Vaccine 34 (2016) 6069–6076

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Hypertensive disorders of pregnancy: Case definitions & guidelines for

data collection, analysis, and presentation of immunization safety data
Caroline E. Rouse a , Linda O. Eckert b , Blair J. Wylie c , Deirdre J. Lyell d ,
Arundhathi Jeyabalan e , Sonali Kochhar f ,
Thomas F. McElrath a,∗ , The Brighton Collaboration Preeclampsia Working Group1
a
Brigham and Women’s Hospital, Boston, MA, USA
b
University of Washington, Seattle, WA, USA
c
Massachusetts General Hospital, Boston, MA, USA
d
Stanford University, Stanford, CA, USA
e
University of Pittsburgh, Pittsburgh, PA, USA
f
Global Healthcare Consulting

a r t i c l e i n f o

Article history:
Available online 15 July 2016

Keywords:
Preeclampsia
Hypertension in pregnancy
Adverse event
Immunization
Guidelines
Case definition

1. Preamble Around 10% of all pregnant women will be affected by a hyper-

tensive disorder during pregnancy [1]. Hypertensive disorders of
1.1. Need for developing case definitions and guidelines for data pregnancy are a significant contributor to maternal and neonatal
collection, analysis, and presentation for the hypertensive morbidity and mortality, and are implicated in 10–15% of mater-
disorders of pregnancy as adverse events following immunization nal deaths worldwide [1,2]. The exact mechanism responsible
for hypertensive diseases of pregnancy, in particular preeclamp-
There is no universally accepted case definition of gestational sia, is not known. One leading hypothesis is that abnormalities
hypertension, preeclampsia or eclampsia that occurs following in the development of the uteroplacental unit lead to increased
immunisations. This is a missed opportunity, as data comparability hypoxemia and oxidative stress, which in turn lead to endothe-
across trials or surveillance systems would facilitate data interpre- lial dysfunction and abnormalities in vascular tone and coagulation
tation and promote the scientific understanding of the event. As [3,4].
immunization is considered an essential element of care in preg- Hypertensive disease in pregnancy encompasses a spectrum
nancy, the potential complications of this procedure should be of conditions, including gestational hypertension, preeclampsia
understood. Additionally, vaccine studies may be conducted in a (which can be further qualified as having severe features), eclamp-
variety of settings, including those with fewer resources to per- sia, chronic hypertension with superimposed preeclampsia and
form the same diagnostic testing as in higher resource settings. It HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) syn-
is important to provide definitions that can be utilized widely. drome. Because of differences among the guidelines issued by
international societies, diagnosis can occasionally become con-
fusing as terminology may vary. Nevertheless, it is important to
∗ Corresponding author at: Brigham & Women’s Hospital, 75 Francis Street,
differentiate hypertensive disorders that predate pregnancy from
those that occur during pregnancy, as well as to categorize patients
Boston, MA 02115, USA. Tel.: +1 617 732 5435.
E-mail address: contact@brightoncollaboration.org (T.F. McElrath). into more or less serious cases. Furthermore, the specific diagnosis
1
Brighton Collaboration homepage: http://www.brightoncollaboration.org. has important treatment implications, such as timing of delivery.

drake@yahoo.co.id)http://dx.doi.org/10.1016/j.vaccine.2016.03.038
at ClinicalKey Global Guest Users from ClinicalKey.com by Elsevier on April 23, 2018.
0264-410X/©
y. No other uses without 2016
permission. Published
Copyright by Elsevier
©2018. ElsevierLtd.
Inc.This is an open
All rights access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
reserved.
6070 C.E. Rouse et al. / Vaccine 34 (2016) 6069 – 6076

