\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Offspring size at birth and maternal risk for cardiovascular disease: a
systematic review and meta-analysis}



\author[1]{Prabha Andraweera}%
\author[2]{Zohra Lassi}%
\author[1]{Maleesa Pathirana}%
\author[3]{Anna Ali}%
\author[4]{Gus Dekker}%
\author[5]{Claire Roberts}%
\author[6]{Margaret Arstall}%
\affil[1]{The University of Adelaide}%
\affil[2]{Robinson Research Institute}%
\affil[3]{Basil Hetzel Institute for Medical Research}%
\affil[4]{The University of Adelaide Adelaide Medical School}%
\affil[5]{University of Adelaide}%
\affil[6]{Lyell McEwin Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background: Offspring size at birth is known to be associated with
maternal cardiovascular disease (CVD) risk. Low birthweight (LBW), small
for gestational age (SGA) and intrauterine growth restriction (IUGR) are
all used to define infants considered small at birth. Objectives: To
determine whether women who give birth to SGA/LBW/IUGR infants have
higher levels of cardio-metabolic risk factors compared to women who
give birth to average for gestational age infants or women. Search
strategy: We performed a systematic literature search using PubMed,
Embase and CINAHL. Selection criteria: Studies that compared
cardio-metabolic risk factors in women who gave birth to SGA/LBW/IUGR
infants compared to a control group. Data collection and analysis: Two
independent authors screened and extracted data. Meta-analysis was
performed on Review Manager 5.3. Main results: The meta-analysis showed
a significantly increased CVD mortality among women who gave birth to
SGA infants compared to AGA infants (relative risk 1.45, 95\% confidence
interval (CI) 1.40 to 1.52; 2,584,533 participants, three studies;
heterogeneity: Chi2 P=0.48; I2=0\%). Women who gave birth to growth
restricted infants had significantly higher mean BMI (1.72kg/m2, 95\% CI
0.97 to 2.47; 77 participants, two studies; heterogeneity: Chi2 P=0.35;
I2=0\%), and higher total mean cholesterol levels (0.32mmol/l, 95\% CI
0.13 to 0.50; 77 participants, two studies; heterogeneity: Chi2 P=0.69;
I2=0\%) compared to women who had uncomplicated pregnancies.
Conclusions: Women who give birth to small infants are at increased risk
of CVD. Postpartum screening for CVD risk factors will help identify
those at risk.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Increasing evidence demonstrates an association between offspring size
at birth and maternal cardiovascular disease (CVD) risk. A meta-analysis
of six studies, published in 2007, showed an inverse relationship
between offspring weight at birth and maternal CVD mortality (pooled
adjusted hazard ratio (aHR) of 0.75 (95\% confidence interval (CI): 0.67
to 0.84) for 1-standard deviation (SD) increase in offspring
birthweight)\textsuperscript{1}. A subsequent study of 1,400,383 women
showed 1.8 times higher risk of mortality from CVD among women who gave
birth to low birth weight (LBW, birthweight \textless{}2500g) infants
compared to those who gave birth to normal birthweight (2500-3999g)
infants (aHR: 1.85; 95\% CI 1.57 to 2.18)\textsuperscript{2}. Recent
studies have shown similar associations for women who give birth to
infants diagnosed as small for gestational age (SGA) at birth compared
to women who give birth to average for gestational age (AGA)
infants\textsuperscript{3, 4}. The terms ``LBW'' and ``SGA'' are both
used to define infants considered small at birth. Although many infants
classified as SGA or LBW have intrauterine growth restriction (IUGR) and
many growth restricted infants are born with LBW or are classified as
SGA, the three terms are not synonymous\textsuperscript{5}. LBW simply
means birthweight \textless{} 2.5 kg and at present, the definition is
mostly used in developing countries where gestational age is often
uncertain, and reliable population centiles let alone customized
centiles are not available. SGA means birthweight \textless{}
10\textsuperscript{th} centile for a given gestational age. Population
centiles use birthweight centiles on a whole population, irrespective of
maternal ethnicity, height and weight and customized centiles provide
birthweight centiles customized for maternal ethnicity, height, weight
and parity. Infants with IUGR are those that do not achieve full\emph{in
utero} growth potential because of genetic or environmental factors and
are at increased risk for significant morbidity and mortality compared
to infants with normal \emph{in utero} growth. Infants born growth
restricted are at increased risk of CVD and type 2 diabetes mellitus in
adulthood and ``programming in response to an adverse intrauterine
environment'' as well as genetic and environmental influences are
proposed to contribute to the risk. However, associations between
offspring SGA/LBW and maternal CVD risk cannot be explained to a large
extent by programming. This, however, can be explained by the presence
of genetic polymorphisms that influence both fetal growth and CVD as
well as by adverse environmental influences that operate across the
parental life course and affect both offspring and adult health. To our
knowledge there is no systematic review and meta-analysis that has
assessed maternal risk for CVD using data from studies reporting on the
three common classifications of offspring size at birth. Therefore, the
aim of this study was to identify the relationship between offspring
size at birth and maternal CVD risk based on different classifications
of offspring size at birth.

\textbf{METHODS}

\textbf{Data sources and Search strategy}

This systematic review and meta-analysis was conducted in accordance
with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE)
guidelines\textsuperscript{6}. The review protocol is registered with
PROSPERO (CRD42019138399). We searched the electronic databases,
MEDLINE, EMBASE, CINHAL, and Web of Science with an end of search date
of May 6, 2019. Subsequently, we updated the literature search to
include all relevant articles published until May 31, 2020. The search
was conducted by ZL. The search strategy is detailed in the
supplementary file. Bibliographies of previously conducted systematic
reviews and meta-analyses on closely related topics, and eligible
studies were checked for additional studies. Two reviewers independently
screened the titles and abstracts of studies (PA, MP, AA, ZL). Data
extraction was also conducted by two reviewers independently (PA, ZL).
Disagreements were resolved by discussion within the team.

