Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

10

The mother e The long-term implications on

metabolic and cardiovascular complications
Terence T. Lao, MBBS, MD, FRCOG, FHKOG, FHKAM, Professor *
Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital,
Shatin, Hong Kong

Keywords:
There is cumulating evidence linking the occurrence of pregnancy
hypertensive disorders of pregnancy complications, including miscarriage, stillbirth, hypertensive dis-
gestational diabetes mellitus orders of pregnancy, gestational diabetes mellitus, preterm birth,
preterm birth and fetal growth restriction, with increased future risk of type 2
fetal growth restriction diabetes mellitus, and hospitalization and death due to cardio-
metabolic complications vascular and cerebrovascular diseases. Such association is largely
cardiovascular diseases related to genetic predisposition and shared pathophysiological
mechanisms and changes, which may precede the index preg-
nancy. Awareness of this association would allow identification of
the at-risk women for implementation of preventive measures to
reduce the recurrence risk of these complications and mitigate the
future development of metabolic and cardiovascular diseases
worldwide.
© 2014 Elsevier Ltd. All rights reserved.

Introduction

Cardiovascular diseases (CVDs) and type 2 diabetes (T2D) mellitus are major noncommunicable
diseases (NCDs) recognized by the World Health Organization (WHO), to which are attributed more
than 9 million deaths [1]. There is now evidence that a history of pregnancy complications, such as
hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM), increased the
future risk of CVD and T2D in women (Table 1). As pregnancy complications occur in 29e36% of
pregnancies in the US [2] and UK [3], obstetric history could help predicting future CVD risk in 20e30%

* Tel.: þ852 2632 1290; Fax: þ852 2636 0008.

E-mail address: lao-tt@cuhk.edu.hk.

http://dx.doi.org/10.1016/j.bpobgyn.2014.06.010
1521-6934/© 2014 Elsevier Ltd. All rights reserved.
 T.T. Lao / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255 245

Table 1
Association between obstetric factors and complications with future metabolic and cardiovascular complications in the mother.

Obstetric factors Cardiac Complicationsa Vascular complicationsb Metabolic Disturbancesc Diabetes mellitusd

Parity ¼ 1 √ √ e e
Parity 5 √ √ e e
TA √ √ e √
Pregnancy loss √ √ √ e
Stillbirth √ √ e e
Abruption √ √ e e
GH √ √ √ e
PE/eclampsia √ √ √ √
GDM √ √ √ √
PTB √ √ √ √
LBW/FGR √ √ e √
LGA e e √ √

TA ¼ threatened abortion, GH ¼ gestational hypertension, PE ¼ preeclampsia, GDM ¼ gestational diabetes mellitus,

PTB ¼ preterm birth (<37 weeks), LBW ¼ low birth weight (<2500 g), FGR ¼ fetal growth restriction including small-for-
gestational age, LGA ¼ large-for-gestational age.
a
Include coronary artery/ischemic heart disease, myocardial infarction, congestive heart failure, and related deaths.
b
Include atherosclerosis, increased intima-media thickness, endothelial dysfunction, increased vascular resistance, hyper-
tension, cerebrovascular diseases and stroke, thromboembolic complications, and related deaths.
c
Include dyslipidaemia, metabolic syndrome, and obesity.
d
Include abnormal glucose tolerance and frank type 2 diabetes mellitus.

of the estimated 80% parous women worldwide [2]. Therefore, it is possible to identify these high-risk
women for preventive measures that impact on future pregnancies and long-term health.

Obstetric conditions and future maternal metabolic complications

There is consensus that GDM is associated with future T2D in the mother [2]. However, other
pregnancy conditions can also increase the risk of T2D and the metabolic syndrome (MS).

Hypertensive pregnancy disorders

This category includes gestational hypertension (GH), preeclampsia (PE), and eclampsia. In the
limited literature on this association, the hazard ratio (HR) for subsequent T2D was 3.12, 3.53, and 3.68
after GH, mild PE, and severe PE, respectively [4]. Another study found the adjusted HR (aHR) for T2D
was significant at 1.52 and 2.22 for GH and superimposed PE, but not for PE/eclampsia (aHR 1.42) [5].
Five years after a pregnancy complicated by the hemolysis, elevated liver enzymes, and low platelets
(HELLP) syndrome, there was 4% increase in new-onset diabetes [6]. Thus, the risk of future T2D is
influenced by the severity of HPD.

