Nutrition, Metabolism & Cardiovascular Diseases (2017) 27, 723e730

Available online at www.sciencedirect.com

Nutrition, Metabolism & Cardiovascular Diseases

journal homepage: www.elsevier.com/locate/nmcd

Maternal pre-gravid cardiometabolic health and infant birthweight:

A prospective pre-conception cohort study
R. Retnakaran a,b,*,1, S.W. Wen c,d,e,1, H. Tan e,1, S. Zhou f, C. Ye a, M. Shen c,d,e,
G.N. Smith g, M.C. Walker c,d
a
Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada
b
Division of Endocrinology, University of Toronto, Toronto, Ontario, Canada
c
OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Canada
d
Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Canada
e
School of Public Health, Central South University, Changsha, China
f
Liuyang Municipal Hospital of Maternal and Child Health, Beizheng, Liuyang, China
g
Queen’s Perinatal Research Unit, Department of Obstetrics and Gynecology, Queen’s University, Kingston, Canada

Received 6 February 2017; received in revised form 11 May 2017; accepted 12 May 2017
Available online 23 May 2017

KEYWORDS Abstract Background and aims: Both low birthweight and high birthweight have been associ-
Cardiovascular risk ated with the development of cardiometabolic disease in adulthood, possibly reflecting the effect
factors; of intrauterine fetal programming. As developmental programming can begin before conception,
DOHaD; pre-gravid factors that predict birthweight may be relevant in this context. However, little is
Predictors; known about such factors. Thus, we established a pre-conception cohort to identify maternal
Birthweight pre-gravid cardiometabolic determinants of infant birthweight.
Methods and results: In this prospective observational cohort study, 1484 newly-married women
in Liuyang, China, underwent baseline (pre-gravid) evaluation and then were followed across a
subsequent pregnancy. Pre-gravid cardiometabolic characterization consisted of clinical (anthro-
pometry, blood pressure) and biochemical evaluation (total/LDL/HDL cholesterol, triglycerides,
glucose) at median 20 weeks before a singleton pregnancy. Mean birthweight was
3294
444 g, with 173 neonates large-for-gestational-age (LGA) and 110 small-for-
gestational-age (SGA). On multiple linear regression analysis, positive determinants of birth-
weight were maternal age, pre-gravid body mass index (BMI), weight gain in pregnancy, length
of gestation, and male infant (all p  0.0003). On logistic regression analysis, independent
predictors of an LGA delivery were maternal age (OR Z 1.10 per year, 95%CI 1.03e1.18), pre-
gravid BMI (OR Z 1.21 per kg/m2, 1.07e1.37), and gestational weight gain (OR Z 1.10 per kg,
1.06e1.14). The only independent predictor of SGA was gestational weight gain (OR Z 0.93
per kg, 0.89e0.97).
Conclusion: Maternal weight before and during pregnancy is the predominant cardiometabolic
determinant of infant birthweight, rather than pre-gravid blood pressure, glucose or lipid profile.
ª 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the
Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Feder-
ico II University. Published by Elsevier B.V. All rights reserved.

Abbreviations: DOHaD, Developmental Origins of Health and Disease; GDM, gestational diabetes mellitus; HDL, high-density-lipoprotein;
LDL, low-density-lipoprotein; LGA, large-for-gestational-age; SGA, small-for-gestational-age.
* Corresponding author. Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, 60 Murray Street, Suite-L5-039, Mailbox-21, Toronto, Ontario,
M5T3L9 Canada. Fax: þ416 586 8853.
E-mail address: ravi.retnakaran@sinaihealthsystem.ca (R. Retnakaran).
1
These authors have contributed equally to this study.

