Hypertension in Pregnancy, 28:1–12, 2009

Copyright © Informa Healthcare USA, Inc.

ISSN: 1064-1955 print / 1525-6065 online
DOI: 10.1080/10641950802001859

In Vitro Fertilization is
1525-6065
1064-1955
LHIP
Hypertension in Pregnancy
Pregnancy, Vol. 28, No. 1, Oct 2008: pp. 0–0

Associated with an Increased

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Risk for Preeclampsia

In Vitro
Chen et al.
Fertilization and Preeclampsia

Xi-Kuan Chen,1 Shi Wu Wen,1 Jim Bottomley,2

Graeme N. Smith,3 Arthur Leader,4 and Mark C. Walker1
1
OMNI Research Group, Clinical Epidemiology Program, Ottawa Health Research
Institute, University of Ottawa, Ottawa, Ontario, Canada
2
Perinatal Partnership Program of Eastern and South-eastern Ontario, Ottawa,
Ontario, Canada
For personal use only.

3
Queen’s Perinatal Research Unit, Kingston General Hospital, Department of
Obstetrics and Gynecology, Queen’s University, Kingston, Ontario, Canada
4
Ottawa Fertility Centre, Division of Reproductive Medicine, Department of Obstetrics
& Gynecology, University of Ottawa, Ottawa, Ontario, Canada
Objective: To assess the association of intrauterine insemination, in vitro fertilization
(IVF) and ovulation induction with the risk of preeclampsia. Methods: We conducted
a population based retrospective cohort study of pregnancies conceived by assisted
reproductive technology (1357 exposure subjects, 5190 controls) based on 2005 Niday
Perinatal Database for Ontario, Canada. All pregnancies conceived by assisted repro-
ductive technology were identified as exposure group. Four controls were randomly
matched for each exposure subject by maternal age, parity, plurality, and delivery
hospital level and residence area. The risks for preeclampsia associated with intrauterine
insemination, IVF, and ovulation induction were evaluated through conditional logistic
regression models compared with their corresponding controls. Results: With adjust-
ment of maternal age, smoking during pregnancy and initiating time of prenatal care, in
vitro fertilization was associated with an increased risk for preeclampsia (OR = 1.78,
95% CI: 1.05, 3.06), whereas intrauterine insemination (OR = 2.44, 95% CI: 0.74, 8.06)
and ovulation induction (OR = 1.34, 95% CI: 0.31, 5.75) was not associated with the
risk for preeclampsia. Conclusion: There was a higher incidence of preeclampsia
among pregnancies conceived by IVF, but no significant association was found in
intrauterine insemination and ovulation induction.

Keywords Preeclampsia, Intrauterine insemination, In vitro fertilization, Ovulation

induction, Assisted reproductive technology.

Address correspondence to Dr. Shi Wu Wen, OMNI Research Group, Clinical Epidemi-
ology Program, Ottawa Health Research Institute, 501 Smyth Rd., Box 241, Ottawa,
Canada, K1H 8L6. E-mail: swwen@ohri.ca
 2 Chen et al.

INTRODUCTION
Assisted reproductive technology (ART) has been widely employed for the treat-
ment of infertility (1). Data from Centers for Disease Control and Prevention
showed that 127,977 ART cycles were performed in 2004 with delivery of
36,760 live births and 49,458 infants in the United States, which accounted
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for slightly more than 1% of total births (2). In Demark, 4.2% of all infants
born in 2002 were the result of ART, which was the highest in European coun-
tries (3). Early research on ART has primarily focused on the efficacy of vari-
ous ART methods, the rates of early pregnancy loss, and its effect on multiple
gestations (4). In recent years, more and more studies have paid attentions
to the effect of ART on maternal complications and birth outcomes; previous
studies of ART primarily focused on in vitro fertilization (IVF). Two meta-
analyses published in 2004 comprising several thousand IVF and approxi-
mately 2 million spontaneously conceived singleton births indicated that
compared with pregnancies conceived naturally, IVF pregnancies were associ-
ated with an increased risk for perinatal mortality, preterm delivery, low
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birth weight, and small-for-gestational-age births (4,5). In vitro fertilization

