The safety of inactivated influenza vaccines in pregnancy for birth outcomes: a systematic review

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ABSTRACT

Pregnant women are at increased risk of morbidity and mortality from influenza and are recognized as a priority group for influenza vaccination. Despite this, uptake is often poor and one reason cited for this is concerns about safety. The objective of this study was to perform a systematic review of the safety of inactivated influenza vaccination (IIV) in pregnancy. Studies were included if they were: (i) observational or experimental design; (ii) included a comparator group comprising of unvaccinated pregnant women; (iii) comprised of either seasonal IIV or monovalent H1N1 IIV (including adjuvanted vaccines); and (iv) addressed one of the following outcomes: preterm birth (PTB), small for gestational age (SGA), fetal death (including stillbirth or spontaneous abortion), low birth weight (LBW) or congenital abnormalities. Two reviewers screened abstracts and titles and selected full texts for retrieval. Crude odds ratios were calculated from reported event rates, using binomial standard errors. Adjusted odds ratios, hazard ratios and relative rates were extracted as reported in each paper. After removal of duplicates and full text eligibility assessment, 40 studies remained. The aOR for PTB was 0.87 (0.78–0.96), for LBW 0.82 (0.76–0.89), congenital abnormality 1.03 (0.99–1.07), SGA 0.99 (0.94–1.04) and stillbirth 0.84 (0.65–1.08). This study contributes to the increasing body of safety data for IIV in pregnancy and reports a protective effect on PTB and LBW.

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Low birth weight: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data

Clare Cutland, Eve Lackritz, Tamala Mallett-Moore … (2017)