http://dx.doi.org/10.1016/j.numecd.2017.05.005
0939-4753/ª 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical
Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
724
Introduction
In the past two decades, high birthweight and particu-
larly low birthweight have been linked to the subsequent
development of cardiometabolic disease in adulthood,
including type 2 diabetes and coronary artery disease
[1e7]. The Developmental Origins of Health and Disease
(DOHaD) paradigm posits that intrauterine programing of
fetal biochemical pathways may contribute to such as-
sociations, wherein birthweight is a composite marker of
developmental exposures in utero and genetic/environ-
mental factors that together may determine later-life
disease trajectories [1]. Accordingly, there is growing
interest in understanding determinants of the intrauter-
ine environment [8], the optimization of which could
provide a means for reducing the likelihood of adult
disease in the offspring [9]. Since effects on develop-
mental programming potentially could begin before
conception and may affect the critical peri-conceptual
environment, pre-gravid factors that predict infant
birthweight are of interest in this context [10]. However,
to date, studies addressing this question [11e13] have
been limited by retrospective designs, thereby precluding
the comprehensive evaluation of both (i) pre-gravid car-
diometabolic risk factors (including anthropometry,
blood pressure, lipid profile, and glycemia) and (ii) rele-
vant antepartum features, such as gestational weight
gain. Thus, in light of this background, we established a
unique prospective pre-conception cohort to compre-
hensively evaluate the maternal pre-gravid car-
diometabolic determinants of infant birthweight.
Methods
Study population
The current analysis was conducted in the setting of an
ongoing prospective observational cohort study, in which
women in the Liuyang region of Hunan province in China
are being recruited at the time of marriage to participate in
a pre-conception cohort [14,15]. In this study, participating
women undergo pre-gravid cardiometabolic characteriza-
tion at recruitment and then, whenever they subsequently
become pregnant, are followed across the pregnancy up to
delivery. Since February 2009, 3375 have been recruited
into this cohort, of whom 2382 have become pregnant. Of
these, 1546 women had complete pre-gravid car-
diometabolic measurements and delivery data with a
singleton pregnancy. After exclusion of 51 women who
were >5 weeks pregnant at baseline assessment (based on
their gestational age at delivery) and 11 others with
weight loss during pregnancy of implausible magnitude,
the study population for the current analysis consisted of
1484 women. The study has been approved by the insti-
tutional research ethics boards of Central South University
(Changsha, Hunan, China), Ottawa Hospital Research
Institute (Ottawa, Canada), and Mount Sinai Hospital
(Toronto, Canada), and all participants have provided
written informed consent.
R. Retnakaran et al.
Recruitment and pre-gravid assessment
The cost-efficient formation of a pre-conception cohort
requires the capacity to identify women who are likely to
get pregnant in the near future. In Liuyang, women typi-
cally attend a pre-marriage health clinic for assessment at
the time of marriage registration. Thus, for this cohort,
women who were planning to have a baby in the next 6
months were recruited from these clinics at Liuyang
Maternal and Infant Hospital. After recruitment, partici-
pants were asked to undergo overnight fast and then
attend a baseline assessment that consisted of (i)
interviewer-administered questionnaires that provide data
on demographic characteristics, lifestyle, and medical
history, (ii) physical examination (including measurement
of height, weight, waist circumference, and blood pres-
sure), and (iii) blood tests for measurement of lipid profile
and glucose. The pre-gravid cardiometabolic character-
ization thus consists of the following components:
(i) Anthropometry e Anthropometric measurements
included weight, height, waist circumference and
calculated body mass index (BMI). The assessors were
trained to provide standardized measurements.
(ii) Blood pressure (BP) e Systolic BP and diastolic BP
were measured using automated non-invasive blood
pressure monitors (BpTRU) in a seated position, after
10 min rest. BP was measured twice 10 min apart,
with the average recorded.
(iii) Biochemical measurement of blood glucose and
lipid profile e Blood samples were put on ice
immediately after collection, transported to the
laboratory within 30 min, and centrifuged at 4  C
and 3000 rpm for 10 min. Tests were performed in
the central laboratory of Central South University.
Total cholesterol, high-density-lipoprotein (HDL)
cholesterol, triglycerides and glucose were measured
by standard clinical biochemistry. Low-density-
lipoprotein (LDL) cholesterol was determined by
Friedewald equation.
Assessment at delivery
Data collected at delivery included gestational age (based
on last menstrual period), total weight gain in pregnancy,
major maternal medical complications in pregnancy
(including gestational diabetes mellitus and pre-
eclampsia), infant sex, and birthweight. Large-for-
gestational-age (LGA) was defined as birthweight for
gestational age above the 90th percentile according to
birthweight centiles for a Chinese population [16]. Small-
for-gestational-age (SGA) was defined as birthweight for
gestational age below the 10th percentile on birthweight
centiles for a Chinese population [16].
Statistical analyses
All analyses were performed using SAS 9.4 (SAS Institute,
Cary, NC). Continuous variables were tested for normality
Pre-gravid predictors of birthweight
of distribution, with natural log-transformation applied
where necessary for skewed variables. The study popula-
tion was first stratified into the following three groups:
women who delivered an SGA infant, women who deliv-
ered an appropriate-for-gestational-age (AGA) infant and
women who delivered an LGA infant. Continuous variables
were compared using analysis of variance for those that
were normally-distributed and Wilcoxon Rank-Sum non-
parametric test for those that were skewed. Categorical
variables were compared using chi-square or Fisher’s exact
test. Pairwise differences between groups were assessed
by t-test, without adjustment for multiple comparisons, at
significance level of p Z 0.05. Furthermore, we stratified
the study population into quintiles based on infant birth-
weight and compared characteristics across these groups
at pre-gravid and delivery, respectively.
Multiple linear regression analysis was conducted to
identify independent determinants of infant birthweight
(dependent variable). Covariates in this model included
pre-gravid factors (maternal age, maternal years of edu-
cation, BMI, waist circumference, systolic BP, LDL choles-
terol, HDL cholesterol, triglycerides, blood glucose) and
relevant antepartum factors that are known or expected to
influence birthweight (length of gestation, weight gain in
pregnancy, gestational diabetes, infant sex). Covariates
were tested for collinearity by variance inflation factor. A
simple linear regression of each covariate was also con-
ducted in parallel to determine the unadjusted association
with infant birthweight. Mean arterial blood pressure was
calculated as diastolic BP þ (systolic BP  diastolic BP)/3.
Logistic regression analysis was conducted to identify
independent determinants of LGA (dependent variable).
This model included the same covariates as the multiple
linear regression of birthweight, with the exception of
length of gestation and infant sex (as both are incorpo-
rated into the definition of LGA). A simple logistic regres-
sion was also applied to each covariate to examine its
unadjusted association with LGA. The same approach was
applied to logistic regression analysis of dependent vari-
able SGA, with the same covariates as those for the LGA
model.
For the multiple linear regression model of birthweight
and the logistic regression models of LGA and SGA, we also
performed sensitivity analyses with restriction of the
study population to the women with term pregnancies
only (n Z 1431).
Results
The study population consisted of 1484 women who had
completed a singleton pregnancy. These women under-
went their baseline assessment at median 20 weeks before
their pregnancy and were of mean age 24.6
3.0 years,
with mean pre-gravid BMI 20.0
2.3 kg/m2. Only 6
women smoked, consistent with the low rate of smoking
that has been reported amongst women in China [17]. The
mean length of gestation of their pregnancies was
39.0
1.3 weeks and mean infant birthweight was
3294
444 g. Comparison of the 1484 women comprising
725
the study population with the 993 women who had not
yet had a pregnancy revealed similar age but higher
baseline BMI (mean 20.6 vs 20.0 kg/m2, p Z 0.0002) in
those that had not yet had a pregnancy (data not shown).
Table 1 shows the pre-gravid characteristics and ob-
stetric outcomes of the study participants, stratified into
the following 3 groups: (i) women who delivered an SGA
infant (n Z 110), (ii) women who delivered an AGA infant
(n Z 1201), and (iii) women who delivered an LGA infant
(n Z 173). Pre-gravid factors that differed between these
groups were age (p < 0.0001), BMI (p < 0.0001), and waist
circumference (p < 0.0001).
Table 2 shows the pre-gravid characteristics and ob-
stetric outcomes of the study participants, stratified into
quintiles of infant birthweight. At the pre-gravid assess-
ment, there was a progressive step-wise increase in
maternal BMI (p < 0.0001) and waist circumference
(p < 0.0001) from the women in the lowest quintile of
subsequent infant birthweight to those in each of the
higher quintiles. The groups also differed in maternal age
(p Z 0.03) and HDL cholesterol (p Z 0.03), but there were
otherwise no significant differences in other lipid mea-
sures, blood glucose, blood pressure, and smoking status.
At delivery, weight gain in pregnancy (p Z 0.0005) pro-
gressively increased from the lowest to the highest quin-
tile. The proportion of male infants similarly increased
across the quintiles, as expected.
Determinants of infant birthweight
We evaluated determinants of infant birthweight in the
study population, after exclusion of the 17 women who
had pre-eclampsia and the 6 women who smoked. The
unadjusted associations between maternal-fetal factors
and birthweight are shown in Table 3. On unadjusted
analysis, maternal age, BMI, waist circumference, weight
gain in pregnancy, GDM, length of gestation, and male
infant were all associated with higher birthweight. On
multiple regression analysis with complete adjustment for
covariates (Table 3), positive determinants of birthweight
were maternal age (p Z 0.0003), pre-gravid BMI
(p < 0.0001), weight gain in pregnancy (p < 0.0001),
length of gestation (p < 0.0001), and male infant
(p < 0.0001). This model explained 29.5% of the variance
in birthweight. Of note, pre-gravid blood pressure, lipid
profile, and blood glucose were not independent pre-
dictors of birthweight. Furthermore, these results were
unchanged in a sensitivity analysis restricted to the
women who with term pregnancies (data not shown).
On logistic regression analysis (Fig. 1), after complete
adjustment for covariates, the significant pre-gravid pre-
dictors of delivery of an LGA infant were maternal age
(OR Z 1.10 per year, 95%CI 1.03e1.18; OR Z 1.34 per SD,
95%CI 1.11e1.63) and BMI (OR Z 1.21 per kg/m2, 1.07e1.37;
OR Z 1.55 per SD, 1.18e2.04), while weight gain in preg-
nancy was an antepartum predictor (OR Z 1.10 per kg,
1.06e1.14; OR Z 1.81 per SD, 1.46e2.24). These results
were unchanged in the sensitivity analysis restricted to
term pregnancies (data not shown).
726 R. Retnakaran et al.