was also found to be associated with higher risk for gestational diabetes,
preeclampsia, placenta previa and neonatal intensive care admission (4).
Preeclampsia is a major cause of maternal and perinatal mortality and
morbidity (6). The incidence of preeclampsia is 2% to 10% depending on the pop-
ulation studied and definitions of preeclampsia (7). Preeclampsia, accounting
for 20% of pregnancy-related deaths (8), ranks third, after embolism and
hemorrhage, as the leading cause of pregnancy-related deaths in industrial-
ized countries (9). The etiology of preeclampsia remains elusive, but several
studies have reported that the incidence of preeclampsia was associated with
advanced maternal age, nulliparity, multiple pregnancy, preexisting medical
conditions and ART (6). Different ART methods may carry different risk for
the development of preeclampsia. Some studies have reported that women
conceived by IVF were at increased risk for preeclampsia (1,10,11) and preg-
nancy-induced hypertension (12–15), while other studies failed to find such an
association (16–18). Wang et al. (19) found that compared with women treated
with IVF or intracytoplasmic sperm injection (ICSI) with ejaculated sperm
(i.e., previously exposed to their partner’s sperm cell and seminal fluid), the
risk for preeclampsia tripled in those treated with ICSI done with surgically
obtained sperm (i.e., never exposed to their partner’s sperm) (19). Salha et al.
(20) found that women conceived by donated gametes were at increased risk
for preeclampsia compared with controls matched by age and parity. On the
other hand, Porreco et al. (21) suggested that there was no increase in the risk
for preeclampsia among donor embryo pregnancies compared with age-like
IVF pregnancies. The relations between ovulation induction and intrauterine
insemination (IUI) and preeclampsia were not well studied. Two previous
 In Vitro Fertilization and Preeclampsia 3

studies found no significant association between ovulation induction and

preeclampsia (1,8), but another study found that ovulation induction was
associated with increased risk for pregnancy-induced hypertension (14).
Smith et al. (22) found that there was an increase risk for preeclampsia in
women conceived by IUI with washed donor sperm compared with IUI with
washed partner sperm.
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Many previous studies have attributed the higher rates of adverse preg-
nancy outcomes associated with ART to the effects of multiple gestations,
advanced maternal age, and nulliparity (4,23,24). However, many of these stud-
ies did not consistently ascertain and adjust for these potential confounders.
Few previous studies have considered the confounding roles of preexisting
chronic diseases and maternal smoking during pregnancy. The objective of the
present study was to assess the association of IUI, IVF, and ovulation induc-
tion with the risk for preeclampsia using a population-based, matched retro-
spective cohort study design.
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MATERIALS AND METHODS

Study Population
This retrospective cohort study was based on 2005 Ontario Niday Perinatal
Database. This regional database was created in 1997 to provide perinatal
data to the Perinatal Partnership Program of Eastern and Southeastern
Ontario (PPPESO), which was housed on the Criticall Ontario System and
managed by the Ontario Perinatal Surveillance System steering committees.
There were 82 participating sites—both hospitals and midwifery practice
groups. Site could either enter data directly into the database (64 sites) or
upload data from their own databases (18 sites). Each organization had
received training to manage the system’s data entry and reporting capabili-
ties. A user guide was used to ensure consistency of the definition for each
variable among the participants. An extensive set of data quality checks were
included in the data entry module of the database and a final set of checks
were done by the analyst to ensure data quality. So far, Niday database has
included more than 95% of all births in Ontario, Canada.
Available information in this dataset included maternal and prenatal
factors (maternal age, parity, aboriginal status, smoking status, multiple
pregnancy, presentation, health problems, previous Cesarean births, group B
Streptococcal status, and reproductive assistance), health service factors (first
trimester visit, prenatal classes, care provider, birth place, and length of stay
in hospital), intrapartum interventions (monitoring, induction methods, pain
relief methods, forceps vacuum, episiotomy, laceration, augmentation of labor,
Cesarean delivery, complications, steroid use, antibiotics, transfer, length of
first and second stage, and fetal surveillance), birth outcome (gestational age,
 4 Chen et al.

