OBSTETRICS

Interpregnancy Interval and Adverse Perinatal

Outcomes: A Record-Linkage Study Using the
Manitoba Population Research Data
Repository
Helen Coo, MSc;1 Marni D. Brownell, PhD;2,3 Chelsea Ruth, MD;3,4 Michael Flavin, MD;1
Wendy Au, BSc;3 Andrew G. Day, MSc5
1
Department of Pediatrics, Queen’s University, Kingston, ON
2
Department of Community Health Sciences, University of Manitoba, Winnipeg, MB
3
Manitoba Centre for Health Policy, Winnipeg, MB
4
Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB
5
Kingston General Hospital Research Institute, Kingston, ON

Abstract Résumé

Objective: To examine the association between the interpregnancy
interval (IPI) and preterm birth, low birth weight, and SGA birth in a
developed country with universal health coverage.
Methods: We conducted a secondary analysis of data housed at the
Manitoba Centre for Health Policy. All live births in Manitoba
hospitals over a 29-year period were identified and consecutive
births to the same mother were grouped into sibling pairs to
calculate the IPI for the younger siblings. Logistic regression models
were fit to examine the association between the IPI and adverse
perinatal outcomes, adjusted for potentially confounding
sociodemographic and clinical factors.
Results: In a cohort of more than 171 000 births and relative to IPIs of
18 to 23 months, IPIs shorter than 12 and longer than 23 months
were associated with significantly increased odds of preterm birth
overall and both medically indicated and spontaneous preterm
births, low birth weight, and SGA birth. The strongest association
observed was for intervals shorter than 6 months and spontaneous
preterm birth (adjusted OR 1.83, 95% CI 1.65-2.03). When the
outcome was modelled as GA categories, the strongest association
observed was for intervals shorter than 6 months and early preterm
birth (<34 weeks’ GA; adjusted OR 2.47, 95% CI 2.07-2.94).
Conclusion: If the associations observed between the IPI and adverse
perinatal outcomes in this large, population-based cohort are
causal, birth spacing could form an important target of public health
messaging in Canada.
Key Words: Interpregnancy interval, perinatal outcomes, preterm
birth, low birth weight, small for gestational age
Corresponding Author: Helen Coo, Department of Pediatrics,
Queen’s University, Kingston, ON. cooh@queensu.ca
Competing interests: None declared.
Received on November 7, 2016
Accepted on January 18, 2017
Objectif : La présente étude visait à étudier l’association entre
l’intervalle entre grossesses et la naissance prématurée, le poids
insuffisant à la naissance et le faible poids pour l’âge gestationnel à
la naissance dans un pays développé doté d’un système universel
de soins de santé.
Méthodologie : Nous avons effectué une analyse secondaire des
données stockées au Manitoba Centre for Health Policy. Toutes
les naissances vivantes survenues dans un hôpital manitobain
sur une période de 29 ans ont été recensées, et les naissances
consécutives issues de la même mère ont été regroupées en
paires fraternelles à des fins de calcul de l’intervalle entre
grossesses associé au frère ou à la sœur plus jeune. Nous
avons employé des modèles de régression logistique pour
étudier la présence d’une association entre l’intervalle entre
grossesses et certaines issues périnatales défavorables, après
avoir tenu compte de facteurs de confusion potentiels de nature
sociodémographique et clinique.
Résultats : Dans une cohorte comptant plus de 171 000 paires de
naissances et par rapport à des intervalles entre grossesses
de 18 à 23 mois, les intervalles de moins de 12 mois et de plus de
23 mois ont été associés à une probabilité accrue de naissance
prématurée, qu’on parle du taux global ou du taux d’accouchements
prématurés spontanés ou indiqués médicalement, ainsi qu’à une
probabilité accrue de poids insuffisant à la naissance et de faible
poids pour l’âge gestationnel à la naissance. L’association la plus
forte a été observée entre les intervalles inférieurs à six mois et le
taux d’accouchement prématuré spontané (RC ajusté : 1,83; IC à
95 % : 1,65-2,03). Lorsque les issues ont été modélisées en
fonction des catégories d’âge gestationnel, l’association la plus forte
était celle entre les intervalles inférieurs à six mois et les naissances
très prématurées (âge gestationnel <34 semaines; RC ajusté :
2,47; IC à 95 % : 2,07-2,94).
Conclusions : Si les associations observées entre l’intervalle entre
grossesses et les issues périnatales défavorables dans cette vaste
cohorte représentative de la population correspondent en fait une
relation causale, il pourrait être judicieux de faire de l’intervalle entre

420 l JUNE JOGC JUIN 2017


les naissances une cible majeure des campagnes de santé
publique au Canada.
Copyright ª 2017 The Society of Obstetricians and Gynaecologists of
Canada/La Société des obstétriciens et gynécologues du Canada.
Published by Elsevier Inc. All rights reserved.
J Obstet Gynaecol Can 2017;39(6):420e433
https://doi.org/10.1016/j.jogc.2017.01.010
INTRODUCTION
S hort and long interpregnancy intervals (IPIs)ddefined
as the interval between birth and subsequent con-
ceptiondhave been associated with a number of adverse
pregnancy and birth outcomes.1 The IPI may also have an
impact on children’s longer-term health and development,
with studies reporting associations with autism spectrum
disorder,2e7 schizophrenia,8 and cerebral palsy.9,10
The more well-established links between the IPI and pre-
term birth, low birth weight, and SGA birth are largely
based on studies done in the United States and developing
countries.11e13 The strength of the associations may vary
depending on factors such as a population’s overall nutri-
tional status and access to prenatal care.14 To our knowl-
edge, only two studies have examined the IPI and adverse
perinatal outcomes in Canada.15,16 The first study examined
the outcome of SGA birth among a cohort of 98 330 in
Montréal.15 The researchers found no evidence of an
increased risk associated with short IPIs (<12 months),
although the reference group was first-born children rather
than another IPI category. The second study analysed data
on 46 243 singleton live births in Northern Alberta.16 Both
short (<6 months) and longer (
24 months) intervals were
associated with significantly increased odds of preterm
birth, low birth weight, and SGA birth relative to IPIs of
12 to 17 months. IPIs of 6 to 11 months were also asso-
ciated with significantly increased odds of preterm birth
and low birth weight, but not SGA birth.
Neither Canadian studydand similar to the majority of
studies from other countries12,17ddifferentiated between
medically indicated and spontaneous preterm birth,
although the risk factors for these do not always overlap.18
Similarly, to our knowledge no previous studies have
examined the IPI and different GA/size for gestation
outcomes (e.g., preterm, SGA birth), although they present
ABBREVIATION
IPI interpregnancy interval
Interpregnancy Interval and Adverse Perinatal Outcomes
differing patterns of morbidity and mortality19 and their
risk factors may also differ. Examining more narrowly
defined outcomes and similarities and differences in how
the IPI relates to those outcomes may provide clues to the
etiologic pathways involved, if the observed associations
are causal (we address the issue of causality in more detail
in the Discussion).
Our primary objective was to investigate the IPI in relation
to the odds of preterm birth, low birth weight, and SGA
birth in a large, population-based cohort from a developed
country with universal health care. Our secondary objec-
tives were to explore associations between the IPI and
medically indicated and spontaneous preterm births, early
and late preterm and early term births, and GA/size for
gestation categories.
METHODS
Data Sources
The Manitoba Population Research Data Repository at
the Manitoba Centre for Health Policy houses linkable
databases that contain de-identified information collected
by a variety of agencies (e.g., Manitoba government
departments, Statistics Canada). Since 1984, everyone
enrolled in Manitoba’s provincial health plan, which
provides coverage of insured health services to most
residents of the province (with the exception of a few
groups, such as individuals who have resided in Manitoba
<3 months, and military personnel), has been assigned
a unique, nine-digit Personal Health Identification
Number. An encrypted version of this number is
attached to person-level records in the repository data-
bases; this provides the ability to link records for the
same individual across datasets and years while main-
taining confidentiality.20 Nine datasets in the Data
Repository were accessed for this study (Table 121).
Study Cohort
The Hospital Discharge Abstracts database was used to
identify all hospital births in Manitoba between April 1,
1985, and March 31, 2014 (the study period; a relatively
higher proportion of birth records between April 1, 1984,
and March 31, 1985, could not be linked to obstetric
records so those births were not included in our cohort).
Each two consecutive live births to the same mother
formed a sibling pair (e.g., if a mother had three live births
over the study period, the first and second births formed
one sibling pair, and the second and third births formed
another sibling pair). Our target population was singleton
live births of 22 to 43 weeks’ GA. Accordingly, multiple
and stillbirths were excluded, as were sibling pairs whereby
JUNE JOGC JUIN 2017 l 421
OBSTETRICS