Table 1 Demographic, clinical and metabolic characteristics of the overall study population and this population stratified into the following 3
groups: (i) women who delivered a small-for-gestational-age (SGA) infant; (ii) women who delivered an appropriate-for-gestational-age (AGA)
infant; and (iii) women who delivered a large-for-gestational-age (LGA) infant.

Characteristics Overall SGA AGA LGA p

N Z 1484 n Z 110 n Z 1201 n Z 173
Pre-gravid
Age (y) 24.6 (3.0) 24.2 (3.0)c 24.5 (2.9) 25.5 (3.9)b <0.0001
Years of education (y) 10.9 (2.7) 10.5 (2.3)a 11.0 (2.7) 10.8 (3.1) 0.0942
Smoke (n (%)) 6 (0.4) 0 (0) 3 (0.3) 3 (1.7)b 0.0126
BMI (kg/m2) 20.0 (2.3) 19.5 (1.9)c 19.9 (2.2) 21.1 (2.8)b <0.0001
BMI category <0.0001
<25 kg/m2 (%) 96.8 100c 97.8 88.5b
25e30 kg/m2 (%) 3.0 0 2.1 10.7
30 kg/m2 (%) 0.2 0 0.1 0.8
Waist (cm) 70.3 (7.4) 69.0 (6.7)c 70.0 (7.2) 73.4 (8.6)b <0.0001
Systolic BP (mm Hg) 111.4 (12.1) 112.0 (12.6) 111.3 (12.1) 111.3 (11.3) 0.9553
Diastolic BP (mm Hg) 71.1 (8.7) 71.2 (8.8) 71.1 (8.8) 71.5 (8.4) 0.7982
Mean arterial BP (mm Hg) 84.5 (9.3) 84.7 (9.5) 84.5 (9.4) 84.8 (8.9) 0.9015
Total cholesterol (mmol/L) 3.78 (1.09) 3.79 (1.21) 3.77 (1.09) 3.89 (0.99) 0.4066
LDL cholesterol (mmol/L) 2.09 (0.77) 2.01 (0.69)c 2.08 (0.78) 2.20 (0.73) 0.0857
HDL cholesterol (mmol/L) 1.52 (0.45) 1.54 (0.52) 1.53 (0.46) 1.45 (0.35)b 0.0720
Triglycerides (mmol/L) 0.87 (0.62, 1.28) 0.84 (0.60, 1.17) 0.86 (0.62, 1.28) 0.94 (0.63, 1.32) 0.4370
Blood glucose (mmol/L) 4.6 (1.1) 4.7 (0.9) 4.5 (1.1) 4.6 (1.0) 0.6038
In pregnancy
Length of gestation (weeks) 39.0 (1.3) 38.8 (1.5)c 39.0 (1.3) 39.2 (1.1) 0.0675
Weight gain in pregnancy (kg) 17.3 (6.2) 14.9 (5.7)a,c 17.0 (6.0) 20.3 (7.2)b <0.0001
Gestational diabetes (n (%)) 33 (2.22) 0 (0)c 19 (1.58) 14 (8.09)b <0.0001
Pre-eclampsia (n (%)) 17 (1.15) 5 (4.55)a,c 11 (0.92) 1 (0.58) 0.0132
Infant sex 0.3401
Male (n (%)) 774 (52.2) 50 (45.5) 632 (52.6) 92 (53.2)
Female (n (%)) 710 (47.8) 60 (54.5) 569 (47.4) 81 (46.8)
Birthweight (g) 3294 (444) 2572 (271)a,c 3254 (311) 4033 (287)b <0.0001
Continuous variables are presented as mean followed by standard deviation in parentheses, with the exception of triglycerides which
are presented as median (interquartile range). Categorical variables are presented as n or proportions.
a
Denotes p < 0.05 for women who delivered SGA vs women who delivered AGA.
b
Denotes p < 0.05 for women who delivered LGA vs women who delivered AGA.
c
Denotes p < 0.05 for women who delivered SGA vs women who delivered LGA.