The definitive treatment for hypertensive diseases of pregnancy is pressure elevation in pregnancy should be further evaluated for the
delivery. development of preeclampsia. It is possible to move from a diagno-
The association of vaccination with the hypertensive diseases sis of gestational hypertension to preeclampsia or eclampsia, but
of pregnancy has not been well studied and the exact incidence is not from preeclampsia to gestational hypertension.
not known. There are observational studies as well as case reports
of hypertensive disease developing in women after vaccine admin- 1.3.2. Formulating a case definition that reflects diagnostic
istration but no causal link has been described. Furthermore, the certainty: weighing specificity versus sensitivity
case definitions for the observational studies are not well defined, The number of symptoms and/or signs that will be documented
with several studies relying solely on ICD-9 codes. for each case may vary considerably. The case definitions have been
formulated such that the Level 1 definition is highly specific for
1.2. Methods for the development of the case definition and the condition. As maximum specificity normally implies a loss of
guidelines for data collection, analysis, and presentation for the sensitivity, one additional diagnostic levels have been included in
hypertensive disorders of pregnancy as adverse events following the definition, offering a stepwise increase of sensitivity from Level
immunization 1 down to Level 2, while retaining an acceptable level of specificity
at all levels. In this way it is hoped that all possible cases of the
Following the process described in the overview paper [5] hypertensive diseases of pregnancy can be captured.
as well as on the Brighton Collaboration Website, http://www. It needs to be emphasized that the grading of definition lev-
brightoncollaboration.org/internet/en/index/process.html, the els is entirely about diagnostic certainty, not clinical severity of
Brighton Collaboration Preeclampsia Working Group was formed an event. Thus, a clinically very severe event may appropriately
in 2015 and included members with clinical, academic and public be classified as Level 2 rather than Level 1 if it could reasonably
health background. The composition of the working and reference be ascribed to an etiology other than the hypertensive diseases of
group as well as results of the web-based survey completed by the pregnancy. Detailed information about the severity of the event
reference group with subsequent discussions in the working group should additionally be recorded, as specified by the data collection
can be viewed at: http://www.brightoncollaboration.org/internet/ guidelines.
en/index/working groups.html.
To guide the decision-making for the case definition and guide- 1.3.3. The timing of development of preeclampsia in the context
lines, a literature search of publications in English was performed of vaccine administration
using Medline, Embase and the Cochrane Libraries, including the Preeclampsia and gestational hypertension are conventionally
terms vaccines, vaccination, or immunization (or terms beginning defined as developing after 20 weeks gestation [10], but there
with vaccin-, immuni-, inoculat-), and [hypertension AND preg- can be great variability in exact timing of presentation of the
nancy] or [preeclampsia or eclampsia] (or preeclam-, eclamp-). The disease. In one study, approximately 10% of the preeclampsia diag-
search resulted in the identification of 516 references. All abstracts noses were made before 34 weeks gestation [11]. Preeclampsia
were screened for possible reports of preeclampsia, eclampsia or can develop up to 6 weeks postpartum and, in fact, 20–50% of
hypertension in pregnancy following immunization. Twenty-seven eclampsia occurs in the postpartum period [12,13]. The progres-
articles with potentially relevant material were reviewed in more sion from normal blood pressure to hypertension to preeclampsia
detail, in order to identify studies using case definitions or, in their can proceed rapidly, gradually, or not at all. Because of the unpre-
absence, providing clinical descriptions of the case material. Data dictability in development and progression of the disease, it is
collected from these 27 articles included information on the study important for the purpose of vaccine trials to record the tempo-
type, the vaccine, the diagnostic criteria or case definition put forth, ral relationship between immunization and development of any
the time interval since time of immunization, and any other symp- preeclampsia-related complication of pregnancy.
toms. References that lacked hypertensive diseases of pregnancy
as an outcome were excluded. 1.3.4. Rationale for individual criteria related to the case
Most publications were of observational studies, though there definition
were also several publications from vaccine adverse event repor- 1.3.4.1. Gestational hypertension. Gestational hypertension refers
ting groups. Only one publication [6] specified the criteria used to new onset hypertension after 20 weeks of gestation [10,14,15].
to diagnose preeclampsia in study participants. Four of the pub- The use of “20 weeks gestation” as a diagnostic criterion is some-
lications reported using ICD-9 diagnostic codes to collect cases what arbitrary, as there is no specific physiologic change known
of preeclampsia/eclampsia or pregnancy related hypertension that occurs at this gestational age that permits the development of
[2,7–9]. preeclampsia. However, given that this convention is widely used,
the Brighton Collaboration will continue to utilize it for the sake of
1.3. Rationale for selected decisions about the case definition of continuity.
preeclampsia as an adverse event following immunization Accurate blood pressure measurement is fundamental for the
diagnosis of a hypertensive disorder of pregnancy. The WHO
1.3.1. The terms for hypertension in pregnancy released a document in 2003 detailing the proper protocols and
The terms “eclampsia,” “preeclampsia,” “gestational hyperten- techniques that should be utilized when measuring blood pres-
sion” and “pregnancy-induced hypertension” are commonly used sure. While it is outside the scope of this document to present
in clinical practice. “Pregnancy-induced hypertension” is a term a comprehensive guide to accurate blood pressure measurement,
referring to hypertensive disorders of pregnancy in general, but several important points should be highlighted. Regardless of the
lacks the specificity of the other terms, and so the Brighton type of device used to measure blood pressure, accuracy should be
definitions will refer only to “eclampsia,” “preeclampsia,” and checked regularly by comparing the measurement device to a cali-
“gestational hypertension.” All of these disorders are character- brated device, and health care providers should be properly trained
ized by elevations in blood pressure. Preeclampsia and eclampsia in taking blood pressure measurements. Blood pressure should be
have additional diagnostic criteria based on laboratory findings measured with the patient in a seated position, with the arm at the
by clinical physical exam or patient reported symptoms reflect- level of the heart. An appropriate cuff size should be chosen based
ing the systemic nature of the disease. The diagnosis of gestational on the patient’s size (generally a length that is 1.5 times the cir-
hypertension is provisional, in that every woman with new blood cumference of the patient’s arm). The systolic blood pressure is the

Downloaded for rachmad sammulia (iwandrake@yahoo.co.id) at ClinicalKey Global Guest Users from ClinicalKey.com by Elsevier on April 23, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 C.E. Rouse et al. / Vaccine 34 (2016) 6069 – 6076 6071