Table 1. Datasets housed at Manitoba Centre for Health Policy used to study the interpregnancy interval and adverse
perinatal outcomes
Dataset
Medical Services
Hospital Discharge
Abstracts
BabyFirst/Families First
Screen
Manitoba Enrollment,
Marks, and
Assessments
Social Assistance
Management
Information Network
Research Data Set
Drug Programs
Information Network
Database
Healthy Baby Prenatal
Benefit
Manitoba Centre for
Health Policy
Research Registry
Census
Description Inception date
Contains physician billing claims, which are submitted by fee-for-service physicians Fiscal 1970 to 1971
and by those paid through alternative payment mechanisms; one “most
responsible” diagnosis is recorded to the third digit of the ICD-9-CM.
Contains information on admissions to acute and chronic care facilities and outpatient Fiscal 1970 to 1971
surgeries provided in a hospital setting; a maximum of 16 diagnoses are coded to
the fifth digit of the ICD-9-CM for encounters from 1979 to March 31, 2004, and a
maximum of 25 diagnoses are coded to the fifth digit of the ICD-10-CA from April 1,
2004, onwards.
Since 2000, Healthy Child Manitoba has partnered with the Manitoba Regional Health 2000
Authorities to screen mothers of newborns for biologic, social, and demographic
risk factors for child abuse and neglect, including alcohol, smoking, and drug use
during pregnancy; parental education; and history of anxiety disorders and
depression. Coverage of families with newborns has been steadily increasing since
the program’s inception, and a program evaluation published in 2010 estimated that
screening was performed for 83% of all births.21 Screens are completed by public
health nurses.
Contains province-wide enrollment and assessment information and graduation status 1995 to 1996 school
for kindergarten through grade 12 students in Manitoba, including those who attend year
private schools or are home-schooled.
Contains records for each month that an individual received support from the Fiscal 1995 to 1996
Employment and Income Assistance Program, which provides financial assistance
to residents of Manitoba who have no other means to pay for food, clothing, and
basic personal and household expenses.
Contains prescription drug claims from the Drug Programs Information Network, which Fiscal 1995 to 1996
captures information on dispensations from all pharmacies in Manitoba for all
Manitoba residents, regardless of insurance coverage or final payer. A key field in
the database is the Drug Identification Number, an 8-digit number assigned by
Health Canada to each drug approved for use in Canada.
Contains sociodemographic data (e.g., education, income) collected through the 2001
Healthy Baby Prenatal Benefit program, which provides financial benefits to help
low-income women obtain adequate nutrition during pregnancy. Approximately one
third of women giving birth in Manitoba receive this benefit.
The Manitoba Centre for Health Policy Research Registry contains information that Fiscal 1970 to 1971
allows for longitudinal tracking of individuals registered with Manitoba’s provincial
health plan, which provides universal coverage of insured health services for
Manitoba residents (excluding those who receive federally administered health
care, such as military personnel and inmates). This information includes, but is not
limited to, dates of coverage under Manitoba’s health plan and residential mobility
within Manitoba and to and from the province.
Contains sociodemographic data from Statistics Canada’s census of the population, 1971 (quinquennial)
which is conducted every 5 years.

either child had a GA of <22 or >43 completed weeks or Study Variables

the GA was not recorded for either sibling. Other exclu-
sion criteria included the following: the mother did not
have continuous health coverage in Manitoba between the
two siblings’ births (to ensure that no child was born out of
province during that interval), a pregnancy loss was
recorded between the two births (which would preclude
the calculation of an accurate IPI), or the younger sibling
was born prior to April 1, 1987 (the algorithm used to
define chronic hypertension required a look-back period of
3 years22).
The definitions and coding of the study variables are pro-
vided in Table 2.23e27 Briefly, the IPI was derived from the
dates of birth of each sibling in a sibling pair and the GA of
the younger sibling. The primary outcomes were preterm
birth (<37 weeks’ GA), low birth weight (<2500 g), and
SGA birth (weight below the 10th percentile for GA and
sex, based on Kramer’s Canadian population-based refer-
ence values23). The secondary outcomes included GA cat-
egories, medically indicated or spontaneous preterm birth,
and GA/size for gestation categories (Table 2).

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 Interpregnancy Interval and Adverse Perinatal Outcomes

Table 2. Definitions and coding of study variables

Exposure
IPI Calculated as the interval between the birth dates of the two siblings in each sibling pair, minus the younger sibling’s
GA at birth in completed weeks. GA in completed weeks is recorded on the newborn’s hospital birth record and is
based on the date of the last menstrual period or ultrasound, where available. To form the categories for the
analysis, we divided the interval in days by 7 (to convert the IPI into weeks) and then created the following
categories by specifying 26 weeks as equal to 6 months: <6, 6 to 11, 12 to 17, 18 to 23 (reference), 24 to 59, and

