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, <1500 g) and extremely low birth weight (ELBW, <1000 g) [1]. Low birth weight
is a result of preterm birth (PTB, short gestation <37 completed weeks), intrauterine
growth restriction (IUGR, also known as fetal growth restriction), or both.
The term low birth weight refers to an absolute weight of <2500 g regardless of gestational
age. Small for gestational age (SGA) refers to newborns whose birth weight is less
than the 10th percentile for gestational age. This report will focus specifically
on birth weight <2500 g. Further details related to case definitions for PTB [2],
IUGR and SGA are included in separate GAIA reports.
Globally, it is estimated that 15–20% of all births, or >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 (<600 Da) cross the placenta by passive mechanism including
diffusion, however, larger 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.