Vaccine safety surveillance in pregnancy in low- and middle-income countries using GAIA case definitions: A feasibility assessment

Background: Global efforts to adequately monitor safety of new vaccines for pregnant women in low and middle-income countries (LMICs) are needed. The Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) project recently published case definitions based on levels of diagnostic certainty for pregnancy- and neonatal outcomes and maternal vaccination. As a preliminary step to assessing the applicability of these definitions in LMICs, WHO selected sites and conducted a feasibility assessment to evaluate their ability to identify and classify selected outcomes (preterm birth, neonatal death, neonatal invasive bloodstream infection (NI-BSI), stillbirth) and maternal vaccination. Methods: Candidate sites were initially screened using a questionnaire. For each outcome, eligible sites were asked to retrospectively identify and collect information for three individuals born in 2016. Subsequently, outcomes were classified by level of diagnostic certainty. Results: Fifty-one sites (15 countries) were screened; 32 of them (9 countries) participated in the assessment and identified 315 subjects with the outcomes of interest. Twenty-four sites (8 countries) identified at least one subject per outcome and agreed to continue participating. The majority (80%) of preterm births, neonatal deaths, and NI-BSI subjects, but only 50% of stillbirths, could be assessed for diagnostic certainty. The main reasons for not classifying stillbirths were insufficient information to distinguish between antepartum and intrapartum stillbirth (29%); or that not all data for one subject fit into a single level of diagnostic certainty (35%). Forty-nine percent of mothers were considered vaccinated, 6% not-vaccinated, and vaccination status could not be assessed in 44% of them. Discussion: GAIA case definitions for four neonatal outcomes and maternal vaccination were successfully piloted in 24 sentinel sites across four WHO regions. Our assessment found that modification of the stillbirth definition could help avoid potential misclassification. Vaccine safety monitoring in LMICs will benefit from systematic recording of all vaccinations during pregnancy

WHO global vaccine safety multi-country collaboration project on safety in pregnancy: Assessing the level of diagnostic certainty using standardized case definitions for perinatal and neonatal outcomes and maternal immunization.

Standardized case definitions strengthen post-marketing safety surveillance of new vaccines by improving generated data, interpretation and comparability across surveillance systems. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project developed standardized case definitions for 21 key obstetric and neonatal terms following the Brighton Collaboration (BC) methodology. In this prospective cohort study, we assessed the applicability of GAIA definitions for maternal immunization exposure and for low birth weight (LBW), preterm birth, small for gestational age (SGA), stillbirth, neonatal death, neonatal infection, and congenital microcephaly. We identified the missing data elements that prevented identified cases and exposures from meeting the case definition (level 1-3 of BC diagnostic certainty). Over a one-year period (2019-2020), all births occurring in 21 sites (mostly secondary and tertiary hospitals) in 6 Low Middle Income Countries and 1 High Income Country were recorded and the 7 perinatal and neonatal outcome cases were identified from routine medical records. Up to 100 cases per outcome were recruited sequentially from each site. Most cases recruited for LBW, preterm birth and neonatal death met the GAIA case definitions. Birth weight, a key parameter for all three outcomes, was routinely recorded at all sites. The definitions for SGA, stillbirth, neonatal infection (particularly meningitis and respiratory infection) and congenital microcephaly were found to be less applicable. The main barrier to obtaining higher levels of diagnostic certainty was the lack of sonographic documentation of gestational age in first or second trimester. The definition for maternal immunization exposure was applicable, however, the highest level of diagnostic certainty was only reached at two sites. Improved documentation of maternal immunization will be important for vaccine safety studies. Following the field-testing of these 8 GAIA definitions, several improvements are suggested that may lead to their easier implementation, increased standardization and hence comparison across studies

Short-Term Use of Parenteral Nutrition With a Lipid Emulsion Containing a Mixture of Soybean Oil, Olive Oil, Medium-Chain Triglycerides, and Fish Oil: A Randomized Double-Blind Study in Preterm Infants