On logistic regression analysis (Fig. 2), after complete
adjustment for covariates, none of the pre-gravid mea-
sures were significant independent predictors of SGA.
Instead, amongst antepartum factors, gestational weight
gain was inversely associated with the risk of SGA
(OR Z 0.93 per kg, 0.89e0.97; OR Z 0.62 per SD,
0.47e0.83). These findings were unchanged in the sensi-
tivity analysis restricted to term pregnancies (data not
shown).
Discussion
In this study, we report 2 main findings. First, although
blood pressure, lipid profile and blood glucose can all be
adversely affected by excess weight, comprehensive eval-
uation of maternal pre-gravid cardiometabolic health sta-
tus reveals that these risk factors are not independent
determinants of infant birthweight. Instead, the dominant
pre-gravid predictor of birthweight is maternal BMI, with
weight gain in pregnancy also emerging as an independent
determinant of neonatal weight at delivery. Overall, these
data are supportive of the concept that targeting healthy
maternal weight prior to pregnancy may be an important
goal for optimizing fetal growth/development, and
possibly improving future cardiometabolic risk in the
offspring.
Growing recognition of the potential trans-generational
implications of intrauterine exposures has led to interest
in the impact of maternal pre-pregnancy status on infant
birthweight. In an analysis from Norway in which they
linked the baseline maternal data from a clinical study
with birth registry delivery records for pregnancies
occurring w2e3 years later [11], Romundstad and col-
leagues reported that pre-gravid maternal blood pressure
was associated with lower birthweight while total
cholesterol, HDL, triglycerides and glucose were related to
higher birthweight. In an similarly-designed analysis from
Finland (i.e. linking baseline data from a clinical study with
that from a birth registry, with median 7.4 years between
the pre-gravid assessment and pregnancy) [12], Harville
et al. noted that higher blood pressure was associated with
lower birthweight but found that cholesterol and tri-
glycerides predicted higher birthweight. Subsequently, in
an analysis of 349 women [13], the same authors reported
that pre-gravid waist circumference was a positive pre-
dictor of LGA. Lastly, there have been retrospective case-
control analyses nested within longitudinal cohorts in
which investigators have evaluated pre-gravid predictors
Pre-gravid predictors of birthweight 727

Table 2 Characteristics of study population (n Z 1484) at pre-gravid assessment and at delivery, by quintile of infant birthweight.