\textbf{Study selection and data extraction}

Studies were considered eligible if they compared CVD risk factors
between the following comparison groups: (1) women who gave birth to SGA
infants compared to women who gave birth to AGA infants, (2) women who
gave birth to LBW infants (birthweight [?]2500g) compared to women who
gave birth to normal birthweight (birthweight \textgreater{}2500g)
infants, (3) women who gave birth to infants diagnosed with IUGR with
women who gave birth to non-IUGR infants. Studies that reported an
association between maternal CVD mortality/CVD occurrence and offspring
size at birth were also included. SGA was defined as birthweight below
the 10\textsuperscript{th} population or customised birthweight centile;
LBW was defined as birthweight below 2500g; and IUGR was defined as true
documented intrauterine growth restriction or an accepted surrogate
diagnosis of IUGR, i.e. birthweight
\textless{}5\textsuperscript{th}population or customised birthweight
centile and abnormal umbilical artery Doppler results. Definitions of
SGA/LBW and IUGR used in the included studies are detailed in table 1.
The outcomes assessed were systolic blood pressure (SBP), diastolic
blood pressure (DBP), body mass index (BMI), total cholesterol, low
density lipoprotein cholesterol (LDL), high density lipoprotein
cholesterol (HDL), triglycerides, fasting blood glucose (BG), fasting
insulin, and CVD mortality. Data from studies classifying infants as
SGA, LBW and IUGR were analysed as separate groups. Studies that did not
have the above definitions, those that did not define the comparison
groups and those that compared women who gave birth to small babies with
another risk group were excluded. All selected studies were published in
peer-reviewed journals, undertaken in humans, and published in English.

\textbf{Statistical analysis}

The meta-analysis was performed using the RevMan software (Review
Manager Version 5.3). For the outcomes of SBP, DBP, BMI, and lipids,
Mean Difference (MD) and the 95\% confidence interval (CI) were
calculated using a fixed effects or random effects model. Where
heterogeneity was substantially high (Chi\textsuperscript{2} P value of
\textless{}0.1 and I\textsuperscript{2} value of \textgreater{}30\%), we
reported the outcomes using random-effect mode, otherwise the outcomes
were reported using a fixed effect model. When standard error of the
mean (SEM) or CI of means were reported instead of the SD, the SEM/CI
were converted to SD. When median and intra-quartile range (IQR) were
reported, the results were extracted as reported and are detailed in
table 1. For the meta-analyses on CVD mortality, the number of deaths
due to CVD and the total number of participants were used in the
meta-analysis to analyse the risk difference. If the study reported the
number as a percentage, then the number of participants/events was
calculated based on the total sample size for each group. The
methodological quality was assessed using the National Heart, Lung and
Blood Institute (NHLBI) Quality Assessment Tool for Observational Cohort
and Cross-Sectional Studies.

\textbf{RESULTS}

A total of 21,884 articles were identified by the search, of which 520
were eligible for full text review (Figure 1) and a further 11 were
identified from bibliographic searches. Of these, 18 studies were
included in the review, and seven were included in the meta-analysis.
The reasons for excluding 513 papers are detailed in figure 1. The
quality assessment showed that no studies were of low quality.

\textbf{Maternal CVD risk factors according to the delivery of a SGA vs
AGA infant}

Four studies reported on conventional CVD risk factors between women who
gave birth to SGA compared to AGA infants (table
1)\textsuperscript{7-10}. Two studies classified SGA as birthweight
\textless{}10\textsuperscript{th} population centile\textsuperscript{7,
10}, one as birthweight \textless{}5\textsuperscript{th} population
centile\textsuperscript{9} and the other as birthweight
\textless{}10\textsuperscript{th} customised birthweight
centile\textsuperscript{8}. Two studies were conducted on normotensive
women who gave birth to SGA infants\textsuperscript{8, 9}. Four studies
compared SBP and DBP between women who gave birth to SGA infants
compared to those who gave birth to AGA infants. Of these, two studies
reported significantly higher SBP\textsuperscript{7, 9} and one study
reported significantly higher DBP\textsuperscript{7} among women who
gave birth to SGA infants after adjusting for confounding factors (table
1). BMI was reported in one study which found no significant difference
between the two comparison groups\textsuperscript{7}. Three studies
compared lipids between the two study groups\textsuperscript{7, 9, 10}.
Of these, two reported significantly higher serum
triglycerides\textsuperscript{9, 10} and one significantly higher LDL
cholesterol\textsuperscript{9} among women who gave birth to SGA infants
compared to those who gave birth to AGA infants (table 1). Blood glucose
was reported in three studies\textsuperscript{7, 9, 10} and insulin
level in one study\textsuperscript{9}. All results on blood glucose and
insulin were not statistically significantly different between the two
comparison groups (table 1). Results of two studies were included in the
meta-analyses on SBP and DBP\textsuperscript{7, 8}. The pooled analyses
did not show a significant difference in SBP or DBP between women who
gave birth to SGA compared to AGA infants (Supplementary figures 1 and
2).

\textbf{Maternal CVD risk factors according to the delivery of a low
birth weight vs normal birth weight infant}

Two studies reported on maternal CVD risk factors based on birthweight
of offspring\textsuperscript{11, 12} (table 1). Catov and colleagues
compared blood pressure, BMI, lipids, fasting blood glucose and fasting
insulin between women who gave birth to low birth weight vs normal
birthweight infants and reported significantly higher SBP and
significantly lower BMI among women who gave birth to LBW
infants\textsuperscript{11} (table 1). Lawlor and colleagues assessed
the relationship between birthweight of offspring and age adjusted BMI,
SBP, LDL, HDL and triglyceride levels in a cohort of 3265
women\textsuperscript{12}. Their study demonstrated that for each
increase of 1kg in offspring birthweight, the logarithm of SBP decreased
by 1.79 and BMI increased by 0.74\textsuperscript{12} (table 1). The
results of the two studies reporting on maternal CVD risk factors based
on birthweight of offspring could not be included in the meta-analyses.

