had wider CIs. No association was found for stillbirths (1.01; 0.90, 1.13). A linear decreasing trend in PTB rate was present in the historical period, with a further reduction after the lockdown. Conclusions We demonstrated a decrease in PTB rate after the introduction of COVID-19 restriction measures, without an increase in stillbirths.
Triaging a patient to colposcopy v. watchful waiting using current and prior HPV type and cytology result will help focus care on those at highest risk, and avoid overtreatment of women at low risk of cancerSarah Feldman MD MPHDivision of Gynecologic Oncology, Department of Obstetrics and GynecologyHarvard Medical SchoolBrigham and Women’s Hospital75 Francis StreetBoston, Ma firstname.lastname@example.orgI have no conflicts of interest to disclose.The findings by Gustafson, et al, that the rate of CIN2+ (high grade cervical precancers) was significantly higher in LLETZ specimens (32.4%) than in biopsies (14.7%) in Danish women age 45+ with type 3 transformations zone (ie part of the upper limit of the transformation zone is not visible) is based on a thoughtful analysis. Patients were screened and managed by Danish guidelines which included predominantly cytology based screening during the period of study, for all but women aged 60-64 (and some up to 69), with HPV testing only being offered to some women ages 30-59. Although the HPV test used in the study (Cobas) automatically provides HPV16 and 18 genotyping, this information was not used for triage. In this study all women underwent colposcopy and diagnostic LLETZ at the same visit. Although the Denmark guidelines recommend blind 4 quadrant biopsies for those without a visible lesion, endocervical curettage, which is a part of many other guidelines (Perkins RB, et al 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2020;24:102–31), is not offered in Denmark. Although the diagnostic LLETZ picked up more CIN2+ than biopsy alone, as the authors state, the majority of women would not have needed the LLETZ if their risk could have been better predicted.Can we use currently available technology and information to more effectively and safely triage patients to detect and treat high grade lesions but avoid aggressive and costly treatment for the majority? Many studies have suggested that knowledge of a patients past screening history in addition to current results, in particular knowledge of the HPV status over time, whether HPV16 or 18 are present, as well as the severity of the cytology smear can help clarify who is at highest risk and who can be followed. (Egemen D, et al. Risk estimates supporting the 2019 ASCCP risk-based management consensus guidelines. J Low Genit Tract Dis 2020 Apr;24:132–43, Smith MA, et al. National experience in the first two years of primary human papillomavirus (HPV) cervical screening in an HPV vaccinated population in Australia: observational study. BMJ. 2022 Mar 30;376)The underlying risk of the population studied affects the results and any downstream conclusions. In this case, the population studied had been predominantly screened by cytology, until the final screen, which was predominantly by HPV. Multiple studies have shown that HPV based screening has a better sensitivity than cytology alone and a reassuring result has as a more reliable negative predictive value than cytology, especially when lesions are in the endocervical canal or not fully visible. A prior negative or positive screen with an HPV based test might have aided in risk assessment and triage in this cohort. Adding p16ki67 staining to the initial cytology would also help to predict long term risk of high grade dysplasia, determining who could be followed and who treated. (Clarke MA, et al Five-Year Risk of Cervical Precancer Following p16/Ki-67 Dual-Stain Triage of HPV-Positive Women. JAMA Oncol. 2019 Feb 1;5(2):181-186.) Finally, an endocervical curettage, even with a brush, might have better sampled the endocervical canal and is less painful and costly than four blind biopsies.Despite some of the limitations of the study, which the authors outline well, there is an important message-the CIN2+ rate in this older cohort of women is high- and if we are to prevent cervical cancer among older women, screening with HPV before exiting screening, and appropriately evaluating and treating women at risk of high grade dyspasia or cancer is essential.
