JOURNAL: BJOGDATE 08_25_2022TITLE: Mini commentary on “Familial aggregation of stillbirth: a pedigree analysis of a matched case control study” BJOG_22-0217Author: Matthew A. Shear, MDa,bAuthor Affiliations:a Department of Obstetrics, Gynecology, & Reproductive Sciences, University of California, San Franciscob Division of Medical Genetics, Department of Pediatrics, University of California, San FranciscoDespite advances in genomics, the underlying cause of many stillbirths remains elusive. The emotional toll that a stillbirth takes on families, as well as the providers caring for them, is hard to overstate. Karyotype may identify a causative aneuploidy or large unbalanced translocation, but only in about 6% of stillbirths. Chromosomal microarray is higher yield, but still only identifies pathogenic copy number variants in about 10% of stillbirth cases (Reddy et al. N Engl J Med. 2012). The addition of exome sequencing to microarray only yielded a plausible genetic explanation in 15 out of 246 cases, or about 6% (Stanley et al. N Engl J Med. 2020). This suggested that non-mendelian mechanisms may play a significant role in stillbirth (Wojcik et al N. Engl J Med. 2020), although single gene pathogenic variants are poorly understood at the fetal level relative to the postnatal setting. The non-genetic mechanisms underlying stillbirth are also poorly understood at present, including viral infections, environmental toxins, and comorbid conditions.Workalemahu and their colleagues present a unique analysis suggesting genomic heritability of stillbirth in some families. Using a robust matched case-control study of over 9000 stillbirths and 390 high-risk pedigrees from the Utah Population Database, they calculated the familial standardized incidence ratio and risk of stillbirth among first, second, and third-degree relatives of the pregnant individuals who had experienced stillbirth. In their adjusted model, among all relatives of an individual who experienced stillbirth, there was a relative risk of stillbirth of 1.1 (95% CI 1.00-1.22). This study adds further evidence there are heritable genetic etiologies of stillbirth not yet fully described.Many non-genetic contributors to stillbirth risk may also cluster in families. In the present study, when adjusting for maternal race/ethnicity, socioeconomic status, and education, the elevations in stillbirth risk became attenuated, although this may be due to collinearity among variables used in the model. Health behaviors are informed through regional and family culture, leading to patterns in diet, nutrition, and exercise. These patterns contribute to modifiable health conditions known to impact stillbirth risk, including hypertension, obesity, diabetes, and smoking status. We also know the incidence of stillbirth is higher in lower income versus higher income countries, higher among individuals of lower educational attainment versus higher education, and higher among African American and Black individuals compared to White, likely complicated by the impacts of systemic racism. This is to say nothing of the additional social determinants of health that may impact families across generations.As Workalemahu and colleagues note, there is still much unknown about complex outcomes such as stillbirth. Their findings support that for a patient with a high-risk pedigree, genomic testing may prove informative. Future epigenetic and functional studies may help understand variants at the tissue level, and the impact of comorbidities on gene expression. Together with fetal genome sequencing, previously unexplained cases of stillbirth might be solved, improving patient counseling, and possibly changing clinical management. While genomic testing offers promise to explain a subset of stillbirths, we should not neglect the “non-mendelian” and non-genetic factors that continue to play a significant role in stillbirth risk.

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 [1]. 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.

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.

Mini Commentary on manuscript ID BJOG-22-0531.R1

Commentary for manuscript BJOG 2022 Gurol-Urganci et al (10.1111/1471-0528.17193)

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 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

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.

A document by Markus Gonser. Click on the document to view its contents.

A document by Awol Yemane. Click on the document to view its contents.

Original Manuscript ID: BJOG-21-1723.R1 Descriptive: The Impact of Respectful and Compassionate Bereavement Care Following Stillbirth Running Title: Respectful Bereavement Care After Stillbirth Author information: Mehali Patel, Senior Research Officer, Saving Babies’ Lives Team, Sands Contact Details: 07709602633 [email protected] Sands Office, CAN Mezzanine, 49-51 East Road, London, N1 6AH

