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

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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 R. Retnakaran et al.

Introduction Recruitment and pre-gravid assessment

In the past two decades, high birthweight and particu- The cost-efficient formation of a pre-conception cohort
larly low birthweight have been linked to the subsequent requires the capacity to identify women who are likely to
development of cardiometabolic disease in adulthood, get pregnant in the near future. In Liuyang, women typi-
including type 2 diabetes and coronary artery disease cally attend a pre-marriage health clinic for assessment at
[1e7]. The Developmental Origins of Health and Disease the time of marriage registration. Thus, for this cohort,
(DOHaD) paradigm posits that intrauterine programing of women who were planning to have a baby in the next 6
fetal biochemical pathways may contribute to such as- months were recruited from these clinics at Liuyang
sociations, wherein birthweight is a composite marker of Maternal and Infant Hospital. After recruitment, partici-
developmental exposures in utero and genetic/environ- pants were asked to undergo overnight fast and then
mental factors that together may determine later-life attend a baseline assessment that consisted of (i)
disease trajectories [1]. Accordingly, there is growing interviewer-administered questionnaires that provide data
interest in understanding determinants of the intrauter- on demographic characteristics, lifestyle, and medical
ine environment [8], the optimization of which could history, (ii) physical examination (including measurement
provide a means for reducing the likelihood of adult of height, weight, waist circumference, and blood pres-
disease in the offspring [9]. Since effects on develop- sure), and (iii) blood tests for measurement of lipid profile
mental programming potentially could begin before and glucose. The pre-gravid cardiometabolic character-
conception and may affect the critical peri-conceptual ization thus consists of the following components:
environment, pre-gravid factors that predict infant
birthweight are of interest in this context [10]. However, (i) Anthropometry e Anthropometric measurements
to date, studies addressing this question [11e13] have included weight, height, waist circumference and
been limited by retrospective designs, thereby precluding calculated body mass index (BMI). The assessors were
the comprehensive evaluation of both (i) pre-gravid car- trained to provide standardized measurements.
diometabolic risk factors (including anthropometry, (ii) Blood pressure (BP) e Systolic BP and diastolic BP
blood pressure, lipid profile, and glycemia) and (ii) rele- were measured using automated non-invasive blood
vant antepartum features, such as gestational weight pressure monitors (BpTRU) in a seated position, after
gain. Thus, in light of this background, we established a 10 min rest. BP was measured twice 10 min apart,
unique prospective pre-conception cohort to compre- with the average recorded.
hensively evaluate the maternal pre-gravid car- (iii) Biochemical measurement of blood glucose and
diometabolic determinants of infant birthweight. lipid profile e Blood samples were put on ice
immediately after collection, transported to the
laboratory within 30 min, and centrifuged at 4  C
Methods
and 3000 rpm for 10 min. Tests were performed in
the central laboratory of Central South University.
Study population
Total cholesterol, high-density-lipoprotein (HDL)
cholesterol, triglycerides and glucose were measured
The current analysis was conducted in the setting of an
by standard clinical biochemistry. Low-density-
ongoing prospective observational cohort study, in which
lipoprotein (LDL) cholesterol was determined by
women in the Liuyang region of Hunan province in China
Friedewald equation.
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- Assessment at delivery
tion at recruitment and then, whenever they subsequently
become pregnant, are followed across the pregnancy up to Data collected at delivery included gestational age (based
delivery. Since February 2009, 3375 have been recruited on last menstrual period), total weight gain in pregnancy,
into this cohort, of whom 2382 have become pregnant. Of major maternal medical complications in pregnancy
these, 1546 women had complete pre-gravid car- (including gestational diabetes mellitus and pre-
diometabolic measurements and delivery data with a eclampsia), infant sex, and birthweight. Large-for-
singleton pregnancy. After exclusion of 51 women who gestational-age (LGA) was defined as birthweight for
were >5 weeks pregnant at baseline assessment (based on gestational age above the 90th percentile according to
their gestational age at delivery) and 11 others with birthweight centiles for a Chinese population [16]. Small-
weight loss during pregnancy of implausible magnitude, for-gestational-age (SGA) was defined as birthweight for
the study population for the current analysis consisted of gestational age below the 10th percentile on birthweight
1484 women. The study has been approved by the insti- centiles for a Chinese population [16].
tutional research ethics boards of Central South University
(Changsha, Hunan, China), Ottawa Hospital Research Statistical analyses
Institute (Ottawa, Canada), and Mount Sinai Hospital
(Toronto, Canada), and all participants have provided All analyses were performed using SAS 9.4 (SAS Institute,
written informed consent. Cary, NC). Continuous variables were tested for normality
Pre-gravid predictors of birthweight 725

of distribution, with natural log-transformation applied the study population with the 993 women who had not
where necessary for skewed variables. The study popula- yet had a pregnancy revealed similar age but higher
tion was first stratified into the following three groups: baseline BMI (mean 20.6 vs 20.0 kg/m2, p Z 0.0002) in
women who delivered an SGA infant, women who deliv- those that had not yet had a pregnancy (data not shown).