birth weight, Apgar score, stillbirth, resuscitation, hypoxia, and cord blood
gases) and infant health (feeding, hearing, congenital anomaly, neonatal
death, health problems, jaundice, and surgery). In this dataset, delivery hospi-
tals were divided into four different levels, i.e., small community hospital, large
community hospital, teaching hospital and midwifery hospital. The province was
divided into 16 residence areas according to geographic location.
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Selection of Exposure Subjects and Controls

All subjects with chronic hypertension (hypertension that predates or is
diagnosed before the 20th week of gestation), diabetes (insulin dependent or
noninsulin dependent diabetes onset before gestation), or heart disease (any
preexisting cardiac diseases including dysrythmias, congenital anomalies,
etc), were excluded from this study, because they might be important con-
founding variables in the observed associations.
In this study, the exposure variable was the use of ART, which included IUI,
IVF, IVF/ ICSI and ovulation induction. Intrauterine insemination was a fertility
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procedure in which sperm were washed, concentrated, and injected directly into a
women’s uterus. Standard IVF was the spontaneous fertilization of eggs by sperm
in vitro under laboratory conditions. Subsequently embryo(s) was (were) trans-
ferred into the uterus. IVF/ICSI was a procedure in which a single sperm was
injected directly into an egg with a micromanipulator in vitro under laboratory
conditions. Ovulation induction involved the use of one or more medication(s) (e.g.,
clomiphene citrate, injectable gonadotropins or pulsatile gonadotropin release
hormone) to stimulate the development of one or more mature egg follicles.
Spontaneously conceived pregnancies (controls) were selected from the
same database. For each exposure subject, four controls were randomly
matched by maternal age (±2 years), parity (nulliparous, multiparous), plurality
(singleton, multiple gestations), delivery hospital level, and residence area.

Definition of Outcome
The concerned outcome of this study was preeclampsia. The diagnosis of
preeclampsia is determined by increased blood pressure accompanied by
proteinuria, occurring after the 20th week of gestation. Diagnostic blood pres-
sure increases are either a systolic blood pressure ≥ 140 mm Hg or a diastolic
blood pressure ≥ 90 mm Hg on at least two occasions at least 6 hours apart.
Proteinuria is defined as the urinary excretion of 300 mg or greater in a 24-hour
specimen or ≥1+ on repeated dipsticks.

Statistical Analysis
We first described the distribution of maternal characteristics between
three exposure groups and their corresponding control groups. The adjusted
 In Vitro Fertilization and Preeclampsia 5

odds ratios and 95% confidence intervals for the risk for preeclampsia associ-
ated with IUI, IVF, and ovulation induction were assessed through condi-
tional logistic regression model with reference to their corresponding controls.
Potential confounding variables included in the multivariable regression
model were smoking during pregnancy and initiating time of prenatal care. To
control the residual confounding of maternal age, it was further adjusted in
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the regression model. Subjects with no available information on maternal

tobacco use during pregnancy and initiating time of prenatal care were set as
an independent category in this study. Because the incidence rate varied in
different control groups, supplement analysis was done to compare the risk for
preeclampsia within three exposed groups. All data were analysed using
Statistical Analysis System, Version 9.1 (SAS Institute Inc., Cary, NC).