BJOG Commentary  Title: Fetal movement trials: where is the evidence in settings with high burden of stillbirths?Authors: Natasha Housseine1,2, [email protected], [email protected] Browne2, [email protected] Maaløe3 [email protected] Sequeira Dmello1,4 [email protected] Ali2,5, [email protected] Abeid1, [email protected] Meguid6, [email protected] J Rijken2,7,8, [email protected] Kidanto1, [email protected] Affiliations 1.      Aga Khan University, Medical College East Africa, Dar es Salaam campus2.      Julius Global Health, Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, The Netherlands3.      Global Health Section, Department of Public Health, University of Copenhagen, Denmark4.      Comprehensive Community Based Rehabilitation in Tanzania, Dar es salaam, Tanzania5.      Research Department, Ernest Cook Ultrasound Research and Education Institute (ECUREI), P.O. Box 7161, Kampala, Uganda6.      Child Health Unit, Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa7.      Vrouw en Baby department, University Medical Centre Utrecht, Utrecht University, The Netherlands8.      Obstetric department, Amsterdam University Medical Center, Amsterdam, The Netherlands Corresponding author:Natasha HousseineThe Aga Khan University Medical CollegeUfukoni Road, P. O. Box 38129, Dar es salaam, Tanzania Telephone: +255 745 338 950  Fetal movement (FM) is a sign of fetal life and wellbeing that is felt by the pregnant woman, and reduced FM is known to precede stillbirths (1,2). Therefore, healthcare providers may advise women to monitor and report if their babies’ movements are fewer than usual. In high-income countries (HIC), there has been a renewed interest in FM with a recent wave of large-scale randomised controlled clinical trials investigating its potential to reduce stillbirths. The My Baby’s Movement trial in Australia/New Zealand, and the Mindfetalness trial in Sweden investigated the effects of intervention aimed at increasing women’s awareness of FM (3,4). The British AFFIRM trial investigated the effects of an FM awareness package coupled with a standardised management protocol (5). The ongoing CEPRA study in the Netherlands, UK and Australia and aims to evaluate Cerebro Placental Ratio as an indicator for delivery in women with reduced FM (6). None of the completed trials, however, found significant reductions in stillbirths. Moreover, they showed conflicting results on some potential harmful consequences, such as increased rates of obstetric interventions. In this commentary, we reflect on these trials through a global lens, and we urgently call for more trials – but this time in settings suffering the majority (98%) of the world’s two million annual stillbirths. Importantly, the global applicability of these HIC trials is questionable. They were conducted in settings where women are aware of the importance of reduced FM and are empowered to access highest standards of care. The contextual realities of pregnancy care are vastly different in low- and middle-income countries (LMICs) where antenatal care and health education are substandard. Women lack health information to self-monitor and report reduced FM. Furthermore, antenatal clinics are often overcrowded and understaffed, with lack of supplies, clinical guidelines, and adequate training of health workers. Recent estimates show stillbirth rates as high as 22 per 1000 per total births in Sub-Saharan Africa, compared to less than 3 per 1000 in HICs (7). Given the downward trend of stillbirths reported in all the HIC trials, it is possible that the completed trials may be demonstrating a lack of evidence rather than a lack of effectiveness. We hypothesise that involving women in their care, through training on how to monitor their baby’s movement and when and how to respond coupled with strengthening healthcare workers’ respect and response to women’s concerns on reduced FM, is a low-cost intervention with potential to significantly reduce stillbirths in high-burden LMICs. Surprisingly, high-quality studies from LMICs that have assessed the effect of FM interventions on perinatal deaths are lacking (2). Of note, the authors of the above-mentioned trials did not consider the well-known major differences in clinical context globally as a limitation while discussing the generalisability of their findings. In fact, the latest My Baby’s Movement trial was not even published open access, limiting access to less privileged clinicians, researchers and policymakers (4). This lack of a global perspective on the international health crisis of preventable stillbirths is an epistemic injustice and a missed opportunity (8). We are concerned that the results of the above trials could prematurely prompt policies discouraging the use of FM awareness among pregnant women (9). It is thus crucial that the lack of generic applicability of these trials’ findings are stressed, and that their high-resource contexts are considered when developing global clinical guidelines and future research priorities. Notably, it has been seen too often how the unbalanced evidence production from HICs has had unintended harmful influences on clinical practice in LMICs (10). For instance, it appears that the breech trials from HICs have led to policy change also in LMICs with increased use of caesarean section in case of breech presentation. However, the risk ratios of vaginal breech births versus caesarean sections differ dramatically between high-resource and low-resource settings with lower surgical safety in LMICs (11,12).The prevailing constraints in LMICs should stimulate innovation and creativity to design low-cost solutions that strengthen three areas 1) FM awareness and monitoring; 2) diagnosis to identify babies truly at risk, and 3) care provision protocols of pregnant women with reduced FM to improve perinatal outcomes. While such strategies or their evidence base are often lacking in LMICs, there is some evidence about possible low-cost diagnostic approaches to assess fetal risk following reduced FM: for example, measuring maternal blood pressure, fetal heart rate, and fundal height (13), or antenatal (hand-held) ultrasound to detect and monitor high-risk pregnancies. Measuring fetal blood flow in Doppler ultrasound studies has also been useful particularly in detecting growth restriction (6,14).  