Gestational diabetes mellitus

The risk of future T2D is associated with GDM diagnosed in the first half of pregnancy, obesity, and
need for insulin treatment [7]. Nevertheless, even among women tested normal or with impaired
glucose tolerance at the postnatal assessment, 10.6% became diabetic 4 years later, which was asso-
ciated with higher glucose at diagnosis and homocysteine levels at the postnatal assessment [8].
Chinese women with prior GDM converted to T2D at 1.6% per year, resulting in significantly increased
T2D (24.4% vs. 5.3%) and impaired glucose regulation (26.6% vs. 14.9%) compared to women with
normal glucose tolerance, 15 years after the index pregnancy [9]. Overall, GDM is associated with a
sevenfold increased risk of later T2D [10]. Of note, the study on the Northern Finland Birth Cohort of
1986 revealed that while the cumulative incidence of diabetes in the whole study population was 1.3%,
concomitant overweight and GDM greatly increased the risk (HR 47.24) [11]. Furthermore, prepreg-
nancy overweight without GDM had a greater effect (HR 12.63) than GDM in normal-weight women
(HR 10.61) on future risk of T2D. Similarly, women with previous diet-treated GDM, compared with
246 T.T. Lao / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255

age-matched controls, had adjusted odds ratio (aOR) of 3.4 for the WHO-defined MS, and body mass
index (BMI) >30 kg/m2 increased prevalence of MS sevenfold compared with BMI <25 kg/m2 [12].
Therefore, maternal overweight plays an important role here.

Preterm birth

The effect is related to the gestation at preterm birth (PTB), with an aHR of 1.89, 2.57, and 2.14 for
T2D following previous PTB at 32e36 weeks, 28e31 weeks, and 27 weeks gestation, respectively [13].
There was also an additive effect, for PTB in the first, second, and in both first and second pregnancies,
which was associated with an aHR 1.58, 1.88, and 2.30.

First-trimester bleeding

In a study on 782,287 women in Denmark who delivered a singleton infant after 20 weeks gestation
in 1978e2007, first-trimester bleeding without miscarriage increased significantly the risk of subse-
quent maternal T2D (HR 1.51) after adjusting for other adverse pregnancy outcomes [14].

Combination effects of pregnancy complications

Combination of obesity and GDM [11], and of PE, PTB, and birth of small-for-gestational-age (SGA)
infant [13] increase further the risk of subsequent T2D.

Obstetric conditions and future maternal cardiovascular complications

Apart from HPD, other pregnancy complications are also associated with subsequent cardiovascular
morbidity and mortality in the mothers [2].

Parity

Parous women have a higher CVD prevalence than nulliparous women, the risk increase for having
1e2, 3e4, and 5 pregnancies was 2.30, 2.00, and 2.88, respectively, after adjustment for age, race, and
smoking, and additional adjustment for statin use, high-density lipoprotein (HDL) cholesterol, and
adverse outcome attenuated the risk to 2.02, 1.74 (not significant), and 2.27, respectively [15]. The
parity effect interacts with pregnancy complications, for parous women with uncomplicated births had
a 1.95-fold higher risk of CVD compared to nulliparous women, while one or more pregnancy com-
plications increased this to 2.67.

Hypertensive pregnancy disorders

A history of HPD impacts on both overall risk of future CVD, as well as on individual categories like
hypertension, ischemic heart disease (IHD), and cerebrovascular disease and stroke [2,3].

Hypertension
Few studies examined the impact on hypertension alone. On an average of 5 years after a pregnancy
complicated by the HELLP syndrome, there was 33% increased new-onset hypertension [6]. In another
study, 7 years after a diagnosis of GH or PE, there was increased hypertension (37% and 20%, respec-
tively, vs. 2%) and microalbuminuria (14% and 20%, respectively, vs. 2%), compared with controls, and
microalbuminuria was one of the significant factors associated with hypertension [16]. The risk is
influenced by the severity of HPD and the order and number of pregnancy affected, as the HR for
subsequent hypertension was 5.31, 3.61, and 6.07 for GH, mild PE, and severe PE, respectively [4], and
was 2.70, 4.34, and 6.00 for the first pregnancy, second pregnancy, and both pregnancies, respectively,
being complicated by PE [4].
 T.T. Lao / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255 247

Ischemic heart disease

When 129,920 women with singleton first-birth deliveries in Scotland between 1981 and 1985
were analyzed 15e19 years later, the aHR for maternal IHD admission or death after prior PE was 2.0
[17]. When parous women aged 66 years with angiographically documented coronary artery disease
were compared with aged-matched controls, PE during any pregnancy increased the risk almost
fivefold (aOR 4.8) [18]. Among 403,550 Swedish women who gave birth to a first child in 1973e1982
and were followed up for 15 years, the adjusted incidence risk ratio (IRR) for dying from or hospitalized
for IHD later was 1.7 for HPD overall, but which increased from 1.6 for GH, 1.9 for mild PE, to 2.8 for
severe PE [19]. Furthermore, GH in the first but not second pregnancy had an adjusted IRR 1.9, which
was increased to 2.8 with HPD in both pregnancies. Thus, the risk is influenced by both severity and
recurrence of HPD.