pressure at which the first sounds can be heard. The disappearance of cerebral malaria or preexisting seizure disorder). Seizures are
of sounds, or the fifth phase, is the best measurement of diastolic often preceded by headaches, visual changes or altered mental
blood pressure. status [21]
Blood pressure is considered elevated if the systolic blood pres- • Hematologic:
sure is ≥140 mmHg or the diastolic blood pressure is ≥90 mmHg, ◦ New onset thrombocytopenia, with platelet count <100,000/␮L
sustained over time. The length of time that the blood pressure • Gastrointestinal:
should remain elevated varies as well, from 15 min [16] to 4 h ◦ New onset of nausea, vomiting, epigastric pain
depending on which organization guidelines are followed [10]. The ◦ Transaminitis (AST and ALT elevated to twice the upper limit of
Brighton Collaboration favors a longer time interval of sustained normal)
blood pressure elevations. However, with respect to the poten- ◦ Liver capsular hemorrhage or liver rupture
tial logistical concerns in some settings of keeping a woman for • Renal:
observation for several hours, we propose that a diagnosis of hyper- ◦ Worsening renal function, as evidenced by serum creatinine level
tension be made if the systolic blood pressure is ≥140 mmHg or the greater than 1.1 mg/dL or a doubling of the serum creatinine
diastolic blood pressure is ≥90 mmHg on two measurements at a (absent other renal disease)
minimum of one hour apart. ◦ Oliguria (urine output <500 mL/24 h)
• Respiratory:
1.3.4.2. Preeclampsia. Preeclampsia has conventionally been ◦ Pulmonary edema (confirmed on clinical exam or imaging)
defined as the development of gestational hypertension and
proteinuria after 20 weeks gestation [2,10,14–16]. We consider While complications of pregnancy such as intrauterine growth
preeclampsia as a systemic condition of endothelial dysfunction restriction, placental abruption and stillbirth are utilized as diag-
in which hypertension is a primary presenting sign. Other organ nostic criteria for preeclampsia with severe features by some
systems will manifest this dysfunction in fashions specific to their societies [15,16], the Brighton Collaboration has chosen not to
physiology. Historically, microvascular dysfunction in the kidney include these in our definition since these conditions frequently
has been recognized as proteinuria. exist independently of the hypertensive disorders of pregnancy and
Proteinuria can be quantified by 24 h urine collection, a spot may represent a separate set of pathologies. We recommend that
protein:creatinine ratio, or with urinary dipstick. Proteinuria of these complications should certainly be reported as pregnancy out-
≥300 mg in a 24 h urine specimen (the gold standard for measure- comes in the context of vaccine and other drug trials. The Brighton
ment of proteinuria), or ≥0.30 on a spot protein:creatinine ratio, or Collaboration working groups on stillbirth, intrauterine growth
≥1+ on a dipstick meets the criteria for preeclampsia [2,10,14–16]. restriction and vaginal bleeding in pregnancy will have publications
Routine visual dipstick urinalysis has been shown to have false forthcoming to help guide diagnosis of these related conditions.
positive rates at “1+” of 67–83%, and false negative rates at “nil” http://www.brightoncollaboration.org.
or “trace” of 8–18% [17]. Automated urinalysis improves the sen-
sitivity of this test to 74% [18]. The sensitivity and specificity of 1.3.5. Related conditions
the protein:creatinine ratio are higher at 93% and 92%, respec- 1.3.5.1. HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) syn-
tively [18]. Given the potential variation in resources available to drome. HELLP syndrome is considered to be a subtype of severe
test for proteinuria, the Brighton Collaboration will permit any of preeclampsia. The diagnosis is based on laboratory evaluation in
these measures of proteinuria, though 24 h urine collection and which all criteria (hemolysis, liver dysfunction, thrombocytopenia)
protein:creatinine ratio are preferred. are met [22,23]. It is important to note that hypertension may be
Preeclampsia can be further classified as having “severe fea- absent in up to 15% of cases of HELLP syndrome. While we recognize
tures” with development of laboratory abnormalities or symptoms. HELLP as part of the preeclampsia spectrum of disease, this diag-
The progression to preeclampsia with severe features represents nosis is not the focus of this document, and so will not be further
the clinical recognition of the additional involvement of mater- addressed.
nal organ systems. Because certain clinical findings associated with
severe disease increase the morbidity and mortality of preeclamp- 1.3.5.2. Chronic hypertension. Chronic hypertension refers to ele-
sia [19], they are included in the Brighton Collaboration definition. vation in the systolic blood pressure to ≥140 mmHg or the diastolic
The diagnosis of severe preeclampsia requires new onset hyper- blood pressure to ≥90 mmHg, sustained over a length of time (as
tension (as described above) and one of the following criteria described above) that is diagnosed either prior to pregnancy or
enumerated below. Given the multi-system nature of preeclamp- prior to 20 weeks gestation. Hypertension that occurs in early ges-
sia, these will be presented by system: tation is likely to predate pregnancy, hence the establishment of
NOTE that preeclampsia with severe features can be diagnosed 20 weeks as a boundary for the diagnosis of chronic hyperten-
in the presence or absence of proteinuria. sion. Chronic hypertension progresses to preeclampsia in 10–50%
of cases, depending on the severity of the preexisting hypertension
• Vascular: [24]. The diagnosis of superimposed preeclampsia (preeclampsia
◦ Severely elevated blood pressures, with systolic blood pressure superimposed on chronic hypertension) is made based on the fol-
≥160 mmHg and/or diastolic blood pressure ≥110 mmHg, which lowing criteria:
is confirmed after only minutes (to facilitate timely antihyper-
tensive treatment) • preexisting hypertension (described above) PLUS any one of the
• Neurologic: following:
◦ Development of a severe headache (which can be dif- ◦ new onset proteinuria (as described above)
fuse, frontal, temporal or occipital) that generally does not ◦ worsening of preexisting proteinuria
improve with over the counter pain medications (such as ◦ development of any of the laboratory abnormalities or clinical
acetaminophen/paracetamol) findings consistent with severe preeclampsia
◦ Development of visual changes (including photopsia, scotomata,
cortical blindness) [20] 1.3.5.3. Postpartum preeclampsia. While some of the physiologic
◦ Eclampsia, or new-onset grand mal seizures in a patient with changes of pregnancy take longer to return to a pre-pregnancy
preeclampsia, without other provoking factors (such as evidence state, the postpartum period, or puerperium, encompasses the