1 Preamble 1.1 Need for developing case definitions and guidelines for data collection, analysis, and presentation for low birth weight as an adverse event following maternal immunization The birth weight of an infant is the first weight recorded after birth, ideally measured within the first hours after birth, before significant postnatal weight loss has occurred. Low birth weight (LBW) is defined as a birth weight of less than 2500 g (up to and including 2499 g), as per the World Health Organization (WHO) [1]. This definition of LBW has been in existence for many decades. In 1976, the 29th World Health Assembly agreed on the currently used definition. Prior to this, the definition of LBW was ‘2500 g or less’. Low birth weight is further categorized into very low birth weight (VLBW, 20 million newborns annually, are low birth weight infants. Low- and middle-income countries account for a disproportionate burden of LBW; over 95% of the world’s LBW infants are born in LMICs. There are marked global and regional variations in LBW rates. An estimated 6% of infants are born LBW in East Asia and the Pacific, 13% in Sub-Saharan Africa, and up to 28% in South Asia [3]. Up to half of all LBW infants are born in south Asia [4]. High-income regions report lower LBW rates, including 6.9% from UK [5]. Of concern is the estimated increase in LBW rates in certain middle-income countries such as Oman, where the LBW rate went from 4% in 1980 to 8.1% in 2000 [6]. One of the major challenges in monitoring the incidence of LBW is that more than half of infants in the LMICs are not weighed [7]. Population-based survey data often rely on modeled estimates, with statistical methods to adjust for underreporting and misreporting of birth weight. In the context of vaccine safety monitoring, accurate ascertainment of birth weight in LMICs will continue to require attention and investment to improve accuracy and reporting of this important health indicator. 1.1.1 Why are we concerned about low birth weight? Low birth weight is a valuable public health indicator of maternal health, nutrition, healthcare delivery, and poverty. Neonates with low birth weight have a >20 times greater risk of dying than neonates with birth weight of >2500 g [8], [9]. Additionally, low birth weight is associated with long-term neurologic disability, impaired language development [10], impaired academic achievement, and increased risk of chronic diseases including cardiovascular disease and diabetes. Preterm infants carry additional risk due to immaturity of multiple organ systems, including intracranial hemorrhage, respiratory distress, sepsis, blindness, and gastrointestinal disorders. Preterm birth is the leading cause of all under-5 child mortality worldwide [11]. In addition, economic studies in low-income settings have demonstrated that reducing the burden of low birth weight would have important cost savings both to the health system and to households [12]. 1.1.2 What leads to low birth weight? The underlying causes of both PTB and IUGR are multifactorial, and the biological pathways and preventive strategies for these two conditions are quite different [13], [14], [15]. The exact cause of PTB may be unknown in many cases, however numerous maternal, fetal and placental factors may contribute to PTB [13]. Significant maternal conditions include extra-uterine infection, chorioamnionitis, trauma and illness (e.g. pre-eclampsia/eclampsia). Significant fetal conditions include IUGR, fetal infection, death and anomalies. Placental pathologic conditions include placental abruption and placenta praevia [13]. In general, the causes of IUGR can be due to maternal, fetal, and placental factors. Although the etiologies are different, they often have the final common pathway of insufficient uterine-placental perfusion and fetal nutrition. IUGR can be asymmetrical IUGR (where babies have features of malnutrition), symmetrical IUGR (hypoplastic small for dates) or mixed IUGR. Asymmetrical IUGR is the most common (70–80%) form of IUGR, resulting from an insult (often utero-placental insufficiency) later in pregnancy, which results in affected babies having normal length and head circumference (brain sparing), but reduced weight. Symmetrical IUGR on the other hand arises from an insult (often genetic, structural or infectious) occurring earlier in pregnancy leading to a reduction in all anthropometric parameters in fetus/newborn [15]. Insufficient perfusion, through abnormal placentation, aberrant placental vascularization, maternal hypertensive disorders, and tobacco use, all result in IUGR. Multiple gestation (i.e., twins, triplets) is associated with increased risk of both IUGR and PTB [16]. Infectious diseases, including intrauterine infections, HIV, and malaria, result in LBW due to both growth restriction and short gestation. Multiple maternal characteristics, risk behaviors, and social determinants are associated with both IUGR and PTB; these include maternal short stature, maternal malnutrition, low body mass index, poverty, black race, narrow child spacing, low maternal education, poor antenatal care, substance abuse, and emotional and physical stress [5], [17], [18], [19]. How these factors are mediated biologically remains poorly understood. Preterm birth may be spontaneous or medically-indicated, such as induction or cesarean section for maternal complications such as pre-eclampsia. Infectious and inflammatory processes are associated with increased risk for PTB, including chorioamnionitis, bacterial vaginosis, bacteriuria, and systemic or remote site infection such as sepsis and periodontal disease. 1.1.3 The importance of short gestation on immune function and vaccine efficacy Transplacental antibody transfer is an active process mediated by Fc receptors in the placental syncytiotrophoblast [20], which increases from 30 weeks gestation. Small molecular weight particles ( 1000 Da) are transported across the placenta by and active receptor-mediated process [21]. Fetal IgG levels are approximately 50% of maternal antibody level at 32 weeks gestation and rises rapidly through the third trimester [22]. Preterm newborns have significantly lower antibody levels than term newborns [22]. LBW term newborns have significantly lower antibody concentrations to Herpes simplex virus type 1, respiratory syncytial virus ad varicella zoster virus than term newborns with birth weight >2500 g [23]. Maternal antibody levels, receptor density and functionality, avidity, antigen nature, and gestational age determine the efficiency of placental antibody transfer [24]. Diseases that are highly prevalent in some areas, such as malaria and human immunodeficiency virus (HIV), are known to cause placental damage, especially placental malaria [25], [26]. Maternal HIV infection has been consistently associated with reduced placental passage of antibodies against several common viral and bacterial antigens [27], [28]. Placental malaria has been associated with maternal hypergammaglobulinemia and reduced transfer of antibodies against measles virus, Clostridium tetani, Streptococcus pneumonia, and varicella-zoster virus in some studies [20], [29], [30], [31]. The transfer during pregnancy of maternal antibodies to the fetus minimizes deficiencies in antibody production in the fetus and provides short-term passive immunity [32], conditioning the success of vaccination in newborns [33] which is especially important in preterm and IUGR newborns. Multiple comorbidities are associated with both LBW and immune suppression, such as malnutrition and infection, thereby further exacerbating diminished immune function in the compromised newborn. 1.1.4 Maternal immunization and birth weight Maternal infections, including influenza, have been associated with increased risk of low birth weight newborns [34]. As a corollary, prevention of certain infections during pregnancy might have a protective effect against LBW. This has been observed in a maternal immunization trial conducted in Bangladesh [35], in which the mean birth weight of infants born to mothers who received an inactivated influenza vaccine during pregnancy was higher than of infants born to mothers who received a pneumococcal polysaccharide vaccine (3178 g vs. 2978 g, p = 0.02). This trend has not been observed in other maternal influenza immunization trials [36]. The field of immunization of pregnant women has highlighted the importance of knowing background rates of adverse pregnancy events, including LBW, PTB, SGA, IUGR, stillbirths, and neonatal death, which can vary markedly between and within regions. The greatest impact of disease prevention from maternal immunization is expected to be observed in LMIC, where the burden of disease is greatest and access to health care services is most limited. For this reason, particular attention is being given to advancing maternal immunization trials in LMICs. Unfortunately, reliable, accurate, and timely reports of vital statistics and demographic data are often limited in these settings. Data Safety Monitoring Boards are established to review clinical trial data, including regular assessment or review of adverse event rates in trial participants. Without accurate information on background rates of low birthweight and other adverse pregnancy outcomes, it will be impossible to detect an increase in adverse events following immunization. Development of standardized methods to collect and report LBW and other essential outcomes will be essential to advancing maternal immunization programs worldwide. Birth weight is usually included under demographics of trial participant infants, and the differences in birth weights between participants enrolled in active and placebo or control arms of interventional trials in pregnancy are usually assessed. The LBW Working Group recommends use of traditional case definitions of LBW as defined by the World Health Organization. This report therefore focuses on delineating data quality related to methods used to estimate birth weight in LMICs, and summarizes some surrogate measurements that are under investigation to assess birth weight and estimate population-level background LBW rates. 1.2 Methods for the review of the case definition and guidelines for data collection, analysis, and presentation for low birth weight in clinical trial and population settings Following the process described in the overview paper [21] as well as on the Brighton Collaboration Website http://www.brightoncollaboration.org/internet/en/index/process.html, the Brighton Collaboration Low birth weight Working Group was formed in 2016 and included 16 members of varied backgrounds including clinical, academic, public health and industry. The composition of the working and reference group as well as results of the web-based survey completed by the reference group with subsequent discussions in the working group can be viewed at: http://www.brightoncollaboration.org/internet/en/index/working_groups.html. To guide the decision-making for the guidelines, a literature search was performed using Medline/PubMed, Embase, ClinicalKey (ebooks), ScienceDirect (eBooks), eBrary (eBooks) and the Cochrane Libraries, including the terms: ‘pregnancy, vaccines and low birth weight’, and restricted to English language publications since 2005. The search resulted in the identification of 41 references. All abstracts were screened for possible reports of Low birth weight following immunization. Thirty-two articles with potentially relevant material were reviewed in more detail, in order to identify studies using case definitions or, in their absence, providing clinical descriptions of the case material. This review resulted in a detailed summary of 19 articles, including information on the study type, the vaccine, the diagnostic criteria or case definition put forth, the time interval since time of immunization, and any other symptoms. Multiple general medical, pediatric and infectious disease book chapters were also searched. The definition of low birth weight used was consistent across all literature reviewed. A second literature search using the search terms ‘birth weight and tools’ was performed using Pubmed, to identify other measurements used as proxies for birth weight. The search, unrestricted for language and year of publication, identified in 235 results. Titles were screened and 10 articles were identified for further review. 1.3 Rationale for selected decisions about the case definition of low birth weight as an adverse event following maternal immunization 1.3.1 The term low birth weight ‘Low birth weight’ (LBW) has been defined as first weight recorded within hours of birth of <2500 g. Very low birth weight (VLBW) is accepted as <1500 g and extremely low birth weight (ELBW) is <1000 g [1]. Within the definition context, however, the three diagnostic levels must not be misunderstood as reflecting different grades of clinical severity. They instead reflect diagnostic certainty. The levels of certainty have been formulated such that the Level 1 definition is highly specific for the condition. Two additional diagnostic levels have been included in the definition, offering a stepwise loss of precision and accuracy from Level One down to Level Three, while retaining an approach to expand utilization of available data. In this way it is hoped that information on low birth weight can be captured more broadly at the population level. 1.3.2 Timing of birth weight assessment The birth weight is described as the first weight measured, however, in settings with low rates of facility-based deliveries, a newborn may not be assessed by a health care worker until several days old. Birth weight should be assessed within hours of birth, prior to significant weight loss [37]. Term neonates lose between 3.5% and 6.6% of their birth weight within the first 2.5–2.7 days of life. Exclusively breastfed neonates have a greater weight loss (Median 6.6%, 95%CI 6.3–6.9%) than formula-fed (Median 3.5%, 95%CI 3.0–3.9%) or mixed fed (5.9%, 95%CI 4.8–6.9%) neonates respectively, and take longer to regain their birth weight (8.3 vs. 6.5 vs. 7.9 days) [37]. The LBW working group decided to restrict ‘birth weight’ to a weight measured in the first 48 h of life. In the absence of a weight measured within the first 48 h of life, a weight measured during the first week of life, could be classified as an ‘early neonatal weight’ but not ‘birth weight’. In a clinical trial scenario, measurement of weight within first 48 h of life should be achievable, as the clinical trial would procure adequate equipment, employ and train staff to assess birth weight in a timely manner, and enroll participants who reside in areas which are relatively easily accessed by trial or health care staff. Many newborns globally are not weighed within hours of birth, mainly due to difficulty in accessing health care personnel, facilities, and essential equipment. Specific time frames for onset of symptoms following immunization are not included for the following main reasons: We postulate that a definition designed to be a suitable tool for testing causal relationships requires ascertainment of the outcome (e.g. low birth weight) independent from the exposure (e.g. immunizations). Therefore, to avoid selection bias, a restrictive time interval from immunization to birth of a LBW newborn should not be an integral part of such a definition. Instead, where feasible, details of this interval should be assessed and reported as described in the data collection guidelines. Further, measurement of birth weight often occurs outside the controlled setting of a clinical trial or hospital. In some settings it may be impossible to obtain a clear timeline of the assessment of a birth weight, particularly in less developed or rural settings. In order to avoid selecting against such cases, the Brighton Collaboration case definition avoids setting arbitrary time frames. The time between delivery and measurement of birth weight should be recorded and accounted for in the analysis. 1.4 Guidelines for data collection, analysis and presentation As mentioned in the overview paper [38], the case definition is accompanied by guidelines which are structured according to the steps of conducting a clinical trial, i.e. data collection, analysis and presentation. Neither case definition nor guidelines are intended to guide or establish criteria for management of ill infants, children, or adults. Both were developed to improve standardization of case definitions and data comparability. 1.5 Periodic review Similar to all Brighton Collaboration case definitions and guidelines, review of the definition with its guidelines is planned on a regular basis (i.e. every three to five years) or more often if needed. 