Cardiovascular diseases
The calculated 10-year CVD risk based on the Framingham prediction score for PE is increased (OR
1.31) [3]. In a review and meta-analysis on a dataset of 3,488,160 women with 198,252 affected by PE,
the relative risk (RR) was 3.70 for hypertension, 2.16 for IHD, 1.81 for stroke, 1.79 for venous throm-
boembolism, and overall mortality after PE increased (RR 1.49) after 14.5 years [20]. McDonald et al.
[21] analyzed five caseecontrol and ten cohort studies that included 116,175 women with and
2,259,576 without PE or eclampsia, and confirmed that PE or eclampsia increased subsequent cardiac
disease in caseecontrol (OR 2.47) and cohort (RR 2.33) studies, and cerebrovascular disease (RR 2.03)
and cardiovascular mortality (RR 2.29). Furthermore, the RR of cardiac disease increased from 2.00 and
2.99 to 5.36 for mild, moderate, and severe PE, respectively. Similarly, in the latest meta-analysis, a
history of PE/eclampsia increased subsequent fatal or diagnosed CVD (OR 2.28), cerebral vascular
disease (OR 1.76), and hypertension (RR 3.13) [22]. In addition, PE increased ischemic stroke in women
aged 15e44 years (aOR 1.63) [23].
The severity of HPD influenced the risk of different cardiovascular events [4]. Compared with GH,
severe PE increased the aHR for first-time cardiovascular events (3.3 vs. 2.8) [24], cardiovascular death
(2.89 vs. 2.47) [25], and thromboembolism (1.91 vs. 1.03 [4] and aHR 2.3 [24]). Concomitant PTB
probably reflected increased severity of PE, thus PTB further increased the aHR for stroke from 2.04
with PE alone to 3.22 [26]. Indeed, women with PE in the first delivery in Norway had a 1.2-fold higher
long-term risk of death, while the risk was 1.56-fold higher for those with additional PTB, and PE
requiring PTB increased greatly the risk of death from cardiovascular causes (HR 8.12) and stroke (HR
5.08), compared to PE with delivery at term (HR 1.65) for death from cardiovascular causes [27].
Similarly, from the perspective of PTB, PE was an independent obstetric risk factor (HR 2.2) for CVD and
total cardiovascular hospitalizations in women followed up for 10 years after PTB [28]. In one of the
longest follow-up studies in which the median age of enrollment was 26 years and median follow-up
time was 37 years, having a PE was independently associated with CVD death (mutually aHR ¼ 2.14),
with the effect greater for PE 34 weeks (HR 9.54) than PE >34 weeks (HR 2.08), and at 30-years
follow-up, the cumulative CVD-death survival for early PE was 85.9%, late PE was 98.3%, and 99.3%
for women without PE [29]. Similarly, a Norwegian study showed increased aHR for cardiovascular
death (3.4), IHD (4.7), and cerebrovascular death (2.1) for one lifetime pregnancy with term PE, and for
preterm PE the aHR increased to 9.4, 9.3, and 10.4, respectively, while one or more subsequent normal
pregnancy following term PE in the first pregnancy attenuated the risk to 1.5, 1.7, and 1.4 (not signif-
icant), respectively, and for preterm PE it was attenuated to 2.4, 3.7, and 1.12 (not significant),
respectively [30]. On the other hand, while the aHR for cardiovascular death for all PE was 1.9, this
increased progressively with recurrence of PE once, one or more, or two or more pregnancies after the
first one to 2.0, 2.3, and 5.0, respectively, while the corresponding risk for women without PE in the first
pregnancy was 2.0, 2.1, and 3.8, respectively. Therefore, the ultimate risk is influenced by the gestation
at, and the order and number of, pregnancies affected by PE. PE after the first pregnancy has a greater
impact than PE in the first pregnancy on cardiovascular death, which was also correlated with the
number of subsequent pregnancies with PE irrespective of the first pregnancy outcome.
The Northern Finnish Birth Cohort of 1966 (n ¼ 10 314), followed-up for an average 39.4 years, was
examined for the impact of GH, PE/eclampsia, and superimposed PE [5]. The aHR for CVD was 1.45, 1.40,
and 2.06, respectively; for IHD, it was 1.44, 1.36, and 1.86, respectively; for myocardial infarction (MI), only
248 T.T. Lao / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255