Involving women and health workers in studies will ensure consideration of health-system constraints and allow these to be embedded in the design, implementation, and evaluation of any new intervention. If proven effective, this will increase the chance of seamless integration of the intervention into existing care, positive perceptions by providers and pregnant women- and not increase the burden on already overwhelmed healthcare workers.  Unfortunately, maternal perception of FM is still too often the only signal of complications in the absence of regular high-quality antenatal checks (15)– and there are possibly many babies’ lives lost by ignoring this danger sign. Given the burden of need and the context-specific realities that determine interventions’ effectiveness, we hope these recent waves of FM trials will continue into LMICs to investigate if and how FM awareness coupled with context-tailored management protocol can reduce stillbirths.    Contribution to AuthorshipNH conceived and wrote the first draft. JB, NM, BSD and MJR contributed to subsequent drafting of the manuscript. All authors revised the commentary for important intellectual content and approved the final version to be published and agree to be accountable for all aspects of the work. Details of ethics approvalNo ethics approval applicable for this commentary FundingThere was no financial support for this commentary Disclosure of interests  Reference1.        Bekiou A, Gourounti K. Reduced Fetal Movements and Perinatal Mortality. Mater Sociomed. 2020;32(3). 2.        Hayes DJL, Smyth R, Heazell AEP. Investigating the significance and current state of knowledge and practice of absent or reduced fetal movements in low and lower middle-income countries : a scoping review. 2019;3:1–12. 3.        Akselsson A, Lindgren H, Georgsson S, Pettersson K, Steineck G, Skokic V, et al. Mindfetalness to increase women’s awareness of fetal movements and pregnancy outcomes: a cluster-randomised controlled trial including 39 865 women. BJOG An Int J Obstet Gynaecol. 2020 Jun 1;127(7):829–37. 4.        Flenady V, Gardener G, Ellwood D, Coory M, Weller M, Warrilow KA, et al. My Baby’s Movements: a stepped-wedge cluster-randomised controlled trial of a fetal movement awareness intervention to reduce stillbirths. BJOG An Int J Obstet Gynaecol. 2022 Jan 1;129(1):29–41. 5.        Norman JE, Heazell AEP, Rodriguez A, Weir CJ, Stock SJE, Calderwood CJ, et al. Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM): a stepped wedge, cluster-randomised trial. www.thelancet.com. 2018;392. 6.        Damhuis SE, Ganzevoort W, Duijnhoven RG, Groen H, Kumar S, Heazell AEP, et al. The CErebro Placental RAtio as indicator for delivery following perception of reduced fetal movements, protocol for an international cluster randomised clinical trial; the CEPRA study. BMC Pregnancy Childbirth. 2021 Dec 1;21(1). 7.        Hug L, You D, Blencowe H, Mishra A, Wang Z, Fix MJ, et al. Global, regional, and national estimates and trends in stillbirths from 2000 to 2019: a systematic assessment. Lancet. 2021 Aug 28;398(10302):772–85. 8.        Bhakuni H, Abimbola S. Epistemic injustice in academic global health. Lancet Glob Heal. 2021;9:e1465–70. 9.        Walker KF, Thornton JG. Encouraging awareness of fetal movements is harmful. Lancet. 2018 Nov 3;392(10158):1601–2. 10.      Maaløe N, Ørtved AMR, Sørensen JB, Sequeira Dmello B, van den Akker T, Kujabi ML, et al. The injustice of unfit clinical practice guidelines in low-resource realities. Lancet Glob Heal. 2021;9(6):e875–9. 11.      van Roosmalen J, Meguid T. The dilemma of vaginal breech delivery worldwide. Lancet. 2014;338(9932): 12.      Sobhy S, Arroyo-Manzano D, Murugesu N, Karthikeyan G, Kumar V, Kaur I, et al. Maternal and perinatal mortality and complications associated with caesarean section in low-income and middle-income countries: a systematic review and meta-analysis. Lancet. 2019 May 11;393(10184):1973–82. 13.      Housseine N, Rijken MJ, Weller K, Nassor NH, Gbenga K, Dodd C, et al. Development of a clinical prediction model for perinatal deaths in low resource settings. eClinicalMedicine. 2022 Feb;44:101288. 14.      Ali S, Kawooya MG, Byamugisha J, Kakibogo IM, Biira EA, Kagimu AN, et al. Middle cerebral arterial flow redistribution is an indicator for intrauterine fetal compromise in late pregnancy in low-resource settings: a prospective cohort study. BJOG An Int J Obstet Gynaecol. 2022 Feb 4; 15.      World Health Organization. WHO recommendations on antenatal care for a positive pregnancy experience [Internet]. 2016 [cited 2020 Jul 30]. Available from: https://www.who.int/reproductivehealth/publications/maternal_perinatal_health/anc-positive-pregnancy-experience/en/ ‘This article has a Video Abstract presented by Natasha Housseine.’

