Introduction
The prevalence of type 2 diabetes is increasing globally, however, with considerable
variation in different countries and regions worldwide [1]. This increase reflects urbanization,
the aging of populations and also reductions in the prevalence of undernutrition and
infectious diseases, which may at least partly explain the variation in trends in
different regions of the world. The increased prevalence of type 2 diabetes is
paralleled by increased rates of gestational diabetes, which affects
6–25% of pregnant women [2]
[3]. However, for many
countries, the true prevalence of gestational diabetes is not known [https://www.diabetesatlas.org]. Since gestational
diabetes puts affected mothers and their children at short-term and long-term risk
[4]
[5]
[6]
[7], WHO and professional
societies recommend screening strategies to identify women with gestational diabetes
and treatment of those affected.
Based on the original recommendations by the International Association of Diabetes
and Pregnancy Groups (IADPSG), many professional societies and WHO recommend a
one-step screening of all pregnant women during weeks 24–28 of pregnancy,
using an oral glucose tolerance test (OGTT) with 75 g of glucose following
an overnight fast [8]
[9]. Gestational diabetes is diagnosed if
any of the following thresholds is met (fasting≥5.1 mmol/L,
1-hour ≥ 10.0 mmol/L,
2-hours≥8.5 mmol/L) [8]. Although widely accepted as a concept, this strategy is not generally
implemented in many countries and has attracted criticism, as it may inappropriately
label women as having gestational diabetes who are at a low absolute risk of
pregnancy complications and may even lead to unnecessary interventions [10]
[11]
[12].
In central Asia, the prevalence of diabetes is increasing rapidly, but data on the
prevalence of gestational diabetes are only available for selected populations [1]
[13]. We, therefore, implemented a screening program in two cities in
Tajikistan, in Dushanbe, the capital, and Qurghonteppa (renamed Bokhtar), a regional
city in the south, close to the Afghan border. In both cities, the Reproductive
Health Centers (antenatal care) and the city hospitals (delivery) are accessible
(and used) by the general population and are free of charge to the women. We
included seven Reproductive Health Centers located throughout the city of Dushanbe
and one in a more rural area to evaluate a representative sample of the population
for the prevalence of gestational diabetes in Tajikistan and relate the results of
the glucose tolerance test to pregnancy outcomes.
Materials and Methods
The study was registered at ClinicalTrials.gov (NCT02436551) and performed between
September 2015 and November 2017, during which time we screened 2643 pregnant women
for gestational diabetes. A total of 1718 women were recruited from seven different
Reproductive Health Centers in Dushanbe (located in different sections of the city).
For delivery, women from all seven Reproductive Health Centers come to the City
Medical Center Karim Akhmedov, which manages approximately 8000 deliveries per year
(the total number of deliveries per year in Tajikistan is approximately 190000). A
total of 925 women were recruited from the Reproductive Health Center in
Qurghonteppa (Bokhtar) and women who delivered in the regional hospital
(approximately 2000 deliveries per year). In each Reproductive Health Center, up to
five subsequent women per day were informed about the study during the initial visit
(usually before pregnancy week 12) and asked to participate. Although more than
20000 children were born during the study period in these maternity hospitals, only
2643 women were recruited due to logistic (handling of glucose tolerance tests) and
budget reasons. Women with any chronic condition (thyroid disease, autoimmune
disease) or those with twin pregnancies were excluded from the study. After
obtaining written informed consent, an OGTT was scheduled between weeks 24 and 28 of
gestation.
On the day of the OGTT, women arrived fasting (8 hours minimum) at the health
center between 7:00 am and 9:00 am. Weight, height, and blood pressure were measured
and a questionnaire (family history, history of previous pregnancies, etc.) was
completed; then, the OGTT (75 g of glucose and venous glucose measurements
at 0, 60, and 120 minutes) was performed. Glucose levels were determined
using a photometer (Photoelectric colorimeter CPC-2 model; presumably 1980).