GH (aHR 1.75) and superimposed PE (aHR 2.18) were significant; for death from MI, only GH (aHR 3.00) and
superimposed PE (aHR 5.12) were significant; for heart failure, it was 1.79, 1.69, and 3.32, respectively; for
ischemic cerebrovascular disease, only GH was significant (aHR 1.59). Superimposed PE therefore posed a
greater risk than PE, probably consequent to preexisting vascular damage from the chronic hypertension.

Gestational diabetes mellitus

Underlying insulin resistance is one of the links between GDM with future T2D and hypertension [7].
Indeed, Chinese women with GDM had a significantly increased rate of hypertension (35.6% vs.16.0%)
compared with women with normal glucose tolerance 15 years after the index pregnancy [9], and an OR
of 1.26 was found in the calculated 10-year CVD risk for GDM [3]. Women with history of GDM had more
noninvasive cardiac diagnostic procedures (OR 1.8), simple cardiovascular events (OR 2.7), and total
cardiac hospitalization (OR 2.3), when followed up for 10 years, and GDM was independently associated
with cardiovascular hospitalizations (aHR 2.6) compared with obesity (aHR 2.5), and preeclampsia (aHR
2.4) [31]. Women with history of GDM had higher risk of CVD (aHR 1.85), which occurred on average 7
years earlier [32]. In women with previous PTB, any form of diabetes mellitus (HR 2.0) was an inde-
pendent risk factor for the increased cardiovascular events and total cardiovascular hospitalizations more
than 10 years later [28]. Therefore, severity of GDM similarly impacts on the subsequent risk of CVD.

Preterm birth

PTB was associated with subsequent higher blood pressure (BP) [3] and IHD (HR 2.09) independent
of major cardiovascular risk factors [33]. Prior PTB also impacts on risk of death, with adjusted IRR of 1.3
for dying from or hospitalized for IHD later in life [19], HR of 1.98 for subsequent cardiovascular death
[13], and HR 1.8 for the risk of IHD admission or death [17]. In addition, PTB increased significantly the
risk of deaths from cardiovascular causes (HR 2.95) and stroke (HR 1.91) [27]. The combination of PTB
with PE in the first delivery increased significantly the risk of death, with relative HR 8.12 and 5.08 for
death from cardiovascular causes and stroke, respectively, while it was only 1.65 for death from car-
diovascular causes for PE with delivery at term [27].
In a study utilizing three Scottish data sources on 750,350 women who delivered a live singleton
infant following their first pregnancy, and between 35 and 65 years of age at their first IHD event, PTB
overall was associated with aHR 2.26 for IHD deaths, but the aHR was lower (2.14) for spontaneous than
for elective (2.49) PTB [34]. Similarly, aHR for total IHD events was 1.58 overall, 1.46 for spontaneous,
and 1.81 for elective PTB. This probably reflected the need for intervention, and the trend of association
between PTB and IHD increased with decreasing age at first event suggested an underlying genetic
predisposition to both placental dysfunction and IHD.
The effect of gestation at and number of PTBs on subsequent CVD risk remains unclear. In one study, PTB
at 27 weeks posed higher risk for hypertension (aHR 1.49) and IHD (aHR 1.61), but not for thrombo-
embolism, compared with PTB at later gestation, while PTB in both first and second pregnancies posed
higher risk for hypertension (aHR 1.39), IHD (aHR 1.36), and thromboembolism (aHR 1.80), compared with
PTB in either the first or the second pregnancy [13]. On the other hand, another study found no difference
between PTB at <34 and 34 weeks gestation, and between those with induced versus spontaneous PTB,
although simple cardiac events increased from 3.6% to 4.1%, and total cardiovascular hospitalizations from
5.0% to 5.5%, for women with one versus with two or more PTBs [28]. Another study showed that the aHR of
1.36 for CVD with prior PTB was attenuated after exclusion of PE or SGA, and although recurrent PTB
increased the risk for ischemic events from 1.22 to 1.78 compared to one PTB, the risk was similar for early,
moderate, and late PTB [35]. In the latest review, for a given history of PTB, the aHR was 1.2e2.9 for CVD
morbidity, 1.3e2.1 for IHD,1.7 for stroke, and 4.1 for atherosclerosis, and that the effect of two previous PTB
was greater than that for two or more pregnancies with only one PTB [36].

