Interpretation
Lipid profile
We observed differences in lipid profiles between ethnicities. Pregnancy
is a state of physiologic hyperlipidaemia to accommodate the growing
fetus,43 but reference values for serum cholesterol
during pregnancy have not been established. Values for both ethnicities
fell within a ‘normal’ range reported in a single cross-sectional
pregnancy study.44 The overall lipid profile was less
favourable among Indian women with increased triglycerides and lower HDL
levels, which are considered important components of the metabolic
syndrome.26,45 In line with our findings and
hypothesis, a systematic review and meta-analysis showed that
triglyceride levels were significantly increased in women with GDM,
compared with those without insulin resistance (across all three
trimesters). In that study, HDL was also reduced among those with GDM
(in the 2nd and 3rd trimesters),
while there were no differences in LDL and total cholesterol
levels.46 In addition to a less favourable lipid
profile, our study showed that adiponectin (i.e. an adipokine protein
with insulin-sensitising and ani-inflammatory effects) was lower among
mothers of Indian ethnicity. Reduced adiponectin has been associated
with obesity, diabetes and components of the metabolic
syndrome,47,48 and the findings in this study may be
of clinical importance to Indian mothers.
Placental biomarkers
As infants of Indian women are generally born with a lower mean
birthweight compared with other ethnic groups,16,49-51and as birthweight and placental weight are highly
correlated,52 one may expect lower levels of PlGF
among Indian mothers. Nonetheless we observed the contrary, in line with
an Asian study that found significantly higher PlGF levels among Indian,
compared with Chinese and Malay women ≥18 weeks gestation (although not
between 11 and 14 weeks).53 PlGF belongs to the
vascular endothelial growth factor family, and is highly expressed in
the placenta throughout pregnancy.54 PlGF promotes
vascular placental growth, but is also found in other organs and
stimulates angiogenesis during inflammatory
response.55 Limited clinical data shows increased PlGF
in obese non-pregnant adults and children with the metabolic syndrome
and diabetes.56-58 While studies are small and data
sometimes conflict, a positive association between elevated PlGF and GDM
has been established.59-61 A recent literature review
concludes that although large-scale research is missing, most studies
agree with this observation.62 Similarly, increased
levels of PlGF have been detected in the placentas of anaemic women,
compared with non-anaemic controls.63 In both diabetic
disease and anaemia the increase in PlGF is thought to be caused by an
adaptive angiogenic response to a relatively hypoxic placental
environment, seen with hyperglycaemia and low
haemoglobin.63,64 While placental hypoxia is
considered physiological during first trimester
pregnancies,65 biomarkers were collected at 15±1 weeks
gestation in this study. As women of Indian ethnicity have higher rates
of both disorders, these pathways may explain some of the differences
seen in PlGF in our study.
Metabolic/obesity biomarkers
Certain adipokines such as NGAL have been positively associated with
low-level systemic inflammation in the metabolic syndrome, obesity,
hyperglycaemia and insulin resistance in human
studies.66,67 We found significantly lower levels of
NGAL among Indian women compared with European. Animal studies, however,
show conflicting results, with some reporting diet-induced obesity and
insulin resistance in NGAL knockout mice, accompanied by an increase in
pro-inflammatory mediators.68,69 The latter finding is
consistent with our hypothesis, that lower NGAL in Indian women is
associated with a less favourable metabolic health profile. Further
research needs to be done into the relationship between NGAL and
metabolic health, to fully understand our findings by ethnicity.
Other significant metabolic biomarkers in multivariable analysis were
periostin and MMP-9. Periostin is an extracellular matrix protein
involved with tissue remodelling and repair,70 and has
been positively associated with obesity, type II diabetes, insulin
resistance, cardiovascular disease, lipids, chronic inflammation, and
polycystic ovarian syndrome.71-74 Periostin levels
were significantly increased among Indian women in this study, compared
with European. MMP-9 is also responsible for tissue remodelling, and is
particularly overexpressed with diabetes and the metabolic syndrome, as
a consequence of oxidative stress in endothelial
cells.75,76 In our analysis MMP-9 levels were
significantly reduced among Indian, compared with European mothers,
which is in contrast to our hypothesis. The reason for this is unknown.