Gestational diabetes was diagnosed if one or more values were at or above the
following thresholds: 0-minute:≥5.1 mmol/L;
60-minutes:≥10.0 mmol/L;
120-minutes:≥8.5 mmol/L). All pregnant women were followed
until delivery and infant (APGAR, 30 min glucose level, survival) and
maternal (mode of delivery, complications such as preeclampsia, infections, and
bleeding, and survival) data were collected. Complications observed during pregnancy
were noted at the time of delivery. Furthermore, the discharging physician indicated
whether the women were healthy or sick (at discharge). Patients with gestational
diabetes were managed according to local standards.
Based on recent publications indicating that women with slightly elevated glucose
levels (in particular fasting values between 5.1–5.6 mmol/L)
have no adverse pregnancy outcome [14]
[15], we reclassified women
with gestational diabetes as either “impaired gestational fasting
glycemia” if fasting glucose levels were
5.1–5.6 mmol/L) or as “impaired gestational glucose
tolerance” if fasting values were>5.6 mmol/L
and/or 1-hour and/or 2-hour values were elevated. This
subclassification was introduced during the study period and was thus, not part of
the sample size calculation.
The sample size calculation and statistical analysis were based on data from a
previous study performed in Turkmenistan (showing a gestational diabetes rate of
6.3%)[13] and the assumption
that at least 100 cases of gestational diabetes are needed to meaningfully relate
data from the glucose tolerance to pregnancy outcome; we thus included a sample size
of 2500 pregnancies (which allows a drop-out rate of 20% at a prevalence of
5%). The sample size calculation was based on the presumed overall rate of
gestational diabetes and did not take the subclassifications (“impaired
gestational fasting glycaemia” and “impaired gestational glucose
tolerance”) into account. All data were noted on paper and then entered into
an Excel file for further analysis. Statistical analysis was performed using the
SPSS Statistics 23 software package (IBM, USA). Analysis of variance (ANOVA) for
independent continuous variables was performed using ANOVA (H –
Kruskal-Wallis test) for multiple comparisons and Mann-Whitney U-test for
comparisons between two groups. Comparisons of distinct variables were carried out
using a contingency table according to the χ2 criterion for the compared
quantities over 10, according to the χ2 criterion with Yates’
correction for the compared quantities over 5, and according to Fisher’s
exact criterion for the compared quantities less than 5. A p-value of<0.05
was considered significant.
The study was performed in accordance with the Helsinki Declaration II and approved
by the Ethics Committee of the Medical Faculty of the University of Munich and by
the Medical Ethics Committee (MEC), Ministry of Health and Social Protection of the
Republic of Tajikistan. Written informed consent was obtained from all
participants.
Results
The characteristics of the women included in the study are shown in [Table 1]. As shown in [Fig. 1], 205 women were excluded from the
analysis (n=65 did not complete OGTT; n=20 were lost to follow-up;
n=1 had diabetes mellitus type 1; n=9 had diabetes mellitus type 2;
n=7 had implausible glucose levels (<2.5 mmol/L);
n=65 had implausible gestational age; n=38 had twin pregnancy).
Fig. 1 Flow diagram of women included in the study. OGTT, oral glucose
tolerance test.
Table 1 Characteristics of study participants.