Birth of SGA and growth-restricted infants

Delivery of an SGA infant was associated with subsequent higher BP [3] and dying from or hospi-
talized for later IHD (adjusted IRR 1.8) [18]. While delivering a singleton SGA infant in the first
 T.T. Lao / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255 249

pregnancy increased subsequent death from cardiovascular causes (HR of 2.56) [25], lower birth
weight short of being SGA still impacts on the risk of IHD. Smith et al. [17] demonstrated that the
maternal risk of IHD admission or death (aHR) for having a baby in the lowest birth weight quintile for
gestational age was 1.9. When birth weight 3500 g was used as the reference group, the aHR for death
due to IHD and admission/death due to IHD were 11.3 and 4.3, respectively, for birth weight <2500 g,
5.4 and 2.7, respectively, for birth weight at 2500e2999 g, and 2.5 (not significant) and 1.5, respectively,
for birth weight at 3000e3499 g. Offspring birth weight is actually inversely correlated with maternal
cardiovascular mortality, the aHR for a 1-standard deviation increase in offspring birth weight was
0.87, an effect that was greater for CVD than other outcomes [37]. Subsequently, another study
confirmed the associated risk between LBW offspring with maternal future CVD mortality (aHR 1.85),
and a 1-standard deviation higher offspring birth weight reduced CVD mortality (aHR 0.89) [38].

Pregnancy loss, including miscarriage, recurrent miscarriage, and stillbirth

Pregnancy loss (miscarriage and stillbirth), in the absence of the aforementioned complications, can
still be associated with increased maternal risk of future CVD.
In the Danish study on 782,287 women who delivered a singleton after 20 weeks, those with
prepregnancy CVD had 2.2-fold increased risk of first-trimester bleeding without miscarriage, while
miscarriage increased significantly the risk of subsequent maternal hypertension (HR 1.20), IHD (HR
1.58), stroke (HR 1.41), and thrombotic event (HR 1.61), after adjusting for other adverse pregnancy
outcomes [14]. Furthermore, the number of miscarriages influenced the risk of MI, with an age-
adjusted OR of 1.4 per miscarriage on top of the overall age-adjusted OR of 2.1 [39]. In the European
Prospective Investigation into Cancer and Nutrition (EPIC) cohort, among the 11,518 women ever
pregnant and assessed at age 35e66 years with a mean follow-up of 10.8 years, previous miscarriage
increased the risk of MI (age-aHR 1.42), and more than two miscarriages increased this risk further
(4.34) [40]. Recurrent miscarriage (>3) remained a significant predictor (aHR 5.06) after full adjust-
ment for confounding factors, while no effect was found with therapeutic abortion. Furthermore, MI,
cerebral infarction, and renovascular hypertension, were increased at 13%, 16%, and 20%, respectively,
for women with miscarriage, and each additional miscarriage increased the rate of these outcomes by
9%, 13%, and 19%, respectively, the association being strongest in women aged <35 years [41]. A meta-
analysis of ten studies with 517,504 subjects in the coronary heart disease and 134,461 subjects in the
cerebrovascular disease analyses confirmed increased risk for coronary heart disease by a history of
miscarriage (OR 1.45) and recurrent miscarriage (OR 1.99), but not for cerebrovascular disease (OR 1.11)
[42]. Familial and genetic factors may be involved, as the incidence of IHD was increased in parents of
women with two miscarriages (HR 1.25) and three or more miscarriages (HR 1.56) before their first
birth, but there was no relationship with the number of therapeutic terminations [43].
In the EPIC cohort, the fully aHR for MI was 3.43 among women with prior stillbirth [40], which
increased by 2.69, 1.74, 2.42 times the rate of MI, cerebral infarction, and renovascular hypertension,
respectively, compared with women who had no stillbirth [41]. Similarly, the history of stillbirth
increased subsequent death from cardiovascular causes (HR 1.80) after a median follow-up of 14.8
years in women with a first singleton delivery [25]. Thus, recurrent miscarriage and stillbirth probably
share common pathophysiological pathways and genetic predispositions with subsequent CVD.