\textbf{Maternal CVD risk factors according to the delivery of an infant
with intrauterine growth restriction vs women who experienced
uncomplicated pregnancies}

Two studies compared maternal CVD risk factors between women who gave
birth to growth restricted infants and women who had uncomplicated
pregnancies\textsuperscript{13, 14} (table 1). Of these one study was
conducted on normotensive women who gave birth to growth restricted
infants\textsuperscript{14}. Manten and colleagues reported a
significantly higher serum total cholesterol level among women who gave
birth to infants diagnosed as having IUGR compared to women who had
uncomplicated pregnancies but the difference was not significant after
excluding women with chronic hypertension, smokers and those with BMI
\textgreater{} 30kg/m\textsuperscript{213} (table 1). Yinon and
colleagues compared BMI, total cholesterol, LDL, HDL, blood glucose and
insulin in women who gave birth to growth restricted infants and those
who had uncomplicated pregnancies\textsuperscript{14}. Both studies were
included in meta-analyses on BMI, total cholesterol, HDL cholesterol and
triglycerides\textsuperscript{13, 14}. The pooled analyses showed that
women who gave birth to infants diagnosed as having IUGR had
significantly higher mean BMI (1.72kg/m\textsuperscript{2}, 95\% CI 0.97
to 2.47; 77 participants, heterogeneity: Chi\textsuperscript{2} P 0.35;
I\textsuperscript{2} = 0\%, figure 2A), and higher total mean
cholesterol levels (0.32mmol/l, 95\% CI 0.13 to 0.50; 77 participants,
heterogeneity: Chi\textsuperscript{2} P 0.69; I\textsuperscript{2} =
0\%) compared to women who had uncomplicated pregnancies (figure
2B)\textsuperscript{13, 14}.

\textbf{Association between offspring size at birth and maternal
cardiovascular disease mortality}

Nine large data linkage studies assessed the association between
offspring birthweight/SGA and maternal cardiovascular disease
mortality\textsuperscript{1, 2, 4, 15-20} and one assessed the
association between delivery of a SGA infant and the occurrence of
maternal CVD\textsuperscript{3} (table 2). Of the studies reporting on
maternal CVD mortality, two studies demonstrated aHRs of 2.0 and 2.2 for
each 1kg decrease in offspring birthweight\textsuperscript{15, 18} and
five studies demonstrated aHRs between 0.75 and 0.89 for each 1 SD
increase in offspring birthweight\textsuperscript{1, 2, 4, 19, 20}(table
2). Four studies assessed maternal CVD mortality in relation to giving
birth to a SGA vs AGA infant and reported aHRs between 1.31 -- 3.5 among
women who gave birth to SGA compared to AGA infants\textsuperscript{2-4,
16} (table 2). A large data linkage study of 812,732 women demonstrated
that, compared to women who gave birth to non-SGA infants, the aHR for
first occurrence of CVD among women who gave birth to moderately SGA
infants (birthweight between 3\textsuperscript{rd} --
10\textsuperscript{th} percentile) was 1.36 (95\% CI, 1.23 to 1.49) and
among women who gave birth to severe SGA infants (birthweight
\textless{}3\textsuperscript{rd} centile) was 1.66 (95\% CI, 1.47 to
1.87)\textsuperscript{3} (table 2). That study also showed a linear
increase in aHR for first occurrence of CVD of 1.42 (95\% CI, 1.30 to
1.54), 1.65 (95\% CI, 1.34 to 2.03) and 2.42 (95\% CI, 1.52 to 3.85) for
women who gave birth to one SGA infant, two SGA infants and three SGA
infants respectively, compared to women who gave birth to non-SGA
infants\textsuperscript{3} (table 2). Three studies were included in the
meta-analysis on CVD mortality among women who gave birth to SGA
compared to AGA infants, providing data on 2,584,533 individuals (figure
3) \textsuperscript{2, 4, 16}. The pooled data shows a significantly
increased CVD mortality among women who gave birth to SGA infants
compared to those who gave birth to AGA infants (RR 1.45, 95\% CI 1.40
to 1.52); heterogeneity: Chi\textsuperscript{2} P 0.48;
I\textsuperscript{2} = 0\%)

\textbf{DISCUSSION}

This systematic review demonstrates an inverse relationship between
offspring birthweight and maternal CVD mortality. Our meta-analysis
shows an approximately 1.5 times increased risk of death from CVD among
women who gave birth to SGA infants compared to women who gave birth to
AGA infants. The meta-analyses also demonstrated that BMI and total
cholesterol levels were higher among women who gave birth to infants
diagnosed as having IUGR compared to women who experienced uncomplicated
pregnancies.

The evidence for the association between offspring birthweight and
maternal CVD mortality was provided by eight large data linkage studies
conducted in six countries\textsuperscript{1, 2, 4, 15-20}. All studies
provided consistent findings and showed a reduction in offspring
birthweight associated with increased maternal CVD mortality or an
increase in offspring birthweight associated with a reduction in
maternal CVD mortality. All of these results were shown to be
significant after adjusting for relevant confounding factors. All
studies that compared CVD mortality among women who gave birth to SGA vs
AGA infants demonstrated a HR between 1.31-3.5 for women who gave birth
to SGA infants after adjusting for relevant confounding
factors\textsuperscript{2, 4, 16} while the pooled analysis showed a RR
of 1.45 with no significant heterogeneity among the three studies
(Chi\textsuperscript{2} P 0.48, I\textsuperscript{2} = 0\%).

A few mechanistic pathways could be implicated in the association
between offspring size at birth and maternal CVD risk. One plausible
mechanism is the genetic contribution. CVD has a substantial genetic
component, and polymorphisms in several genes encoding
glucokinase\textsuperscript{21}, angiogenic pathway\textsuperscript{22},
angiotensinogen\textsuperscript{23}, clotting
factors\textsuperscript{24} are associated with both restricted fetal
growth and risk of CVD. The evidence for a genetic link between
offspring birthweight and maternal risk for CVD is supported by studies
that have shown an association between offspring birthweight and
parental CVD risk. Li and colleagues (2010) in a data linkage study of
1,400,383 primigravida and their spouses demonstrated an adjusted HR of
1.13 (95\% CI: 1.03 to 1.24) among fathers of low birth weight
infants\textsuperscript{2}. Consistent with the above findings, Davey
Smith and colleagues reported an adjusted HR of 0.94 (95\% CI: 0.89 to
0.99) for CVD mortality among fathers for each one SD increase in
offspring birthweight\textsuperscript{1}. The theory for a genetic
association is further strengthened by a number of multigenerational
studies, reporting a strong association between birthweight of
grandchild and CVD mortality in grandparents (HR of 0.86, 95\% CI: 0.83
to 0.89 for 1kg increase in birthweight \textsuperscript{25} and HR
between 0.95-0.99 for one quintile increase in
birthweight)\textsuperscript{26}. The genetic theory is further
supported by a recent study of 1,353,956 births that showed an
association between offspring birthweight and CVD mortality among aunts
and uncles (HRs between 0.90 (95\% CI 0.86 to 0.95) and 0.93 (95\% CI
0.91 to 0.95) for one SD increase in offspring
birthweight)\textsuperscript{4}.