2 Case definition of low birth weight3 Level 1 of diagnostic certainty Newborn infant weighed within 24 h of birth AND Use electronic scale which is graduated to 10 g AND Scale is calibrated at least once a year AND Scale placed on level, hard surface AND Scale tared to zero grams AND Weight recorded as <2500 g OR Birth weight recorded as <2500 g AND Birth weight assessed as per health care facility’s standard operating procedure, which fulfills criteria 1 to 5 of LOC1 Level 2 of diagnostic certainty Newborn infant weighed within 24 h of birth AND Scale (electronic/spring) is graduated to at least 50 g AND Scale is calibrated at least once a year, or more often if moved AND Scale tared to zero grams or 0.00 kg AND Weight recorded as <2500 g OR Birth weight recorded as <2500 g AND Birth weight assessed as per health care facility’s standard operating procedure, which fulfills criteria 1 to 4 of LOC2 Scale used: could be electronic or spring scale, including color-coded scale. Level 3 of diagnostic certainty Newborn infant weighed on day 1 or 2 of life (first 48 h of life) AND Weight measured using dial/spring/color-coded scale AND Weight assessed as <2500 g Level 4 of diagnostic certainty Newborn infant ‘weight’ assessed on day 1 or 2 of life (first 48 h of life) AND Proxy measure of birth weight used AND Weight CATEGORY assessed as <2500 g In many settings, including high-income countries, birth weight is assessed by a health care provider who is attendant during/soon after delivery, and not the vaccine trialist/researcher. The details of time of birth weight assessment, and details of scale used and calibration details are usually not recorded in newborn assessment medical notes. The newborn weight assessment is presumed to be assessed accurately as per health care center’s standard operating procedures. In many instances, trialists need to rely on the attending medical staff at health care facility for birth weight assessment. Strengthening training and oversight of birth weight measurement would be expected to strengthen data both in clinical trials and post-marketing surveillance. 2.1 Other tools under investigation to estimate birth weight in individuals and populations Up to 60 million infants are born at home annually [39], and up to 48% of infants worldwide are not weighed at birth [3]. Lack of access to health care facilities or health care workers hampers accurate assessment of low birth weight rates in many regions. In order to identify small newborns, who could be preterm, IUGR, or both, who require additional care, inexpensive tools are required which can be utilized in the field. The lack of data available has encouraged the development of a mathematical model to calculate the expected number of adverse events, including neonatal and maternal deaths, SGA, preterm birth and major congenital malformations [40]. Several anthropometric measurements, including chest circumference, foot length and mid-upper arm circumference, have been assessed as proxies for birth weight [41], [42], [43], [44]. Table 1 summarizes these tools and their validity for identifying low birth weight newborns. These tools at this point are considered investigational and have been included in level 4 definition only, which indicates that evidence is inadequate to meet the definition, however, may be useful for population background LBW estimates. Table 1 Validated tools used as proxy measures of birth weight. Measurement Method of assessment Cut-off values used Comments Newborn foot length [41], [42], [43], [46] Foot length from center of heel pad to tip of big toe in millimeters Hard plastic ruler pressed vertically against sole of foot (highest AUC) 7.2 cm for 2000 g Weakest correlation with LBW of all anthropometric measurements [47], [48] Sole of foot placed on solid board with measuring tape 7.8 cm for preterm [41] ⩽7.4 cm (7.3–7.4 cm) for 2500 g [43] AUC 0.94, 95%CI 0.92–0.96 [43] For <2500 g Footprint made on White paper, and tip of big toe and heel marked with pencil 7.2 cm (Europe) <8 cm at birth was 87% sensitive for LBW [46] 6.3–7.85 cm (Asia) 7.4–8 cm (Africa) Chest circumference [42], [43] Chest circumference at level of nipples in centimeters Non-elastic, flexible measuring tape graduated to nearest 0.1 cm, measured during expiration ⩽30.4 cm (30.0–30.4 cm) [43] Highly predictive of LBW if measured at <24 h of age (AUC 0.98, 95%CI 0.96–0.99) [43] In meta-analysis, best anthropometric measurement to predict LBW [47] Risk of hypothermia Mid upper arm circumference [43] Mid-point between tip of acromion process and olecranon process in centimeters Non-elastic, flexible measuring tape graduated to nearest 0.1 cm ⩽9.0 cm (8.7–9.0 cm) [43] Highly predictive of LBW if measured at <24 h of age (AUC 0.98, 95%CI 0.96–0.99) [43] AUC – area under curve. In addition to these measurements, other tools are utilized in some communities to assess birth weight, including difference between adult weight with and without newborn in arms (see Fig. 1). Fig. 1 Tools used to measure birth weight (See above-mentioned references for further information.). 3 Guidelines for data collection, analysis and presentation of low birth weight It was the consensus of the Brighton Collaboration Working Group for Low birth weight to recommend the following guidelines to enable meaningful and standardized collection, analysis, and presentation of information about low birth weight. However, implementation of all guidelines might not be possible in all settings. The availability and quality of information may vary depending upon resources, geographical region, and whether the source of information is a prospective clinical trial, epidemiological study, post-marketing surveillance, or an individual report. Also, as explained in more detail in the overview paper [38], these guidelines have been developed by this working group for guidance only, and are not to be considered a mandatory requirement for data collection, analysis, or presentation. 3.1 Data collection These guidelines represent a desirable standard for the collection of data on availability following immunization to allow for comparability of data, and are recommended as an addition to data collected for the specific study question and setting. The guidelines are not intended to guide the primary reporting of low birth weight to a surveillance system or study monitor. Investigators developing a data collection tool based on these data collection guidelines also need to refer to the criteria in the case definition, which are not repeated in these guidelines. Guidelines numbers below have been developed to address data elements for the collection of adverse event information as specified in general drug safety guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [49], and the form for reporting of drug adverse events by the Council for International Organizations of Medical Sciences [50]. These data elements include an identifiable reporter and patient, one or more prior immunizations, and a detailed description of the adverse event, in this case, of low birth weight following immunization. The additional guidelines have been developed as guidance for the collection of additional information to allow for a more comprehensive understanding of low birth weight following maternal immunization. 3.1.1 Source of information/reporter For all cases and/or all study participants, as appropriate, the following information should be recorded: (1) Date of report. (2) Name and contact information of person reporting4 and/or diagnosing low birth weight as specified by country-specific data protection law. (3) Name and contact information of the investigator responsible for the subject, as applicable. (4) Relation to the patient (e.g., healthcare provider, immunizer, community health worker, family member [indicate relationship], other). 3.1.2 Vaccinee/control 3.1.2.1 Demographics For all cases and/or all study participants, as appropriate, the following information should be recorded: (5) Case/study participant identifiers for mother and newborn (e.g. first name initial followed by last name initial) or code (i.e. hospital identifier or in accordance with country-specific data protection laws). Each newborn should have a unique identifier, ideally linked to mother’s identifier (e.g. participant code could be same for mother and baby(ies), with an added prefix/suffix to identify mother/baby). (6) Maternal date of birth, or if not available, maternal age. (7) For each infant: Date and time of delivery, single or multiple, live birth vs. fetal death (fresh or macerated), estimated gestational age, method of determination of gestational age (LMP, fundal height, first trimester ultrasound) and birth weight. • For collection of birth weight, ideally record timeline of weight measurement (e.g. time of delivery to time of weight), type of scale used (e.g. surface-mounted spring) and place where birth weight was measured (e.g. health care facility, mobile health worker visiting home). 3.1.2.2 Clinical and immunization history For all cases and/or all study participants, as appropriate, the following information should be recorded: (8) Maternal past medical history, including hospitalizations, gravidity and parity, underlying diseases/disorders; complications of pregnancy, labor, or delivery; pre-immunization signs and symptoms including identification of indicators for, or the absence of, a history of allergy to vaccines, vaccine components or medications; food allergy; allergic rhinitis; eczema; asthma. (9) Any medication history (other than treatment for the event described) prior to, during, and after immunization including prescription and non-prescription medication as well as medication or treatment with long half-life or long term effect. (E.g. immunoglobulins, blood transfusion and immunosuppressants). (10) Immunization history (i.e. previous immunizations and any adverse event following immunization (AEFI)), in particular occurrence of low birth weight after a previous maternal immunization. 3.1.3 Details of the immunization For all cases and/or all study participants, as appropriate, the following information should be recorded: (11) Date and time of maternal immunization(s). (12) Description of vaccine(s) (name of vaccine, manufacturer, lot number, dose (e.g. 0.25 mL, 0.5 mL), vaccine diluent (composition and lot number) and number of dose if part of a series of immunizations against the same disease). (13) The anatomical sites (including left or right side) of all immunizations (e.g. vaccine A in proximal left lateral thigh, vaccine B in left deltoid). (14) Route and method of administration (e.g. intramuscular, intradermal, subcutaneous, and needle-free (including type and size), other injection devices). (15) Needle length and gauge. 3.1.4 The adverse event (16) For all cases at any level of diagnostic certainty and for reported events with insufficient evidence, the criteria fulfilled to meet the case definition should be recorded. Specifically document: (17) Severity of Low birth weight (LBW, VLBW or ELBW), and if there was medical confirmation of the LBW (i.e. patient seen by physician/other health care worker). (18) Date/time of observation,5 and diagnosis.6 (19) Concurrent signs, symptoms, and diseases, including prematurity. (20) Measurement/testing. • Values and units of routinely measured parameters (grams for birth weight); • Method of measurement (e.g. type of scale.); • Weight should be recorded with minimal or ideally no clothing; (21) Objective clinical evidence supporting classification of the event as “serious”.7 (22) Exposures other than the immunization 24 h before and after immunization (e.g. infection, environmental) considered potentially relevant to the reported event.8 3.1.5 Miscellaneous/general (23) The duration of surveillance for low birth weight should be from 0 to 48 h of life. Any weight measured after 48 h of age should not be considered a ‘birth weight’.9 (24) Methods of data collection should be consistent within and between study groups, if applicable.10 (25) Investigators of patients with low birth weight should provide guidance to reporters to optimize the quality and completeness of information provided. 3.2 Data analysis The following guidelines represent a desirable standard for analysis of data on low birth weight to allow for comparability of data, and are recommended as an addition to data analyzed for the specific study question and setting. (26) Reported events should be classified in one of the following five categories including the three levels of diagnostic certainty. Events that meet the case definition should be classified according to the levels of diagnostic certainty as specified in the case definition. Events that do not meet the case definition should be classified in the additional categories for analysis. Event classification in 5 categories Event meets case definition (1) Level 1: Criteria as specified in the Low birth weight case definition (2) Level 2: Criteria as specified in the Low birth weight case definition (3) Level 3: Criteria as specified in the Low birth weight case definition Event does not meet case definition Additional categories for analysis (4) Reported Low birth weight with insufficient evidence to meet the case definition.7 (5) Birth weight not assessed, therefore data unavailable. (27) The interval between immunization and reported Low birth weight could be defined as the date/time of immunization to the date/time of assessment4 of birth weight. If few cases are reported, the concrete time course could be analyzed for each; for a large number of cases, data can be analyzed in the following increments. (28) If birth weight is assessed by more than one method, the value recorded which fulfills the highest level of certainty should be used as the basis for analysis. (29) The distribution of birth weight data could be analyzed in predefined increments (e.g. LBW < 2500 g, VLBW < 1500 g, ELBW < 1000 g). Increments specified above should be used. When only a small number of cases are presented, the respective values can be presented individually. (30) Data on Low birth weight obtained from participants whose mothers received a vaccine should be compared with those obtained from an appropriately selected and documented control group to assess background rates of LBW in non-exposed populations, and should be analyzed by study arm and dose where possible, e.g. in prospective clinical trials. 3.3 Data presentation These guidelines represent a desirable standard for the presentation and publication of data on Low birth weight following immunization to allow for comparability of data, and are recommended as an addition to data presented for the specific study question and setting. Additionally, it is recommended to refer to existing general guidelines for the presentation and publication of randomized controlled trials, systematic reviews, and meta-analyses of observational studies in epidemiology (e.g. statements of Consolidated Standards of Reporting Trials (CONSORT) [51], of Improving the quality of reports of meta-analyses of randomized controlled trials (QUORUM) [52], and of meta-analysis Of Observational Studies in Epidemiology (MOOSE) [53], respectively). (31) All reported events of Low birth weight should be presented according to the categories listed in guideline 31. (32) Data on Low birth weight events should be presented in accordance with data collection guidelines 1–25 and data analysis guidelines 26–30. (33) Data should be presented as rates with a numerator and denominator (n/N) (and not only in percentages), with confidence intervals around the point estimates. Although immunization safety surveillance systems denominator data are usually not readily available, attempts should be made to identify approximate denominators. The source of the denominator data should be reported and calculations of estimates be described (e.g. manufacturer data like total doses distributed, reporting through Ministry of Health, coverage/population based data, etc.). (34) The incidence of cases in the study population should be presented and clearly identified as such in the text. (35) If the distribution of birth weight data is skewed, median and range are usually the more appropriate statistical descriptors than a mean. However, the mean and standard deviation should also be provided. (36) Any publication of data on Low birth weight should include a detailed description of the methods used for data collection and analysis as possible. It is essential to specify: • The study design; • The method, frequency and duration of monitoring for Low birth weight; • The trial profile, indicating participant flow during a study including drop-outs and withdrawals to indicate the size and nature of the respective groups under investigation; • The type of surveillance (e.g. passive or active surveillance); • The characteristics of the surveillance system (e.g. population served, mode of report solicitation); • The search strategy in surveillance databases; • Comparison group(s), if used for analysis; • The instrument of data collection (e.g. standardized questionnaire, diary card, report form); • Whether the day of immunization was considered “day one” or “day zero” in the analysis; • Whether the date of onset4 and/or the date of first observation5 and/or the date of diagnosis6 was used for analysis; and • Use of this case definition for Low birth weight, in the abstract or methods section of a publication.11 Disclaimer The findings, opinions and assertions contained in this consensus document are those of the individual scientific professional members of the working group. They do not necessarily represent the official positions of each participant’s organization (e.g., government, university, or corporation). Specifically, the findings and conclusions in this paper are those of the authors and do not necessarily represent the views of their respective institutions.

