Appendix 1: Search strategy used for each database

Hypertensive disorders of pregnancy:

H1 Antenatal
H2 Ante-natal
H3 Prenatal
H4 Pre-natal
H5 Pregnan*
H6 Gestation*
H7 H1 OR H2 OR H3 OR H4 OR H5 OR H6
H8 Pre Eclampsia
H9 Preeclampsia
H10 Pre-eclampsia
H11 Eclampsia
H12 Edema-Proteinuria-Hypertension
H13 Edema Proteinuria Hypertension
H14 Oedema-Proteinuria-Hypertension
H15 Oedema Proteinuria Hypertension
H16 EPH
H17 Toxemia*
H18 Toxaemia*
H19 Gestosis
H20 (H19 OR H7)
H21 Toxemia* OR Toxaemia* or EPH
H22 H21 AND H20
H23 Gestational hypertension
H24 Pregnancy-induced hypertension
H25 Pregnancy induced hypertension
H26 Hypertensi*
H27 Blood pressure
H28 H26 OR H27
H29 H28 AND H7
H30 H8 OR H9 OR H10 OR H11 OR H12 OR H13 OR H14 OR H15 OR H22
OR H23 OR H24 OR H25 OR H29

Stroke:
A1 Cerebrovascular
A2 Intracerebral
A3 Brain
A4 Intracranial
A5 Subdural
A6 Cerebral
A7 Midbrain
A8 Cerebellar
A9 Lacunar
A10 Lenticostriatal
A11 A1 OR A2 OR A3 OR A4 OR A5 OR A6 OR A7 OR
A8 OR A9 OR A10
A12 Haemorrhag*
A13 Hemorrhag*
A14 A13 OR A14
A15 Bleed*
A16 Clot*
A17 Haematoma*
A18 Hematoma*
A19 A17 OR A18
A20 Ischaemi*
A21 Ischemi*
A22 A20 OR A21
A23 Infarct*
A24 Accident*
A25 Event*
A26 Disorder*
A27 A14 OR A15 OR A16 OR A19 OR A22 OR A23 OR
A24 OR A25 OR A26
A28 A11 AND A27
A29 Stroke*
A30 Embolic
A31 Cryptogenic
A32 Cardioembolic
A33 A11 OR A14 OR A22 OR A30 OR A31 OR A32
A34 A33 AND A29
A35 Transient ischaemic attack
A36 Transient ischemic attack
A37 TIA
A38 A35 OR A36 OR A37
A39 A34 OR A38

Women:
 W1 woman
W2 Women
W3 Female*
W4 Mother*
W5 Maternal
W6 W1 OR W2 OR W3 OR W4 OR W5

Final search:
H30 AND A39 AND W6
Appendix 2: Table of eligibility criteria

Inclusion Exclusion
Case control studies or cohort studies Studies focused on CVA during pregnancy
(prospective or retrospective)
Human study Case reports, case series, commentaries, notes
and editorials
English language Studies focused on CVA in offspring
At least 20 cases Studies not available in English
Exposure variable measured: History of HDP Studies published after 1st June 2021
Outcome variable measured: diagnosis of
CVA/ischemic stroke/hemorrhagic stroke
Measure of association between exposure and
outcome
Diagnosis of outcome must take at least 3
months place after delivery
Studies from database conception to 1st June
2021
Appendix 3: Newcastle-Ottawa Scale for Quality Appraisal (25)
NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
CASE CONTROL STUDIES
Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Exposure categories.
A maximum of two stars can be given for Comparability.

Selection
1) Is the case definition adequate?
a) yes, with independent validation ¯
b) yes, eg record linkage or based on self-reports
c) no description
2) Representativeness of the cases
a) consecutive or obviously representative series of cases ¯
b) potential for selection biases or not stated
3) Selection of Controls
a) community controls ¯
b) hospital controls
c) no description
4) Definition of Controls
a) no history of disease (endpoint) ¯
b) no description of source
Comparability
1) Comparability of cases and controls on the basis of the design or analysis
a) study controls for _______________ (Select the most important factor.) ¯
b) study controls for any additional factor ¯ (This criteria could be modified to indicate specific control for a
second important factor.)