Downloaded for rachmad sammulia (iwandrake@yahoo.co.id) at ClinicalKey Global Guest Users from ClinicalKey.com by Elsevier on April 23, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
6072 C.E. Rouse et al. / Vaccine 34 (2016) 6069 – 6076

six weeks following delivery [25]. The exact incidence of new- PREECLAMPSIA WITH SEVERE FEATURES
onset postpartum preeclampsia or hypertension is difficult to For All Levels of Diagnostic Certainty
Preeclampsia with severe features is a clinical syndrome characterized by
measure since most women do not return to their care provider
pregnancy ≥20 weeks
until 6 weeks after the delivery, but estimates range from 0.3% AND
to 27%[26]. The criteria for a postpartum diagnosis of the hyper- new onset hypertension (systolic blood pressure ≥140 mmHg and/or
tensive disorders of pregnancy are the same as the antepartum diastolic
criteria. blood pressure ≥90 mmHg) sustained on two measurements over a
minimum of 1 h
AND
1.3.6. Timing post immunization At least one of the criteria for severe disease:
We postulate that a definition designed to be a suitable tool
Level 1 of diagnostic certainty
for testing associations requires ascertainment of the outcome At least one of the following:
(e.g. a hypertensive disorder of pregnancy) independent from the Systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110
exposure (e.g. immunisations). Therefore, to avoid selection bias, a mmHg, which is confirmed after only minutes OR
restrictive time interval from immunization to onset of a hyperten- Development of severe, persistent headache OR
Development of visual changes OR
sive disorder of pregnancy should not be an integral part of such
Eclampsia OR
a definition. Instead, where feasible, details of this interval should New onset thrombocytopenia (platelets <100,000/␮L) OR
be assessed and reported as described in the data collection guide- New onset unremitting epigastric pain OR
lines. Care should be taken to avoid creating spurious associations AST and ALT elevated to twice upper limit of normal OR
Evidence of liver capsular hematoma or liver rupture (diagnosed on
between vaccine administration and hypertensive disorders, given
clinical exam or with imaging) OR
that vaccines are generally administered during specific times dur- Worsening renal function, as evidenced by serum creatinine level greater
ing pregnancy. Case–control studies are needed to further evaluate than 1.1 mg/dL or a doubling of the serum creatinine (absent other renal
the potential link. disease) or oliguria (<500 cc/24 h) OR
Further, hypertensive disorders of pregnancy are common, Pulmonary edema (confirmed on imaging with chest X-ray, or on clinical
exam)
affecting up to 10% of pregnant women [1], and can occur outside
the controlled setting of a clinical trial or hospital. In some sett- Level 2 of diagnostic certainty
ings it may be impossible to obtain a clear timeline of the event, new onset nausea and vomiting

particularly in less developed or rural settings. In order to avoid Insufficient evidence

selecting against such cases, the Brighton Collaboration case defini- blood pressure cannot be measured
tion avoids setting arbitrary time frames, though the immunization
GESTATIONAL HYPERTENSION
should precede the hypertensive disorder.
For All Levels of Diagnostic Certainty
Gestational Hypertension is a clinical syndrome characterized by
1.3.7. Differential diagnoses pregnancy ≥20 weeks
Other diagnoses should be considered during the workup of AND
hypertension in pregnancy. The differential is broad, including new onset hypertension (systolic blood pressure ≥140 mmHg and/or
diastolic
but not limited to conditions such as preexisting renal dis- blood pressure ≥90 mmHg) sustained on two measurements over a
ease, thrombotic thrombocytopenic purpura/hemolytic uremic minimum of 1 h
syndrome, acute fatty liver of pregnancy, primary liver disease, car- WITHOUT
diomyopathy, pheochromocytoma, and thyrotoxicosis. Seizures in severe features (see preeclampsia with severe features category) and
WITHOUT
pregnancy can be caused by a preexisting seizure disorder, cerebral
proteinuria
malaria, metabolic abnormalities, or cerebral anatomic abnormal-
ities such as a space-occupying lesion. Ensuring accurate diagnosis Level 1 of diagnostic certainty
no proteinuria (as defined by 24 h urine collection < 300 mg, spot
is of great importance, as treatment can vary widely based on the protein:creatinine ratio <0.3)
etiology of the patient’s symptoms.
Level 2 of diagnostic certainty
no proteinuria (as defined by urine dipstick negative or trace)
2. Case definitions
Insufficient evidence
PREECLAMPSIA blood pressure cannot be measured OR
For All Levels of Diagnostic Certainty no proteinuria evaluation is available
Preeclampsia is a clinical syndrome characterized by
pregnancy ≥20 weeks
AND
2.1. Guidelines for data collection, analysis and presentation
new onset hypertension (systolic blood pressure ≥140 mmHg and/or
diastolic
blood pressure ≥90 mmHg) sustained on two measurements over a As mentioned in the overview paper, the case definition is
minimum of 1 h accompanied by guidelines which are structured according to the
AND
steps of conducting a clinical trial, i.e. data collection, analysis and
new onset proteinuria
presentation. Neither case definition nor guidelines are intended to
Level 1 of diagnostic certainty guide or establish criteria for management of ill infants, children,
proteinuria diagnosed with ≥300 mg of protein on 24 h urine collection OR
or adults. Both were developed to improve data comparability.
≥0.3 on spot protein:creatinine ratio

Level 2 of diagnostic certainty

proteinuria diagnosed with ≥1+ protein on urine dipstick
2.2. Periodic review
Insufficient evidence
blood pressure cannot be measured OR
Similar to all Brighton Collaboration case definitions and guide-
no proteinuria evaluation is available (note diagnosis of preeclampsia with
severe lines, review of the definition with its guidelines is planned on a
features does not require proteinuria, see definition below) regular basis (i.e. every three to five years) or more often if needed.