ered an appropriate-for-gestational-age (AGA) infant and Table 1 shows the pre-gravid characteristics and ob-
women who delivered an LGA infant. Continuous variables stetric outcomes of the study participants, stratified into
were compared using analysis of variance for those that the following 3 groups: (i) women who delivered an SGA
were normally-distributed and Wilcoxon Rank-Sum non- infant (n Z 110), (ii) women who delivered an AGA infant
parametric test for those that were skewed. Categorical (n Z 1201), and (iii) women who delivered an LGA infant
variables were compared using chi-square or Fisher’s exact (n Z 173). Pre-gravid factors that differed between these
test. Pairwise differences between groups were assessed groups were age (p < 0.0001), BMI (p < 0.0001), and waist
by t-test, without adjustment for multiple comparisons, at circumference (p < 0.0001).
significance level of p Z 0.05. Furthermore, we stratified Table 2 shows the pre-gravid characteristics and ob-
the study population into quintiles based on infant birth- stetric outcomes of the study participants, stratified into
weight and compared characteristics across these groups quintiles of infant birthweight. At the pre-gravid assess-
at pre-gravid and delivery, respectively. ment, there was a progressive step-wise increase in
Multiple linear regression analysis was conducted to maternal BMI (p < 0.0001) and waist circumference
identify independent determinants of infant birthweight (p < 0.0001) from the women in the lowest quintile of
(dependent variable). Covariates in this model included subsequent infant birthweight to those in each of the
pre-gravid factors (maternal age, maternal years of edu- higher quintiles. The groups also differed in maternal age
cation, BMI, waist circumference, systolic BP, LDL choles- (p Z 0.03) and HDL cholesterol (p Z 0.03), but there were
terol, HDL cholesterol, triglycerides, blood glucose) and otherwise no significant differences in other lipid mea-
relevant antepartum factors that are known or expected to sures, blood glucose, blood pressure, and smoking status.
influence birthweight (length of gestation, weight gain in At delivery, weight gain in pregnancy (p Z 0.0005) pro-
pregnancy, gestational diabetes, infant sex). Covariates gressively increased from the lowest to the highest quin-
were tested for collinearity by variance inflation factor. A tile. The proportion of male infants similarly increased
simple linear regression of each covariate was also con- across the quintiles, as expected.
ducted in parallel to determine the unadjusted association
with infant birthweight. Mean arterial blood pressure was Determinants of infant birthweight
calculated as diastolic BP þ (systolic BP  diastolic BP)/3.
Logistic regression analysis was conducted to identify We evaluated determinants of infant birthweight in the
independent determinants of LGA (dependent variable). study population, after exclusion of the 17 women who
This model included the same covariates as the multiple had pre-eclampsia and the 6 women who smoked. The
linear regression of birthweight, with the exception of unadjusted associations between maternal-fetal factors
length of gestation and infant sex (as both are incorpo- and birthweight are shown in Table 3. On unadjusted
rated into the definition of LGA). A simple logistic regres- analysis, maternal age, BMI, waist circumference, weight
sion was also applied to each covariate to examine its gain in pregnancy, GDM, length of gestation, and male
unadjusted association with LGA. The same approach was infant were all associated with higher birthweight. On
applied to logistic regression analysis of dependent vari- multiple regression analysis with complete adjustment for
able SGA, with the same covariates as those for the LGA covariates (Table 3), positive determinants of birthweight
model. were maternal age (p Z 0.0003), pre-gravid BMI
For the multiple linear regression model of birthweight (p < 0.0001), weight gain in pregnancy (p < 0.0001),
and the logistic regression models of LGA and SGA, we also length of gestation (p < 0.0001), and male infant
performed sensitivity analyses with restriction of the (p < 0.0001). This model explained 29.5% of the variance
study population to the women with term pregnancies in birthweight. Of note, pre-gravid blood pressure, lipid
only (n Z 1431). profile, and blood glucose were not independent pre-
dictors of birthweight. Furthermore, these results were
Results unchanged in a sensitivity analysis restricted to the
women who with term pregnancies (data not shown).