DEATH AND SEVERE MORBIDITY IN ISOLATED PERIVIABLE SMALL-FOR-GESTATIONAL-AGE FETUSESBy Meler et alDescriptive title:Middle cerebral artery Doppler improves risk stratification of SGA babies at a peri-viable gestationMini-commentary by Lawrence ImpeySmall for gestational age (SGA) babies identified before 26 weeks are a heterogenous group but the largest contributor is ‘isolated’ SGA’. Most are ‘constitutionally’ small, but placental issues are common. Traditionally, the ultrasound Doppler parameters used to identify the most at risk are the umbilical artery (UA) and uterine artery (UtA). This paper (Meler et al, BJOG, 2022) challenges the dogma that MCA Doppler in early onset-SGA babies is of limited use, reporting an 87% detection rate for a 14% false positive rate for UA and MCA together in predicting a severe composite adverse outcome (CAO).The analysis uses Doppler findings at referral, thereby reducing but not eliminating the ‘intervention paradox’, common to many analyses, whereby an ‘abnormal’ finding’s association with an outcome is altered because it leads to intervention.The group is defined by local centiles and only comprises those referred but, by including both apparently FGR and SGA babies, is less subject to selection bias. Because of the high risk nature and size of this cohort, the frequency of adverse outcomes is adequate for analysis of a severe CAO (20.4%), of death (15.4%) or long term morbidity that is sufficiently serious and includes postnatal follow up (minimum 9 months).The role of MCA Doppler with placental failure is poorly understood. Near term, as part of the cerebroplacental ratio (CPR), it helps identify the at-risk SGA baby (Veglia et al, UOG, 2018), and even some at-risk normally grown babies. Earlier, however, the role of UA Doppler is clear (Alfirevic et al, Cochrane, 2017). That MCA Doppler adds predictive value at diagnosis is important because it will allow enable more appropriate counselling, follow up and potentially better timing of iatrogenic birth.What does the analysis make of UtA Doppler and the ductus venosus (DV)? It is surprising (Allen et al, UOG 2016) that the former was not predictive, but as its role is well established, this could be the subject of intervention bias. Mild abnormalities (PI>95th c) of the DV were not useful, but severe ones, occurring late in the deterioration in FGR, will still be useful to time iatrogenic birth (Lees et al, Lancet, 2015).MCA Doppler in referred small peri-viable babies improves risk stratification, a process central to maternity care. The ‘checklist’ approach to risk must be replaced by models using continuous variables (as opposed to cut offs of ‘abnormal’) of multiple independent risk factors: as with aneuploidy screening. Only then can we better identify high risk (sensitivity) whilst not over-medicalising pregnancy (specificity). Developing this is complex, not least because of the rarity and gestation-dependence of serious perinatal events and because of the presence of the intervention paradox in large datasets. Nevertheless, the Tommy’s app (https://www.tommys.org/) is a welcome start. Such screening is likely to need to be staged, and this analysis demonstrates one risk factor potentially worth including following a 20 week scan.
BJOG mini-commentary on BJOG-22-0097This manuscript by McCall et al reports that UK and France have very different approaches to managing women with PAS. More women in France received a uterus conserving approach. Major haemorrhage was more common in the UK series. The authors speculate that this may be related to treatment modality. The ACOG/SMFM committee opinion (Obstet Gynecol 2018;132:e259–75) recommends caesarean hysterectomy as the most generally accepted approach. Does this report imply that we should stop offering hysterectomies and recommend conservative treatment?Before we make up our mind, it is important to consider what else was different in the two cohorts. The case definitions used by UK OSS and PACCRETA investigators were different. However, the authors of the current report have included only those cases that satisfied a harmonised definition. UK prevalence (1.7/10 000) was significantly lower as compared to that from France (4.2/10 000). This raises the question: Is UK under-reporting or is France over-reporting? Screening studies may give some idea about the ‘true’ prevalence. A prevalence of 5.8/10 000 (Panaiotova et al, Ultrasound Obstet Gynecol 2019; 53: 101–106) was reported with screening for Caesarean scar pregnancies. Coutinho et al (Ultrasound Obstet Gynecol 2021; 57: 91–96) reported a prevalence of 3.8/10 000 with screening for PAS in late pregnancy. In both these reports all women had either placenta previa or a low-lying placenta. In contrast, placenta previa was present in 64% and 63% of women from UK and France, respectively. In this light, one would expect a higher, rather than lower prevalence of PAS as compared to the two screening studies. One explanation could be increasing Caesarean section rate and better awareness with time.A systematic review reported high (>90%) sensitivity for the detection of PAS using ultrasound in women at high risk of PAS (D’Antonio et al, Ultrasound Obstet Gynecol 2013; 42: 509–517). The prenatal detection was disappointingly low at < 50% in both UK and France. Before we begin to berate ourselves, it is noteworthy that these are 7-12 year-old data. The current study took place between May 2010 - April 2011(UK) and November 2013 - October 2015(France).What about the differences in median blood loss? Manual removal of the placenta was attempted in fewer women in France. Even then, unplanned hysterectomy was more common in the French group. The blood loss may be lower with conservative management, but this advantage should be weighed against the uncertainty about the possibility and timing of developing major haemorrhage in the post-operative period. Moreover, it is possible that the UK series had particularly severe cases as compared to the French cohort given the significantly lower prevalence. A head-to-head comparison of the two treatment modalities has never been reported. This will necessitate a unified definition and accurate prenatal detection. Such a study would be extremely challenging given the strong views of women regarding fertility preservation and of physicians regarding ongoing uncertainty with complications and personal experience. The jury is still out on this one.