Downloaded for rachmad sammulia (iwandrake@yahoo.co.id) at ClinicalKey Global Guest Users from ClinicalKey.com by Elsevier on April 23, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 C.E. Rouse et al. / Vaccine 34 (2016) 6069 – 6076 6073

3. Guidelines for data collection, analysis and presentation 4) Relation to the patient (e.g., immunizer [clinician, nurse], family
of the hypertensive disorders of pregnancy, as presented in member [indicate relationship], other).
document

It was the consensus of the Brighton Collaboration Hypertensive 3.1.2. Vaccinee/control

Disorders of Pregnancy Working Group to recommend the follow- 3.1.2.1. Demographics. For all cases and/or all study participants,
ing guidelines to enable meaningful and standardized collection, as appropriate, the following information should be recorded:
analysis, and presentation of information about these conditions.
However, implementation of all guidelines might not be possible
in all settings. The availability of information may vary depend-
5) Case/study participant identifiers (e.g. first name initial followed
ing upon resources, geographical region, and whether the source
by last name initial) or code (or in accordance with country-
of information is a prospective clinical trial, a post-marketing
specific data protection laws).
surveillance or epidemiological study, or an individual report of
6) Date of birth, age, and sex.
hypertension in pregnancy. Also, as explained in more detail in the
7) For infants: Gestational age and birth weight.
overview paper in this volume, these guidelines have been devel-
oped by this working group for guidance only, and are not to be
considered a mandatory requirement for data collection, analysis,
or presentation. 3.1.2.2. Clinical and immunization history. For all cases and/or
all study participants, as appropriate, the following information
should be recorded:
3.1. Data collection

These guidelines represent a desirable standard for the col-

8) Past medical history, including hospitalisations, underlying
lection of data on availability following immunization to allow
diseases/disorders, pre-immunization signs and symptoms
for comparability of data, and are recommended as an addi-
including identification of indicators for, or the absence of, a
tion to data collected for the specific study question and setting.
history of allergy to vaccines, vaccine components or medica-
The guidelines are not intended to guide the primary repor-
tions; food allergy; allergic rhinitis; eczema; asthma.
ting of the hypertensive disorders of pregnancy to a surveillance
9) Any medication history (other than treatment for the event
system or study monitor. Investigators developing a data col-
described) prior to, during, and after immunization including
lection tool based on these data collection guidelines also need
prescription and non-prescription medication as well as med-
to refer to the criteria in the case definition, which are not
ication or treatment with long half-life or long term effect.
repeated in these guidelines. The Brighton Collaboration has devel-
(e.g. immunoglobulins, blood transfusion and immunosup-
oped guidelines for data collection https://brightoncollaboration.
pressants).
org/public/resources/standards/guidelines.html; and data col-
10) Immunization history (i.e. previous immunisations and any
lection forms https://brightoncollaboration.org/public/resources/
adverse event following immunization (AEFI)), in particular
data-collection-forms.html.
occurrence of a hypertensive disorder in pregnancy after a pre-
Guidelines below have been developed to address data ele-
vious immunization.
ments 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 [27], and the form for reporting 3.1.3. Details of the immunization
of drug adverse events by the Council for International Organi- For all cases and/or all study participants, as appropriate, the
zations of Medical Sciences [28]. These data elements include an following information should be recorded:
identifiable reporter and patient, one or more prior immunisa-
tions, and a detailed description of the adverse event, in this case,
of a hypertensive disorder of pregnancy following immunization. 11) Date and time of immunization(s).
The additional guidelines have been developed as guidance for the 12) Description of vaccine(s) (name of vaccine, manufacturer, lot
collection of additional information to allow for a more comprehen- number, dose (e.g. 0.25 mL, 0.5 mL, etc.) and number of dose if
sive understanding of development of the hypertensive disorders part of a series of immunisations against the same disease).
of pregnancy following immunization. 13) The anatomical sites (including left or right side) of all immu-
nisations (e.g. vaccine A in proximal left lateral thigh, vaccine
B in left deltoid).
3.1.1. Source of information/reporter
14) Route and method of administration (e.g. intramuscular, intra-
For all cases and/or all study participants, as appropriate, the
dermal, subcutaneous, and needle-free (including type and
following information should be recorded:
size), other injection devices).
15) Needle length and gauge.
1) Date of report.
2) Name and contact information of person reporting2 and/or diag-
nosing the hypertensive disorder of pregnancy as specified by 3.1.4. The adverse event
country-specific data protection law. 16) For all cases at any level of diagnostic certainty and for reported
3) Name and contact information of the investigator responsible events with insufficient evidence, the criteria fulfilled to meet
for the subject, as applicable. the case definition should be recorded.
Specifically document:
17) Clinical description of signs and symptoms of the hypertensive
2
If the reporting center is different from the vaccinating center, appropriate and
disorder of pregnancy, and if there was medical confirmation
timely communication of the adverse event should occur. of the event (i.e. patient seen by physician).