The study population consisted of 1484 women who had On logistic regression analysis (Fig. 1), after complete
completed a singleton pregnancy. These women under- adjustment for covariates, the significant pre-gravid pre-
went their baseline assessment at median 20 weeks before dictors of delivery of an LGA infant were maternal age
their pregnancy and were of mean age 24.6  3.0 years, (OR Z 1.10 per year, 95%CI 1.03e1.18; OR Z 1.34 per SD,
with mean pre-gravid BMI 20.0  2.3 kg/m2. Only 6 95%CI 1.11e1.63) and BMI (OR Z 1.21 per kg/m2, 1.07e1.37;
women smoked, consistent with the low rate of smoking OR Z 1.55 per SD, 1.18e2.04), while weight gain in preg-
that has been reported amongst women in China [17]. The nancy was an antepartum predictor (OR Z 1.10 per kg,
mean length of gestation of their pregnancies was 1.06e1.14; OR Z 1.81 per SD, 1.46e2.24). These results
39.0  1.3 weeks and mean infant birthweight was were unchanged in the sensitivity analysis restricted to
3294  444 g. Comparison of the 1484 women comprising 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 possibly improving future cardiometabolic risk in the
adjustment for covariates, none of the pre-gravid mea- offspring.
sures were significant independent predictors of SGA. Growing recognition of the potential trans-generational
Instead, amongst antepartum factors, gestational weight implications of intrauterine exposures has led to interest
gain was inversely associated with the risk of SGA in the impact of maternal pre-pregnancy status on infant
(OR Z 0.93 per kg, 0.89e0.97; OR Z 0.62 per SD, birthweight. In an analysis from Norway in which they
0.47e0.83). These findings were unchanged in the sensi- linked the baseline maternal data from a clinical study
tivity analysis restricted to term pregnancies (data not with birth registry delivery records for pregnancies
shown). occurring w2e3 years later [11], Romundstad and col-
leagues reported that pre-gravid maternal blood pressure
Discussion was associated with lower birthweight while total
cholesterol, HDL, triglycerides and glucose were related to
In this study, we report 2 main findings. First, although higher birthweight. In an similarly-designed analysis from
blood pressure, lipid profile and blood glucose can all be Finland (i.e. linking baseline data from a clinical study with
adversely affected by excess weight, comprehensive eval- that from a birth registry, with median 7.4 years between
uation of maternal pre-gravid cardiometabolic health sta- the pre-gravid assessment and pregnancy) [12], Harville
tus reveals that these risk factors are not independent et al. noted that higher blood pressure was associated with
determinants of infant birthweight. Instead, the dominant lower birthweight but found that cholesterol and tri-
pre-gravid predictor of birthweight is maternal BMI, with glycerides predicted higher birthweight. Subsequently, in
weight gain in pregnancy also emerging as an independent an analysis of 349 women [13], the same authors reported
determinant of neonatal weight at delivery. Overall, these that pre-gravid waist circumference was a positive pre-
data are supportive of the concept that targeting healthy dictor of LGA. Lastly, there have been retrospective case-
maternal weight prior to pregnancy may be an important control analyses nested within longitudinal cohorts in
goal for optimizing fetal growth/development, and 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 maternal weight gain in pregnancy [11e13], which is a crit-
affect birthweight [18,19]. ical antepartum determinant of fetal growth [20] (as
However, there are important limitations in the studies apparent in its emergence as an independent predictor of
comprising this literature, such that definitive commentary birthweight (Table 3), LGA (Fig. 1) and SGA (Fig. 2), respec-
on pre-gravid cardiometabolic determinants of birthweight tively). Second, none of these studies [11e13] undertook
has not been possible to date. First, owing to their retro- comprehensive metabolic characterization in which
spective designs, these studies were not able to adjust for 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- until they have a pregnancy [21]. In light of this potentially
tors) in order to identify independent pre-pregnancy pre- critical obstacle, we reasoned that the cost-efficient for-
dictors of birthweight (although it should be noted that the mation of a pre-conception cohort requires a setting in
studies did adjust for the key factor BMI). Third, the preg- which it is possible to identify women who are likely to get
nancies generally occurred several years after the baseline pregnant in the near future. With these requirements in
assessment such that the degree to which the reported pre- mind, the Liuyang region of China was specifically selected
gravid measurements may relate to maternal health at as a setting in which soon-to-be or newly-married women
conception was uncertain. Ideally, the study design that is (i) could be identified (through the pre-marriage health
required for addressing these limitations is a prospective pre- clinics as described in the Methods section) and (ii) were
conception cohort in which there is a short duration between likely to undergo a first pregnancy relatively shortly
pre-gravid assessment and the subsequent pregnancy. thereafter (based on societal practices in the region).
The importance of a prospective pre-conception Accordingly, we have been able to establish a unique
approach for elucidating the potential impact of intra- prospective pre-conception cohort that has made it
uterine and early life exposures on outcomes in the possible to evaluate pre-gravid cardiometabolic predictors
offspring was recognized by the National Institutes of of infant birthweight, while addressing the aforemen-
Health (NIH) with its initiation of the National Children’s tioned limitations of this literature. Specifically, strengths
Study (NCS) in the United States in the late 1990’s [21]. of this study include (i) the prospective design that has
However, the NCS also illustrated the technical difficulties enabled comprehensive evaluation of both pre-pregnancy
of such an undertaking when, after the expenditure of over and antepartum factors of interest, (ii) the assessment of
$1 billion, it was terminated prematurely in December their respective independent associations with infant
2014. One of the contributing factors in this decision was birthweight after complete adjustment for one another,
the enormous cost associated with recruiting a large and (iii) a median duration of 20 weeks between baseline
cohort of women and then waiting for long periods of time assessment and pregnancy.