Exposure
1) Ascertainment of exposure
a) secure record (eg surgical records) ¯
b) structured interview where blind to case/control status ¯
c) interview not blinded to case/control status
d) written self report or medical record only
e) no description
2) Same method of ascertainment for cases and controls
a) yes ¯
b) no
3) Non-Response rate
a) same rate for both groups ¯
b) non respondents described
c) rate different and no designation
 NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
COHORT STUDIES
Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories.
A maximum of two stars can be given for Comparability

Selection
1) Representativeness of the exposed cohort
a) truly representative of the average _______________ (describe) in the community ¯
b) somewhat representative of the average ______________ in the community ¯
c) selected group of users eg nurses, volunteers
d) no description of the derivation of the cohort
2) Selection of the non exposed cohort
a) drawn from the same community as the exposed cohort ¯
b) drawn from a different source
c) no description of the derivation of the non exposed cohort
3) Ascertainment of exposure
a) secure record (eg surgical records) ¯
b) structured interview ¯
c) written self report
d) no description
4) Demonstration that outcome of interest was not present at start of study
a) yes ¯
b) no
Comparability
1) Comparability of cohorts on the basis of the design or analysis
a) study controls for _____________ (select the most important factor) ¯
b) study controls for any additional factor ¯ (This criteria could be modified to indicate specific control for a
second important factor.)
Outcome
1) Assessment of outcome
a) independent blind assessment ¯
b) record linkage ¯
c) self report
d) no description
2) Was follow-up long enough for outcomes to occur
a) yes (select an adequate follow up period for outcome of interest) ¯
b) no
3) Adequacy of follow up of cohorts
a) complete follow up - all subjects accounted for ¯
b) subjects lost to follow up unlikely to introduce bias - small number lost - > ____ % (select an adequate %)
follow up, or description provided of those lost) ¯
c) follow up rate < ____% (select an adequate %) and no description of those lost
d) no statement
 7

Appendix 4: Table detailing quality appraisal

Author Selection Comparability Exposure/Outcome Total Verdict
Bhattacharya 3/4 2/2 1/3 6/9 Moderate
et. al (31) risk
Blomstrand 3/4 2/2 2/3 7/9 Low risk
et. al (32)
Brown et. al 3/4 2/2 1/3 6/9 Moderate
(33) risk
Canoy et. al 3/4 2/2 3/3 8/9 Low risk
(34)
Chuang et.al 4/4 2/2 3/3 9/9 Low risk
(35)
Garovic et. al 3/4 2/2 1/3 6/9 Moderate
(36) risk
Hannaford et. 2/4 2/2 1/3 5/9 Moderate
al (37) risk
Huang et. al 4/4 2/2 2/3 8/9 Low risk
(38)
Hung et. al 4/4 2/2 3/3 9/9 Low risk
(39)
Kuo et. al 4/4 1/2 2/3 7/9 Low risk
(40)
L Lin et. al 4/4 0/2 2/3 7/9 Low risk
(43)
Langlois et. al 4/4 2/2 2/3 8/9 Low risk
(41)
Leon et. al 3/4 1/2 3/3 7/9 Low risk
(42)
Lin et. al (44) 4/4 2/2 3/3 8/9 Low risk
Lykke et. al 4/4 2/2 2/3 8/9 Low risk
(45)
Männistö et. 3/4 2/2 2/3 7/9 Low risk
al (46)
Miller et. al 2/4 2/2 2/3 6/9 Moderate
(47) risk
Nelander et. 2/4 2/2 2/3 6/9 Moderate
al (48) risk
Park et. al 4/4 0/2 2/3 6/9 Moderate
(49) risk
Savitz et. al 4/4 2/2 2/3 8/9 Low risk
(50)
Schokker et. 2/4 2/2 1/3 5/9 Moderate
al (51) risk
Tang et. al 4/4 2/2 3/3 9/9 Low risk
(52)
Tooher et. al 4/4 1/2 2/3 7/9 Low risk
(53)
Wilson et. al 3/4 0/2 2/3 5/9 Moderate
(54) risk