Downloaded for rachmad sammulia (iwandrake@yahoo.co.id) at ClinicalKey Global Guest Users from ClinicalKey.com by Elsevier on April 23, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
6074 C.E. Rouse et al. / Vaccine 34 (2016) 6069 – 6076

18) Date/time of onset,3 first observation4 and diagnosis,5 end of 3.2. Data analysis
episode6 and final outcome.7
19) Concurrent signs, symptoms, and diseases. The following guidelines represent a desirable standard for anal-
20) Measurement/testing ysis of data on the hypertensive disorders of pregnancy to allow for
• Values and units of routinely measured parameters (e.g. tem- comparability of data, and are recommended as an addition to data
perature, blood pressure)–in particular those indicating the analyzed for the specific study question and setting.
severity of the event;
• Method of measurement (e.g. type of thermometer, oral or 31) Reported events should be classified in one of the following
other route, duration of measurement, etc.); five categories including the three levels of diagnostic cer-
• Results of laboratory examinations, surgical and/or pathologi- tainty. Events that meet the case definition should be classified
cal findings and diagnoses if present. according to the levels of diagnostic certainty as specified in
21) Treatment given for the hypertensive disorder of pregnancy, the case definition. Events that do not meet the case definition
especially any antihypertensive medication, magnesium sul- should be classified in the additional categories for analysis.
fate and steroid medications.
22) Outcome7 at last observation. Event classification in 5 categories9
23) Objective clinical evidence supporting classification of the Event meets case definition
event as “serious”.8
24) Exposures other than the immunization 24 h before and after 1) Level 1: Criteria as specified in the Hypertensive Disorders of
immunization (e.g. food, environmental) considered poten- Pregnancy case definition
tially relevant to the reported event. 2) Level 2: Criteria as specified in the Hypertensive Disorders of
Pregnancy case definition

3.1.5. Miscellaneous/general
Event does not meet case definitionAdditional categories for
25) The duration of surveillance for the hypertensive disorders of analysis
pregnancy should be predefined based on
• Biologic characteristics of the vaccine e.g. live attenuated 3) Reported hypertensive disorder of pregnancy with insufficient
versus inactivated component vaccines; evidence to meet the case definition10 ,11
• Biologic characteristics of the vaccine-targeted disease; 4) Not a case of a hypertensive disorder of pregnancy
• Biologic characteristics of the hypertensive disorders of preg-
nancy including patterns identified in previous trials (e.g. 32) The interval between immunization and reported hyperten-
early-phase trials); and sive disorder of pregnancy could be defined as the date/time
• Biologic characteristics of the vaccinee (e.g. nutrition, underly- of immunization to the date/time of onset3 of the first symp-
ing disease like immunodepressing illness). toms and/or signs consistent with the definition. If few cases
26) The duration of follow-up reported during the surveillance are reported, the concrete time course could be analyzed for
period should be predefined likewise. It should aim to continue each; for a large number of cases, data can be analyzed in the
to resolution of the event. following increments:
27) Methods of data collection should be consistent within and
between study groups, if applicable. Subjects with a hypertensive disorder of pregnancy by inter-
28) Follow-up of cases should attempt to verify and complete the val to presentation
Interval* Number
information collected as outlined in data collection guidelines
<1 week after immunization
1–24. <1 week <1 month after immunization
29) Investigators of patients with a hypertensive disorder of preg- 1 month – <3 months after immunization
nancy should provide guidance to reporters to optimize the <3 months – <6 months after immunization
quality and completeness of information provided. Every 3 months increments thereafter through 6 weeks postpartum
Total
30) Reports of hypertensive disorders of pregnancy should be col-
lected throughout the study period regardless of the time
33) The duration of a possible hypertensive disorder of pregnancy
elapsed between immunization and the adverse event. If this is
could be analyzed as the interval between the date/time of
not feasible due to the study design, the study periods during
onset2 of the first symptoms and/or signs consistent with
which safety data are being collected should be clearly defined.
the definition and the end of episode6 and/or final outcome.7

3 9
The date and/or time of onset is defined as the time post immunization, when the To determine the appropriate category, the user should first establish, whether
first sign or symptom indicative of a hypertensive disorder of pregnancy occurred. a reported event meets the criteria for the lowest applicable level of diagnostic
This may only be possible to determine in retrospect. certainty, e.g. Level two. If the lowest applicable level of diagnostic certainty of the
4
The date and/or time of first observation of the first sign or symptom indicative definition is met, and there is evidence that the criteria of the next higher level of
for a hypertensive disorder of pregnancy can be used if date/time of onset is not diagnostic certainty are met, the event should be classified in the next category.
known. This approach should be continued until the highest level of diagnostic certainty
5
The date of diagnosis of an episode is the day post immunization when the event for a given event could be determined. Major criteria can be used to satisfy the
met the case definition at any level. requirement of minor criteria. If the lowest level of the case definition is not met, it
6
The end of an episode is defined as the time the event no longer meets the case should be ruled out that any of the higher levels of diagnostic certainty are met and
definition at the lowest level of the definition. the event should be classified in additional categories four or five.
7 10
E.g. recovery to pre-immunization health status, spontaneous resolution, ther- If the evidence available for an event is insufficient because information is miss-
apeutic intervention, persistence of the event, sequelae, death. ing, such an event should be categorized as “Reported hypertensive disorder of
8
An AEFI is defined as serious by international standards if it meets one or pregnancy with insufficient evidence to meet the case definition”.
11
more of the following criteria: (1) it results in death, (2) is life-threatening, (3) it An event does not meet the case definition if investigation reveals a negative
requires inpatient hospitalization or results in prolongation of existing hospitaliza- finding of a necessary criterion (necessary condition) for diagnosis. Such an event
tion, (4) results in persistent or significant disability/incapacity, (5) is a congenital should be rejected and classified as “Not a case of a hypertensive disorder of preg-
anomaly/birth defect, (6) is a medically important event or reaction. nancy”.