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Maternal Influenza Immunization and Reduced Likelihood of Prematurity and Small for Gestational Age Births: A Retrospective Cohort Study

Saad B Omer, David Goodman, Mark C. Steinhoff … (2011)

Introduction Infections during pregnancy have the potential to adversely impact birth outcomes and fetal growth and development. Respiratory infections—particularly those resulting in pneumonia—have been associated with low birth weight and increased risk of preterm birth [1],[2]. Influenza virus is an important respiratory pathogen that causes substantial burden of disease—including morbidity and mortality among pregnant women, with greater risk of influenza-related morbidity among pregnant women than among non-pregnant and postpartum women [3]. Vaccination against influenza is the most effective tool to prevent morbidity and mortality due to influenza. Influenza vaccination during pregnancy provides protection for the infant as well as the mother. A randomized controlled clinical trial in Bangladesh demonstrated that vaccination of pregnant women with the inactivated influenza vaccine had 63% effectiveness in reducing laboratory-confirmed influenza in their infants [4]. Since there is evidence of adverse fetal/newborn outcomes after infection during pregnancy [5],[6], including influenza infection [2], it is plausible that influenza vaccination in pregnancy could mitigate adverse birth outcomes such as prematurity and small for gestational age (SGA) births. The potential impact of maternal influenza immunization on birth outcomes could have important public health implications for developed as well as developing countries and may be of particular interest during influenza pandemics. The objective of this study was to evaluate whether there is an association between receipt of inactivated influenza vaccine during pregnancy and birth outcomes using a multiyear, population-based, state-wide dataset from the state of Georgia (in the United States). Methods We conducted a retrospective cohort analysis of a large surveillance dataset. The primary exposure variable was receipt of inactivated influenza vaccine during any trimester of pregnancy by mothers of infants born between 1 June 2004 and 30 September 2006. The study period encompassed the 2004–2005 and the 2005–2006 influenza seasons (the two most recent seasons for which the data were available at the time of analysis). The main outcomes assessed were prematurity and SGA. Data Sources and Study Population We analyzed pregnancy- and birth-related data from the Georgia Pregnancy Risk Assessment Monitoring System (PRAMS) and influenza activity information compiled by Georgia for the Council of State and Territorial Epidemiologists (CSTE) reports. PRAMS is a multistate surveillance system managed by the US Centers for Disease Control and Prevention and state health departments, including the Georgia Department of Community Health [7],[8]. The PRAMS sample is drawn monthly from the state's birth file and includes resident women who have experienced a live birth. Georgia PRAMS oversamples women based on race (black) and birth weight ( 4,000 g; previous preterm, SGA, or low birth weight delivery; renal disease; Rh sensitization; rubella; syphilis; and uterine bleeding. e Labor/delivery complications include abruptio placenta, anesthetic complications, breech presentation, cephalopelvic disproportion, cord prolapse, dysfunctional labor, excessive bleeding, febrile (100°F/38°C), fetal distress, moderate to heavy meconium staining, placenta previa, labor 12 h, labor >20 h, and seizures during labor. Based on the approach of identifying covariates that produce adjusted ORs of 1 during the pre-influenza period, the group of covariates in the prematurity multivariate models included gestational age for first antenatal visit, maternal diabetes (gestational and/or non-gestational), multivitamin use in pregnancy, history of alcohol use during pregnancy, education less than 12th grade, and mother married. The covariates in the primary multivariate models for SGA included maternal age less than 19 y, maternal medical risk factors, labor/delivery complications, hypertension (treated or untreated), birth defects, and history of alcohol use during pregnancy. In unadjusted models, and in models with covariates based on lack of effects in the pre-influenza season, infants born during the putative influenza season (1 October–31 May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature than infants of unvaccinated mothers born in the same period (adjusted OR = 0.60; 95% CI, 0.38–0.94). The magnitude of effect of maternal influenza vaccine on prematurity increased during the period when there was at least local influenza activity in any part of the state (adjusted OR = 0.44; 95% CI, 0.26–0.73) and was the highest for those born during the period of widespread influenza activity (adjusted OR = 0.28; 95% CI, 0.11–0.74) (Table 2). The adjusted and unadjusted ORs were not significant for the association between receipt of maternal influenza vaccine and prematurity for the pre-influenza activity period or for the analysis without consideration of influenza activity (Table 2). 10.1371/journal.pmed.1000441.t002 Table 2 ORs of prematurity by maternal influenza vaccine status (ORs 0.05—detailed data available on request). Moreover, the association between maternal influenza vaccine and birth outcomes was qualitatively similar for the two influenza seasons. For example, during the period of widespread influenza activity, the adjusted ORs for prematurity were 0.17 (95% CI, 0.03–0.86) for the 2004–2005 season and 0.32 (95% CI, 0.10–1.14) for the 2005–2006 season. The fraction of prematurity prevented in the population during the study period (population prevented fraction of prematurity) was 0% for the pre-influenza activity period and 7.9% for the putative influenza season. The population prevented fraction increased during the periods of influenza activity (at least local activity, 15.7%; at least regional activity, 17.5%; widespread activity, 17.5%). Discussion This study demonstrates an association between immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. For births during the 8 wk of widespread influenza activity, the odds of prematurity were approximately 70% lower among the newborns of the vaccinated mothers compared to mothers who did not receive the influenza vaccine. During the period of widespread influenza activity there was also an association between maternal receipt of influenza vaccine and reduced likelihood of SGA. The magnitude of association between influenza vaccine and prematurity (as measured by the values of ORs) increased with the increase in the intensity of influenza activity and was higher for the 2004–2005 season than for the 2005–2006 season. Based on laboratory and epidemiologic criteria, the 2004–2005 influenza season was more intense than the 2005–2006 season in the US [16]. Although the SGA-related ORs were not statistically significant for influenza activity periods except for the period of widespread activity, the overall “gradient” of effect in the point estimates of the ORs was qualitatively similar to that of prematurity. The increase in the impact of maternal influenza vaccines on birth outcomes by influenza activity, both in terms of ORs and population prevented fractions, supports the validity of our findings. The possibility of confounding due to differences between vaccinated and unvaccinated individuals included in observational studies of influenza immunization is well recognized [12]. The most significant type of confounding in influenza studies is due to a higher likelihood of individuals with high functional capacity (i.e., healthier individuals) to get vaccinated—a phenomenon often known as the “healthy user effect.” However, most observational studies where significant confounding has been documented were conducted in the elderly and included a relatively nonspecific end point of all-cause mortality. It is reasonable to assume that, compared to older individuals, women of reproductive age may be less likely to have significant functional limitation even in the presence of co-morbidities. Therefore, influenza vaccine studies in this age group may be less likely to suffer from bias due to the healthy user effect. Moreover, we found no statistically significant difference between the vaccinated women and the unvaccinated women in terms of gestational age at which they sought antenatal care. On the other hand, the possibility of other confounders cannot be discounted in studies involving pregnant women. In order to address confounding, we used the pre-influenza period (i.e., the season where vaccine was available but there was minimal circulation of influenza virus) as the “control” period. The use of the pre-influenza period for selecting confounders from a broad set of covariates is an approach suggested by Nelson et al. [12] and Jackson et al. [11] that takes advantage of the seasonality of influenza circulation. The associations observed in our study were robust to adjustment for confounders identified using this approach (and the more traditional approach)—supporting the validity of our findings. Influenza virus, particularly seasonal influenza virus, rarely crosses the placenta [3],[17],[18]. However, the effect of infection on prematurity is thought be at least partially mediated through inflammatory pathways [5],[6]. Increase in pro-inflammatory cytokines (e.g., IL-1, IL-6 and TNF-α) and reduction in anti-inflammatory cytokines (e.g., IL-10) have been linked to preterm labor [6],[19],[20]. IL-1 stimulates the amnion and the decidua to produce prostaglandins and can stimulate myometrial contractions [20]. Prostaglandins are known to play an important role in the initiation and progression of labor [21]. Moreover, in animal models, administration of IL-1 results in preterm birth [20]. Similarly, TNF-α induces the amnion, the decidua, and the myometrium to produce prostaglandins, and administration of TNF-α to pregnant animals can induce preterm labor [19],[22]. Recent studies have shown that influenza virus infection induces gene expression of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, interferon (IFN)-β, IFN-α, and granulocyte macrophage colony-stimulating factor (GM-CSF) [19]. In addition to biological plausibility, there is epidemiological evidence of an association between maternal infection and preterm birth [5]. The association is strongest for intrauterine viral infections and systemic and intrauterine bacterial infections [5],[6]. Viral infection outside the reproductive tract, including influenza infection, may also play a role in the etiology of prematurity. For example, in an analysis of 1957–1958 data, newborns of women who had serological evidence of “Asian” (pandemic) influenza during pregnancy were 50% more likely to be premature compared to newborns of uninfected women [2]. Moreover, a recent literature review found that SARS infection in the second or third trimester of pregnancy may be associated with spontaneous preterm delivery and early cesarean sections for deteriorating medical condition, although only 16 such cases were identified in the literature [23]. Moreover, in studies in China and Hungary, birth defects were associated with history of influenza [24],[25]. However, a few observational studies have failed to demonstrate an association between influenza infection and birth outcomes [26],[27]. The lack of observed effect in some studies could be due to a true lack of association, small or difficult to measure effect size, challenges related to the study population (e.g., administrative datasets), or non-differential misclassification due to challenges in retrospectively identifying influenza infection. Although less than ideal, modeling receipt of influenza vaccine as the exposure/independent variable reduces the likelihood and the intensity of non-differential misclassification bias. Preterm births represent a significant burden to health care and society [5]. Like several developed countries, there has been an increase in the rate of preterm births in the US, which rose from 9.5% in 1981 to 12.8% in 2006 [28],[29]. Although the etiology of prematurity is complex [5] and not completely understood, our results suggest that at least a fraction of preterm births may be preventable through maternal influenza vaccination. The association between maternal influenza vaccination and SGA was only statistically significant (and the highest in magnitude) for the period of widespread influenza activity. Possible reasons for the effect being limited to the period of highest influenza activity include the following: (a) in a developed country setting, the effect of maternal influenza infection on fetal growth is milder than the effect on prematurity; (b) SGA represents fetal compromise resulting from infection that is insufficient to trigger early parturition, but may result in the delayed observation of growth restriction (i.e., the observation in the widespread activity period may be the cumulative effect of previous periods). Moreover, in the vaccinated group, the birth weight distribution in the pre-influenza period was different from the distribution in the period of widespread activity (see Text S1). However, the difference in mean birth weights (in the vaccinated group) between these two periods was not statistically significant (p = 0.74). Since the ostensible increase in birth weight in the widespread activity period compared to the pre-influenza period in the vaccinated group cannot easily be explained by vaccine action, this difference—although non-significant—may suggest confounding vis-à-vis the birth weight outcome. This study has a few limitations and strengths. Although we assessed and adjusted for many covariates, like any observational study, there is a possibility of residual confounding and selection bias. Moreover, data on influenza infection during pregnancy were not included in the PRAMS dataset. Although the primary explanation of the effects of influenza immunization in pregnancy on birth outcomes is through prevention of infection, having influenza infection data would have provided additional support for our findings. Another issue is that the information regarding maternal influenza immunization was based on recall and could be susceptible to information bias. However, the vaccination rates in our study are similar to the rates computed by other authors for Georgia, and to the United States national level coverage estimated by the National Health Interview Survey [30],[31]. The PRAMS dataset does not contain information regarding the precise trimester of vaccination. Therefore, the effect of vaccination in a specific trimester could not be evaluated. Moreover, it is possible that mothers of premature infants had less time to receive influenza vaccine than mothers of term infants (i.e., reverse causality). On the other hand, since this was a population-based study with a sampling strategy aimed at producing representative estimates, the temporal distribution of influenza vaccination in pregnancy would be similar to that of the general population, hence adding to the generalizability of our findings. The results of this study, nevertheless, need to be replicated in other populations as it is plausible that the impact of vaccines on birth outcomes would vary with the underlying influenza epidemiology and demographic characteristics. Supporting Information Text S1 Impact of maternal influenza immunization on likelihood of prematurity and SGA births. (0.21 MB DOC) Click here for additional data file.

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Stillbirth: Case definition and guidelines for data collection, analysis, and presentation of maternal immunization safety data☆

Fernanda Tavares Da Silva, Bernard Gonik, Mark McMillan … (2016)