60 months. These categories were used to allow a better comparison of our findings with a previous meta-
analysis of the association between the IPI and preterm birth, low birth weight, and SGA birth.12
Primary outcomes
Preterm birth Categorized as “Yes” if delivery occurred prior to 37 weeks of gestation. Otherwise, categorized as “No” (reference).
Low birth weight Categorized as “Yes” if birth weight <2500 g, as recorded in the Hospital Discharge Abstracts data. Otherwise,
categorized as “No” (reference).
SGA birth Categorized as “Yes” if birth weight <10th percentile for GA and sex, based on Kramer’s Canadian population-based
reference values.23 Otherwise, categorized as “No” (reference).
Secondary outcomes
GA at birth Categorized as early preterm (<34 weeks), late preterm (34 to 36 weeks), early term (37 to 38 weeks), or
39 weeks
(reference category).
Medically indicated or If delivery occurred at less than 37 weeks’ GA, it was coded as “Medically indicated preterm birth” if any of the
spontaneous following criteria were met for the index pregnancy/birth:24
preterm birth - Gestational hypertension, which was considered to be present if any of the following criteria were met during
the index pregnancy:
- Medical services:
1 physician visit with ICD-9-CM code 401 to 405 or 642
or
- Hospital Discharge Abstracts:
1 hospitalization with ICD-9-CM code 401 to 405 or 642 or ICD-10-CA
code I10 to I13, I15, or O10 to O16
or
- Drug Programs Information Network Database:
2 prescriptions for hypertension drugs (a list of these is
available on request from the authors)
or
- Maternal preexisting or gestational diabetes (see definition later in this table under “Covariates”)
or
- Placental abruption (ICD-9-CM code 641.2 or ICD-10-CA code O45 in Hospital Discharge Abstracts data)
or
- Placental previa (ICD-9-CM code 641.0, 641.1, or 762.0, or ICD-10-CA code O44 in Hospital Discharge
Abstracts data)
or
- Congenital anomaly in index child, considered to be present if any of the diagnostic codes used by the
Canadian Congenital Anomalies Surveillance Network25 were recorded in the Hospital Discharge Abstracts
data up to child’s first birthday.
If none of the above criteria was met and the child was born prior to 37 weeks’ GA, coded as “Spontaneous
preterm birth.” Otherwise, coded as “Term birth” (reference).
GA/size for gestation Coded as preterm, SGA; preterm, appropriate for GA (birth weight 10th to 90th percentile for GA and sex); preterm,
LGA (birth weight >90th percentile for GA and sex); term, SGA; term, LGA; term, appropriate for GA (reference).
(Note that a small proportion of births occurred at 42 or 43 weeks of gestation [2.1%; data not shown in tabular
format], and those were included in the “term” category.)
Covariates (reference categories are not shown, because findings for covariates are not presented in this paper)
Birth year Continuous variable, using the date of birth recorded on the newborn’s hospital birth record.
Child’s sex Recorded on the newborn’s hospital birth record.
Maternal age at delivery Calculated by subtracting the child’s date of birth from the mother’s date of birth. Categorized as <20, 20 to 24, 25 to
29, 30 to 34, 35 to 39, or
40 years.
Parity Parity is recorded on the hospital obstetrics record. Because of its highly skewed distribution, it was categorized as 1,
2, or
3. When there was no information about parity on the obstetrics record, coded as “Unknown.”
Adequacy of prenatal Measured using the R-GINDEX,26 which is derived using the GA at delivery, the trimester in which prenatal care
care began, and the number of prenatal care visits during pregnancy. The R-GINDEX is classified into five categories
of prenatal care utilization: no care; inadequate; intermediate; adequate; and intensive. If the R-GINDEX could not
be calculated due to missing or implausible values for any of the variables used in its derivation (for example, if
the trimester in which prenatal care began was “3” and the GA at delivery was <25 weeks), coded as “Unknown.”
Continued

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OBSTETRICS

Table 2. Continued
Graduated high school Coded as “Yes” if any of the following criteria were met:
(mother) - Mother responded “Graduated Grade 12 or GED” or “Post-secondary Degree or Certificate” on the Healthy
Baby Prenatal Benefit application
or
- Response to “Mother’s highest level of education completed is less than Grade 12” was “No” on the Families
First Screening form
or
- According to the Manitoba Enrollment, Marks, and Assessments dataset, the mother had graduated from
Grade 12 at the time of delivery of the index child.
Coded as “No” if any of the following criteria were met:
- Mother responded “Elementary, Less than Grade 9 ” or “Secondary, Grades 9-11” on the Healthy Baby
Prenatal Benefit application
or
- The “Low education status (i.e., did not complete Grade 12 or equivalent)” box on the BabyFirst screening
form was checked, or if the response to “Mother’s highest level of education completed is less than Grade
12” was “Yes” on the Families First screening form
or
- According to the Manitoba Enrollment, Marks, and Assessments dataset, the mother had not graduated from
grade 12 at the time of delivery of the index child.
Coded as “Unknown” if there was no record for the mother in the Healthy Baby Prenatal Benefit; BabyFirst/
Families First Screening; or Manitoba Enrollment, Marks, and Assessments datasets; or if there was no infor-
mation on high school graduation in any of those data sources.
Ever-receipt of income Coded as “Yes” if the mother had at least one record in the Social Assistance Management Information Network
assistance (mother) Research Data Set. Otherwise, coded as “No.”
Socioeconomic Factor A single factor score that is based on four variables that come directly or are derived from Census data (at the
Index-Version 2 dissemination area level) for the year closest to the child’s birth year: unemployment rate among those 15 or
(SEFI-2)27 older, average household income among those 15 or older, proportion of single parent households, and
proportion of those 15 or older who did not graduate high school. The SEFI-2 is a continuous variable. Negative
scores indicate more favourable neighbourhood socioeconomic conditions and positive scores indicate less
favourable socioeconomic conditions. Because the SEFI-2 scores in our cohort were not linear with respect to the
outcomes of interest, they were grouped into the following categories: <e3, e3 to <e1, e1 to <1, 1 to <3,
3, or
unknown (the SEFI-2 cannot be calculated if the postal code is not included in the postal code conversion file or if
census data were suppressed because of small cell counts).
Maternal smoking Coded as “Yes” if any of the following criteria were met:
during pregnancy - Any of “0” to “9” response options for “Maternal smoking during pregnancy” on BabyFirst screening form was
selected (all these response options indicate that the mother smoked during pregnancy)
or
- Response to “Maternal smoking during pregnancy” was “Yes” on Families First screening form
or
- Mother’s hospital delivery record indicated that she smoked while pregnant
or
- During pregnancy, at least one diagnostic code for smoking (ICD-9-CM 305.1; ICD-10-CA F17) was
recorded in the Hospital Discharge Abstracts data.
Coded as “No” if response to “Maternal smoking during pregnancy” was “No” on Families First screening form.
Otherwise, coded as “Unknown.”
Maternal alcohol Coded as “Yes” if any of the following criteria were met:
consumption during - Response to “Alcohol use during pregnancy” was “Yes” on Families First screening form
pregnancy or
- Mother’s hospital delivery record indicated that she consumed alcohol during pregnancy
or
- During pregnancy, at least one diagnostic code for alcohol consumption (ICD-9-CM 303; ICD-10-CA F10)
was recorded in the Hospital Discharge Abstracts data
or
- During pregnancy, at least one diagnostic code for alcohol consumption (ICD-9-CM 303) was recorded in the
Medical Services data
Coded as “No” if response to “Alcohol use during pregnancy” was “No” on Families First screening form.
Otherwise, coded as “Unknown.”
Continued