RESULTS
There were 1357 exposure subjects (313 for IUI, 622 for IVF, and 422 for
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ovulation induction) and 5190 matched controls included in the present study.
In total, 86.2% of exposure subjects were matched with four controls, 10.3%
for 3 controls, and the left were matched 1 or 2 controls. The maternal charac-
teristics of the six study groups are described in Table 1. Most study subjects
were older than 30 years, nulliparous, had a singleton gestation, initiated
prenatal care in the first trimester, and delivered at a large community hospital
or teaching hospital. There were significant different in maternal age, smok-
ing during pregnancy, and status of prenatal care between exposure groups
and their corresponding control groups.
Table 2 presents the incidence rate of preeclampsia for different ART
group and control group, and corresponding adjusted odds ratios and 95%
confidence intervals. After controlling for maternal age, smoking during preg-
nancy and initiating prenatal care in the first trimester, IVF was associated
with an increased risk of preeclampsia, whereas IUI and ovulation induction
was not significantly associated with the risk of preeclampsia (Table 2).
With adjustment for potential confounders, further analysis among three
exposure groups showed that pregnancies conceived by IVF had an increased
risk for preeclampsia (OR: 4.13, 95% CI: 1.18, 14.49) with reference to those
by ovulation induction, whereas IUI was not associated with a higher risk for
preeclampsia (OR: 2.32, 95% CI: 0.56, 9.60).

DISCUSSION
If ART use is associated with increased risk of maternal complications during
pregnancy, it is of concern to both pregnant women and health care profes-
sionals. This population based cohort study demonstrated that IVF was
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6
Table 1: Characteristics of the study population (n, %).*

Intrauterine In vitro Ovulation

Characteristics insemination Controls 1 fertilization Controls 2 induction Controls 3

No. of subjects 313 1212 622 2320 422 1658

Maternal age (years) 33.43 ± 4.01 32.57 ± 3.88 34.61 ± 4.51 33.50 ± 4.33 31.35 ± 4.30 30.84 ± 4.22
<25 5 (1.60) 24 (1.98)† 7 (1.13) 30 (1.29)† 28 (6.64) 110 (6.63)†
25–29 39 (12.46) 214 (17.66) 65 (10.45) 378 (16.29) 117 (27.73) 501 (30.22)
30–34 147 (46.96) 610 (50.33) 254 (40.84) 984 (42.42) 168 (39.80) 727 (43.85)
≥35 122 (38.98) 364 (30.03) 296 (47.58) 928 (40.00) 109 (25.83) 320 (19.30)
Parity
Nulliparous 217 (69.33) 842 (69.47) 450 (72.35) 1668 (71.90) 276 (65.40) 1084 (65.38)
Multiparous 96 (30.67) 370 (30.53) 172 (27.65) 652 (28.10) 146 (34.60) 574 (34.62)
Plurality
Singleton 222 (70.93) 882 (72.77) 347 (55.79) 1358 (58.53) 343 (81.28) 1368 (82.51)
Multiple births 91 (29.07) 330 (27.23) 275 (44.21) 962 (41.47) 79 (18.72) 290 (17.49)
Smoking during pregnancy
No 283 (90.42) 1026 (84.65)† 552 (88.75) 1978 (85.26)† 366 (86.73) 1375 (82.93)
Yes 14 (4.47) 101 (8.33) 28 (4.50) 175 (7.54) 31 (7.35) 145 (8.75)
Not reported 16 (5.11) 85 (7.02) 42 (6.75) 167 (7.20) 25 (5.92) 138 (8.32)
Initiating prenatal care in the 1st
trimester
Yes 212 (67.73) 740 (61.06)† 412 (66.24) 1378 (59.40)† 376 (89.10) 1227 (74.00)†
No 29 (9.27) 91 (7.50) 38 (6.11) 157 (6.77) 20 (4.74) 149 (8.99)
Not reported 72 (23.00) 381 (31.44) 172 (27.65) 785 (33.83) 26 (6.16) 282 (17.01)
Delivery Hospital level
Small community 11 (3.52) 42 (3.46) 25 (4.02) 92 (3.97) 28 (6.64) 111 (6.69)
Large community 168 (53.67) 661 (54.54) 344 (55.31) 1322 (56.98) 318 (75.36) 1252 (75.51)
Teaching 132 (42.17) 501 (41.34) 251 (40.35) 900 (38.79) 73 (17.30) 285 (17.19)
Midwifery 2 (0.64) 8 (0.66) 2 (0.32) 6 (0.26) 3 (0.70) 10 (0.60)

*four controls were matched with each exposure subject by maternal age, parity, plurality, delivery hospital level and residence area.
†
Statistically difference between exposed group and corresponding controls (p < 0.05).
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Table 2: Assisted reproductive technology and the risk of preeclampsia.