Inflammatory biomarkers
In a recent study we reported that Indian mothers have higher rates of
perinatal death at extremely preterm gestations.8 We
hypothesised that a pro-inflammatory environment during these early
weeks may lead to preterm birth, as an important antecedent factor for
perinatal death.77 In the current study, several
important pro-inflammatory biomarkers were increased among women of
Indian ethnicity, compared with European. For example, levels of ICAM-1
were significantly higher, which has been associated with an increased
risk of preterm birth when analysed in serum,78-80cervicovaginal fluid,81 and
amnion.82 Of these studies, only Chen et al. included
serum samples at early gestation (mean=16 weeks), granted with a
standard deviation of ±4.5 weeks.78 ICAM-1 is a
surface glycoprotein expressed on endothelium and immune cells which
regulates several inflammatory pathways.83 It is
elevated in activated endothelium,83 in the metabolic
syndrome,84,85 and seems to be inversely correlated to
HDL.85 Another biomarker with pro-inflammatory
properties, CXCL10, was significantly increased among Indian mothers
compared with European. CXCL10 has been associated with a range of
chronic inflammatory disorders, including type II diabetes and the
metabolic syndrome.86-88 Some studies even suggest
that CXCL10 is a potential biomarker for the onset of adipose tissue
inflammation in obese people.89,90
Cardiovascular biomarkers
ANP is mostly known for its properties in cardiovascular, endocrine and
renal functions, and is stored as the biologically inactive variant
proANP in atrial myocytes.91 In addition, ANP
indirectly influences glucose metabolism.92,93 In this
study we observed significantly lower levels of proANP among women of
Indian ethnicity. This is in line with our hypothesis, as other studies
report an inverse relationship between different fragments of proANP
(NT-ANP, MR-ANP) and the risk of developing
diabetes.94,95 Furthermore, a Turkish study found
progressively lower ANP levels in women with GDM,96although non-significant, while another study was able to confirm
this.97
Furthermore, our findings are consistent with a previous study observing
overall higher angiogenin levels among South Asian subjects, compared
with European ethnicities in the United States.98Angiogenin levels rise during pregnancy with increasing
gestation,99 and seem to promote placental vascular
development during the prenatal period.99,100 Although
not widely investigated, a meta-analysis found decreased levels of
angiogenin among patients with type II diabetes, but this was not
statistically significant.101 It is unclear whether
this also occurs with GDM. We hypothesise that relative placental
hypoxia (e.g. due to maternal hyperglycaemia or low haemoglobin) may
play a role in the observed increased angiogenin level in pregnant
Indian women in our study. Finally, ST2, a cardiovascular biomarker
positively associated with diabetes and the metabolic syndrome
(including related markers such as triglycerides, liver function and
glucose),102-104 was found in lower levels among
Indian women compared with European in the current study. The reason for
this is unclear.
Routine testing
Although it is widely recognised that women of Indian ethnicity have
higher rates of pre-existing diabetes,8,17,18 and
increased odds of developing GDM,9-12,16 random blood
glucose levels at 15±1 and 20±1 weeks did not differ between groups.
This is not surprising, as women with pre-existing diabetes were
excluded from enrolment in the SCOPE study. Additionally, there was a
statistically significant difference in mean haemoglobin between ethnic
groups. It is, however, unclear whether this finding is of clinical
relevance as both mean values fell within normal range for pregnant
women (>110 g/L). It may indicate that women of Indian
ethnicity have a lower threshold for developing anaemia and associated
disorders, as pregnancy progresses further into a physiologic anaemic
state. In this study there was no difference in haemoglobin levels
between non-vegetarian and vegetarian women of Indian ethnicity. While
we observed a large difference in rates of anaemia between Indian and
European (6.5% vs. 1.8% respectively), when anaemic women were
excluded in sensitivity analyses biomarker profiles between Indian and
European women did not change. This may be due to the low number of
women with anaemia in each ethnic group, and further investigation is
warranted.