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Table 2. Continued
Maternal substance use
during pregnancy
Maternal chronic
hypertension
Preexisting or
gestational diabetes
Previous pregnancy
loss or stillbirth
Adverse perinatal Coded as “Yes” if the older sibling of the sibling pair was born preterm, had a low birth weight, or was SGA. If birth
outcome for older
sibling of sibling pair
Exclusion criteria
Multiple birth Recorded on hospital birth record. In the case of a multiple birth, coded as “Yes.” If singleton or multiple birth status
Lack of continuous The Research Registry was searched to ascertain whether the mother resided continuously in Manitoba between the
health coverage
between births
Pregnancy loss
between births
R-GINDEX: Revised-Graduated Prenatal Care Utilization Index; SEFI-2: Socioeconomic Factor Index-Version 2.
Interpregnancy Interval and Adverse Perinatal Outcomes
Coded as “Yes” if any of the following criteria were met:
- Response to “Current substance abuse by mother” was “Yes” on Families First screening form
or
- During pregnancy, at least one diagnostic code for substance use (ICD-9-CM 291, 292, 303 to 305; ICD-10-
CA F10, F55) was recorded in the Hospital Discharge Abstracts data
or
- During pregnancy, at least one diagnostic code for substance use (ICD-9-CM 291, 292, 303 to 305) was
recorded in the Medical Services data.
Coded as “No” if response to “Current substance abuse by mother” was “No” on Families First screening form.
Otherwise, coded as “Unknown.”
Coded as “Yes” if mother met any of the following criteria in 3-year period prior to start of index pregnancy,
excluding any codes recorded during other pregnancies within that 3-year period.
- Medical Services:
2 physician visits with ICD-9-CM code 401 to 405
or
- Hospital Discharge Abstracts:
1 hospitalization with ICD-9-CM code 401 to 405 or ICD-10-CA code I10 to
I13 or I15
or
- Drug Programs Information Network Database:
2 prescriptions for hypertension drugs (a list of these is
available on request from the authors).
Otherwise, coded as “No.”
Coded as “Yes” if mother met any of the following criteria:
- Medical Services:
2 physician visits with ICD-9 code 250 in 2-year period prior to beginning of index
pregnancy up to and including 20 weeks of gestation or
1 physician visit with ICD-9 code 250 at 21 weeks
of gestation up to index child’s birth
or
- Hospital Discharge Abstracts:
1 hospitalization with ICD-9-CM code 250, 648.0 or 648.8, or ICD-10-CA
code E10 to E14, 024, P70.0, P70.1, or R73.0 in 2-year period prior to beginning of index pregnancy up to
index child’s birth.
Otherwise, coded as “No.”
Coded as “Yes” if any of the following were recorded for the mother prior to the index child’s birth:
- Medical Services:
1 physician visit with ICD-9-CM code 630 to 632 or 634 to 637
or
- Hospital Discharge Abstracts:
1 hospitalization with ICD-9-CM code 630 to 632, 633.1, 633.2, 633.8, 633.9,
634 to 637, or 656.4, or ICD-10-CA code D39.2, O00 to O05, O08, O09, O36.4
or
- Fetal death at
20 weeks’ GA or birth weight
500 g.
weight was missing for the older sibling and he or she was not born preterm, coded as “Unknown.” Otherwise,
coded as “No.”
was missing in the birth record, coded as “Unknown.” Otherwise, coded as “No.” Sibling pairs for whom either
sibling had a “Yes” or “Unknown” value for this variable were excluded.
birth of the older sibling of the sibling pair and conception of the younger sibling (index child). If the registry
indicated any break in health coverage during that period, coded as “Yes.” Otherwise, coded as “No.” Sibling pairs
with a “Yes” value for this variable were excluded.
The Hospital Discharge Abstracts and Medical Services data were searched for the period between the births of
the older and younger siblings in each sibling pair for the following codes. If one of the following codes was found,
coded as “Yes.” Otherwise, coded as “No.”
- Medical Services: ICD-9-CM code 630 to 632 or 634 to 637
- Hospital Discharge Abstracts: ICD-9-CM code 630 to 632, 633.1, 633.2, 633.8, 633.9, 634 to 637, or 656.4 or
ICD-10-CA code D39.2, O00 to O05, O08, O09, or O36.4.
Sibling pairs with a “Yes” value for this variable were excluded.
JUNE JOGC JUIN 2017 l 425
OBSTETRICS
A priori, we selected the following covariates for inclusion
in the adjusted models (unless otherwise specified in
Table 2, these were measured in relation to the index child
[i.e., the younger sibling of the sibling pair]): birth year;
child’s sex; maternal age at delivery; parity; adequacy of
prenatal care (measured using the Revised-Graduated
Prenatal Care Utilization Index26); whether the mother
graduated high school or ever received income assistance;
a neighbourhood measure of socioeconomic status (the
Socioeconomic Factor Index-Version 227); whether the
mother smoked, drank alcohol, or used substances during
pregnancy; maternal chronic hypertension; preexisting or
gestational diabetes; whether the mother had any previous
pregnancy losses or stillbirths; and whether the older sib-
ling of the sibling pair was born preterm, had a low birth
weight, or was SGA. These covariates were selected based
on the following considerations/strategies: 1) Where
possible (i.e. the information was available in the data
sources housed at the Manitoba Centre for Health Policy),
we wanted to include in the adjusted models the same
factors that were controlled for in other studies of the IPI
and adverse perinatal outcomes (the “other studies”
comprised those that were included in two meta-analyses
published in 200612 and 2012,11 as well as a recent Cana-
dian study16); 2) We searched for papers that documented
associations between sociodemographic factors and the IPI
in developed countries,28,29 as well as review articles and
publications containing Canadian empirical data on risk
factors for preterm birth,30e32 low birth weight,33 and
SGA birth,31,34 to determine whether there were other
potentially important confounders that should be included
in the regression models; and 3) We did not want to adjust
for covariates that may lie on the pathway between the IPI
and the outcomes of interest, such as preeclampsia17 and
congenital anomalies.35e38
Analysis
The data were analysed at the Manitoba Centre for Health
Policy using SAS 9.4 (SAS Institute Inc., Cary, NC).
Unadjusted and adjusted logistic regression models were fit
to examine the association between the IPI and adverse
perinatal outcomes in the younger siblings of each sibling
pair (to avoid any confusion that might arise with the term
“sibling pairs,” our analysis constituted an examination of
the effects of the IPI between unrelated groups of younger
siblings; we did not examine the effects between siblings
from the same mother). Because two or more younger
siblings born to the same mother may have been included
in the cohort, we used the GENMOD procedure with the
REPEATED statement to fit generalized estimating
equations models and specified an exchangeable correla-
tion structure within mothers.
426 l JUNE JOGC JUIN 2017
Multinomial logistic regression models were fit to examine
the association between the IPI and the secondary outcomes.
The GENMOD procedure does not support unordered
multinomial modelling and therefore the SURVEYLO-
GISTIC procedure was used instead. Generalized estimating
equations modelling is not available with the latter, but the
“cluster” statement produces similar results.39
Data on smoking and alcohol consumption during preg-
nancy have been more routinely and reliably collected since
the Families First screening program was introduced in
Manitoba in 2003. We therefore conducted sensitivity
analyses for the main outcomes of preterm birth, low birth
weight, and SGA birth, in which the cohort of younger
siblings was restricted to those born from April 1, 2003 to
March 31, 2014 (“sensitivity cohort”). This also allowed us
to examine the association between the IPI and adverse
perinatal outcomes in a contemporary cohort with more
complete information on health-related behaviours.
All references to significance are based on a P value of <0.05.
Study Approvals
This study was approved by research ethics boards at
Queen’s University (PAED-361-14) and the University of
Manitoba (H2014:268) and by Manitoba’s Health Infor-
mation Privacy Committee (HIPC No. 2014/2015e13).
Approvals were also granted by Manitoba Education and
Training, Healthy Child Manitoba, and Manitoba Families
for the use of their data.
RESULTS
There were 448 638 hospital births in Manitoba between
April 1, 1985, and March 31, 2014. Records for a pro-
portionally small number of births (n ¼ 1886; 0.4%) could
not be linked to maternal records, and no siblings were
born over the study period for 92 078 individuals. The
remaining 354 674 births were grouped into 217 264 sibling
pairs. After the exclusion criteria were applied, 171 688
sibling pairs remained for the preterm birth analysis and
171 626 for the low birth weight and SGA analyses
(Figure 1). The number (%) of younger siblings who were
born preterm, had a low birth weight, or were SGA was
9116 (5.3%), 5624 (3.3%), and 10 906 (6.4%), respectively.
Table 3 provides characteristics of the main cohort
(younger siblings born April 1, 1987eMarch 31, 2014) and
the sensitivity cohort (younger siblings born April 1,
2003eMarch 31, 2014) for the preterm birth analysis
(corresponding data are not provided for the cohort used
for the low birth weight and SGA birth analyses: it