Intrauterine Ovulation
Variable insemination Controls 1 In vitro fertilization Controls 2 induction Controls 3

No. of subjects 313 1212 622 2320 422 1658

Incidence rate (%) 6 (1.92) 14 (1.16) 25 (4.02) 53 (2.28) 3 (0.71) 11 (0.66)
Crude ORs and 95% CIs 1.66 (0.62, 4.48) Referent 1.84 (1.10, 3.07) Referent 1.07 (0.29, 3.93) Referent
Adjusted ORs and 95% CIs* 2.44 (0.74, 8.06) Referent 1.78 (1.05, 3.06) Referent 1.34 (0.31, 5.75) Referent

*Odds ratio was evaluated through conditional logistic regression model with adjustment for maternal age, smoking during pregnancy and
initiating prenatal care in the first trimester.

7
 8 Chen et al.

associated with increased risk for preeclampsia, whereas no significant associ-

ation was found between IUI and ovulation induction and preeclampsia.
Previous studies have found that ovulation induction was not associated
with an increased risk for preeclampsia (1,8), which was consistent with our
present study. However, a hospital-based retrospective cohort study matching
by maternal age, gestational age and parity found that pregnancies conceiving
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by ovulation induction had higher risk for pregnancy-induced hypertension

(OR = 1.5, 95% CI: 1.04, 2.02) (14). This study did not control the confounding
role of preexisting chronic hypertension, diabetes and heart disease, prenatal
care status, and smoking during pregnancy. Our study found that the risk for
preeclampsia was not significantly associated with pregnancies conceiving by
IUI. Our previous study (22) showed that IUI with washed donor sperm was
associated with an increased risk for preeclampsia compared with IUI with
washed partner sperm. The present dataset did not differentiate between IUI
with partner sperm and IUI with donor sperm. Most IUI uses partner sperm,
which accounted for the apparently lack of risk for preeclampsia compared
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with controls.
Our study demonstrated that an increased risk for preeclampsia was
associated with pregnancies conceiving by IVF, which has been previously
reported (1,4,10–15). In a meta- analysis based on 8 studies (2256 IVF sin-
gleton pregnancies and 217, 126 controls), Jackson et al. (4) concluded that
IVF was associated with an increased risk of preeclampsia (OR = 1.55, 95%
CI: 1.23, 1.95). However, three previous studies found that IVF was not
associated with an increased risk for hypertensive disorders in singleton
gestations (17,18) and preeclampsia in twin gestations (16). In a retrospec-
tive cohort study, 260 singleton IVF pregnancies and 260 naturally con-
ceived singleton controls were 1:1 matched for maternal age, parity, ethnic
origin, and location and date of delivery (17). Reubinoff et al. (17) found
that the risk of pregnancy-induced hypertension was comparable in two
study groups (11.2% vs. 8.1%). In a hospital-based retrospective cohort
study matching by parity, maternal age, maternal weight and height (140
IVF gestations, 140 controls), Verlaenen et al. (18) found that the risk of
hypertensive disorders was not significantly associated with IVF pregnan-
cies. In these two studies (17,18), the observed outcomes were pregnancy-
induced hypertension and hypertensive disorders, which differed from the
present study. In another study, Pinborg et al. (16) found that the risk
for preeclampsia was not significant between IVF/ICSI twin and non-IVF/
ICSI twin pregnancies after stratification for maternal age and parity, in
which the information on maternal complications were collected by ques-
tionnaire completed by survey subjects. In these three abovementioned
studies (16–18), some important confounding variables were not controlled,
such as preexisting chronic diseases, smoking during pregnancy, and pre-
natal care status.
 In Vitro Fertilization and Preeclampsia 9