1 Preamble 1.1 Need for developing case definitions and guidelines for data collection, analysis, and presentation for stillbirth as an adverse event following immunization during pregnancy One of the most common adverse pregnancy outcomes is the death of the fetus. Fetal death has a great number of different and legally mandated definitions and particularly, different reporting requirements among different countries and states, which sometimes use different parameters, including birth weight, body length and/or the clinical estimate of gestational age thresholds [1]. Miscarriage (spontaneous abortion) and stillbirth are two general terms describing the death of the fetus, but they refer to losses that occur at different times during pregnancy. The distinction of these definitions affects the prospects for their accurate recording in vital registration systems or national stillbirth registries, community and hospital surveys, clinical research studies, together with those for measurements and comparisons. There is no universally accepted definition when a fetal death is called a stillbirth vs. spontaneous abortion; the reporting policies in the different countries and within the states of a same country are not uniformly followed and there are also differences in terms of how the gestational age is assessed and interpreted [1], [2], [3], [4]. The various definitions used therefore pose a methodological difficulty when attempting to interpret and accurately compare stillbirth rates and associated risk factors. It is therefore necessary to reach a consensus on the definition and classification for the adverse events in pregnancy data to be comparable as well as steps toward a more comprehensive evaluation of stillbirth. Based on the WHO definition of third-trimester stillbirth used for international comparability, i.e. dead fetus of 1000 g or more at birth, or after 28 completed weeks of gestation, or attainment of at least 35 cm crown-heel length (see Table 1), at least 2.65 million cases of annual stillbirths were calculated worldwide in 2008, with 1.2 million of these fetal deaths occurring intrapartum [5], [6], [7]. The reported incidence of stillbirth varies significantly between studies from different countries and depending on the definitions used, but generally ranges from 3.1 to 6.2/1000 births or 1 in 160 deliveries [2], [8], [9]. The large majority of stillbirths (∼98%) occur in low/middle-income countries [1], [6], [7], [10], [11], [12]. With improvement in prenatal care, some of these deaths can be preventable. It is a fact that the overall incidence of stillbirth has declined overtime in developed countries by implementing appropriate healthcare policies for handling high-risk pregnant women. In low/middle-income countries, prevalence rates can be however inaccurate due to underreporting and documentation (e.g. home delivery) and reliable data are often difficult to obtain [10], [13], [14], [15], [16], [17]. 1.1.1 Causes and risk factors of stillbirth The cause of the death of a fetus is often unknown, but can be attributable to various origins [2], [18], [19], [20], [21], [22], [23], [24], [25], [26]. It is important to recognize that there is a distinction between the underlying cause of the death (the disease process), the mode of death (for example asphyxia) and the classification of the death (e.g. growth restriction). Causes of stillbirth may also differ at different gestational ages. A stillbirth of unknown cause is one that cannot be explained by any identifiable cause. The prevalence of stillbirths due to unknown causes varies from 25 to 60% of all fetal deaths, depending on the classification systems and evaluation of the deadborn fetus, e.g. the cause of death of the fetus who is small for gestational age can be attributed to the fetal growth restriction in some systems, but others consider it inexplicable if the underlying cause of the growth restriction is unknown [26], [27].The proportion of unclassified stillbirths can be significantly reduced with systems that use customized weight-for-gestational-age charts, such as the relevant condition at death (ReCoDe) system [22], or with systems that capture multiple and/or sequential contributing factors, such as Tulip, Perinatal Society of Australia and New Zealand – Perinatal Death Classification (PSANZ-PDC) or Causes Of Death and Associated Conditions (CODAC) [28]; moreover, stillbirth rates may differ when there is association with underlying determinants, for example, a lower risk of stillbirth is observed in a small for gestational age fetus if the mother is of short stature and has a multiple gestation [29]. Traditionally, the causes of stillbirth have been differentiated in maternal, fetal, placental and external factors. The most commonly quoted causes in the literature are as follows: - Maternal causes: Maternal infection is one of the most important causes for stillbirth [20]. Common ascending infections (with or without membrane rupture) are due to Escherichia coli, Klebsiella, Group B Streptococcus, Enterococcus, Mycoplasma/Ureaplasma, Haemophilus influenzae and Chlamydia [30], [31]. In developing countries, other infectious agents can also be considered, e.g. malaria, syphilis and HIV [5]. One database cohort study conducted in England assessing viral infections as a cause of fetal loss in data from 1988 to 2008 concluded that more than one-third (37%) of the viral-attributed fetal deaths occurred antepartum, from parvovirus (63%) or cytomegalovirus (33%) [32]. Diabetes mellitus, thyroid abnormalities, hypertensive disorders, systemic lupus erythematosus, cholestasis of the pregnancy, renal disease, sickle-cell disease and other maternal medical conditions are also causes for stillbirth [2]. Anemia and nutritional deficiencies in the mother, common in low/middle-income countries, have been long debated to be also a cause of stillbirths or other adverse pregnancy outcomes [5]. In contrast, a high first hemoglobin measurement in early pregnancy has been shown to be associated with an almost 2-fold increase in risk of stillbirth [33]. - Fetal causes: Among these, poor fetal growth or intrauterine fetal growth restriction (IUGR) is considered one of the most frequent causes of stillbirth. Presumably, the growth restriction is due to a placental dysfunction which may be related to numerous maternal diseases or infections described above [34], [35], [36]. Other cited causes are: multiple gestation, congenital anomalies, genetic abnormalities, fetal infection, and post maturity [19], [20], [37], [38]. The most common genetic etiology for stillbirth is due to karyotype abnormalities, however many stillborn fetuses with normal karyotypes also have genetic abnormalities [39]. - Placental causes include placental abruption, premature rupture of membranes, vasa previa, chorioamnionitis, vascular malformations and umbilical cord accidents such as knots or abnormal placement [21], [40]. - External causes: Some common examples are: antepartum mother's injuries/trauma or delivery/labor incidents such as birth asphyxia and obstetric trauma. Where modern obstetric care is not available, deaths can be frequent. It is estimated that in developing countries asphyxia causes around seven deaths per 1000 births, whereas in developed countries this proportion is less than one death per 1000 births (5, 20). Availability of good delivery facilities also affects the pregnancy outcomes, as it was observed in a study that availability of skilled attendant during delivery (one of the factors in delivery process) lead to decline in stillbirth rate, however the authors concluded that this needs further analysis [41]. There are many known epidemiological risk factors for stillbirth. Systematic reviews have confirmed very early or advanced maternal age as risk factors. Moreover, nulliparous women have a higher risk of stillbirth than multiparous women across all ages. Of these, nulliparous women aged 35 years and older have been shown to have a 3.3-fold increase in the risk of unexplained fetal death compared with women younger than 35 years of age. The odds ratio for maternal age 40 years and older is 3.7 [42], [43]. Other factors associated with increased risk of stillbirth are: body mass index (BMI) ≥30, smoking (which includes active and passive smoking), substance abuse (especially cocaine, but also cannabis and alcohol), and multifetal gestation, with significantly higher rates of stillbirth observed in monochorionic twins than in dichorionic [2], [44], [45], [46], [47], [48]. One study showed that maternal overweight (i.e. Body Mass Index ≥25) increases the risk of antepartum stillbirth, especially term antepartum stillbirth, whereas weight gain per se during pregnancy was not associated with the risk of fetal death [49]. Women with a previous stillbirth are well known to be at 5- to 10-fold increased risk of recurrence for stillbirth. Also AB blood group appeared to be preferentially associated with stillbirth before 24 completed weeks of gestation [50]. Globally, black women have 2.2 fold increased risk of stillbirth compared to white women [51]. The black/white disparity in stillbirth hazard at 20–23 weeks is 2.75, decreasing to 1.57 at 39–40 weeks. Medical, pregnancy and labor complications account for 30% of the risk of stillbirth in Blacks and 20% in Whites and Hispanics. Trends have also show that stillbirth rates are slightly higher among male compared to female fetuses [51]. Worldwide, 67% of stillbirths occur in rural families, where skilled birth attendance and cesarean sections are much lower than that for urban births [52]. 1.1.2 Diagnosis of stillbirth There are diverse existing methods/criteria for identifying stillbirths: - Clinical signs: They are those that reflect absence of fetal vitality, either antepartum or by direct examination postpartum: a. Antepartum: mother does not feel fetal activity; the maternal weight is maintained or decreased, the fundal height stops increasing or even decreases if the reabsorption of amniotic fluid occurs. At the medical examination, intrauterine ascertainment of death is confirmed by the absence of fetal heart tones before delivery by auscultation methods (e.g. using Pinard horn, handheld Doppler, fetoscopy, doptone or stethoscope) or after electronic fetal heart monitoring/non-stress test. Auscultation of the fetal heart tones by Pinard horn, stethoscope or even handheld Doppler is insufficiently sensitive for a confirmatory diagnosis. In a series of 70 late pregnancies in which fetal heart tones were inaudible on auscultation, 22 were found to have viable fetuses [53]. Auscultation of fetal heart tones or misinterpreted experiences of fetal movements can also give false reassurance [54]; maternal pelvic blood flow can result in an apparently normal, but low, fetal heart rate pattern with handheld Doppler. The sign of Boero is the clear auscultation of maternal aortic beats due to the eventual absorption of amniotic fluid. The fetus becomes less perceptible to palpation as maceration progresses. The sign of Negri is the crackling or crepitation of the fetal head during its palpation. Sometimes vaginal dark blood loss is noted, there might be increased consistency of cervix because of the hormonal decline and also, appearance of secretion of colostrum in the mammary glands, although these signs are not specific. b. Postpartum ascertainment of death is confirmed by Apgar scores of 0 at 1 and 5 min, absence of vital signs including the documentation of no heart rate and respirations, absence of pulsation of the umbilical cord, and no definitive movement of voluntary muscles. Heartbeats are to be distinguished from transient cardiac contractions; respirations are to be distinguished from transient fleeting respiratory efforts or gasps. Macroscopic appearance of the fetus may show signs of maceration and the level of maceration can determine time of death. The earliest sign of macerations are seen in the skin 4–6 h after intrauterine death; desquamated skin measuring 1 cm or more in diameter and red or brown discoloration of the umbilical cord correlate with fetal death 6 or more hours before birth; desquamation involving the skin of face, back or abdomen with 12 or more hours; desquamation of 5% or more of the body surface with 18 or more hours; moderate to severe desquamation, brown skin discoloration of the abdomen with 24 or more hours and mummification is seen in fetuses who died 2 or more weeks before birth [55]. - Radiologic studies: In addition to the above clinical signs, other secondary features might be seen antepartum if eventually imaging techniques such as X-ray radiography are used: collapse of the fetal skull with overlapping bones due to liquefaction of the brain, hydrops, flattening of the cranial cavity, head asymmetry, fall of the mandible (sign of open mouth), or fetal bunching due to a loss of the normal curvature of the spine due to macerating spinal ligaments, which may appear completely collapsed resulting in unrecognizable fetal mass. In addition, there might be also intra-fetal gas within the heart, blood vessels and joints or a translucent peri-cranial halo due to accumulation of fluid in the subcutaneous tissue; when the image is complete gives double cranial halo called “holy crown” [56], [57], [58], [59], [60]. - Ultrasound (US): real-time ultrasonography is the gold standard for the accurate diagnosis of stillbirth antepartum. The advantage of this method lies in the precocity with which the diagnosis can be made, because real time ultrasound allows direct visualization of the fetal heart and the absence of cardiac activity, absence of aortic activity and the absence of movements of the body or limbs of the fetus (to be distinguished from periods of fetal physiological rest). Imaging can be technically difficult, particularly in the presence of maternal obesity, abdominal scars and oligohydramnios, but views can often be improved with new generation US or with color Doppler of the fetal heart and umbilical cord. Other secondary signs that can be seen at US are: the accumulation of fluid in the subcutaneous tissue (anasarca), pleural and peritoneal effusion, and the loss of the definition of fetal structures, which often reflect maceration. 1.1.3 Stillbirth following immunization Decades of vaccine use and evidence from clinical trial data and observational studies have shown the safety of traditional non-live vaccines (e.g. tetanus, pertussis or influenza) during pregnancy. Currently inactivated influenza virus, and pertussis vaccines are recommended for use during pregnancy in many parts of the world. Pertussis vaccines are generally available as part of combined vaccines such as tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines, or Tdap with inactivated poliomyelitis virus vaccines (Tdap-IPV). Systematic reviews for inactivated influenza virus vaccines have concluded that the vaccine is not associated with an increased risk of stillbirth [61], [65], [67], [70]. One review paper describes that influenza vaccination might decrease the incidence of adverse outcomes of pregnancy such as stillbirth, as a result of the prevention of influenza infection related inflammation [61]. These findings were generalizable to monovalent influenza A (H1N1) vaccines, with the majority of evidence obtained for women immunized during their 2nd or 3rd trimester of pregnancy [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75]. Fewer studies have examined stillbirth following Tdap administration during pregnancy, including two large retrospective studies completed in the US and the UK where stillbirth rates were compared to matched unvaccinated pregnant women and the authors concluded that the vaccine is not associated with an increased risk of stillbirth [76], [77], [78]. Remaining stillbirth data on pertussis containing vaccines comes from adverse event registries and small studies having similar findings [79], [80], [81]. Tetanus toxoid (TT) monovalent and tetanus toxoid reduced diphtheria (Td) vaccines are recommended for use in pregnancy in some countries where elimination of maternal and neonatal tetanus remains a priority [82]. Most live vaccines are contraindicated or not recommended for use during pregnancy [83]. Many of the live attenuated vaccines also come with a recommendation to avoid pregnancy for the month following immunization. This is due to the theoretical risk of transmission of the virus through the placenta to the fetus [82], [83]. Stillbirth data on many of these vaccines is derived from the follow up of women inadvertently immunized during early pregnancy. Rubella and varicella are of specific interest due to the potentially severe consequences of wild-type infection in susceptible pregnant women, which can lead to congenital rubella syndrome (CRS), and congenital varicella syndrome. Much of the research investigating the safety of the MMR and varicella vaccine has therefore looked at congenital anomalies outcomes. However, there is some data available on stillbirth rates following immunization showing no safety concerns [84], [85], [86]. A meta-analysis of eleven studies reported data on stillbirth (defined as fetal death ≥20 weeks of gestation) and found that the smallpox vaccination is not associated with an increased risk of stillbirth, pooled RR 1.03 (95% CI: 0.75–1.40) [87]. A study conducted in Finland during a mass oral poliovirus immunization campaign conducted between 1984 and 1986 reported stillbirth rates among women who were pregnant during the period of vaccination and whose infants were delivered at the three major hospitals in the Helsinki area between 0.4% and 0.6%, depending on their trimester of exposure, compared with 0.45% in the reference cohort [88]. 