Another plausible mechanism linking offspring size at birth with
maternal CVD risk is shared environmental and behavioural factors. For
example, smoking is a risk factor for both low birthweight and CVD.
Women who smoke during pregnancy are at a higher risk of giving birth to
growth restricted infants. These women are likely to continue smoking,
increasing their subsequent risk of CVD. Partners of women who smoke are
likely to be smokers themselves and hence would also be at higher risk
of developing CVD. Hence, the association between offspring size at
birth and paternal CVD risk could also be explained by environmental and
behavioural factors shared by both parents.

The third plausible theory on the association between offspring size at
birth and maternal CVD risk suggests maternal/fetal nutritional factors
and intrauterine programming as a potential contributor. Women who
themselves had poor intrauterine growth and LBW tend to give birth to
SGA infants\textsuperscript{27}. This association may be mediated via
poor placentation or effects of intrauterine programming. Pregnancy may
also act as a ``second hit'' for women who were born
small\textsuperscript{28}. Pregnancy is increasingly being considered as
a physiological stress test for the female cardiovascular system and
those who were born ``small'', when exposed to a second hit of
pregnancy, may develop pregnancy complications including intrauterine
growth restriction\textsuperscript{28}.

This systematic review and meta-analysis demonstrates evidence of an
association between offspring size at birth and maternal CVD mortality.
However, there was insufficient data to compare conventional CVD risk
factors among women who gave birth to small babies compared to women who
have birth to AGA infants due to the limited number of studies reporting
on the outcomes. Pooled evidence from two small studies demonstrate
higher BMI and higher serum total cholesterol levels among women who
gave birth to growth restricted infants compared to women who had
uncomplicated pregnancies. However, the sample sizes in these analyses
were very small. Hence, larger studies are required for meaningful
comparisons. In addition, only few studies reported on cohorts of
normotensive women who gave birth to small infants, hence, confounding
due to maternal gestational hypertension and preeclampsia is a real
possibility. Another limitation in the current literature is the paucity
of information on women's age in studies reporting on the associations
between offspring size at birth and maternal CVD mortality. The reported
follow up periods of the included studied varied from 4 years to
\textasciitilde{}47 years postpartum. Hence, some of the studies
reported CVD mortality among old aged women.

Overall, this systematic review and meta-analysis shows that women who
give birth to SGA infants are at higher risk of CVD mortality compared
to women who give birth to AGA infants. Genetic, environmental and
behavioural factors could all contribute to this association. Larger
well characterised cohorts with the ability to distinguish CVD risk
factor profiles at a young age between normotensive and hypertensive
women who give birth to SGA infants are required to identify the true
association between offspring size at birth and maternal risk for CVD.

\textbf{Disclosure of interests}

The authors declare no conflicts of interest

\textbf{Contribution to authorship}

PHA, ZSL, MAA, CTR and GAD conceived and designed the study. ZSL
conducted the search. PHA, ZSL, MMP and AA screened the papers and
extracted data. ZSL conducted the meta-analysis. PHA wrote the
manuscript. All authors read and approved the final version of the
manuscript.

\textbf{Details of ethics approval}

Since this study was a systematic review and meta-analysis, ethics
approval was not required.

\textbf{Funding:} NHMRC Peter Doherty Early Career Fellowship awarded to
PHA (GNT (GNT1090778), NHMRC Public Health Early Career Fellowship
awarded to ZSL (GNT1141382). CTR is supported by a NHMRC Investigator
Grant (GNT1174971) and a Matthew Flinders Fellowship from Flinders
University.

\textbf{REFERENCES}

1. Davey Smith G, Hypponen E, Power C, Lawlor DA. Offspring birth weight
and parental mortality: prospective observational study and
meta-analysis. American journal of epidemiology. 2007 Jul
15;166(2):160-9.

2. Li CY, Chen HF, Sung FC, Chen CC, Lu TH, Yang CH, et al. Offspring
birth weight and parental cardiovascular mortality. International
journal of epidemiology. 2010 Aug;39(4):1082-90.

3. Ngo AD, Roberts CL, Chen JS, Figtree G. Delivery of a
Small-For-Gestational-Age Infant and Risk of Maternal Cardiovascular
Disease--A Population-Based Record Linkage Study. Heart, lung \&
circulation. 2015 Jul;24(7):696-704.

4. Shaikh F, Kjolllesdal MK, Carslake D, Stoltenberg C, Davey Smith G,
Naess O. Birthweight in offspring and cardiovascular mortality in their
parents, aunts and uncles: a family-based cohort study of 1.35 million
births. International journal of epidemiology. 2019 Jul 20.

5. Gardosi J. Intrauterine growth restriction: new standards for
assessing adverse outcome. Best practice \& research Clinical obstetrics
\& gynaecology. 2009 Dec;23(6):741-9.

6. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et
al. Meta-analysis of observational studies in epidemiology: a proposal
for reporting. Meta-analysis Of Observational Studies in Epidemiology
(MOOSE) group. Jama. 2000 Apr 19;283(15):2008-12.

7. Fraser A, Nelson SM, Macdonald-Wallis C, Cherry L, Butler E, Sattar
N, et al. Associations of pregnancy complications with calculated
cardiovascular disease risk and cardiovascular risk factors in middle
age: the Avon Longitudinal Study of Parents and Children. Circulation.
2012 Mar 20;125(11):1367-80.

8. Hillman SL, Kubba T, Williams DJ. Delivery of
small-for-gestational-age neonate and association with early-onset
impaired maternal endothelial function. Ultrasound in obstetrics \&
gynecology : the official journal of the International Society of
Ultrasound in Obstetrics and Gynecology. 2017 Jan;49(1):150-4.

9. Kanagalingam MG, Nelson SM, Freeman DJ, Ferrell WR, Cherry L, Lowe
GD, et al. Vascular dysfunction and alteration of novel and classic
cardiovascular risk factors in mothers of growth restricted offspring.
Atherosclerosis. 2009 Jul;205(1):244-50.