First quintile Second quintile Third quintile Fourth quintile Fifth quintile p
[1250e2950 g] [3000e3150 g] [3200e3350 g] [3400e3610 g] [3650e6000 g]
n Z 280 n Z 284 n Z 268 n Z 353 n Z 299
Pre-gravid
Age (y) 24.2 (3.01) 24.7 (2.89) 24.7 (2.52) 24.5 (2.30) 25.0 (3.57) 0.0271
Years of education (y) 10.7 (2.39) 10.9 (2.70) 11.1 (2.67) 11.0 (2.79) 10.9 (3.01) 0.5022
Smoking (n (%)) 0 (0) 1 (0.4) 0 (0) 1 (0.3) 4 (1.3) 0.0802
BMI (kg/m2) 19.5 (2.14) 19.6 (2.70) 20.0 (2.26) 20.1 (2.27) 20.7 (2.60) <0.0001
BMI category 0.0037
<25 kg/m2 (%) 98.4 99.5 97.3 97.4 92.1
25e30 kg/m2 (%) 1.6 0.5 2.7 2.2 7.4
30 kg/m2 (%) 0 0 0 0.4 0.5
Waist (cm) 68.4 (6.96) 69.1 (7.09) 70.1 (7.41) 71.0 (7.30) 72.3 (7.77) <0.0001
Systolic BP (mm Hg) 111.7 (12.3) 111.4 (12.0) 112.6 (12.1) 110.6 (12.0) 110.8 (12.1) 0.2641
Diastolic BP (mm Hg) 71.1 (8.86) 70.9 (8.69) 71.9 (8.58) 70.8 (8.79) 70.9 (8.65) 0.5632
Mean arterial BP (mm Hg) 84.6 (9.44) 84.4 (9.25) 85.5 (9.23) 84.1 (9.36) 84.2 (9.24) 0.3967
Total cholesterol (mmol/L) 3.69 (1.05) 3.74 (1.14) 3.84 (1.17) 3.84 (1.12) 3.8 (0.97) 0.3991
LDL cholesterol (mmol/L) 2.04 (0.74) 2.10 (0.78) 2.06 (0.76) 2.06 (0.75) 2.16 (0.81) 0.3023
HDL cholesterol (mmol/L) 1.51 (0.43) 1.50 (0.45) 1.57 (0.50) 1.56 (0.46) 1.47 (0.43) 0.0336
Triglycerides (mmol/L) 0.85 (0.60, 1.27) 0.86 (0.60, 1.33) 0.91 (0.59, 1.33) 0.86 (0.64, 1.20) 0.89 (0.63, 1.27) 0.9354
Blood glucose (mmol/L) 4.5 (0.94) 4.6 (1.10) 4.6 (1.15) 4.5 (1.12) 4.6 (1.05) 0.9360
At delivery
Length of gestation (weeks) 38.1 (1.70) 39.0 (1.08) 39.1 (1.09) 39.3 (1.00) 39.5 (0.97) <0.0001
Weight gain in pregnancy (kg) 15.4 (6.17) 15.6 (5.50) 17.1 (5.40) 17.5 (5.92) 20.1 (6.93) <0.0001
Gestational diabetes (n (%)) 3 (1.1) 6 (2.1) 3 (1.1) 7 (2.0) 14 (4.7) 0.0383
Pre-eclampsia (n (%)) 10 (3.6) 2 (0.7) 1 (0.4) 1 (0.3) 3 (1.0) 0.0030
Infant sex <0.0001
Male (n (%)) 121 (43.2) 127 (44.7) 128 (47.8) 210 (59.5) 188 (62.9)
Female (n (%)) 159 (56.8) 157 (55.3) 140 (52.2) 143 (40.5) 111 (37.1)
Continuous variables are presented as mean followed by standard deviation in parentheses, with the exception of triglycerides which are
presented as median (interquartile range). Categorical variables are presented as n or proportions.

of antepartum conditions such as GDM, which itself can
affect birthweight [18,19].
However, there are important limitations in the studies
comprising this literature, such that definitive commentary
on pre-gravid cardiometabolic determinants of birthweight
has not been possible to date. First, owing to their retro-
spective designs, these studies were not able to adjust for
maternal weight gain in pregnancy [11e13], which is a crit-
ical antepartum determinant of fetal growth [20] (as
apparent in its emergence as an independent predictor of
birthweight (Table 3), LGA (Fig. 1) and SGA (Fig. 2), respec-
tively). Second, none of these studies [11e13] undertook
comprehensive metabolic characterization in which
maternal BMI, waist, blood pressure, lipids and glucose were

Table 3 Impact of pre-gravid and pregnancy factors on infant birthweight. Data are presented as the change in birthweight per unit change in
the indicated variable, first unadjusted (crude) and then after adjustment for all of the other listed variables.