1.2 Methods for the development of the case definition and guidelines for data collection, analysis, and presentation for stillbirth as an adverse events following immunization during pregnancy Following the process described in the overview paper [89] as well as on the Brighton Collaboration Website http://www.brightoncollaboration.org/internet/en/index/process.html, the Brighton Collaboration Stillbirth Working Group was formed in 2015 and included members of clinical, academic, public health, research and industry background. The composition of the working and reference group as well as results of the web-based survey completed by the reference group with subsequent discussions in the working group can be viewed at: http://www.brightoncollaboration.org/internet/en/index/working_groups.html. To guide the decision-making for the case definition and guidelines, a literature search was performed using Medline, Embase and the Cochrane Libraries, including the terms stillbirth, stillborn, intrauterine death, fetal demise, fetal mortality, fetal death, dead-born, fetal loss, intrapartum death, antepartum death, perinatal audit, perinatal death, perinatal mortality, pregnancy loss and vaccine, immunization and vaccination. Exhaustive search strategies were implemented using appropriate key words, accepted MeSH words, and combinations thereof. All abstracts were screened for possible reports of stillbirth following immunization. Searches were restricted to references in English, published since 1970 and involving only human subjects. Multiple general medical, pediatric, obstetrics and infectious disease text books were also searched. The search and screening resulted in the identification of articles with potentially relevant material for further evaluation. This literature provided several different general definitions for stillbirth, its epidemiology, numerous descriptions for stillbirth causes and/or risk factors and the diagnostic criteria put forth. Most publications addressing stillbirth following immunization were case reports of single cases or case series describing various pregnancy outcomes, for which terminology was very inconsistent and very few used case definitions. 1.3 Rationale for selected decisions about the case definition of stillbirth as an adverse event following immunization during pregnancy 1.3.1 The term stillbirth In general, stillbirth is defined as a fetus with no signs of life prior to the complete expulsion or extraction from its mother, and after a pre-defined duration of gestation; after delivery, it is confirmed that the fetus does not show any evidence of life, and cannot be resuscitated. The basic WHO definition for “stillbirth” is the intrauterine death of the fetus at any time during pregnancy [90]. However, for practical purposes, legal definitions usually require reportable fetal deaths to attain a gestational age (for stillbirth the GA generally considered is between 20 and 28 weeks) or a birth weight (generally between 350 and 1000 g). The minimum gestational age cut-off defining stillbirth vs. miscarriage generally varies from 20 to 28 weeks of gestation based on standards of fetal viability across countries, based on available medical care and health infrastructure [6]. In most high income and some middle income countries, thresholds vary from 18 to 22 weeks while in low income areas/countries thresholds are higher, up to 28 weeks [18]. The definition and ascertainment could be therefore different in developing/low-middle income vs. developed/high income countries. For international comparability, the WHO recommends using the cut-off of 1000 g or more at birth (if available), or after 28 completed weeks of gestation, or attainment of at least 35 cm crown-heel length [5]. In the United States, there are eight different definitions by combinations of gestational age and weight, and at least as many in Europe [91], [92]. In general, stillbirths are classified according to the gestational age, and are typically divided into early stillbirths (from 20 to 28 weeks gestation) and late stillbirths (after 28 weeks gestation). This division is based on those stillbirths that are difficult to prevent compared with those that are potentially preventable (i.e. late stillbirths). Stillbirths are also classified by whether death occurred before or after the onset of labor, referred as antepartum stillbirth and intrapartum stillbirth, respectively. Despite all these sub classifications, the primary method for classification of stillbirth is according to the presumed cause [93]. In addition, there are over 35 classification systems to define stillbirth or perinatal death used in different countries around the world [18], [42], [94], [95], [96], [97], the most recent are the suggested ReCoDe [98], the modified Whitfield-Australia/New Zealand Classifications [99], and the World Health Organization's International Classification of Disease (ICD-10) systems [90] (see Table 1). In this article, we will use the general term stillbirth, to refer to fetal deaths occurring after a pre-defined duration of gestation, in accordance with selected/preferred definitions used to fulfill the research needs in a given setting or to fit a reporting purpose, regardless of whether the death of the fetus could have occurred in utero (antepartum) or at the time of delivery (intrapartum). The case definition presented in this document does not prescribe the use of a specific gestational age cut off or combination of gestational age and/or weight and size assessments to differentiate between miscarriage and stillbirth, but rather considers the currently utilized definitions of stillbirth worldwide and the importance of having a definition that is applicable in different clinical settings and environments. The variability in the definition of stillbirth stems from variability in viability cut offs in different settings, available resources, local practices, cultural influences, legal implications, and local and international reporting requirements. The WHO definitions take these elements in consideration and are widely used [5]. The working group emphasizes the importance of consistently and systematically capturing all cases of stillbirth in clinical trials assessing the safety of vaccines given during pregnancy. The study protocol should clearly describe the selected definition of a case of stillbirth and utilize it consistently throughout all study sites for data collection and analysis to ensure data comparability and a better understanding of this adverse pregnancy outcome. The working group recommends to make explicit a working definition of stillbirth to capture all events, for example “deadborn fetus at or after 22 completed weeks of gestation” and to consider categorization into other subgroups based on the goals of the study and relevant analyses, for example “early (after 22 weeks)” vs. “late (after 28 weeks)” stillbirth. The working group suggests that differentiation of antepartum and intrapartum stillbirth is relevant, whenever possible, to understand potential underlying etiologies and mechanisms leading to the event. However, when this differentiation is not possible, the outcome will be recorded as a stillbirth, defined as the delivery of a fetus with no signs of life and assessed by the attendant and/or investigator to be within the gestational age consistent with the selected cut off in the definition. 1.3.2 Related term(s) of stillbirth There are different terms used within this context. Those terms are: stillborn, intrauterine death, fetal/fetal demise, fetal/fetal mortality, fetal/fetal death, dead-born and fetal/fetal loss. Other less specific terms are sometimes used as well: intrapartum death, antepartum death, perinatal audit, perinatal death, perinatal mortality, pregnancy loss. 1.3.3 Formulating a case definition that reflects diagnostic certainty: weighing specificity vs. sensitivity It needs to be re-emphasized that the grading of definition levels is entirely about diagnostic certainty, not clinical severity or causality of an event. Detailed information about the severity of the event should additionally always be recorded, as specified by the data collection guidelines. The number of symptoms and/or signs that will be documented for each case may vary considerably. The case definition has been formulated such that the Level 1 definition is highly specific for the condition. As maximum specificity normally implies a loss of sensitivity, two additional diagnostic levels have been included in the definition, offering a stepwise increase of sensitivity from Level One to Level Three, while retaining an acceptable level of specificity at all levels. In this way it is hoped that all possible cases of stillbirth can be captured. 1.3.4 Rationale for individual criteria or decision made related to the case definition There is a need to consider data sources and availability of existing data when defining pregnancy outcomes in research. The interpretation of data is difficult when cut-off values of the definitions differ, and it is also problematic in multiple gestations with both live and dead siblings. Flexibility and alignment with existing definitions where studies/surveillance are performed are necessary to ensure comparability and interpretation of data. Another consideration for case inclusion criteria are deliveries that occur outside of the hospital setting (e.g. home delivery), in the absence of medical personnel, and then are presented to the hospital as a death. Sometimes these data are not made available. In addition, under these circumstances, it is not always possible to determine whether the fetus was stillborn, or if the fetus lived for any length of time. Although very few data may be available to determine a cause of stillbirth, the assessment of the cause includes the macroscopic examination of the fetus for congenital malformations, and if available, autopsy and karyotype; cord and placental examination and pathology, documenting antepartum events such as maternal factors, fetal factors (e.g. intrauterine growth restriction), external factors (e.g. trauma), and peri-partum events such as preterm premature rupture of membranes (PPROM), infection, abruption, cord events, laboratory findings, etc. These data (i.e. pathology and laboratory findings) may not be included in the case definition of stillbirth, but are recommended to be obtained in the data analysis to ascertain the possible cause. 1.3.5 Determination of the gestational age at death The gestational age (GA) seems to be the most widely used criterion to define stillbirth. Several algorithms are available for assessment of gestational age at death based on available clinical data and simple examination of the infant after delivery [100]. These may be used when other means of determining gestational age are unavailable. The most common method for the ascertainment of estimated Gestational Age (GA) at time of fetal death is based on the Last Menstrual Period (LMP): The duration of gestation is measured from the first day of the last normal menstrual period. Gestational age is expressed in weeks. Other methods include measurement of fundal height, biometric parameters of the fetus which can be determined antepartum by US or by other less accurate measurement methods post-partum, such as fetal crown-to-heel length or foot length [100], [101], or the direct observation of the fetal maturation, if no measurement methods are available. Different scoring systems are also used to estimate the gestational age after birth but all involve neurologic reflexes and/or physical characteristics such as skin and cartilage changes, however all these neurologic measures are not possible for stillbirths and skin and cartilage changes are unreliable if there is maceration. A proposed algorithm for estimating GA for studies in various community settings is presented in a related manuscript (Preterm Birth Definition and GA assessment algorithm – available at http://www.brightoncollaboration.org). This algorithm presents criteria based on different parameters that could be available, including LMP and different measurement methods including ultrasound scan, or stillborn assessment immediately after birth. In obese women, or when uterine anatomy is otherwise compromised (e.g. multiple fibroids), clinician determination of GA by “best assessment” is to be used. Although GA is determined antepartum, findings must be consistent with immediate and simple examination of the stillborn fetus after delivery, otherwise a post hoc determination is needed. Assessment of gestational age of the fetus is a key component of the case definition of stillbirth. The working group recommends the use of the GA assessment algorithm in the “Preterm Birth” Brighton Collaboration Case Definition for the assessment of gestational age in the mother or fetus. 1.3.6 Timing post immunization in pregnancy We postulate that a definition designed to be a suitable tool for testing causal relationships requires ascertainment of the outcome (e.g. stillbirth) independent from the exposure (e.g. immunizations). Further, stillbirth often occurs outside the controlled setting of a clinical trial or hospital. In some settings it may be impossible to obtain a clear timeline of the event, particularly in less developed or rural settings and in the observational research setting via retrospective medical record reviews. In order to avoid selecting against such cases, the Brighton Collaboration case definition avoids setting arbitrary time frames. An exact time-frame should not be offered since it would have to refer to a wide range of signs and symptoms without a scientific evidence base. Using an arbitrarily restrictive set point might bias future data collection unnecessarily. Therefore, to avoid selection bias, a restrictive time interval from immunization to onset of stillbirth should not be an integral part of such a definition, but is recommended to be used in the data analysis to examine factors such as temporal clusters. Where feasible, details of this interval should be assessed and reported as described in the data collection guidelines (see guideline 34, section 3.2). 1.4 Guidelines for data collection, analysis and presentation As mentioned in the overview paper, the case definition is accompanied by guidelines which are structured according to the steps of conducting a clinical trial, i.e. data collection, analysis and presentation. Neither case definition nor guidelines are intended to guide or establish criteria for management of ill infants, children, or adults. Both were developed to improve data comparability. 1.5 Periodic review Similar to all Brighton Collaboration case definitions and guidelines, review of the definition with its guidelines is planned on a regular basis (i.e. every three to five years) or more often if needed. 2 Case definition of stillbirth2 2.1 Stillbirth Is a fetal death occurring before birth after a selected, pre-defined duration of gestation (see Table 1). The death of the fetus could have occurred before the onset of labor3 (antepartum) or at the time of delivery (intrapartum). For all levels of diagnostic certainty, the definition of stillbirth must include: - Determination of absence of signs of life4 in the fetus or newborn AND - Determination of fetal/newborn gestational age through maternal information or through fetal/newborn evaluation (see Preterm Birth Definition – Assessment of Gestational Age) 2.1.1 Antepartum stillbirth Antepartum stillbirth is defined as fetal death occurring during pregnancy and prior to delivery, before the onset of labor. It is usually diagnosed prior to delivery, but may not be diagnosed until after the infant is delivered. The infant is born without signs of life.3 2.1.2 Intrapartum stillbirth Intrapartum stillbirth is defined as fetal death occurring after the onset of labor and prior to delivery. The infant is born without signs of life.3 Documentation of a live fetus prior to or at the onset of labor exists. Additional findings that might be helpful to differentiate between Antepartum and Intrapartum Stillbirth at the time of delivery: • Physical Examination: Fetuses who died antepartum can have skin changes consistent with maceration, tissue injury, meconium staining, and edema. • Laboratory/pathology: Autopsy examination of the fetus and/or the placenta. 