10. King TF, Bergin DA, Kent EM, Manning F, Reeves EP, Dicker P, et al.
Endothelial progenitor cells in mothers of low-birthweight infants: a
link between defective placental vascularization and increased
cardiovascular risk? The Journal of clinical endocrinology and
metabolism. 2013 Jan;98(1):E33-9.

11. Catov JM, Newman AB, Roberts JM, Sutton-Tyrrell KC, Kelsey SF,
Harris T, et al. Association between infant birth weight and maternal
cardiovascular risk factors in the health, aging, and body composition
study. Annals of epidemiology. 2007 Jan;17(1):36-43.

12. Lawlor DA, Davey Smith G, Ebrahim S. Birth weight of offspring and
insulin resistance in late adulthood: cross sectional survey. BMJ
(Clinical research ed). 2002 Aug 17;325(7360):359.

13. Manten GT, Sikkema MJ, Voorbij HA, Visser GH, Bruinse HW, Franx A.
Risk factors for cardiovascular disease in women with a history of
pregnancy complicated by preeclampsia or intrauterine growth
restriction. Hypertension in pregnancy. 2007;26(1):39-50.

14. Yinon Y, Kingdom JC, Odutayo A, Moineddin R, Drewlo S, Lai V, et al.
Vascular dysfunction in women with a history of preeclampsia and
intrauterine growth restriction: insights into future vascular risk.
Circulation. 2010 Nov 2;122(18):1846-53.

15. Davey Smith G, Hart C, Ferrell C, Upton M, Hole D, Hawthorne V, et
al. Birth weight of offspring and mortality in the Renfrew and Paisley
study: prospective observational study. BMJ (Clinical research ed). 1997
Nov 8;315(7117):1189-93.

16. Pariente G, Sheiner E, Kessous R, Michael S, Shoham-Vardi I.
Association between delivery of a small-for-gestational-age neonate and
long-term maternal cardiovascular morbidity. International journal of
gynaecology and obstetrics: the official organ of the International
Federation of Gynaecology and Obstetrics. 2013 Oct;123(1):68-71.

17. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal
risk of ischaemic heart disease: a retrospective cohort study of 129,290
births. Lancet (London, England). 2001 Jun 23;357(9273):2002-6.

18. Smith GD, Harding S, Rosato M. Relation between infants' birth
weight and mothers' mortality: prospective observational study. BMJ
(Clinical research ed). 2000 Mar 25;320(7238):839-40.

19. Smith GD, Sterne J, Tynelius P, Lawlor DA, Rasmussen F. Birth weight
of offspring and subsequent cardiovascular mortality of the parents.
Epidemiology (Cambridge, Mass). 2005 Jul;16(4):563-9.

20. Smith GD, Whitley E, Gissler M, Hemminki E. Birth dimensions of
offspring, premature birth, and the mortality of mothers. Lancet
(London, England). 2000 Dec 16;356(9247):2066-7.

21. Hattersley AT, Tooke JE. The fetal insulin hypothesis: an
alternative explanation of the association of low birthweight with
diabetes and vascular disease. Lancet (London, England). 1999 May
22;353(9166):1789-92.

22. Andraweera PH, Dekker GA, Thompson SD, Roberts CT. Single-nucleotide
polymorphisms in the KDR gene in pregnancies complicated by gestational
hypertensive disorders and small-for-gestational-age infants.
Reproductive sciences (Thousand Oaks, Calif). 2012 May;19(5):547-54.

23. Zhang XQ, Varner M, Dizon-Townson D, Song F, Ward K. A molecular
variant of angiotensinogen is associated with idiopathic intrauterine
growth restriction. Obstetrics and gynecology. 2003 Feb;101(2):237-42.

24. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, et
al. Increased frequency of genetic thrombophilia in women with
complications of pregnancy. The New England journal of medicine. 1999
Jan 7;340(1):9-13.

25. Smith GC, Wood AM, White IR, Pell JP, Hattie J. Birth weight and the
risk of cardiovascular disease in the maternal grandparents. American
journal of epidemiology. 2010 Mar 15;171(6):736-44.

26. Naess O, Stoltenberg C, Hoff DA, Nystad W, Magnus P, Tverdal A, et
al. Cardiovascular mortality in relation to birth weight of children and
grandchildren in 500,000 Norwegian families. European heart journal.
2013 Nov;34(44):3427-36.

27. Andraweera PH, Dekker G, Leemaqz S, McCowan L, Myers J, Kenny L, et
al. Effect of Birth Weight and Early Pregnancy BMI on Risk for Pregnancy
Complications. Obesity (Silver Spring, Md). 2019 Feb;27(2):237-44.

28. Cheong JN, Wlodek ME, Moritz KM, Cuffe JS. Programming of maternal
and offspring disease: impact of growth restriction, fetal sex and
transmission across generations. The Journal of physiology. 2016 Sep
1;594(17):4727-40.

\textbf{Figure Legends}

Figure 1: PRISMA flow diagram of study selection process

Figure 2: Cardio-metabolic risk factors between women who gave birth to
infants with IUGR and women who had uncomplicated pregnancies

Figure 3: Cardiovascular disease mortality between women who gave birth
to SGA infants and women who gave birth to AGA infants