Variables Change in infant birthweight (g) p*

Crude (95% CI) Adjusted (95% CI)a
Age (y) 8.9 (1.3e16.4) 14.6 (6.6e22.5) 0.0003
Years of education 5.3 (2.9 to 13.5) 8.4 (0.9 to 17.7) 0.076
Pre-gravid BMI (kg/m2) 30.7 (19.3e42.2) 29.4 (14.7e44.0) <0.0001
Pre-gravid waist (cm) 9.9 (6.4e13.4) 3.5 (0.9 to 7.9) 0.12
Pre-gravid systolic BP (mm Hg) 0.03 (1.9 to 1.8) 0.6 (2.5 to 1.4) 0.57
Pre-gravid LDL (mmol/L) 25.0 (4.5 to 54.4) 12.1 (20.5 to 44.7) 0.47
Pre-gravid HDL (mmol/L) 5.5 (55.1 to 44.0) 9.5 (71.4 to 52.4) 0.76
Pre-gravid triglycerides (mmol/L) 3.0 (36.5 to 30.6) 17.3 (58.6 to 24.0) 0.41
Pre-gravid blood glucose (mmol/L) 2.9 (18.2 to 24.0) 14.4 (10.3 to 39.1) 0.25
Length of gestation (weeks) 136.0 (119.7e152.3) 139.3 (119.9e158.7) <0.0001
Weight gain in pregnancy (kg) 16.9 (12.7e21.1) 17.8 (13.9e21.6) <0.0001
Gestational diabetes 200.6 (44.7e356.4) 68.8 (104.0 to 241.2) 0.44
Male infant 136.9 (92.4e181.4) 122.6 (74.7e170.6) <0.0001
*p value refers to estimate for indicated variable in adjusted model.
a
Adjusted for all of the other listed variables. The adjusted estimates can be interpreted in the following way: infant birthweight increases by
139.3 g per additional week of gestation, after adjustment all of the other variables. Overall, the adjusted model explains 29.5% of the variance in
infant birthweight.
728 R. Retnakaran et al.

Figure 1 Pre-gravid and antepartum predictors of having a large-for-gestational-age (LGA) infant. Data are presented as the odds ratio for LGA per
standard deviation change in the indicated variable (for continuous variables), first unadjusted and then after adjustment for all of the other listed
variables.

Figure 2 Pre-gravid and antepartum predictors of having a small-for-gestational-age (SGA) infant. Data are presented as the odds ratio for SGA per
standard deviation change in the indicated variable (for continuous variables), first unadjusted and then after adjustment for all of the other listed
variables.