Downloaded for rachmad sammulia (iwandrake@yahoo.co.id) at ClinicalKey Global Guest Users from ClinicalKey.com by Elsevier on April 23, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 C.E. Rouse et al. / Vaccine 34 (2016) 6069 – 6076 6075

Whatever start and ending are used, they should be used con- • The study design;
sistently within and across study groups. • The method, frequency and duration of monitoring for the hyper-
34) If more than one measurement of a particular criterion is taken tensive disorders of pregnancy;
and recorded, the value corresponding to the greatest magni- • The trial profile, indicating participant flow during a study includ-
tude of the adverse experience could be used as the basis for ing drop-outs and withdrawals to indicate the size and nature of
analysis. Analysis may also include other characteristics like the respective groups under investigation;
qualitative patterns of criteria defining the event. • The type of surveillance (e.g. passive or active surveillance);
35) The distribution of data (as numerator and denominator data) • The characteristics of the surveillance system (e.g. population
could be analyzed in predefined increments (e.g. measured served, mode of report solicitation);
values, times), where applicable. Increments specified above • The search strategy in surveillance databases;
should be used. When only a small number of cases is pre- • Comparison group(s), if used for analysis;
sented, the respective values or time course can be presented • The instrument of data collection (e.g. standardized question-
individually. naire, diary card, report form);
36) Data on hypertensive disorders of pregnancy obtained from • Whether the day of immunization was considered “day one” or
subjects receiving a vaccine should be compared with those “day zero” in the analysis;
obtained from an appropriately selected and documented con- • Whether the date of onset3 and/or the date of first observation4
trol group(s) to assess background rates of hypersensitivity in and/or the date of diagnosis5 was used for analysis; and
non-exposed populations, and should be analyzed by study • Use of this case definition for the hypertensive disorders of preg-
arm and dose where possible, e.g. in prospective clinical trials. nancy, in the abstract or methods section of a publication.12

3.3. Data presentation Disclaimer

These guidelines represent a desirable standard for the pre- The findings, opinions and assertions contained in this consen-
sentation and publication of data on hypertensive disorders of sus document are those of the individual scientific professional
pregnancy following immunization to allow for comparability of members of the working group. They do not necessarily repre-
data, and are recommended as an addition to data presented for the sent the official positions of each participant’s organization (e.g.,
specific study question and setting. Additionally, it is recommended government, university, or corporation). Specifically, the findings
to refer to existing general guidelines for the presentation and pub- and conclusions in this paper are those of the authors and do not
lication of randomized controlled trials, systematic reviews, and necessarily represent the views of their respective institutions.
meta-analyses of observational studies in epidemiology (e.g. state-
ments of Consolidated Standards of Reporting Trials (CONSORT), of Acknowledgements
Improving the quality of reports of meta-analyses of randomized
controlled trials (QUORUM), and of Meta-analysis Of Observational The authors are grateful for the support and helpful
Studies in Epidemiology (MOOSE), respectively) [29–31]. comments provided by the Brighton Collaboration (Jan Bon-
hoeffer, Jorgen Bauwens) and the reference group (see https://
37) All reported events of hypertensive disorders of pregnancy brightoncollaboration.org/public/what-we-do/setting-standards/
should be presented according to the categories listed in guide- case-definitions/groups.html for reviewers), as well as other
line 31. experts consulted as part of the process. Finally, we would like to
38) Data on possible hypertensive disorders of pregnancy should thank the members of the ISPE Special Interest Group in Vaccines
be presented in accordance with data collection guidelines (VAX SIG) for the review of, constructive comments on. Brighton
1–24 and data analysis guidelines 31–36. Collaboration would like to acknowledge The Global Alignment
39) Terms to describe hypertensive disorders of pregnancy such of Immunization Safety Assessment in Pregnancy (GAIA) Project,
as “low-grade”, “moderate”, “high”, or “significant” are highly funded by the Bill and Melinda Gates Foundation.
subjective, prone to wide interpretation, and should be
avoided, unless clearly defined. References
40) Data should be presented with numerator and denominator
(n/N) (and not only in percentages), if available. [1] Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol
2009;33:130–7.
[2] Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet
Although immunization safety surveillance systems denomi- 2010;376:631–44.
nator data are usually not readily available, attempts should be [3] LaMarca BD, Gilbert J, Granger JP. Recent progress toward the understanding
of the pathophysiology of hypertension during preeclampsia. Hypertension
made to identify approximate denominators. The source of the 2008;51:982–8.
denominator data should be reported and calculations of estimates [4] Gilbert JS, Ryan MJ, LaMarca BB, Sedeek M, Murphy SR, Granger JP. Pathophy-
be described (e.g. manufacturer data like total doses distributed, siology of hypertension during preeclampsia: linking placental ischemia with
endothelial dysfunction. Am J Physiol Heart Circ Physiol 2008;294:H541–50.
reporting through Ministry of Health, coverage/population based
[5] Kohl KS, Gidudu J, Bonhoeffer J, Braun MM, Buettcher M, Chen RT, et al. The
data, etc.). development of standardized case definitions and guidelines for adverse events
following immunization. Vaccine 2007;25:5671–4.
[6] Coenders A, Koopmans NK, Broekhuijsen K, Groen H, Karstenberg-Kramer JM,
41) The incidence of cases in the study population should be pre- van Goor K, et al. Adjuvanted vaccines in pregnancy: no evidence for effect of
sented and clearly identified as such in the text. the adjuvanted H1N1/09 vaccination on occurrence of preeclampsia or intra-
42) If the distribution of data is skewed, median and range are usually uterine growth restriction. Eur J Obstet Gynecol Reprod Biol 2015;187:14–9.
[7] Millar MR, Sanz MG. The administration of pertussis vaccine to pregnant
the more appropriate statistical descriptors than a mean. How- women was associated with a small increased risk of chorioamnionitis, but
ever, the mean and standard deviation should also be provided.
43) Any publication of data on the hypertensive disorders of preg-
nancy should include a detailed description of the methods used 12
Use of this document should preferably be referenced by referring to the respec-
for data collection and analysis as possible. It is essential to spec- tive link on the Brighton Collaboration website (http://www.brightoncollaboration.
ify: org).