Combination of pregnancy complications and the placental syndrome

The additive effects of PTB and FGR on the impact of PE on future CVD risk [26e30] are illustrated by
the observation that HPD, PTB, and SGA together increased the adjusted IRR to 2.6, higher than that for
any individual complication [19]. Different combinations can come up with different effect magnitudes.
For instance, HR for future IHD is 3.9 for PTB plus birth weight in the lowest quintile, 4.5 for PTB plus PE,
3.3 for PE plus birth weight in the lowest quintile, and 7.0 for all three complications together [17].
Likewise, the aHR for stroke increased from 2.04 with PE alone to 3.22 with PTB in addition, which was
further aggravated by the effects of age to become highest among the 15e18-year-olds in the HPD
group (HR 13.4) followed by women 35 years (HR 5.56) [26]. Indeed, PE, PTB, and SGA together
increased further the HR for hypertension, IHD, stroke, congestive heart failure, T2D, and
250 T.T. Lao / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255

thromboembolism [4]; and for cardiovascular mortality, the HR for SGA plus PTB increased from 1.90
for PTB alone to 3.30, while the combination of PTB, SGA, and PE increased this to 3.85 [25].
The additive effect of PE, PTB, and FGR/LBW could be attributed to maternal placental syndrome,
which include HPD and abruption or infarction of placenta, and which arise most often in women with
metabolic risk factors for CVD. In 1.03 million women free from CVD before their first documented
pregnancy, with the mean age at index pregnancy of 28.2 years, 7% were found with placental syn-
drome, which was significantly associated with future CVD (aHR 2.0), coronary heart disease (aHR 2.0),
cerebrovascular disease (aHR 1.9), peripheral vascular disease (aHR 3.0), and composite CVD (aHR 2.0)
[44]. For individual manifestations, the aHR was 1.7 for abruption or placental infarction, 1.8 for GH, and
2.1 for PE. Placental syndrome resulting in poor fetal growth increased the HR to 3.1 and to 4.4 when
intrauterine fetal death occurred.
As alluded to before, maternal age and obesity could influence the ultimate risk of CVD. The
Northern Finland Birth Cohort of 1986 showed that HPD concomitant with overweight and GDM
increased the HR to 9.16, while in normal-weight women GDM increased only the risk for T2D (HR
10.61) but not hypertension. On the other hand, even if the antenatal OGTT was normal, prepregnancy
overweight increased the risk for hypertension (HR 2.86), indicating that overweight exerts an effect as
important, if not greater, than some of the pregnancy complications on future CVD risk [11].

Mechanisms linking pregnancy conditions with metabolic and cardiovascular complications

Multiple mechanisms operating before, during, and after pregnancy are involved.

Genetic factors and predisposition

The increased incidence of IHD in parents of women who experienced two or more miscarriages,
but not with therapeutic terminations, pointed to genetic predispositions [43]. In an intergenerational
caseecontrol study conducted in the Dutch population on women who had PE or FGR and their par-
ents, and compared with a control group with a median follow-up of 7.1 years, not only did women
with PE have significantly higher fasting glucose levels, larger waist circumferences, fivefold increased
prevalence of hypertension, their parents also had higher glucose levels, and their mothers had larger
waist circumferences and higher BP [45]. Similarly, while women with FGR had higher glucose levels
and increased prevalence of hypertension, their fathers also had higher glucose, and MS was more
prevalent in both women with history of PE and their mothers. Women with PE or FGR also had a
strong family history of CVD [46]. These observations indicate similar intergenerational cardiovascular
risk profiles, which suggest shared constitutional risks for vascular-related pregnancy complications
and future risk of CVD in parous women.

Endothelial dysfunction

Upregulation of mediators of endothelial dysfunction is found in PE [47]. When studied on day 10 of

the luteal phase of an ovulatory cycle 11e27 months after the index pregnancy, a significant decrease in
endothelium-dependent dilatation as reflected in brachial arterial reactivity, a higher rate of endo-
thelial dysfunction, lower serum nitrates, and higher cholesterol, together with higher BP and a greater
parental prevalence of CVD, were found in women with previous PE [48]. Women with recurrent
pregnancy loss had similar findings together with significantly lower endothelium-independent
vasodilatation [48]. Women with PTB, including spontaneous PTB, have elevated levels of soluble
intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and sol-
uble E-selectin (sE-selectin) which was only elevated in PTB complicated by PE [49]. As these are also
pathogenic precursors to CVD, underlying endothelial dysfunction probably plays a role here.