|
General characteristics
|
Overall
|
No gestational diabetes
|
Gestational diabetes
|
p-value†
|
No gestational diabetes
|
Impaired gestational fasting glycaemia
|
Impaired gestational glucose tolerance
|
p-value‡
|
|
Sample size n (%)
|
2438 (100)
|
1647 (100)
|
791 (100)
|
|
1647 (100)
|
723 (100)
|
68 (100)
|
|
|
Age (y)*
|
24.8±5.1
|
24.6±4.9
|
25.3±5.3
|
0.001
|
24.6±4.9
|
25.4±5.3§
|
24.3±5.2
|
0.001
|
|
Body mass index (kg*m−2)*
|
23.4±4.1
|
23.2±4.0
|
23.8±4.3
|
0.002
|
23.2±4.0
|
23.9±4.3§
|
23.0±4.2 ||
|
0.001
|
|
Mean art. pressure (mm Hg)*
|
75.9±7.8
|
75.8±7.6
|
76.2±8.3
|
ns
|
75.8±7.6
|
75.6±7.5
|
81.7±13.0|§
|
<0.001
|
|
Gestational age at OGTT (wk)*
|
26.3±2.5
|
26.3±2.8
|
26.3±2.7
|
ns
|
26.3±2.8
|
26.3±2.8
|
26.4±2.4
|
ns
|
|
Parity n (%)
|
|
|
|
0.005
|
|
|
|
0.006
|
|
1
|
812 (33.3)
|
560 (34.0)
|
252 (31.9)
|
|
560 (34.0)
|
222 (30.7)
|
30 (44.1) ||
|
|
|
2
|
691 (28.3)
|
487 (29.6)
|
204 (25.8)
|
|
487 (29.6)
|
189 (26.1)
|
15 (22.1)
|
|
|
≥3
|
935 (38.4)
|
600 (36.4)
|
335 (42.4) §
|
|
600 (36.4)
|
312 (43.2)
|
23 (33.8)
|
|
|
Previous pregnancy complications n (%)
|
844 (34.6)
|
576 (35.0)
|
268 (33.9)
|
ns
|
576 (35.0)
|
247 (34.2)
|
21 (30.9)
|
ns
|
|
Family history for diabetes mellitus n (%)
|
248 (10.2)
|
167 (10.1)
|
81 (10.2)
|
ns
|
167 (10.1)
|
72 (10.0)
|
9 (13.2)
|
ns
|
|
Consanguinity n (%)
|
377 (15.5)
|
255 (15.5)
|
122 (15.4)
|
ns
|
255 (15.5)
|
111 (15.4)
|
11 (16.2)
|
ns
|
*Mean±SD and n (%); † comparison
of p-values of no gestational diabetes and gestational diabetes; ‡
comparison of p-values of no gestational diabetes, impaired gestational
fasting glycaemia, and impaired gestational glucose tolerance; §
p<0.01 compared to no gestational diabetes; | p<0.01
compared to impaired gestational fasting glycemia; ||
p<0.05 compared to impaired gestational fasting glycemia.
[Fig.1] indicates a very high rate of
gestational diabetes in Tajikistan (32.4%), mostly based on elevated fasting
glucose levels (women with impaired gestational fasting glycemia). The rate of
gestational diabetes is much lower (2.8%) when the diagnosis was limited to
women with either more than one elevated glucose level or severely elevated fasting
glucose (5.6–7.0 mmol/l) or elevated 1 h or
2 h glucose levels (women with impaired gestational glucose tolerance),.
Compared to women without gestational diabetes, those with gestational diabetes were
older and had a higher BMI and parity ([Table
1]). A similar result was seen when women with impaired gestational
fasting glycemia are compared to women without gestational diabetes, while women
with impaired gestational glucose tolerance were slimmer, had higher blood pressure,
and were more likely to be parity 1.
Maternal and neonate outcomes of women without gestational diabetes, those with
impaired gestational fasting diabetes, and those with impaired glucose tolerance are
mentioned in [Tables 2]
[3]. No clinically significant difference
in outcome was observed between women without gestational diabetes and those with
gestational diabetes under fasting only (impaired gestational fasting glycemia),
while women with impaired gestational glucose tolerance had more complications,
infections, preeclampsia, and emergency cesarean sections. Similarly, in the
neonates, offspring from mothers with impaired gestational fasting glycemia had a
similar outcome as those from mothers without gestational diabetes. Offspring from
women with impaired gestational glucose tolerance had a poor prognosis with lower
APGAR values, more hypoglycemia, and a much higher perinatal mortality rate. As
expected, the rate of neonatal hypoglycemia was much higher in women with impaired
gestational glucose tolerance compared to those with impaired gestational fasting
glycemia and no gestational diabetes. Only a few children with glucose levels below
2 mmol/L received intra-venous glucose.