Figure 1. Selection of study cohorts.
Sibling pairs born in Manitoba to same mother between April 1, 1985, and March 31, 2014, inclusive (n = 217 264)
171 688 sibling pairs
Cohort for examining association between IPI and
preterm birth
included only 62 fewer individuals and therefore the dis-
tributions were almost identical). Table 4 provides the
unadjusted and adjusted ORs and 95% CIs for the IPI and
the primary and secondary outcomes (for the main cohort
only). Significant associations were detected between
IPIs of <12 months and
24 months and all three pri-
mary outcomes, although for the shortest IPIs
(<6 months), the observed effects were much stronger for
preterm birth and low birth weight than for SGA birth.
The findings for the sensitivity cohort were similar to those
for the main cohort (data not shown). The biggest
discrepancy between the two cohorts was for IPIs of
<6 months and low birth weight: in the main cohort the
adjusted OR was 1.70 (95% CI 1.52 to 1.91) and in the
sensitivity cohort it was 1.57 (95% CI 1.31 to 1.89), a
difference of 7.6% in the observed effect.
In terms of the secondary GA outcomes, for the shorter
(<12 months) and longest IPI (
60 months) categories,
the strongest associations were observed for early preterm
birth (<34 weeks’ GA) relative to birth at
39 weeks’
gestation (Table 4). Significant associations were also
detected for IPIs of <18 months and
24 months and
both medically indicated and spontaneous preterm birth,
relative to term birth (herein defined as delivery that
occurred at 37 to 43 weeks of gestation). However, IPIs of
60 months or longer were more strongly associated with
medically indicated than spontaneous preterm birth and
the CIs did not overlap. The shortest IPIs (<6 months)
Interpregnancy Interval and Adverse Perinatal Outcomes
Exclude multiple births and births where singleton/multiple status
unknown for either sibling of pair (n = 5815)
Exclude sibling pairs where either sibling stillborn (n = 1416)
Exclude sibling pairs where mother did not have continuous health
coverage between births (n = 2910)
Exclude sibling pairs where pregnancy loss recorded between births (n =
31 313)
Exclude sibling pairs where younger sibling born prior to April 1, 1987
(n = 1274)
Exclude sibling pairs where GA missing or <22 or >43 completed weeks
for either sibling (n = 2772)
Exclude sibling pairs where calculated IPI had negative value (n = 76)
Exclude sibling pairs where birth weight for younger
sibling unknown (n = 62)
Cohort for examining association between IPI and low
birth weight and SGA birth (n = 171 626)
were associated with significantly increased odds of pre-
term birth regardless of size for gestation (Table 4), and for
the longest IPIs (
60 months), the strongest association
observed was for preterm, SGA birth (although the CIs for
all preterm birth/size for gestation categories overlapped).
DISCUSSION
In our cohort, IPIs of <12 months and
24 months were
associated with significantly increased odds of preterm
birth, low birth weight, and SGA birth. IPIs of 12 to 17
months were also associated with small but significantly
increased odds of preterm birth (Table 4). A similar pattern
of associations was observed for both medically indicated
and spontaneous preterm births. Interestingly, in our
cohort there was a stronger association between IPIs of <6
months and preterm birth (adjusted OR 1.78; 95% CI 1.63
to 1.95) compared with that reported by Conde-Agudelo
et al. in their meta-analysis (pooled adjusted OR 1.40;
95% CI 1.24 to 1.58)12 and by Chen et al. for a Northern
Alberta cohort (adjusted OR 1.37; 95% CI 1.18 to 1.59),16
and the lower limit of our CI did not overlap with the
upper limits of their CIs. The reasons for this are un-
known, but it could be due to chance, population-specific
effectsdfor example, in the study by Chen et al., the
lowest risks were associated with IPIs of 12 to 17
months,16 whereas in our cohort, 18 to 23 months was the
lowest-risk categorydor methodologic differences. In
terms of the latter, a key difference between our study and
JUNE JOGC JUIN 2017 l 427
OBSTETRICS

Table 3. Characteristics of study populationa Table 3. Continued

Main cohort Sensitivity cohort Main cohort Sensitivity cohort
(younger siblings (younger siblings (younger siblings (younger siblings
born April 1, 1987 born April 1, 2003 born April 1, 1987 born April 1, 2003
to March 31, 2014) to March 31, 2014) to March 31, 2014) to March 31, 2014)
n ¼ 171 688 n ¼ 69 568 n ¼ 171 688 n ¼ 69 568
IPI in months, Socioeconomic Factor
n (%) Index-Version
<6 15 033 (8.8) 5731 (8.2) 2, n (%)
6 to 11 30 636 (17.8) 11 525 (16.6) <e3 421 (0.3) 55 (0.1)
12 to 17 34 379 (20.0) 13 840 (19.9) e3 to <e1 20 220 (11.8) 6510 (9.4)
18 to 23 26 317 (15.3) 10 624 (15.3) e1 to < 1 109 952 (64.0) 45 196 (65.0)
24 to 59 53 378 (31.1) 21 655 (31.1) 1 to <3 38 350 (22.3) 16 190 (23.3)

3 2247 (1.3) 1466 (2.1)

60 11 945 (7.0) 6193 (8.9)
Birth year, n (%) b Unknown 498 (0.3) 151 (0.2)
1987 to 1991 28 641 (16.7) e Maternal smoking
during pregnancy,
1992 to 1996 35 311 (20.6) e
n (%)
1997 to 2002 36 841 (21.5) e
Yes 22 129 (12.9) 16 607 (23.9)
2003 to 2008 36 344 (21.2) 35 017 (50.3)
No 50 425 (29.4) 49 681 (71.4)
2009 to 2014 34 551 (20.1) 34 551 (49.7)
Unknown 99 134 (57.7) 3280 (4.7)
Boy, n (%) 87 838 (51.2) 35 490 (51.0) Maternal alcohol
Maternal age at consumption
delivery in during pregnancy,
years, n (%) n (%)
<20 6817 (4.0) 2401 (3.5) Yes 6268 (3.7) 5838 (8.4)
20 to 24 34 739 (20.2) 13 388 (19.2) No 61 268 (35.7) 60 488 (86.9)
25 to 29 55 992 (32.6) 21 243 (30.5) Unknown 104 152 (60.7) 3242 (4.7)
30 to 34 51 546 (30.0) 21 495 (30.9) Maternal substance
35 to 39 19 734 (11.5) 9447 (13.6) use during