Vascular factors

Women with history of PE or FGR had higher brachial diastolic pressure, central systolic pressure,
mean arterial pressure (MAP), and peripheral vascular resistance (PVR) than controls [46]. The higher BP
 T.T. Lao / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255 251

and PVR are probably attributable to changes in the arterial wall, as mean carotid intima-media thick-
ness (IMT) was increased in women with chronic hypertension after PE as compared with those without
hypertension [45]. However, normal pregnancy alone is also associated with significantly increased
common carotid IMT compared with nulliparous women [50]. When nulliparous women, primiparous
women with normal pregnancy, and with pregnancy complicated by early-onset PE were studied 3
months postpartum and 6 weeks after cessation of lactation, the PE group had increased common
femoral artery IMT, and significantly higher BP, triglycerides (TG), and homocysteine, compared with the
other two groups [50]. Underlying atherosclerotic changes are also involved, as when women with
previous pregnancy that was normal, with proteinuria alone, with nonproteinuric hypertension, and
with PE were compared, the incidence of carotid plagues increased from 42%, 43%, and 53% to 52%,
respectively (p ¼ 0.018), total carotid plague area increased from 7.09, 8.18, and 10.70 to 10.00 mm2,
respectively (p ¼ 0.001), and mean carotid IMT increased from 0.82, 0.82, 0.84, to 0.86 mm, respectively
(p ¼ 0.001) [51]. This was accompanied by increased hypertension from 13%, 15%, and 28% to 25%,
respectively (p < 0.001), and CVD and/or stroke from 4.2%, 5.7%, and 7.1% to 7.7% (p < 0.001).
Increased common carotid IMT is also found after the diagnosis of GDM, together with higher mean
TG and very low-density lipoprotein (VLDL)-cholesterol, homocysteine, and fasting glucose [52]. The
higher carotid IMT was positively correlated with age, BMI, homocysteine levels, and fasting and 1-h
glucose levels at the OGTT, and GDM and BMI at testing were independently related to carotid IMT.
Furthermore, compared with healthy controls at similar age, women with pervious GDM had signifi-
cantly higher carotid IMT, but which was similar compared with women with MS [53]. Indeed, previous
GDM was independently associated with increased composite carotid IMT generated from different
sites of measurement.

Cardiac factors

PE at term is associated with maternal biventricular diastolic dysfunction (40%), altered geometry,
and left ventricular (LV) remodeling, with 20% of these women having more evident myocardial
damage [54]. Women with preterm PE have more severe cardiac impairment characterized by
biventricular systolic dysfunction (26%) and severe LV hypertrophy (19%) [55]. When assessed at 20e23
weeks gestation, women who subsequently developed PE irrespective of gestation had LV concentric
remodeling (33%) not found in the controls, but only women with preterm PE exhibited a high-
resistance-low volume hemodynamic state together with LV diastolic or systolic dysfunction (33%)
and segmental impaired myocardial relaxation (72%) [56]. One-year postpartum, asymptomatic LV
moderateesevere dysfunction/hypertrophy could still be found in preterm (56%), term PE (14%), and
matched controls (8%). The risk of developing hypertension within 2 years was significantly higher in
both women with preterm PE (40%) who had stage B asymptomatic heart failure postpartum and those
with persistent LV moderateesevere abnormal function or geometry [57]. Similarly women with
normotensive FGR pregnancies assessed during pregnancy and 12 weeks postpartum had lower car-
diac index, higher total vascular resistance index for gestation, increased prevalence of asymptomatic
LV diastolic dysfunction, and widespread impaired myocardial relaxation, but unlike in women with
previous PE, cardiac geometry and intrinsic myocardial contractility were preserved [58]. Indeed,
previous FGR is characterized by a low-output high-resistance circulatory state, higher prevalence of
asymptomatic global diastolic dysfunction, and poor cardiac reserve. Diastolic dysfunction usually
precedes systolic dysfunction in the evolution of IHD or hypertensive cardiac diseases, and this
probably linked previous PE and FGR with future CVD-related morbidity and mortality.

Metabolic abnormalities

The association between HPD and future CVD is related in part to common metabolic disturbance,
as HPD was associated with higher BMI, waist circumference, BP, lipids, and insulin [3]. In fact, women
with PE had more risk factors for future CVD like dyslipidemia, hypertension, obesity, and increased
insulin resistance (HOMA score) even after excluding those with smoking, hypertension, and BMI
>30 kg/m2; while women with pregnancy complicated by FGR have higher concentration of cholesterol
and a tendency towards higher BMI, higher TG concentrations and increased insulin resistance,
252 T.T. Lao / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255