Table 2 Pregnancy and maternal outcome according to
gestational diabetes status in this study.
|
|
No gestational diabetes (n=1647)
|
Impaired gestational fasting glycaemia (n=723)
|
Impaired gestational glucose tolerance (n=68)
|
p-value*
|
|
Pregnancy
|
|
|
Any complication
|
461 (28.0%)
|
111 (15.4%)†
|
39 (57.4%)†‡
|
<0.001
|
|
Threatening miscarriage
|
278 (16.9%)
|
56 (7.7%)†
|
21 (30.9%†)‡
|
<0.001
|
|
Preeclampsia
|
26 (1.6%)
|
5 (0.7%)
|
7 (10.3%)†‡
|
<0.001
|
|
Urinary tract infection
|
80 (4.9%)
|
13 (1.8%)†
|
6 (8.8%)‡
|
<0.001
|
|
Delivery
|
|
|
Gestational weeks at delivery
|
39.2±2.5
|
39.3±2.2
|
37.2±4.6†‡
|
0.001
|
|
<37 weeks
|
146 (8.9%)
|
62 (8.6%)
|
17 (25.0%)†‡
|
<0.001
|
|
Spontaneous delivery
|
1504 (91.3%)
|
659 (91.1%)
|
58 (85.3%)
|
ns
|
|
Cesarean section
|
142 (8.6%)
|
63 (8.7%)
|
9 (13.2%)
|
ns
|
|
Emergency Cesarean s.
|
102 (6.2%)
|
32 (4.4%)
|
9 (13.2%)†§
|
<0.01
|
|
Mother
|
|
|
Healthy
|
1623 (98.5%)
|
702 (97.1%)
|
68 (100%)
|
ns
|
|
Sick
|
24 (1.5%)
|
21 (2.9%)
|
0
|
ns
|
|
Dead
|
0
|
0
|
0
|
|
*refers to significant differences between groups;
† p<0.01 compared to no gestational diabetes; ‡
p<0.01 compared to impaired gestational fasting glycemia; §
p<0.05 compared to no gestational diabetes.
Table 3 Neonatal outcome according to gestational diabetes
status.
|
No gestational diabetes (n=1647)
|
Impaired gestational fasting glycaemia (n=723)
|
Impaired gestational glucose tolerance (n=68)
|
p-value*
|
|
Neonate
|
|
|
Alive at birth
|
1624 (98.6%)
|
719 (99.4%)
|
61 (89.7%)†‡
|
<0.001
|
|
Antenatal death
|
23 (1.3%)
|
4 (0.6%)
|
4 (5.9%)†‡
|
<0.001
|
|
Postnatal death
|
45 (2.7%)
|
13 (1.8%)
|
11 (16.2%)†‡
|
<0.001
|
|
Discharged alive
|
1599 (97.1%)
|
710 (98.2%)
|
57 (83.8%)†‡
|
<0.001
|
|
Birth weight
|
3229±607
|
3246±587
|
2899±1003§||
|
<0.05
|
|
>4000 g
|
135 (8.2%)
|
65 (9.0%)
|
6 (8.8%)
|
ns
|
|
<1500 g
|
40 (2.4%)
|
15 (2.1%)
|
12 (17.6%)†‡
|
<0.001
|
|
APGAR 1 min
|
7.21±0.91
|
7.28±0.91†
|
6.68±1.30†‡
|
<0.001
|
|
<7
|
111 (6.7%)
|
49 (6.8%)
|
11 (16.2%)
|
ns
|
|
APGAR 5 min
|
7.91±0.76
|
7.86±0.71
|
7.68±1.30
|
ns
|
|
<7
|
150 (9.1%)
|
73 (10.1%)
|
11 (16.2%)||
|
ns
|
|
APGAR 10 min
|
8.65±0.94
|
8.47±0.86†
|
8.65±1.49§‡
|
<0.001
|
|
<7
|
36 (2.2%)
|
14 (1.9%)
|
4 (5.9%)
|
ns
|
|
30 min glucose (mmol/L)
|
3.38±0.76
|
3.41±0.64
|
2.97±1.24
|
ns
|
|
<2.0 mmol/L
|
60 (3.6%)
|
14 (1.9%)†
|
9 (13.8%)†‡
|
<0.001
|
|
IV treatment for children with
glucose<2.0 mmol/L
|
6 (10%)
|
2 (14%)
|
2 (22%)||
|
<0.05
|
|
Deceased children with
glucose<2.0 mmol/L
|
2 (3.3%)
|
1 (7.1%)
|
1 (11%)||
|
ns
|
*refers to significant differences between groups;
† p<0.01 compared to no gestational diabetes; ‡
p<0.01 compared to impaired gestational fasting glycemia; §
p<0.05 compared to no gestational diabetes; ||
p<0.05 compared to impaired gestational fasting glycemia.