40 2860 (1.7) 1594 (2.3) pregnancy, n (%)
Parity, n (%) Yes 6126 (3.6) 1484 (2.1)
1 90 789 (52.9) 35 458 (51.0) No 32 352 (18.8) 31 571 (45.4)
2 44 250 (25.8) 17 372 (25.0) Unknown 133 210 (77.6) 36 513 (52.5)

3 35 950 (20.9) 16 455 (23.7) Maternal chronic 3229 (1.9) 1817 (2.6)
hypertension, n (%)
Unknown 699 (0.4) 283 (0.4)
Adequacy of prenatal Preexisting or 9338 (5.4) 4745 (6.8)
care, n (%) gestational
diabetes, n (%)
No care 296 (0.2) 135 (0.2)
Inadequate 39 674 (23.1) 9614 (13.8) Previous pregnancy 38 876 (22.6) 18 602 (26.7)
loss or stillbirth, n
Intermediate 76 195 (44.4) 35 181 (50.6) (%)
Adequate 29 175 (17.0) 20 592 (29.6) Adverse perinatal
Intensive 4288 (2.5) 3341 (4.8) outcomec for older
Unknown 22 060 (12.9) 705 (1.0) sibling of sibling
pair, n (%)
Mother graduated high
school, n (%) Yes 23 435 (13.7) 9124 (13.1)
Yes 34 333 (20.0) 33 295 (47.9) No 148 180 (86.3) 60 434 (86.9)
No 16 300 (9.5) 13 110 (18.8) Unknown 73 (0.04) 10 (0.01)
a
Unknown 121 055 (70.5) 23 163 (33.3) Cohort of younger siblings of sibling pairs used in analysis that examined
preterm birth as the outcome. The cohort for analyses of low birth weight and
Mother ever received 49 701 (28.9) 22 914 (32.9) SGA birth had 62 fewer individuals (n ¼ 171 626; see Figure 1).
income assistance, b
Modelled as a continuous variable.
n (%)
c
Preterm birth, low birth weight, or SGA.
Continued

428 l JUNE JOGC JUIN 2017

 Table 4. Unadjusted and adjusted ORs for the IPI and adverse perinatal outcomes among children born in Manitoba, relative to an IPI of 18 to 23 months
a
IPI (months)
<6 6 to 11 12 to 17 24 to 59
60
Unadjusted OR Adjustedb OR Unadjusted OR Adjustedb OR Unadjusted OR Adjustedb OR Unadjusted OR Adjustedb OR Unadjusted OR Adjustedb aOR
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
Preterm birth, n ¼ 9116 2.01 (1.84 to 2.19) 1.78 (1.63 to 1.95) 1.29 (1.19 to 1.39) 1.26 (1.16 to 1.36) 1.12 (1.04 to 1.21) 1.14 (1.05 to 1.24) 1.19 (1.11 to 1.28) 1.15 (1.07 to 1.24) 1.75 (1.60 to 1.92) 1.37 (1.24 to 1.51)
Low birth weight, n ¼ 5624 2.08 (1.87 to 2.32) 1.70 (1.52 to 1.91) 1.42 (1.28 to 1.57) 1.34 (1.21 to 1.48) 1.09 (0.99 to 1.21) 1.10 (0.99 to 1.22) 1.32 (1.20 to 1.45) 1.24 (1.13 to 1.36) 1.87 (1.66 to 2.10) 1.52 (1.34 to 1.72)
SGA birth, n ¼ 10 906 1.36 (1.26 to 1.48) 1.13 (1.04 to 1.23) 1.19 (1.11 to 1.27) 1.11 (1.03 to 1.19) 1.07 (1.00 to 1.14) 1.05 (0.98 to 1.13) 1.17 (1.10 to 1.25) 1.15 (1.08 to 1.23) 1.46 (1.34 to 1.59) 1.42 (1.30 to 1.56)
Secondary outcomes
GA
Early preterm,c n ¼ 2113 3.17 (2.68 to 3.75) 2.47 (2.07 to 2.94) 1.54 (1.31 to 1.82) 1.45 (1.23 to 1.70) 1.15 (0.97 to 1.36) 1.16 (0.98 to 1.38) 1.25 (1.07 to 1.46) 1.13 (0.97 to 1.32) 2.14 (1.77 to 2.59) 1.52 (1.25 to 1.86)
Late preterm,d n ¼ 7003 2.17 (1.97 to 2.39) 1.76 (1.59 to 1.95) 1.31 (1.20 to 1.43) 1.25 (1.14 to 1.37) 1.15 (1.05 to 1.25) 1.16 (1.06 to 1.27) 1.23 (1.13 to 1.33) 1.16 (1.07 to 1.27) 1.84 (1.66 to 2.04) 1.36 (1.21 to 1.52)
Early term,e n ¼ 35 591 1.30 (1.24 to 1.37) 1.25 (1.19 to 1.32) 1.05 (1.00 to 1.09) 1.06 (1.01 to 1.10) 1.02 (0.98 to 1.07) 1.04 (0.99 to 1.08) 1.05 (1.02 to 1.09) 1.02 (0.98 to 1.06) 1.29 (1.23 to 1.36) 1.05 (0.99 to 1.11)

39 weeks, n ¼ 126 981 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
Type of preterm birth
Medically indicated 1.88 (1.62 to 2.19) 1.70 (1.44 to 2.00) 1.27 (1.11 to 1.46) 1.29 (1.11 to 1.49) 1.14 (1.00 to 1.31) 1.19 (1.03 to 1.38) 1.31 (1.15 to 1.48) 1.26 (1.10 to 1.44) 2.64 (2.28 to 3.06) 1.71 (1.45 to 2.02)
preterm birth,f
n ¼ 2994
Spontaneous preterm 2.41 (2.18 to 2.66) 1.83 (1.65 to 2.03) 1.38 (1.25 to 1.51) 1.26 (1.14 to 1.38) 1.14 (1.04 to 1.26) 1.13 (1.03 to 1.25) 1.18 (1.08 to 1.28) 1.10 (1.01 to 1.21) 1.40 (1.24 to 1.58) 1.20 (1.06 to 1.36)
birth, n ¼ 6122
Term birth,g n ¼ 162 572 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
GA/size for gestation
Preterm birth, SGA, 1.96 (1.41 to 2.72) 1.48 (1.06 to 2.08) 1.33 (0.99 to 1.79) 1.23 (0.91 to 1.66) 0.92 (0.67 to 1.26) 0.94 (0.68 to 1.28) 1.54 (1.18 to 2.02) 1.40 (1.07 to 1.83) 2.62 (1.90 to 3.60) 1.91 (1.36 to 2.66)
n ¼ 645
Preterm birth, AGA, 2.36 (2.14 to 2.60) 1.87 (1.69 to 2.08) 1.38 (1.26 to 1.51) 1.29 (1.18 to 1.42) 1.18 (1.08 to 1.30) 1.19 (1.08 to 1.31) 1.23 (1.13 to 1.34) 1.16 (1.07 to 1.27) 1.82 (1.63 to 2.02) 1.43 (1.28 to 1.61)
n ¼ 6769