\textbf{Table 1 Published studies of the association between offspring
size at birth and maternal cardiovascular disease risk factors}\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Study}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Study design}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Country}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Age}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Post partum follow up time}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Inclusion criteria:} \textbf{Cases}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Inclusion criteria:} \textbf{Controls}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Exclusion criteria}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Birthweight Cases/Controls (g), Gestational age Cases/Controls
(wks)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Findings} \textbf{*Significant findings}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Small for gestational age (SGA)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hillman \emph{et al.} 2017\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Case Control\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
UK\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Approx.33-38\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6 - 9 months\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to infant with a BW \textless{}10th customised
centile (n=15)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to infant with a BW between the 10th and 95th
centile (n=29)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Fetal anomaly, smoking, pregnancy complicated by preeclampsia or
gestational hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
BW Case:2254 \selectlanguage{ngerman}± 547 Con:3566 ± 350 Cus centiles: Case:1.9 ± 2.3 Con:47.5
± 26.3 GA Case:268 ± 19.4 Con:285 ± 9.6\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who had SGA infants vs women who had AGA infants. Results as mean
\selectlanguage{ngerman}± SD SBP 105.6 ± 13 vs 109.1 ± 7.9 (p = 0.15) DBP 64.0 ± 7.68 vs 63.9 ±
7.68 (p = 0.15)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Kanagalingam \emph{et al.} 2009\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Case Control\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
UK\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
29-48\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4 years\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to a first child with a BW below the 5th centile at
36-43 weeks gestation (n=28)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to a first child with a BW between the 25th and
90th centile (n = 29)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Pre-existing hypertension, DM, gestational hypertension, preeclampsia,
genetic anomaly Cases and controls were matched for age at index
pregnancy, parity, BMI at booking, GA at booking and delivery\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
BW Case:2.47 (2.24-2.62) Con:3.43 (3.35-3.61) Cus centiles: Case:1.0
(0-3) Con: 47 (36-74) GA Case: 40 (39-40) Con: 40 (39.5-40)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who had SGA infants vs women who had AGA infants. Results as
median (interquartile range) SBP (mmHg): 120 (110-130) vs 110 (108-118),
p = 0.031* DBP (mmHg): 70 (60-80) vs 70 (60-70), p = 0.16 TC (mmol/l):
4.50 (3.80-4.79) vs 3.84 (3.36-4.52), p = 0.09 HDL (mmol/l): 1.43
(1.18-1.56) vs 1.62 (1.22-1.92), p = 0.12 LDL (mmol/l): 2.35 (1.94-2.97)
vs 2.04 (1.67-2.04), p = 0.022* TG (mmol/l): 0.95 (0.67-0.95) vs 0.64
(0.49-0.84), p = 0.028* VLDL(mmol/l): 0.43 (0.30-0.65) vs 0.29
(0.22-0.38), p = 0.03* LDL:HDL, 1.71 (1.24-2.45) vs 1.41 (0.89-1.88), p
= 0.01* TC:HDL, 3.06 (2.65-3.89) vs 2.64 (2.10-3.10), p = 0.004* BG
(mmol/l): 4.90 (4.55-5.08) vs 4.80 (4.65-5.05), p = 0.82 Insulin
(mIUl/l): 6.15 (4.45-9.55) vs 5.60 (3.85-6.90), p = 0.29 The p values
are adjusted for age, BMI, smoking status, height, parity, contraceptive
use, the Carstairs Deprivation Category score, a measure of social
deprivation\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
King \emph{et al.} 2013\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Ireland\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
27-37\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to an infant with a BW \textless{}10th centile
(n=23) Subsequently classified as Preeclampsia/ GH = 3\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to an infant with a BW [?] 10th centile (n = 23)
Subsequently classified as Preeclampsia/GH = 2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Pre-existing diabetes mellitus, hypertension, CVD GDM, smoking,
significant medical/psychiatric illness\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
BW Case:2.34 (2.13-2.65) Con:3.6 (3.17-3.85) GA Case:271 (260-278)
Con:278 (270-286)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who had SGA infants vs women who had AGA infants. Results as
median (interquartile range) SBP (mmHg): 110 (110-117) vs 110 (105-117),
p = 0.772 DBP (mmHg): 72 (65-79) vs 70 (70-75), p = 0.477 TC (mmol/l):
5.5 (34.45-5.85) vs 5.1 (4.5-5.4), p = 0.333 HDL (mmol/l): 1.63
(1.41-1.93) vs 1.76 (1.57-2.02), p = 0.368 LDL (mmol/l): 3.08
(2.24-3.51) vs 2.8 (2.29-3.19), p = 0.231 TG (mmol/l): 0.98 (0.81-1.38)
vs 0.78 (0.66-0.91), p = 0.006* BG(mmol/l): 4.4 (4.15-4.65) vs 4.3
(3.95-4.5), p = 0.256\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Fraser \emph{et al.} 2012\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
UK\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Approx. 42-52\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
18 years\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to an infant with a BW \textless{}10th centile (n =
262)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to an infant with a BW between
10\textsuperscript{th} -- 90\textsuperscript{th} centile (n =
2630)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who had SGA infants vs women who had AGA infants. Results as age
adjusted mean (SE) for SGA vs AGA groups and mean difference (confidence
interval) BMI (kg/m\textsuperscript{2}):29.35 (0.99) vs 29.69 (0.96);
-0.17 (-0.59, 0.25) SBP (mmHg): 105.19 (2.42) vs 102.85 (2.34); 1.93
(0.46, 3.41)* DBP (mmHg): 70.50 (1.59) vs 68.50 (1.54); 1.72 (0.75,
2.70)* HDL (mmol/l): 0.82 (0.08) vs 0.79 (0.07); 0.04 (-0.01, 0.09) LDL
(mmol/l): 1.32 (0.16) vs 1.35 (0.15); -0.05 (-0.15, 0.05) BG (mmol/l):
4.93 (0.20) vs 5.00 (0.19); -0.06 (-0.17, 0.05) Mean difference (CI) are
adjusted for age at measurement, prepregnancy BMI, education, parity,
smoking during pregnancy, pregnancy diabetes mellitus, hypertensive
disorders of pregnancy and preterm delivery\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Low birthweight (LBW)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Catov \emph{et al.} 2007\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
USA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
70-79\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Approx. 47-51 years\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to first born LBW \textless{}2500g (n=56)
\textbf{18/56 preterm}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to first born Normal BW [?] 2500g (n=390)
\textbf{12/390 preterm}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hypertension, preeclampsia\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Maternal characteristics according to the delivery of a LBW vs Normal BW
infant Results are means adjusted for age, BMI, race SBP (mmHg): 143.1,
vs 137.3, p = 0.048* DBP (mmHg): 73.5 vs 72.2, p = 0.359 BMI
(kg/m\textsuperscript{2}): 26.7 vs 28.4, p = 0.018* TC (mg/dl): 218.5 vs
220.3, p = 0.618 LDL (mg/dl): 128.1 vs 129.9, p = 0.726 HDL (mg/dl):
61.3 vs 60.2, p = 0.611 TG (mg/dl): 142 vs 126.7, p = 0.071 BG (mg/dl):