2.2 Stillbirth ascertainment of levels of certainty 2.2.1 Antepartum Stillbirth Fetal death occurs prior to the evidence of labor. Level 1 • Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical cord pulse, no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined by physical examination after delivery (with or without electronic monitoring of heart rate, respiratory rate, and pulse oximetry). AND • Prenatal ultrasound examination documenting lack of fetal cardiac activity or movement before the onset of labor. OR • Auscultation for fetal heart tones (using electronic devices or non-electronic devices) documenting lack of fetal heartbeat. AND • Maternal report of lack of fetal movement for 24 h or more. OR • Maternal physical examination confirming lack of fetal movement. OR • Radiology findings consistent with intrauterine fetal death. AND • Attended delivery followed by fetal physical examination after birth consistent with antepartum death, by obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, or pathologist. In the setting where access to a specialist is not feasible, diagnosis by a health care provider trained or experienced to make the diagnosis is acceptable (e.g. general practice physician, mid-wife, nurse practitioner, a physician's assistant or other qualified trained practitioner). OR • Fetal/placental pathology report consistent with antepartum death. AND • Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or fetal parameters (Level 1 or 2 in GA assessment algorithm). Level 2 • Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical cord pulse, no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined physical examination after delivery. AND • Maternal report of lack of fetal movement for 24 h or more. OR • Maternal physical examination confirming lack of fetal movement. OR • Auscultation for fetal heart tones (using electronic or non-electronic devices) documenting lack of fetal heartbeat. AND • Attended delivery followed by physical examination after birth consistent with antepartum death, by specialist or qualified trained practitioner appropriate to the health care setting. OR • Fetal/placental pathology report consistent with antepartum death. AND • Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or fetal parameters (Level 1–2 in GA assessment algorithm). Level 3 • Delivery of an infant reported to have no of signs of life at birth (No spontaneous movements, no umbilical cord pulse, no heartbeat, no cry or spontaneous respirations, no chest movement, and whole body cyanosis). AND • Maternal report of lack of fetal movement for 24 h or more prior to delivery. OR • Report of auscultation for fetal heart tones (using electronic or non-electronic devices) documenting lack of fetal heartbeat. AND • Non-attended delivery followed by physical examination of the fetus after birth consistent with antepartum death by a health care professional appropriate to the level of standard of care in the health care setting. OR • Verbal history by a trained health care provider, non-medical witness or the mother of a fetus born with no signs of life or unresponsive to resuscitation efforts immediately after birth and with physical features consistent with antepartum death. AND • Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or fetal parameters (Level 2–3 in GA assessment algorithm). Level 4 • Report of stillbirth but fetus is not available for physical examination after birth (no objective assessment can be made). • Maternal information insufficient to assess gestational age. 2.2.2 Intrapartum stillbirth Fetal death occurs during labor and before delivery Level 1 • Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, no umbilical cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min. • Determination of the absence of signs of life is made by physical examination after delivery, with or without electronic monitoring of heart rate, respiratory rate, and pulse oximetry. AND • Evidence of live fetus prior to onset of labor (documentation of fetal movement and of fetal heart tones by ultrasound prior to onset of labor) (Note: in the absence of evidence of a live fetus prior to the onset of labor, the fetal death should be reported as a stillbirth or an antepartum stillbirth). AND • Attended delivery followed by physical examination after birth consistent with intrapartum death by obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, pathologist. In the setting where access to a specialist is not feasible, diagnosis by a health care provider trained or experienced to make the diagnosis is acceptable (e.g. general practice physician, mid-wife, or other qualified trained practitioner). AND • Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or fetal-neonatal parameters (Level 1 in GA assessment algorithm) Level 2 • Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, no umbilical cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min. • Determination of the absence of signs of life is made by physical examination after delivery, with or without electronic monitoring of heart rate, respiratory rate, and pulse oximetry OR documentation of lack of response to resuscitation efforts. AND • Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset of labor and documentation of fetal heart tones by auscultation or hand held Doppler) (Note: in the absence of evidence of a live fetus prior to the onset of labor, the fetal death should be reported as a stillbirth or an antepartum stillbirth). AND • Attended delivery followed by physical examination after birth consistent with intrapartum death by a health care professional appropriate to the level of standard of care in the health care setting. AND • Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or fetal parameters (Level 1–2 in GA assessment algorithm). Level 3 • Delivery of an infant reported to have no of signs of life at birth, including: No spontaneous movements, no umbilical cord pulse, no heartbeat, no cry, no spontaneous respirations or chest movement, and whole body cyanosis. AND • Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset of labor OR auscultation of fetal heart tones) (Note: in the absence of evidence of a live fetus prior to the onset of labor, the fetal death should be reported as a stillbirth or an antepartum stillbirth). AND • Non-attended delivery followed by physical examination of the fetus after birth consistent with intrapartum death by a health care professional appropriate to the level of standard of care in the health care setting OR verbal history by a trained health care provider, non-medical witness or the mother of a fetus born with no signs of life or unresponsive to resuscitation efforts immediately after birth. AND • Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or fetal parameters (Level 2–3 in GA assessment algorithm). Level 4 • Report of stillbirth but fetus is not available for physical examination after birth (no objective assessment can be made). • Maternal information insufficient to assess gestational age. 3 Guidelines for data collection, analysis and presentation of stillbirth It was the consensus of the Brighton Collaboration Stillbirth Working Group to recommend the following guidelines to enable meaningful and standardized collection, analysis, and presentation of information about stillbirth. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographical region, and whether the source of information is a prospective clinical trial, a post-marketing surveillance or epidemiological study, or an individual report of stillbirth. Also, these guidelines have been developed by this working group for guidance only, and are not to be considered a mandatory requirement for data collection, analysis, or presentation. 3.1 Data collection These guidelines represent a desirable standard for the collection of available pregnancy outcome data following immunization to allow comparability. The guidelines are not intended to guide the primary reporting of stillbirths to a surveillance system. Investigators developing a data collection tool based on these data collection guidelines also need to refer to the criteria in the case definition. Guidelines 1–43 below have been developed to address data elements for the collection of adverse event information as specified in general drug safety guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [107], and the form for reporting of drug adverse events by the Council for International Organizations of Medical Sciences [108]. These data elements include an identifiable reporter and patient, one or more prior immunizations, and a detailed description of the adverse event, in this case, of stillbirth following immunization. The additional guidelines have been developed as guidance for the collection of additional information to allow for a more comprehensive understanding of stillbirth following immunization. 3.1.1 Source of information/reporter For all cases and/or all study participants, as appropriate, the following information should be recorded: (1) Date of report. (2) Name and contact information of person reporting5 and/or diagnosing the stillbirth as specified by country-specific data protection law. (3) Name and contact information of the investigator responsible for the subject, as applicable. (4) Relation to the patient (e.g. immunizer [clinician, nurse], family member [indicate relationship], other). 3.1.2 Vaccinee/control 3.1.2.1 Demographics For all cases and/or all study participants (i.e. pregnant women and newborn), as appropriate, the following information should be recorded: (5) Case/study participant identifiers (e.g. participant's first name initial followed by last name initial) or code (or in accordance with country-specific data protection laws). (6) Participant's age at enrolment, race/ethnicity and gestational age at the time of enrolment. (7) For dead newborn: Gestational age and birth weight/height. 3.1.2.2 Clinical and immunization history For all cases and/or all study participants, as appropriate, the following information should be recorded: (8) Past medical history, including hospitalizations, underlying diseases/disorders, pre-immunization signs and symptoms including identification of indicators for, or the absence of, a history of allergy to vaccines, vaccine components or medications; food allergy; allergic rhinitis; eczema; asthma. (9) Any medication history (including treatment for the event described) prior to, during, and after immunization including prescription and non-prescription medication as well as medication or treatment with long half-life or long term effect (e.g. immunoglobulins, blood transfusion and immune-suppressants) or substance abuse (e.g. narcotics or other recreational drug, alcohol or smoking). (10) Immunization history (i.e. previous immunizations and any adverse event following immunization (AEFI), in particular occurrence of stillbirth after a previous immunization. (11) Medical confirmation of live fetus prior to maternal immunization. 3.1.3 Details of the immunization For all cases and/or all study participants, as appropriate, the following information should be recorded: (12) Date and time of maternal immunization(s). (13) Description of vaccine(s) (name of vaccine, manufacturer, lot number, dose (e.g. 0.25 mL, 0.5 mL, multi-dose vial, etc.), number of dose if part of a series of immunizations against the same disease and vaccine diluent if separate from the vaccine container itself). (14) The anatomical sites (including left or right side) of all immunizations (e.g. vaccine A in proximal left lateral thigh, vaccine B in left deltoid). (15) Route and method of administration (e.g. intramuscular, intradermal, subcutaneous, and needle-free (including type and size), other injection devices). (16) Needle length and gauge. (17) Gestational age of the pregnancy at the time of immunization 3.1.4 The adverse event (18) For all cases at any level of diagnostic certainty and for reported events with insufficient evidence, the criteria fulfilled to meet the case definition should be recorded. Specifically document (if available): (19) Clinical description of signs and symptoms of stillbirth, and if there was medical confirmation of the event (i.e. patient seen by physician). (20) Date/time of onset,6 first observation7 and diagnosis8; as well as end of episode9 and final outcome,10 if appropriate (e.g. if the event no longer meets the case definition of stillbirth at the lowest level of the definition). For an event that meets the case definition of stillbirth, the end of episode is the same as date/time of onset, and the outcome is fatal (i.e. it results in death of the fetus). (21) Concurrent signs, symptoms, and diseases. (22) Pregnancy, labor and delivery details: • Pregnancy details: date of last normal menstrual period, ultrasound examinations, antenatal care visits, pregnancy-related illnesses and complications. • Labor and delivery details: for intrapartum fetal death specifically document (if available) mode of delivery and complications (e.g. fetal distress, antepartum/postpartum hemorrhage, assisted delivery, etc.). (23) Measurement/testing • Values and units of routinely measured parameters (e.g. temperature, blood pressure) – in particular those indicating the severity of the event; • Method of measurement (e.g. type of thermometer, oral or other route, duration of measurement, etc.); • Results of laboratory examinations, surgical and/or pathological findings and diagnoses if present. (24) Treatment given for stillbirth, especially specify what medications and dosing, as well as other interventions. (25) Outcome9 at last observation (e.g. for an event that meets the case definition of stillbirth, it results in death of the fetus). Add descriptions if antepartum/intrapartum or postpartum maternal death occurred. Also, for multiple gestation, if concomitant twin death occurred. (26) Objective clinical evidence supporting classification of the event as “serious”11 (i.e. results in death of the fetus). (27) Exposures other than the immunization before and after immunization (e.g. food, environmental) considered potentially relevant to the reported event. 3.1.5 Miscellaneous/general (28) The duration of follow-up reported during the surveillance period should be predefined likewise (in this case, birth or delivery). It should aim to continue to resolution of the event (i.e. the outcome of the pregnancy is captured). (29) Methods of data collection should be consistent within and between study groups, if applicable. (30) Follow-up of cases should attempt to verify and complete the information collected as outlined in data collection guidelines 1–27. (31) Investigators of patients with stillbirth should provide guidance to reporters to optimize the quality and completeness of information provided. (32) Reports of Stillbirth should be collected throughout the study period regardless of the time elapsed between immunization and the adverse event. If this is not feasible due to the study design, the study periods during which safety data are being collected should be clearly defined. 3.2 Data analysis The following guidelines represent a desirable standard for analysis of data on Stillbirth to allow for comparability of data, and are recommended as an addition to data analyzed for the specific study question and setting. (33) Reported events should be classified in one of the following five categories including the three levels of diagnostic certainty. Events that meet the case definition should be classified according to the levels of diagnostic certainty as specified in the case definition. Events that do not meet the case definition should be classified in the additional categories for analysis. Event classification in 5 categories 12 • Event meets case definition (1) Level 1: Criteria as specified in the Stillbirth case definition (2) Level 2: Criteria as specified in the Stillbirth case definition (3) Level 3: Criteria as specified in the Stillbirth case definition • Event does not meet case definition Additional categories for analysis (4) Reported stillbirth with insufficient evidence to meet the case definition13 (5) Not a case of stillbirth14 (34) The interval between immunization and reported stillbirth could be defined as the date/time of immunization (last vaccination) to the date/time of onset8 of the event, consistent with the definition. If few cases are reported, the concrete time course could be analyzed for each; for a large number of cases, data can be analyzed in the following increments for identification of temporal clusters: Subjects with Stillbirth by Interval to Presentation. Interval* Number (Percentage) ≤24 h after immunization 2–≤7 days after immunization 8–≤42 days after immunization >42 days after immunization Weekly unit increments thereafter Total (35) If more than one measurement of a particular criterion is taken and recorded, the value corresponding to the greatest magnitude of the adverse experience could be used as the basis for analysis. Analysis may also include other characteristics like qualitative patterns of criteria defining the event. (36) The distribution of data (as numerator and denominator data) could be analyzed in predefined increments (e.g. measured values, times), where applicable. Increments specified above should be used. When only a small number of cases is presented, the respective values or time course can be presented individually. (37) Data on stillbirth obtained from subjects receiving a vaccine should be compared with those obtained from an appropriately selected and documented control group(s) and whenever possible with background rates of the event in non-exposed populations. Data should be analyzed by study arm and dose where possible, e.g. in prospective clinical trials. 3.3 Data presentation These guidelines represent a desirable standard for the presentation and publication of data on stillbirth following immunization to allow for comparability of data, and are recommended as an addition to data presented for the specific study question and setting. Additionally, it is recommended to refer to existing general guidelines for the presentation and publication of randomized controlled trials, systematic reviews, and meta-analyses of observational studies in epidemiology (e.g. statements of Consolidated Standards of Reporting Trials (CONSORT), of Improving the quality of reports of meta-analyses of randomized controlled trials (QUORUM), and of Meta-analysis Of Observational Studies in Epidemiology (MOOSE), respectively) [109], [110], [111]. (38) All reported events of stillbirth should be presented according to the categories listed in guideline 33. (39) Data on possible stillbirth events should be presented in accordance with data collection guidelines 1–32 and data analysis guidelines 33–37. (40) Data should be presented with numerator and denominator (n/N) (and not only in percentages), if available.Although immunization safety surveillance systems denominator data are usually not readily available, attempts should be made to identify approximate denominators. The source of the denominator data should be reported and calculations of estimates be described (e.g. manufacturer data like total doses distributed, reporting through Ministry of Health, coverage/population based data, etc.). (41) The incidence of cases in the study population should be presented and clearly identified as such in the text. (42) If the distribution of data is skewed, median and inter-quartile range are usually the more appropriate statistical descriptors than a mean. However, the mean and standard deviation should also be provided. (43) Any publication of data on stillbirth should include a detailed description of the methods used for data collection and analysis as possible. It is essential to specify: • The study design; • The method, frequency and duration of monitoring for stillbirth; • The trial profile, indicating participant flow during a study including drop-outs and withdrawals to indicate the size and nature of the respective groups under investigation; • The type of surveillance (e.g. passive or active surveillance); • The characteristics of the surveillance system (e.g. population served, mode of report solicitation); • The search strategy in surveillance databases; • Comparison group(s), if used for analysis; • The instrument of data collection (e.g. standardized questionnaire, diary card, report form); • Whether the day of immunization was considered “day one” or “day zero” in the analysis; • Whether the date of onset8 and/or the date of first observation9 and/or the date of diagnosis10 was used for analysis; and • Use of this case definition for stillbirth, in the abstract or methods section of a publication.15