Interpregnancy Interval and Adverse Perinatal Outcomes

Preterm birth, 2.02 (1.68 to 2.44) 1.56 (1.28 to 1.91) 1.21 (1.01 to 1.44) 1.13 (0.94 to 1.36) 1.06 (0.89 to 1.27) 1.07 (0.89 to 1.28) 1.14 (0.97 to 1.34) 1.12 (0.95 to 1.32) 1.79 (1.46 to 2.20) 1.19 (0.95 to 1.48)
LGA, n ¼ 1679
Term birth,g 1.44 (1.32 to 1.57) 1.15 (1.05 to 1.26) 1.20 (1.11 to 1.29) 1.10 (1.03 to 1.19) 1.06 (0.99 to 1.14) 1.06 (0.98 to 1.14) 1.18 (1.10 to 1.26) 1.15 (1.07 to 1.23) 1.49 (1.36 to 1.62) 1.42 (1.30 to 1.56)
SGA, n ¼ 10 261
Term birth,g LGA, 0.92 (0.86 to 0.97) 0.89 (0.84 to 0.94) 0.93 (0.89 to 0.97) 0.92 (0.87 to 0.96) 0.97 (0.92 to 1.01) 0.96 (0.92 to 1.01) 1.01 (0.97 to 1.05) 1.01 (0.97 to 1.05) 1.05 (0.99 to 1.12) 0.96 (0.90 to 1.02)
n ¼ 25 855
Term birth,g AGA, 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
n ¼ 126 417
SGA: birth weight <10th percentile for GA and sex; AGA: appropriate for GA (birth weight 10th to 90th percentile for GA and sex); LGA: birth weight >90th percentile for GA and sex.
a
Reference category (18 to 23 months) not shown.
b
Adjusted for birth year, child’s sex, maternal age at delivery, parity, adequacy of prenatal care, whether mother graduated high school, whether mother ever received income assistance, Socioeconomic Factor Index-
JUNE JOGC JUIN 2017

Version 2, maternal smoking during pregnancy, maternal alcohol consumption during pregnancy, maternal substance use during pregnancy, chronic hypertension, preexisting or gestational diabetes, any previous
pregnancy losses or stillbirths, and outcome of previous birth (whether preterm, low birth weight, or SGA).
c
<34 weeks’ GA.
d
34 to 36 weeks’ GA.
e
37 to 38 weeks’ GA.
f
Medically indicated preterm birth was defined as birth at less than 37 weeks’ GA accompanied by one or more of the following conditions: gestational hypertension, preexisting or gestational diabetes, placental abruption,
placenta previa, infant diagnosed with congenital anomaly (see Table 2). All other preterm births were defined as spontaneous.
g
37 to 43 weeks’ GA.
l
429
OBSTETRICS
the one by Chen et al.,16 as well as many of the studies
included in the meta-analysis by Conde-Agudelo et al.,12 is
that we excluded pairs of live-born siblings when a preg-
nancy loss occurred between the two births. Failure to
exclude these sibling pairs would result in some misclas-
sification of exposure12 and could attenuate the observed
associations for shorter IPIs.
As previously noted, the studies included in the 2006 meta-
analysis12 and a subsequent one published in 2012 that
confined its investigation to short IPIs11 were largely
conducted in the United States and developing countries.
Although the inclusion of American data suggests that the
associations observed between the IPI and adverse peri-
natal outcomes are not confined to developing countries,40
our findings with those of Chen et al.16 and Basso et al.41
demonstrate that birth spacing is also associated with an
increased risk of certain adverse perinatal outcomes in
developed countries with universal health care. The latter
characteristic may be an important factor when considering
population-specific effects41 because it may have an impact
on access to prenatal care (although the data pertaining to
adequacy of prenatal care in our cohort [Table 3] illustrate
that universal health care does not necessarily translate into
equal access/utilization).
IPIs of <6 months were associated with significantly
increased odds of preterm birth for all size for gestation
categories (relative to IPIs of 18 to 23 months and
appropriate for GA term births; Table 4). A priori power
calculations were performed to ensure that our study
would have >80% power to detect effect sizes as low as
1.30 for the shortest (<6 months) and longest (
60
months) IPIs and the primary outcomes. Similar calcula-
tions were not performed for the secondary outcomes, and
thus our findings for those outcomes should be considered
exploratory and are meant to provide data for generating
hypotheses. For example, the strongest point estimate
observed in relation to the longest IPIs (
60 months) was
for preterm, SGA birth (Table 4). This may be a particu-
larly vulnerable group in terms of increased morbidity and
mortality,19 and thus it may be worthwhile in a future study
to test the hypothesis that long IPIs are more strongly
associated with being born preterm and SGA (compared
with being born preterm or SGA, not both).
We are not aware of any national recommendations per-
taining to birth spacing in Canada, although at least one
health unit in Ontario advises that mothers are at greater
risk of preterm delivery when the time between birth and
subsequent conception is <18 or >59 months,42 and Zhu
and Le suggest an optimal IPI of 18 to 23 months.43
430 l JUNE JOGC JUIN 2017
Uniform recommendations may be difficult to implement
because they would need to take into account the findings
of studies examining a variety of outcomes, which again,
may be population-specific. Any such recommendations
would also, presumably, be premised on a causal associa-
tion between the IPI and these outcomes. One of the
strongest criteria for causality in observational studies is
consistency of an association.44 All three primary outcomes
meet this criterion if one takes the results of the 2006 meta-
analysis12 as indicative of overall consistencydalthough it
is important to note that there was statistical heterogeneity
among the studies includeddand those of a more recent
meta-analysis of short IPIs and preterm birth and low birth
weight.11
In terms of biologic plausibility, various hypotheses have
been proposed to explain how both short and long IPIs
may lead to adverse perinatal outcomes. These include, for
short IPIs, insufficient recovery of maternal nutrients to
the extent that fetal development is affected, and unre-
solved intrauterine inflammation from the previous preg-
nancy.1,45 Either hypothesis could account for the
increased odds of both medically indicated and sponta-
neous preterm births observed for short IPIs in our cohort
(Table 4): deficiencies in micronutrients and inflammation
have been associated with spontaneous preterm delivery,46
and they may also cause complications related to placental
dysfunction, which could result in medically indicated
preterm delivery.45
“Physiological regression,” or the process whereby a
woman’s body slowly returns to a nulligravida state
following pregnancy, is one hypothesis to explain how long
IPIs may increase the risk of adverse perinatal outcomes.
The researchers who formulated this hypothesis based it
on the observation that births among primigravid women
and long IPIs were both associated with an increased risk
of adverse perinatal outcomes in their cohort.47 However,
they also acknowledged that metabolic or other factors
may confound the association if such factors increase the
risk of adverse birth outcomes and also affect fertility, thus
contributing to longer IPIs.
Long IPIs may also affect the risk of preterm birth through
some mediating factor. For example, they have been
associated with an increased risk of preeclampsia,17 which
is an indication for preterm delivery.48 Although our study
was not designed to test mechanistic hypotheses, if pre-
eclampsia (or gestational hypertension) at least partially
mediates the association, it could explain why long IPIs
(
60 months) were more strongly associated with medi-
cally indicated than spontaneous preterm birth in our