Compared with previous studies, the most important strength of this

study was that the confounding roles of maternal age, parity, multiple preg-
nancies, and delivery hospital levels were effectively controlled by individual
matching. The ART use was highly related with social economic status,
because the cost of ART was not covered by health program in Ontario,
Canada, and was paid by patients themselves. In this study, the subjects were
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individually matched by residence area, which could represent for social

economical status in some degree. Chance and confounding were unlikely to
explain the findings of our study, because of the large sample size, individual
data matching, and adjustment of potential confounders using multivariable
regression models. The exposure and outcome variables were collected
prospectively; all eligible exposure subjects were included in the present
study; the controls were randomly selected from the base population; there-
fore, it was less likely to be affected by information bias and selection bias.
The most likely source of bias in our study was related to incomplete ascer-
tainment of preeclampsia in this administrative dataset. The incidence of
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preeclampsia in our control group, who had no preexisting chronic hyperten-

sion, diabetes, and heart disease, ranged from 0.66% to 2.28%, which was lower
than previously reported rates (2% to 10%) (7). The incidence of preeclampsia
varied greatly according to the population profile and the diagnosis criteria of
preeclampsia. There was also great geographic variation in the incidence (7).
Indeed, few previous studies on the incidence of preeclampsia were population
based (25). Most of these studies originated from one or a few tertiary hospitals
where women who had preeclampsia or were at high risk of developing preec-
lampsia were more likely to be referred. Other studies have been limited to
nulliparous women, who were at high risk for preeclampsia (25). In the present
study, more subjects in the ART groups initiated their prenatal care in the 1st
trimester than in the control groups. Potential under-reporting of preeclampsia
was likely to be more frequent in control groups than in exposure groups,
which might bias the observed association between ART and preeclampsia. As
most previous studies on ART, there was no available information on the cause
of infertility and length of infertility in our dataset, and therefore we could not
explore how these differences may affect the risk of preeclampsia. As an obser-
vational study using a second-hand dataset, this study might be affected by
residual confounding and coding errors. Some other potential risk factors asso-
ciated with both ART and preeclampsia, such as prepregnancy body mass
index, and folic acid and multivitamin supplementation before and during
pregnancy were not collected in the present dataset, so we could not control the
effect of these confounding variables. In this study, we could not identify that
gametes were either from a third party or from couples themselves.
The conclusions on association of different exposures with preeclampsia
might be affected by the “statistical power” of different sub-cohorts to detect
the significant differences, which was largely dependent on the sample size
 10 Chen et al.

and study design. In this study, there is a tendency toward increased risk for
preeclampsia among pregnancies conceived by IUI and ovulation induction.
Further comparison among three exposure groups showed that pregnancies
conceived by IVF had an increased risk for preeclampsia with reference to
those by ovulation induction, whereas IUI was not associated with higher risk
of preeclampsia, which indicated that the observed association was less likely
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to due to different statistical power among exposure groups.

The mechanisms by which IVF might lead to the increased risk for preec-
lampsia were unclear, and our study was not designed to explore the mecha-
nism. The association between IVF and preeclampsia might be attributable to
IVF procedure itself, or to components of the IVF procedure, which has been
proposed by previous study (1,26,27). An alternative explanation was that the
risk of preeclampsia was associated with the different indications of IVF, IUI,
and ovulation induction. The subgroup of patients with ‘subfertility’ requiring
only ovulation induction might be different from those requiring IVF, which
might affect the risk of obstetric and birth outcomes (28,29). Further research
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is needed to determine if there are differences in the fetoplacental unit

between those gestations conceiving by IVF and natural gestations, which
might lead to further understanding of the etiology and pathology of preec-
lampsia. Giving our findings, we suggest that informed consent of women
undergoing IVF should include a discussion of possibly increased maternal
complications such as preeclampsia.

ACKNOWLEDGMENTS
This study was supported by a grant for the PE-NET from the Heart & Stroke
Foundation of Canada (HSF, PG-03-0175-PE-NET), the Canadian Institute of
Health Research (CIHR, FMI-63194), and a grant from the Program on
Oocyte Health (http://www.ohri.ca/oocyte) funded under the Healthy Gametes
and Great Embryos Strategic Initiative of the Canadian Institutes of Health
Research (CIHR) Institute of Human Development, Child and Youth Health
(IHDCYH) (HGG62293).

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