Downloaded for rachmad sammulia (iwandrake@yahoo.co.id) at ClinicalKey Global Guest Users from ClinicalKey.com by Elsevier on April 23, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
6076 C.E. Rouse et al. / Vaccine 34 (2016) 6069 – 6076

not an increased risk of hypertensive disorders or preterm birth. Evid Based [20] Roos NM, Wiegman MJ, Jansonius NM, Zeeman GG. Visual disturbances in
Med 2015;20:73. (pre)eclampsia. Obstet Gynecol Surv 2012;67:242–50.
[8] Kharbanda EO, Vazquez-Benitez G, Lipkind H, Naleway A, Lee G, Nordin JD. [21] Cooray SD, Edmonds SM, Tong S, Samarasekera SP, Whitehead CL. Charac-
Inactivated influenza vaccine during pregnancy and risks for adverse obstetric terization of symptoms immediately preceding eclampsia. Obstet Gynecol
events. Obstet Gynecol 2013;122:659–67. 2011;118:995–9.
[9] Conlin AM, Bukowinski AT, Sevick CJ, DeScisciolo C, Crum-Cianflone NF. Safety [22] Sibai BM. Diagnosis, controversies, and management of the syndrome of
of the pandemic H1N1 influenza vaccine among pregnant U.S. military women hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol
and their newborns. Obstet Gynecol 2013;121:511–8. 2004;103:981–91.
[10] Hypertension in pregnancy. Report of the American College of Obstetricians [23] Martin Jr JN, Rinehart BK, May WL, Magann EF, Terrone DA, Blake PG. The
and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis,
2013;122:1122–31. elevated liver enzyme levels, and low platelet count) syndrome classification.
[11] Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes Am J Obstet Gynecol 1999;180:1373–84.
associated with early- versus late-onset disease. Am J Obstet Gynecol 2013;209, [24] Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol
544 e1–e12. 2002;100:369–77.
[12] Sikorski J, Wilson J, Clement S. The changing pattern of eclampsia over a 60-year [25] Gabbe SG, Niebyl JR, Simpson JL. Obstetrics: normal and problem pregnancies.
period. Br J Obstet Gynaecol 1998;105:473. Philadelphia, PA: Churchill Livingstone/Elsevier; 2007.
[13] Berhan Y, Berhan A. Should magnesium sulfate be administered to women with [26] Sibai BM. Etiology and management of postpartum hypertension-
mild pre-eclampsia? A systematic review of published reports on eclampsia. J preeclampsia. Am J Obstet Gynecol 2012;206:470–5.
Obstet Gynaecol Res 2015;41:831–42. [27] International conference on harmonization of technical requirements for reg-
[14] Hypertension in pregnancy: the management of hypertensive disorders during istration of pharmaceuticals for human use. http://www.ich.org/home.html
pregnancy. London: Royal College of Obstetricians and Gynaecologists; 2010. [accessed 11.12.15].
[15] Lowe SA, Brown MA, Dekker GA, Gatt S, McLintock CK, McMahon LP, et al. [28] Council for International Organizations of Medical Sciences. http://www.cioms.
Guidelines for the management of hypertensive disorders of pregnancy 2008. ch/ [accessed 12.12.15].
Aust N Z J Obstet Gynaecol 2009;49:242–6. [29] Moher D, Schulz KF, Altman D, Group C. The CONSORT statement: revised
[16] Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P. Diagnosis, evaluation, and recommendations for improving the quality of reports of parallel-group ran-
management of the hypertensive disorders of pregnancy: executive summary. domized trials. JAMA 2001;285(15):1987–91.
J Obstet Gynaecol Can 2014;36:575–6. [30] Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving
[17] Brown MA, Buddle ML. Inadequacy of dipstick proteinuria in hypertensive the quality of reports of meta-analyses of randomised controlled trials:
pregnancy. Aust N Z J Obstet Gynaecol 1995;35:366–9. the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet
[18] Saudan PJ, Brown MA, Farrell T, Shaw L. Improved methods of assessing pro- 1999;354(9193):1896–900.
teinuria in hypertensive pregnancy. Br J Obstet Gynaecol 1997;104:1159–64. [31] Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-
[19] von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton Pipkin F, Cote AM, analysis of observational studies in epidemiology: a proposal for reporting.
et al. Prediction of adverse maternal outcomes in pre-eclampsia: development Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA
and validation of the fullPIERS model. Lancet 2011;377:219–27. 2000;283(15):2008–12.

Downloaded for rachmad sammulia (iwandrake@yahoo.co.id) at ClinicalKey Global Guest Users from ClinicalKey.com by Elsevier on April 23, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.