BACKGROUND: For premature neonates needing parenteral nutrition (PN), a balanced lipid supply is crucial. The authors hypothesized that a lipid emulsion containing medium-chain triglycerides (MCTs) and soybean, olive, and fish oils would be as safe and well tolerated as a soybean emulsion while beneficially influencing the fatty acid profile. METHODS: Double-blind, controlled study in 53 neonates (<34 weeks' gestation) randomized to receive at least 7 days of PN containing either an emulsion of MCTs and soybean, olive, and fish oils or a soybean oil emulsion. Target lipid dosage was 1.0 g fat/kg body weight [BW]/d on days 1-3, 2 g/kg BW/d on day 4, 3 g/kg BW/d on day 5, and 3.5 g/kg BW/d on days 6-14. RESULTS: Test emulsion vs control, mean ± SD: baseline triglyceride concentrations were 0.52 ± 0.16 vs 0.54 ± 0.19 mmol/L and increased similarly in both groups to 0.69 ± 0.38 vs 0.67 ± 0.36 on day 8 of treatment (P = .781 for change). A significantly higher decrease in total and direct bilirubin vs baseline was seen in the test group compared with the control group P < .05 between groups). In plasma and red blood cell phospholipids, eicosapentaenoic acid and docosahexaenoic acid were higher, and the n-6/n-3 fatty acid ratio was lower in the test group (P < .05 vs control). CONCLUSIONS: The lipid emulsion, based on a mixture of MCTs and soybean, olive, and fish oils, was safe and well tolerated by preterm infants while beneficially modulating the fatty acid profile.status: publishe

Belgian End-Of-Life Care Study Did Not Include French-speaking Units

Dear Editors, We have read with interest the article by Dombrecht et al. (2019) published in your journal in its edition of March 2019. The authors address a sensitive topic, namely the reported attitudes of neonatologists and neonatal nurses in the Flanders region of Belgium regarding complex issues around active end-of-live (EOL) practices for foetuses and neonates facing life-limiting conditions. As the authors correctly state in the abstract and full text, the survey was conducted among 8 centres located in the Flemish Community and did not include the 11 centres of the French Community of Belgium. This means that the title which presents the study as “a nationwide survey” is not correct. Furthermore, another representative study conducted collaboratively by those 11 French speaking neonatal intensive care units, with a very high response rate, was not taken into account (Aujoulat et al. 2018). Yet, this study led to quite different results and conclusions which could have broadened the discussion and nuanced the ethical and legal implications as well as the conclusions drawn by Dombrecht et al. (2019). Based on our clinical experience, we do acknowledge that EOL decisions in the perinatal period are complex, but that international guidelines and best practices regarding breaking bad news, involving parents in the decision-making process, dealing with uncertainty about prognosis, ensuring continuity of care by bereavement support, and offering supervision to teams might be helpful. In this respect, the absence of formal training in neonatal palliative care currently offered in Belgium is unfortunate (Arias et al., 2019). However, since 2014, despite some cultural or linguistic differences, the Belgian Paediatric Palliative Care group (www.bppc.be) brings together nurses, physicians, psychologists and social workers from all regions in Belgium, to discuss and elaborate national guidelines regarding paediatric palliative care. This may pave the way for future, hoped for, fruitful collaborations also in the field of neonatology, not only across Belgian teams but also at international level, where the complex psychosocial, medical, ethical and legal issues surrounding decisions and practices around EOL care to neonates are the object of much debate and controversies. Marie Friedel, paediatric nurse; Dr Marleen Renard, paediatrician, Prof. Hugo Devlieger neonatologist; Prof. Gaston Verellen, neonatologist. References: Arias N, Garralda E, Rhee JY. et al. EAPC Atlas of Palliative Care in Europe 2019. Vilvoorde: EAPC Press, 2019. Aujoulat I, Henrard S, Charon A, Johansson AB, Langhendries JP, Mostaert A, Vermeylen D, Verellen G; 11 neonatal intensive care units in the Wallonia-Brussels Federation. End-of-life decisions and practices for very preterm infants in the Wallonia-Brussels Federation of Belgium. BMC Pediatr. 2018; 26;18(1):206. doi: 10.1186/s12887-018-1168-x. Dombrecht L, Deliens L, Chambaere K, Baes S, Cools F, Goossens L, Naulaers G, Roets E, Piette V, Cohen J, Beernaert K; NICU consortium. Neonatologists and neonatal nurses have positive attitudes towards perinatal end-of-life decisions, a nationwide survey. Acta Paediatr. 2019. doi: 10.1111/apa.14797. Pag