all adjusted for one another (in addition to antepartum fac-
tors) in order to identify independent pre-pregnancy pre-
dictors of birthweight (although it should be noted that the
studies did adjust for the key factor BMI). Third, the preg-
nancies generally occurred several years after the baseline
assessment such that the degree to which the reported pre-
gravid measurements may relate to maternal health at
conception was uncertain. Ideally, the study design that is
required for addressing these limitations is a prospective pre-
conception cohort in which there is a short duration between
pre-gravid assessment and the subsequent pregnancy.
The importance of a prospective pre-conception
approach for elucidating the potential impact of intra-
uterine and early life exposures on outcomes in the
offspring was recognized by the National Institutes of
Health (NIH) with its initiation of the National Children’s
Study (NCS) in the United States in the late 1990’s [21].
However, the NCS also illustrated the technical difficulties
of such an undertaking when, after the expenditure of over
$1 billion, it was terminated prematurely in December
2014. One of the contributing factors in this decision was
the enormous cost associated with recruiting a large
cohort of women and then waiting for long periods of time
until they have a pregnancy [21]. In light of this potentially
critical obstacle, we reasoned that the cost-efficient for-
mation of a pre-conception cohort requires a setting in
which it is possible to identify women who are likely to get
pregnant in the near future. With these requirements in
mind, the Liuyang region of China was specifically selected
as a setting in which soon-to-be or newly-married women
(i) could be identified (through the pre-marriage health
clinics as described in the Methods section) and (ii) were
likely to undergo a first pregnancy relatively shortly
thereafter (based on societal practices in the region).
Accordingly, we have been able to establish a unique
prospective pre-conception cohort that has made it
possible to evaluate pre-gravid cardiometabolic predictors
of infant birthweight, while addressing the aforemen-
tioned limitations of this literature. Specifically, strengths
of this study include (i) the prospective design that has
enabled comprehensive evaluation of both pre-pregnancy
and antepartum factors of interest, (ii) the assessment of
their respective independent associations with infant
birthweight after complete adjustment for one another,
and (iii) a median duration of 20 weeks between baseline
assessment and pregnancy.
Pre-gravid predictors of birthweight
Supported by these strengths in its design, the current
study demonstrates that the main determinant of infant
birthweight before pregnancy is maternal weight, rather
than weight-related sequelae such as blood pressure, lipid
profile, and glucose. Indeed, when considered in fully-
adjusted models, maternal BMI is the only independent
pre-gravid metabolic predictor of birthweight. This rela-
tionship is also distinct from that of gestational weight
gain, which itself is an independent determinant of fetal
growth. Taken together, these data suggest that the impact
of pre-gravid maternal adiposity on infant birthweight is
likely not mediated by its effects on blood pressure, lipids,
and glucose prior to conception. In addition, it is apparent
that, even in this relatively lean population, larger women
tend to have larger babies.
There is an emerging perspective that the achievement
of a healthy body weight prior to pregnancy may be an
important strategy for breaking the vicious cycle of trans-
generational weight-related cardiometabolic dysfunction
[9,22,23]. Of note, recent randomized controlled trials,
such as the LIMIT [24] and UPBEAT [25] studies, have
found that intensive interventions to improve diet and
physical activity during pregnancy were not able to reduce
the incidence of LGA, GDM and other adverse obstetrical
outcomes. It has thus been suggested that the ideal time
for lifestyle intervention targeting healthy maternal
weight is likely prior to conception [26]. In this context,
the current study provides evidence in support of maternal
pre-gravid weight as indeed an appropriate target for
intervention towards the goal of optimizing subsequent
infant birthweight.
While we conceptualize pre-pregnancy health status as
ideally a reflection of peri-conception health, it should be
noted that our pre-gravid assessment at mean 20 weeks
before pregnancy may not necessarily reflect maternal
status at the time of conception. Another limitation is that
t-test without adjustment for multiple comparisons was
used for post-hoc testing to examine pairwise differences
between any two of the three unequal sized groups in
Table 1 (LGA, AGA, SGA). The pairwise t-test may over-
estimate the individual pairwise t-statistics (i.e. differ-
ences among the pairs) and have a higher possibility of
Type I error. In addition, the setting of this study in Liuyang
may limit its generalizability to non-Chinese populations.
Ethnic differences in body habitus and lifestyle practices
could be relevant in other populations. Furthermore, as the
study population consisted of young soon-to-be or
recently-married women, these findings potentially may
not be fully applicable to subsequent pregnancies in older
parous women. The participants were believed to be
nulliparous, though if any were not, then birth order could
be an unrecognized confounder. These limitations
notwithstanding, it should be recognized that the estab-
lishment of this unique pre-conception cohort has made it
feasible to comprehensively evaluate maternal pre-gravid
cardiometabolic determinants of birthweight in a pro-
spective fashion, resulting in novel insights that should
lead to further studies. In particular, further studies are
warranted to prospectively evaluate the relationship
729
between maternal pre-gravid weight and the long-term
trajectories of cardiometabolic risk factors in the
offspring, as well as their respective capacities for modi-
fication through changes in maternal weight prior to
conception.
In conclusion, the dominant pre-gravid determinant of
infant birthweight is maternal weight status. When
considered in a comprehensive analysis of pre-gravid and
antepartum determinants, maternal blood pressure, lipid
profile and blood glucose before pregnancy are not inde-
pendent predictors of birthweight. Overall, these data are
supportive of the concept of targeting a healthy maternal
weight prior to pregnancy and highlight the importance of
further research on the impact of maternal pre-conception
status on fetal growth and infant outcomes.
Funding
This study was supported by operating grants from the
Canadian Institutes of Health Research (CIHR) (MOP
115183 and MOP 86562) and the Natural Science Foun-
dation of China (30872167). The funding bodies had no
role in any of the following: design and conduct of the
study; collection, management, analysis, and interpreta-
tion of the data; and preparation, review, or approval of
the manuscript.
Disclosure of interests
The authors have no conflicts to declare.
Contribution to authorship
R Retnakaran, SW Wen, H Tan, GN Smith, and MC Walker
conceived the study plan. H Tan and S Zhou led the
implementation of the study, in conjunction with SW Wen
and M Shen. R Retnakaran and C Ye designed the analysis
plan. C Ye performed the analyses. R Retnakaran wrote the
manuscript. All of the authors interpreted the data and
critically revised the manuscript for important intellectual
content. All authors approved the final manuscript. All
authors had full access to all of the data in the study and
can take responsibility for the integrity of the data and the
accuracy of the data analysis.
Acknowledgements
The authors wish to thank the study participants. R
Retnakaran is supported by a Heart and Stroke Foundation
of Ontario Mid-Career Investigator Award and his research
program is supported by an Ontario Ministry of Research
and Innovation Early Researcher Award.
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