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Author and article information

Journal

Journal ID (nlm-ta): Hum Vaccin Immunother

Journal ID (iso-abbrev): Hum Vaccin Immunother

Journal ID (publisher-id): KHVI

Journal ID (publisher-id): khvi20

Title: Human Vaccines & Immunotherapeutics

Publisher: Taylor & Francis

ISSN (Print): 2164-5515

ISSN (Electronic): 2164-554X

Publication date Collection: 2019

Publication date (Electronic): 15 November 2018

Publication date PMC-release: 15 November 2018

Volume: 15

Issue: 3

Pages: 687-699

Affiliations

[a ]Department of Obstetrics and Gynaecology and Department of Infectious Diseases, Monash University and Alfred Health , Melbourne, Australia

[b ]Department of Obstetrics and Gynaecology and Department of Infectious Diseases, Monash University and Monash Health , Melbourne, Australia

[c ]National Centre for Immunisation Research and Surveillance, University of Sydney , Sydney, Australia

[d ]Department of Epidemiology and Infectious Diseases, Monash University and Alfred Health , Melbourne, Australia

Author notes

CONTACT Michelle L. Giles michelle.giles@ 123456monash.edu Department of Infectious Diseases, Infectious Diseases Unit, Alfred Health,Level 2, Burnet Institute , 85 Commercial Road, Prahran 3181.

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Michelle L. Giles http://orcid.org/0000-0003-3007-1822

Article

Publisher ID: 1540807

DOI: 10.1080/21645515.2018.1540807

PMC ID: 6605784

PubMed ID: 30380986

SO-VID: f61d1ec1-9610-4b16-8d22-1806386e831c

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

History

Date received : 15 August 2018

Date revision received : 26 September 2018

Date accepted : 18 October 2018

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Figures: 6, References: 73, Pages: 13

Funding

Funded by: Australian Government, Office of Health Protection and contracted to the National Centre for Immunisation Research and Surveillance

This project was commissioned by the Australian Government, Office of Health Protection and contracted to the National Centre for Immunisation Research and Surveillance.

The safety of inactivated influenza vaccines in pregnancy for birth outcomes: a systematic review

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Stillbirth: Case definition and guidelines for data collection, analysis, and presentation of maternal immunization safety data☆

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