99.2 vs 97.9, p = 0.723 Insulin ((IU/ml): 8.10 vs 7.07, p = 0.064
Results were significant after excluding current smokers = 37\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Lawlor \emph{et al.} 2002\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Cross sectional survey\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
UK\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
68.1 -- 69.4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3265 randomly selected women. Details of pregnancy obtained at interview
and blood samples taken for assessment of insulin. Women groups
according to BW of first child as 1.56-2.94kg, 2.95-3.26kg, 3.27-3.58kg,
3.59-4.98kg\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3265 randomly selected women. Details of pregnancy obtained at interview
and blood samples taken for assessment of insulin. Women groups
according to BW of first child as 1.56-2.94kg, 2.95-3.26kg, 3.27-3.58kg,
3.59-4.98kg\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3265 randomly selected women. Details of pregnancy obtained at interview
and blood samples taken for assessment of insulin. Women groups
according to BW of first child as 1.56-2.94kg, 2.95-3.26kg, 3.27-3.58kg,
3.59-4.98kg\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3265 randomly selected women. Details of pregnancy obtained at interview
and blood samples taken for assessment of insulin. Women groups
according to BW of first child as 1.56-2.94kg, 2.95-3.26kg, 3.27-3.58kg,
3.59-4.98kg\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Results are odds ratio for age adjusted difference per kg offspring BW
SBP (mmHg): -1.79 (-3.42 to -0.15), p = 0.03* BMI
(kg/m\textsuperscript{2}): 0.74 (0.41 to 1.07), p\textless{}0.001* LDL
(mmol/l): -0.03 (-0.10-0.05), p = 0.49 HDL (mmpl/l): 0.003 (-0.03 --
0.03), 0.85 TG (mmol/l): -0.01 (-0.04 -- 0.02), 0.48\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Intrauterine growth restriction (IUGR)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Manten \emph{et al.} 2007\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Case Control\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
The Netherlands\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Approx. 27-37\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3 -- 25 months\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to an infant with BW \textless{}5th percentile for
the Dutch population and delivery \textless{} 34 weeks' gestation due to
fetal distress (n=59) Chronic hypertension = 5\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who had uncomplicated pregnancies (n=53)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
BW Case: 972 \selectlanguage{ngerman}± 763 Con: 3635 ± 462 GA Case: 210 ± 37 Con: 283 ±10\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to infants with IUGR vs women who had uncomplicated
pregnancies. Results are expressed as mean (SD) SBP (mmHg): 124 (11) vs
116 (14) DBP (mmHg): 79 (9) vs 75 (7) BMI (kg/m\textsuperscript{2}): 25
(5) vs 23 (3) TC (mmol/l): 5.3 (0.9) vs 4.7 (0.8)* HDL (mmpl/l): 1.38
(0.40) vs 1.37 (0.34) TG (mmol/l): 1.17 (0.48 -3.77) vs 1.04 (0.44-6.78)
*Not significant after excluding women with chronic hypertension,
smokers and those with BMI\textgreater{}30\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Yinon \emph{et al.} 2010\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Case Control\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Canada\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Approx. 31-36\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6-24 months\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Normotensive IUGR Women who gave birth to an infant with BW
\textless{}5th percentile accompanied by abnormal umbilical artery
Doppler (absence or reverse of end diastolic velocity) in the absence of
hypertensive disease in pregnancy -n=9 All 9 had severe IUGR and were
delivered \textless{}34 weeks' gestation\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who had uncomplicated pregnancies (n=16)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Current or past hypertension, diabetes mellitus, pregestational renal
disease, BMI \textgreater{}30kg/m2, multiple gestation in index
pregnancy, smoking, those living with smokers, those using oral
contraceptive pill\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
BW Case: 841 \selectlanguage{ngerman}± 133 Con: 3417 ± 88 GA Case: 29.2 ± 0.9 Con: 39.6 ±
0.3\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Women who gave birth to infants with IUGR vs women who had uncomplicated
pregnancies. Results are expressed as mean (SEM) BMI
(kg/m\textsuperscript{2}): 25.0 \selectlanguage{ngerman}± 1.2 vs 22.1 ± 0.6 TC (mmol/l): 4.4 ±
0.3 vs 4.1 ± 0.1 HDL (mmpl/l): 1.3 ± 0.1 vs 1.5 ± 0.1 LDL (mmol/l): 2.6
± 0.3 vs 2.3 ± 0.1 TG (mmol/l): 1.2 ± 0.4 vs 0.8 ± 0.1 BG (mmol/l): 4.6
± 0.1 vs 4.6 ± 0.1 Insulin (pmol/l): 45.3 ± 8.5 vs 23.3 ± 2.4\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 2 Published studies of the association between offspring
size at birth and maternal cardiovascular disease mortality}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Study}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Study design}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Country}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Follow up}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Population}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Outcome measures reported}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Significant findings}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Davey Smith \emph{et al.} 1997}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Scotland\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
15 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
794 married couples from the west of Scotland\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CVD mortality\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
For 1 kg decrease in offspring BW, HR = 2.0 (95\% CI, 1.18, 3.33) For 1
quartile increase in offspring BW, HR = 0.83 (95\% CI, 0.68, 1.02)
Adjusted for offspring sex, parental age Adjustment for blood pressure,
cholesterol, body mass index, smoking, social class, area deprivation,
lung function, bronchitis, angina and ECG evidence of CHD at baseline
had only modest effects on the point estimates but reduced the
statistical significance\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Davey Smith \emph{et al.} 2000}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
UK\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
10 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Information from birth registrations of infants during 1976-97 is linked
to data from the census and death registration. Data from 44,813 women
aged 15-45 years at birth registration.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CVD mortality\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
For 1kg decrease in offspring BW HR = 2.22 (95\% CI, 1.46, 3.38)
(adjusted for maternal age SES and marital status).\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Davey Smith \emph{et al.} 2000}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Finland\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
34 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3706 women who gave birth to live born singletons between 1954 -- 1963
and followed up through the Finnish Central population and cause of
death registries\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CVD mortality\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
For 1SD increase in offspring BW HR = 0.77 (95\% CI, 0.65, 0.90)
Adjusted for maternal age, height, marital status, use of private health
care during pregnancy, use of hormones during pregnancy and offspring