cohort (Table 4). Gestational hypertension also increases
the risk of SGA birth,49 and the stronger association
observed for SGA birth and IPIs of 60 months or longer
(compared with SGA birth and IPIs of <6 months) lends
further, albeit indirect support for the hypothesis of an
effect mediated by gestational hypertension/preeclampsia
(Table 4).
Another measure used to assess potential causality is the
presence of a dose-response effect. We observed a type
of dose-response effect in our study, with the associa-
tions growing stronger for all three primary outcomes
moving in both directions away from the reference
category of 18 to 23 months (Table 4). Similarly, the
associations for the shortest and longest IPIs exhibited a
gradient in terms of the observed effects across gesta-
tional age categories.
Despite this support for a causal association, a group of
researchers recently analyzed the same dataset using a
more traditional cohort design (similar to the one described
here) and a sibling comparison design.50 The odds of
preterm birth, low birth weight, and SGA birth were
significantly increased for short and long IPIs in the overall
cohort, but the effects were attenuated and no longer
significant when the association was investigated within
matched pairs of siblings nested in the cohort. The re-
searchers concluded that the positive associations reported
in other studies were likely due to unmeasured con-
founding, although a more recent and larger study reported
that the significant association between short IPIs and
preterm birth persisted in their sibling comparison analysis
(they did not examine other outcomes).51 Thus, it appears
that the correlation versus causation debate has not been
resolved with respect to the IPI and adverse perinatal
outcomes.52 (The number of mothers with at least three
live births over the study period was too small in our
cohort to perform a sibling comparison analysis.)
Potential Limitations
Manitoba’s administrative health data capture information
on almost all residents’ encounters with the health care
system. Although our cohort only included hospital births,
these account for the vast majority of births in Manitoba32
and thus our cohort can be considered truly population-
based. Nevertheless, the use of administrative data to
study the impact of the IPI has drawn criticism53 because
such data may lack information on stillbirths and preg-
nancy losses, which would preclude the calculation of the
true interval between the end of one pregnancy and sub-
sequent conception. This type of information is captured
in Manitoba’s data, and we were able to exclude stillbirths
Interpregnancy Interval and Adverse Perinatal Outcomes
and sibling pairs where a known pregnancy loss occurred
between the two births (although it is likely that not every
pregnancy loss was recorded).
A further criticism of using administrative data to study the
effects of the IPI concerns the absence of information on
key confounders, such as outcome (e.g., GA) of the pre-
vious birth.53 Again, this information is available in Man-
itoba’s administrative data and we were able to control for
it and for a broad range of other potential confounders. We
were unable to control for all potentially confounding
variables, however, such as duration of breastfeeding for
the older sibling of the sibling pair and maternal BMI.
These may be important covariates in relation to the hy-
pothesis discussed earlier concerning insufficient recovery
of maternal nutrients. Moreover, certain variables (e.g.,
maternal education) had large numbers of missing values,
which hindered our ability to fully control for their effects.
Misclassification may also have been an issue with some of
the study variables we used. For example, prior to 2001
physicians billed for all prenatal services using a global
tariff (as of 2001, these services have been billed on a per-
visit basis). Accordingly, prenatal care visits in outpatient
settings may have been undercounted prior to 2001, which
may have affected the accuracy of the derived variable used
to characterize the adequacy of prenatal care. This could
account for the differences in the proportions of those
whose prenatal care was classified as “inadequate” and
“adequate” between the main and sensitivity cohorts
(Table 3). Several variables (e.g., smoking) were based on
maternal self-report, which could also have resulted in
misclassification (although many of the observed associa-
tions for these variables were in the expected direction; e.g.,
smoking was associated with a significantly increased risk
of low birth weight [data not shown]). The definition of
medically indicated (vs. spontaneous) preterm birth was
based on the presence of medical or obstetric indications
for preterm delivery.24 This administrative definition was
necessitated by the fact that there is no variable that directly
captures this information in the data sources used. Of
note, however, is that 32.8% of preterm births in our
cohort were classified at medically indicated (Table 4),
which accords with the proportions reported
elsewhere.42,54
Because many of those included in our cohort were born
prior to the routine use of ultrasound for estimating GA,
it is possible that GA was misclassified for some mem-
bers of the cohort. Given that even an error of 4 weeks in
the recorded GA would equate to at most 1 month of
difference between the calculated and actual IPI, this
JUNE JOGC JUIN 2017 l 431
OBSTETRICS
would have little impact in terms of misclassification of
the exposure. Inaccuracies in estimating the GA at birth
could also have resulted in some misclassification of
preterm birth status. Because the parameter estimates for
preterm birth were very similar for the main and sensi-
tivity cohorts (data not shown)dthe latter of which was
restricted to births from April 1, 2003, onwards and thus
to a period when ultrasound dating would have been
more routinely useddwe suspect that any such misclas-
sification had little impact on the findings for the overall
cohort.
Finally, the large number of analyses and comparisons
undertaken increased the probability of type 1 errors. Thus,
although our findings for the primary outcomes are
generally consistent with those from previous studies, any
statistically significant results for the secondary outcomes
should be interpreted with some caution.
CONCLUSION
If the reported associations between the IPI and adverse
perinatal outcomes are causal, birth spacing could form an
important target of public health messaging in Canada.
Given the findings of two recent studies that provide
conflicting evidence in terms of causality (at least for short
IPIs and preterm birth),50,51 additional research is war-
ranted that incorporates methods that will allow for
stronger inferences regarding causality.55 In the meantime,
it would be prudent to advise women and families on the
current state of evidence so they may judge the risks for
themselves, and to continue efforts to support women in
making informed choices about their reproductive health.
ACKNOWLEDGEMENTS
This work was supported by an operating grant from the
Children’s Hospital Foundation of Manitoba and the
Manitoba Institute of Child Health (now the Children’s
Hospital Research Institute of Manitoba). The authors
acknowledge the Manitoba Centre for Health Policy for
use of data contained in the Manitoba Population Research
Data Repository (Health Information Privacy Committee
[HIPC] No. 2014/2015e13). The results and conclusions
are those of the authors and no official endorsement by the
Children’s Hospital Foundation of Manitoba, the Children’s
Hospital Research Institute of Manitoba, the Manitoba
Centre for Health Policy, Manitoba Health, Seniors and
Active Living, or other data providers is intended or should
be inferred. Data used in this study are from the Manitoba
Population Research Data Repository housed at the
Manitoba Centre for Health Policy, University of Manitoba,
432 l JUNE JOGC JUIN 2017
and were derived from data provided by Manitoba Health,
Seniors and Active Living, Manitoba Education and
Training, Healthy Child Manitoba, and Manitoba Families.
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