compared with normal controls when studied postpartum after ending lactation [59]. Women with
previous GH, and to a lesser extent PE, during their first pregnancy at the average age of 25 years were
subsequently found not only to have higher BP but also higher waist circumference, waist/hip ratio, and
BMI, increased serum insulin, and lower glucose/insulin ratio, compared to women at the same age
[60]. Features of MS have also been demonstrated 18 years after a pregnancy complicated by HPD [3].
The metabolic disturbance associated with prior PE may be related in part to chronic inflammatory
changes. When postmenopausal women with prior eclampsia, who had higher C-reactive protein (CRP)
after adjustment for confounders, were clustered into either having high or low CRP, the former group
had significantly elevated systolic BP, lower HDL cholesterol, higher apolipoprotein B, higher fasting
insulin and HOMA values, while the latter group only had marginally raised apolipoprotein [61].
Therefore, the triad of inflammation, low HDL cholesterol, and insulin resistance may be a common link
between GDM, HPD, and future CVD.
Nevertheless, a study on Norwegian women showed that while those with PE or GH had sub-
stantially higher BMI, systolic and diastolic pressure, and unfavorable lipids, the difference in BMI and
BP were attenuated by 65% and 50%, respectively, while HDL-cholesterol and TG were attenuated by
40% and 72%, respectively, after adjusting for prepregnancy measurements [62]. Therefore, the positive
association of HPD with postpregnancy CVD risk reflects to a large extent shared prepregnancy risk
factors.
The higher mean TG and VLDL-cholesterol, homocysteine, and fasting glucose, found together with
increased common carotid artery IMT after the diagnosis of GDM [52], suggested that metabolic and
vascular abnormalities are related. Indeed, common carotid IMT correlated positively with age, BMI,
homocysteine levels and fasting and 1-h glucose at OGTT in that study [52]. These disturbances
probably predate the pregnancy, as unfavorable prepregnancy levels of TG, cholesterol, HDL-
cholesterol, and glucose were associated with increased risk of PTB and shorter gestational length,
and TG level above 1.6 mmol/L was associated with 60% higher risk of PTB compared with TG level
<0.7 mmol/L [63].

Inflammatory response

As mentioned above, Icelandic postmenopausal women with prior eclampsia had higher CRP after
adjustment for confounders, and high CRP was related to metabolic disturbances [61]. A hitherto
overlooked underlying inflammatory reaction could be a common cause of some of the aforemen-
tioned disturbances linking pregnancy complications with future metabolic and cardiovascular
complications.

Conclusion

Pregnancy complications predict future metabolic and CVDs in the affected mothers. The effect is
however variable as shown by the wide range of HR in the literature, due to modification by maternal
factors, combination and severity of the pregnancy complications, and the number and order of
pregnancies being affected. Common pathophysiological mechanisms, some predating the index
pregnancy, and genetic predisposition, are largely responsible for this association. Enhancing the
knowledge on this association among obstetricians/gynecologists is one means to help preventing
future CVD in the affected women [64].

Summary

Most of the important pregnancy complications, especially those affected fetal growth and
outcome, are associated with increased future risk of metabolic and especially cardiovascular com-
plications in the mother. The common pathophysiological factors for these two groups of conditions are
likely related to genetic predisposition and prepregnancy changes that become unmasked by the stress
of pregnancy. Pregnancy outcome therefore could be used to identify the high-risk women for inter-
vention to mitigate future morbidity and mortality related to metabolic and cardiovascular
complications.
 T.T. Lao / Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 244e255 253

Practice points

 The hypertensive disorders of pregnancy, GDM, PTB, fetal growth restriction, and pregnancy
loss are all associated with future risk of metabolic and cardiovascular complications.
 The risk is influenced by the number of order of pregnancy affected, being especially
increased in women with recurrent or multiple concurrent pregnancy complications.
 Underlying changes in cardiac structure and function, increased arterial media-intima
thickening, and atherosclerotic plagues are changes that could select out the especially
high-risk women.
 Women identified as high risk by pregnancy complications should be followed up for
monitoring and effective intervention as appropriate where indicated.

Research agenda

 Effect of antenatal treatment on the associated pathophysiological changes in hypertensive

disorders of pregnancy
 Effect of metabolic control on the metabolic disturbances associated with GDM and on
subsequent metabolic changes after delivery
 Preconceptional treatment on metabolic disturbances associated with GDM and HDP in the
prevention of recurrence of these complications
 Prophylactic treatment of metabolic and cardiovascular disturbances on long-term health
outcome in the mother

Conflict of interest statement

The author has no conflict of interest in the preparation of the manuscript.

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