sex\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Smith \emph{et al.} 2001}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Scotland\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Routine discharge data of all singleton births in Scotland between
1981-1985 linked to mothers' subsequent admissions and deaths at 15-19
years follow up (129, 920 women)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CHD mortality\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
For CHD mortality comparing the lowest fifth of offspring BW with the
highest four fifth: HR = 2.8 (95\% CI, 1.5, 5.2) Adjusted for maternal
age, height, social class and preeclampsia and offspring sex and pre
term birth HR = 2.4 (95\% CI, 1.3, 4.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Davey Smith \emph{et al.} 2005}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Sweden\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Average 20.4 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Data from the Swedish Medical Birth register for all 783,814 children
born in Sweden between 1973 - 1980 were linked with parents' death
records (783,340 women)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CVD mortality CHD mortality\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
For 1SD (0.53kg) increase in offspring BW, Gestational age adjusted CVD
mortality, HR = 0.75 (0.70 -- 0.80) Gestational age adjusted CHD
mortality, HR = 0.72 (0.65 -- 0.80)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Davey Smith \emph{et al.} 2007}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
UK\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
26.2-27.5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12,086 women from the 1958 British Birth Cohort\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CHD mortality\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CHD mortality For a 1-SD increase in BW; HR = 0.80 (95\% CI: 0.74, 0.87)
After adjustment for: birth year, offspring gestational age, social
class in 1958, maternal parity, preeclamptic pregnancy, maternal height
and BMI in 1958, maternal smoking during pregnancy HR = 0.84 (95\% CI:
0.77, 0.91)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Li \emph{et al.} 2010}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Taiwan\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
30 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Linkage of data of 1,400,383 women with singleton births recorded in the
Taiwan Birth Registry between 1978-2006 with mortality data recorded in
the Taiwan Death Registry\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CVD mortality\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CVD mortality for: (a)1 SD increase in offspring BW:
HR\textsuperscript{a} = 0.89 (95\% CI, 0.85, 0.94) (b)Offspring
BW\textless{}2500g HR = 1.93 (95\% CI, 1.65, 2.27) HR\textsuperscript{a}
= 1.85 (95\% CI, 1.57, 2.18) (c) SGA Offspring HR = 1.38 (95\% CI, 1.19,
1.59) HR\textsuperscript{a} = 1.31 (95\% CI, 1.13, 1.52)
\textsuperscript{a}Adjusted for gestational age, year of offspring
birth, urbanization of residential area and parental ages, education
levels, employment status, marital status at the time of offspring
birth\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Pariente \emph{et al.} 2013}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Israel\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Perinatal database of women who delivered between Jan 1988-Dec 1998 was
linked with hospitalization data collected up until 31 Dec 2010. SGA was
defined as BW below the 10\textsuperscript{th} population centile Risk
for mortality due to CVD among those who delivered SGA infants (n=4414)
was compared with those who delivered non-SGA infants (n=47612)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CVD mortality\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
After adjusting for diabetes, preeclampsia obesity, maternal age, and
ethnicity, SGA was associated with increased cardiovascular mortality
(adjusted HR 3.5, 95\% CI, 1.5-8.2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Ngo \emph{et al.} 2015}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Australia\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Median 7.4 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Linkage of data of 812,732 women using four databases: Perinatal data
collection (birth data), admitted patient data collection (hospital
data), registrar of births, deaths and marriages (death data),
Australian Bureau of Statistics (cause of death data)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CVD occurence\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Compared to women of non-SGA infants, first occurrence of CVD among
women of (a) Moderate SGA infants (3\textsuperscript{rd}
-10\textsuperscript{th} percentile) HR\textsuperscript{a} = 1.36 (95\%
CI, 1.23, 1.49) (b)Severe SGA infants (\textless{}3\textsuperscript{rd}
percentile) HR\textsuperscript{a} = 1.66 (95\% CI, 1.47, 1.87) (c) One
SGA infant HR\textsuperscript{a} = 1.42 (95\% CI, 1.30, 1.54) (d) Two
SGA infants HR\textsuperscript{a} = 1.65 (95\% CI, 1.34, 2.03) (e) [?]
three SGA infants HR\textsuperscript{a} = 2.42 (95\% CI, 1.52, 3.85)
\textsuperscript{a}Adjusted for maternal age at index birth, parity,
country of birth, socioeconomic status, chronic and pregnancy
hypertension, pre-gestational and gestational diabetes, maternal smoking
during pregnancy\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Shaikh \emph{et al.} 2019}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Record linkage study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Norway\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Mean follow up time 47 \selectlanguage{ngerman}± 5 years Mean age at follow up 55 ± 10.4
years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Linkage of data from cardiovascular health surveys, the medical birth
registry, the cause of death registry, the educational registry and a
multigenerational database containing information on familial
relationships for the whole population of Norway. Offspring born between
1967-2012 were included\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CVD mortality\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(a) CVD mortality for 1 SD increase in offspring BW (b) CVD mortality in
women who had SGA vs AGA offspring Model 1: adjusted for maternal age at
offspring birth (a) HR = 0.72 (95\% CI, 0.69, 0.75) (b) HR = 2.02 (95\%
CI, 1.85, 2.21) Model 2: adjusted for model 1 + offspring year of birth,
mother's parity, mother's diseases before and during pregnancy, diseases
in offspring (a) HR = 0.74 (95\% CI, 0.71, 0.78) (b) HR = 1.87 (95\% CI,
1.71, 2.05) Model 3: adjusted for model 1+2 + parental marital status,
educational level in parents (a) HR = 0.77 (95\% CI, 0.74, 0.80) (b) HR
= 1.74 (95\% CI, 1.59, 1.91)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Hosted file}

\verb`Figure 1 PRISMA flow diagram of study selection process.docx`  available at \url{https://authorea.com/users/351873/articles/476315-offspring-size-at-birth-and-maternal-risk-for-cardiovascular-disease-a-systematic-review-and-meta-analysis}

\textbf{Hosted file}

\verb`Figure 2 Cardio-metabolic risk factors between women who gave birth to infants with IUGR and women who had uncomplicated pregnancies.docx`  available at \url{https://authorea.com/users/351873/articles/476315-offspring-size-at-birth-and-maternal-risk-for-cardiovascular-disease-a-systematic-review-and-meta-analysis}

\textbf{Hosted file}

\verb`Figure 3 Cardiovascular disease mortality between women who gave birth to SGA infants and women who gave birth to AGA infants.docx`  available at \url{https://authorea.com/users/351873/articles/476315-offspring-size-at-birth-and-maternal-risk-for-cardiovascular-disease-a-systematic-review-and-meta-analysis}

\selectlanguage{english}
\FloatBarrier
\end{document}