*≥7- low risk of bias, 4-6- moderate risk of bias, ≤3- high risk of bias
 8

Appendix 5: Forest plots of adjusted estimates

95% Prediction interval – (0.99, 3.05)

Figure 5.1: Forest plot of HDP (exposure) and any stroke (outcome)

Figure 5.2: Forest plot of HDP (exposure) and ischemic stroke (outcome)

Figure 5.3: Forest plot of HDP (exposure) and hemorrhagic stroke (outcome)
 9

95% Prediction interval – (1.01, 3.02)

Figure 5.4a: Forest plot of PE (exposure) and any stroke (outcome)

Figure 5.4b: Forest plot of PE (exposure) and any stroke (outcome) prior to removal of L.
Lin et al

95% Prediction interval – (1.18, 2.56)

Figure 5.5: Forest plot of PE (exposure) and ischemic stroke (outcome)
 10

95% Prediction interval – (1.30, 5.90)

Figure 5.6: Forest plot of PE (exposure) and hemorrhagic stroke (outcome)

95% Prediction interval – (1.20, 1.26)

Figure 5.7: Forest plot of GH (exposure) and any stroke (outcome)

95% Prediction interval – (0.07, 107.74)

Figure 5.8: Forest plot of GH (exposure) and hemorrhagic stroke (outcome)

95% Prediction interval – (1.19, 1.53)

Figure 5.9: Forest plot of GH (exposure) and ischemic stroke (outcome)
 11

Figure 5.10: Forest plot of CH (exposure) and ischemic stroke (outcome)

Figure 5.11: Forest plot of superimposed PE on CH (exposure) and ischemic stroke

(outcome)
 12

Appendix 6: Forest plots of Subgroup Analyses

Figure 6.1: PE and CVA by Study Quality

 13

Figure 6.2: PE and CVA by Location

Figure 6.3: PE and CVA by Method of Data Ascertainment

 14

Figure 6.4: PE and CVA by Study Type

Figure 6.5: HDP and CVA by Study Quality

 15

Figure 6.6: HDP and CVA by Study Location

Figure 6.7: HDP and CVA by Method of Data Ascertainment

 16

Figure 6.8: HDP and CVA by Study Type

 17

Appendix 7: Funnel plot to assess publication bias and results of Egger’s test with trim and
fill plot

Figure 7.1: Funnel plot for PE and CVA

Figure 7.2: Funnel plot for PE and CVA with Trim and Fill
Appendix 8: Results of meta-regression of comparison group “PE and any stroke”
 18

Table of univariate meta-regression results for “PE v any stroke”

Number of Coefficient 95% CI P-value Q-value for

studies heterogeneity

Study Location
North 3 0 (reference)
America
Europe 5 0.07 (-0.24,0.37) 0.66
Asia 4 0.20 (-0.09,0.49) 0.17
Australia 1 0.26 (-0.79,1.31) 0.63 0.06
Risk of bias
Low risk 8 0 (reference)
Moderate risk 5 -0.16 (-0.39,0.08) 0.20 0.08
Study type
Prospective 4 0 (reference)
cohort study
Retrospective 9 0.10 (-0.24,0.26) 0.94 0.05
cohort study
Method of data ascertainment
Record 10 0 (reference)
linkage
Self-reported 3 -0.23 (-0.51,0.05) 0.11 0.10
 19

Appendix 9: Table of fragility indices of meta-analyses

Exposure Outcome Number of studies Fragility Index
Any stroke 6ad 10
HDP Ischemic stroke 1b NA (1 study)
Hemorrhagic stroke 1b NA (1 study)
Any stroke 8abcde 42
PE Ischemic stroke 4bde 41
Hemorrhagic stroke 3bcde 3
Any stroke 3ad 0
GH Ischemic stroke 2d 44
Hemorrhagic stroke 2d 0
Any stroke 1 NA (1 study)
Superimposed PE on
Ischemic stroke 1d NA (1 study)
CH
Hemorrhagic stroke 1 NA (1 study)
Any stroke 1 NA (1 study)
CH Ischemic stroke 1d NA (1 study)
Hemorrhagic stroke 1 NA (1 study)

Studies without necessary data:

a. (53)
b. (50)
c. (42)
d. (39)
e. (32)