TYPE OF ARTICLE: LETTER TO EDITOR

Objective To determine if stillbirth aggregates in families and quantify its familial risk using extended pedigrees. Design State-wide matched case-control study. Setting Utah, United States. Population Stillbirth cases (n=9 404) and live-birth controls (18 808) between 1978 and 2019. Methods Using the Utah Population Database, a population‐based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardized Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR), and third-degree relatives (TDR) of parents with a stillbirth and live-birth were estimated using logistic regression models. Results We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR≥2.00 and P-value<0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI: 1.11-1.33), and 1.15-fold (95% CI: 1.08-1.21) higher stillbirth odds compared to FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI: 1.02-1.47), 1.38-fold (95% CI: 1.17-1.62), 1.17-fold (95% CI: 1.05-1.30) higher stillbirth odds compared to those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI: 0.98-1.28), 1.09-fold (95% CI: 0.96-1.24), and 1.15-fold (95% CI: 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. Conclusions We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine its genetic architecture.

Letter to Editor:

A document by Angélica Diniz. Click on the document to view its contents.

Objective To examine the association of DNA copy number variants (CNVs) with pathologic placental lesions (PPLs) in stillborn fetuses. Design A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network case-control study. Setting Multicenter, 59 hospitals in 5 geographic regions in the USA. Population 387 stillbirth cases (2006-2008). Methods Using standard definitions, PPLs were categorized by type including maternal and fetal vascular, inflammatory and immune/idiopathic lesions. Using single-nucleotide polymorphism array, CNVs of at least 500 kb were detected. CNVs were classified into two groups: normal, defined as no CNVs>500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. Main outcome measures The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without PPLs using the Wald Chi-squared test. Results Of 387 stillborn fetuses, 327 (84.5%) had maternal vascular PPLs and 60 (15.6%) had abnormal CNVs. Maternal vascular PPLs were more common in stillborn fetuses with abnormal CNVs compared with those with normal CNVs (81.7% vs. 64.2%; p=0.008). The proportions of fetal vascular, maternal/fetal inflammatory, and immune/idiopathic PPLs were similar among stillborn fetuses with abnormal CNVs compared to those with normal CNVs. Pathogenic CNVs in stillborn fetuses with maternal vascular PPLs spanned several genes with known relevant mechanisms. Conclusions Abnormal placental/fetal CNVs were associated with maternal vascular PPLs in stillborn fetuses. Findings may provide insight on the mechanisms of specific genetic abnormalities associated with placental dysfunction and stillbirth.

Objective To establish pregnancy-specific reference ranges for fasting and postprandial total serum bile acids (TSBA) levels. Design Cross-sectional study. Setting Tertiary care university hospital. Population Healthy pregnant women at term admitted to the Obstetrics Department over one year. Exclusion criteria were an established diagnosis of intrahepatic cholestasis of pregnancy (ICP) or any co-existing condition of increased risk for ICP. Methods and Main Outcome Measures Both fasting and postprandial TSBA levels were measured in 612 women (528 fasting and 377 postprandial samples). Results Reference intervals of 4.4-14.1 µmol/L for fasting TSBA, and 4.7-20.2 µmol/L for postprandial TSBA were established. The postprandial values were significantly higher than the fasting measurements, with a mean increase of 1.77 µmol/L (22%). A correlation between fasting TSBA levels and postprandial levels was found, as well as with fetal gender, parity, and the use of assisted reproductive technologies. A seasonal pattern was noticed for both fasting and postprandial TSBA, with the highest values in the winter season (p < 0.01 and 0.02, respectively). Conclusions Normal pregnancy is a sub-cholestatic state and is associated with a physiological elevation of TSBA levels, therefore a higher threshold should be considered for the diagnosis of ICP. We suggest using the upper reference limit observed in our healthy pregnant population (fasting ≥14 µmol/L and postprandial ≥20 µmol/L). As the fasting measurement is more specific for the diagnosis, and the postprandial is essential for severity assessment, it is recommended to measure both values, rather than use random samplings. Funding No funding to declare.