Pre-gravid predictors of birthweight 729

Supported by these strengths in its design, the current between maternal pre-gravid weight and the long-term
study demonstrates that the main determinant of infant trajectories of cardiometabolic risk factors in the
birthweight before pregnancy is maternal weight, rather offspring, as well as their respective capacities for modi-
than weight-related sequelae such as blood pressure, lipid fication through changes in maternal weight prior to
profile, and glucose. Indeed, when considered in fully- conception.
adjusted models, maternal BMI is the only independent In conclusion, the dominant pre-gravid determinant of
pre-gravid metabolic predictor of birthweight. This rela- infant birthweight is maternal weight status. When
tionship is also distinct from that of gestational weight considered in a comprehensive analysis of pre-gravid and
gain, which itself is an independent determinant of fetal antepartum determinants, maternal blood pressure, lipid
growth. Taken together, these data suggest that the impact profile and blood glucose before pregnancy are not inde-
of pre-gravid maternal adiposity on infant birthweight is pendent predictors of birthweight. Overall, these data are
likely not mediated by its effects on blood pressure, lipids, supportive of the concept of targeting a healthy maternal
and glucose prior to conception. In addition, it is apparent weight prior to pregnancy and highlight the importance of
that, even in this relatively lean population, larger women further research on the impact of maternal pre-conception
tend to have larger babies. status on fetal growth and infant outcomes.
There is an emerging perspective that the achievement
of a healthy body weight prior to pregnancy may be an
Funding
important strategy for breaking the vicious cycle of trans-
generational weight-related cardiometabolic dysfunction
This study was supported by operating grants from the
[9,22,23]. Of note, recent randomized controlled trials,
Canadian Institutes of Health Research (CIHR) (MOP
such as the LIMIT [24] and UPBEAT [25] studies, have
115183 and MOP 86562) and the Natural Science Foun-
found that intensive interventions to improve diet and
dation of China (30872167). The funding bodies had no
physical activity during pregnancy were not able to reduce
role in any of the following: design and conduct of the
the incidence of LGA, GDM and other adverse obstetrical
study; collection, management, analysis, and interpreta-
outcomes. It has thus been suggested that the ideal time
tion of the data; and preparation, review, or approval of
for lifestyle intervention targeting healthy maternal
the manuscript.
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 Disclosure of interests
intervention towards the goal of optimizing subsequent
infant birthweight. The authors have no conflicts to declare.
While we conceptualize pre-pregnancy health status as
ideally a reflection of peri-conception health, it should be Contribution to authorship
noted that our pre-gravid assessment at mean 20 weeks
before pregnancy may not necessarily reflect maternal R Retnakaran, SW Wen, H Tan, GN Smith, and MC Walker
status at the time of conception. Another limitation is that conceived the study plan. H Tan and S Zhou led the
t-test without adjustment for multiple comparisons was implementation of the study, in conjunction with SW Wen
used for post-hoc testing to examine pairwise differences and M Shen. R Retnakaran and C Ye designed the analysis
between any two of the three unequal sized groups in plan. C Ye performed the analyses. R Retnakaran wrote the
Table 1 (LGA, AGA, SGA). The pairwise t-test may over- manuscript. All of the authors interpreted the data and
estimate the individual pairwise t-statistics (i.e. differ- critically revised the manuscript for important intellectual
ences among the pairs) and have a higher possibility of content. All authors approved the final manuscript. All
Type I error. In addition, the setting of this study in Liuyang authors had full access to all of the data in the study and
may limit its generalizability to non-Chinese populations. can take responsibility for the integrity of the data and the
Ethnic differences in body habitus and lifestyle practices accuracy of the data analysis.
could be relevant in other populations. Furthermore, as the
study population consisted of young soon-to-be or
Acknowledgements
recently-married women, these findings potentially may
not be fully applicable to subsequent pregnancies in older
The authors wish to thank the study participants. R
parous women. The participants were believed to be
Retnakaran is supported by a Heart and Stroke Foundation
nulliparous, though if any were not, then birth order could
of Ontario Mid-Career Investigator Award and his research
be an unrecognized confounder. These limitations
program is supported by an Ontario Ministry of Research
notwithstanding, it should be recognized that the estab-
and Innovation Early Researcher Award.
lishment of this unique pre-conception cohort has made it
feasible to comprehensively evaluate maternal pre-gravid
cardiometabolic determinants of birthweight in a pro- References
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