Discussion
In this study, we evaluated the prevalence of gestational diabetes in Tajikistan and
studied the association between glucose levels during OGTT with pregnancy outcomes.
The data shown in [Table 1] indicate
that our cohort is representative of pregnant women in Tajikistan with respect to
age and parity (https://dhsprogram.com/pubs/pdf/SR203/SR203.pdf).
Since we included women from different parts of Dushanbe (seven large Reproductive
Health Centers) and a rural city, we believe that the cohort is also representative
of the socio-economic status.
Based on the WHO criteria, we found a very high rate of gestational diabetes in
Tajikistan (32.4%). In most patients, the diagnosis was based on a slightly
elevated fasting glucose value, while the severe elevation of fasting glucose
(>5.6 mmol/L) and/or elevated 1-hour and/or
2-hour values were present only in 2.8% of the participants. As expected,
women with impaired gestational fasting glycemia were older and had a higher BMI
than women without gestational diabetes; surprisingly women with impaired
gestational glucose tolerance did not differ from women without gestational diabetes
with respect to age and BMI. When the clinical outcome in mothers and newborns were
evaluated, we found no difference between women with impaired gestational fasting
glycemia and those with all normal values (no gestational diabetes). On the other
hand, those with impaired gestational glucose tolerance characterized by severely
elevated fasting values and/or elevated 1-hour and/or 2-hour values
had a much higher complication rate, higher emergency caesarian section rate, and
their neonates had more complications. This finding can be interpreted in multiple
ways.
First, women classified as having impaired gestational fasting glycemia may have no
gestational diabetes because the obtained value may not represent a true and
adequately obtained fasting value. Although the women were instructed to fast before
coming for the OGTT (and were asked about their feeding status at the beginning of
the test), this may not have always been the case as these women sometimes have to
leave the house very early to reach the Health Center. Also, these women may have
been relatively nervous about the upcoming OGTT, which may have increased cortisol
levels and thus glucose values. On the other hand, long ways to the Health Care
Centers and thus more physical activity could also decrease glucose levels and thus
result in false negative results. In addition, measurements of glucose levels may
not have been very precise as photometric results were directly read by a technician
from the photometer (slightly swinging needle indicator) (Photoelectric colorimeter
CPC-2 model; presumably 1980). All centers are now (since 2018) equipped with more
modern techniques, which allow a more precise determination of glucose levels.
Second, these women may have a very mild form of gestational diabetes, which does not
translate into adverse pregnancy outcome. In this sense, our study corroborates with
recently published studies also confirming that a diagnosis of gestational diabetes
only based on elevated fasting glucose levels does not translate into adverse
clinical outcomes [14]
[15]
[16]
[17]. For example, a recent
observational study in Denmark in 1,516 women revealed a gestational diabetes rate
of>40% (based on elevated fasting glucose levels) with normal
pregnancy outcomes in those having fasting glucose levels between 5.1 and
5.6 mmol/L [15].
Similarly, a recent evaluation in the US indicates that a two-step screening
approach (compared to a one-step screening) results in a considerably lower
prevalence of gestational diabetes with similar clinical outcomes in mothers and
offspring, again indicating that some forms of gestational diabetes may not
translate into clinical problems [14].
Finally, our observations are also consistent with the interpretation that the
diagnosis of gestational diabetes induced a therapeutic action (lifestyle
modification), which normalized glucose levels and led to a normal pregnancy
outcome. This, however, is unlikely as gestational diabetes was largely
“unknown” in the Reproductive Health Centers until our project
started. To our knowledge, no formal diabetes counseling was performed, and very few
(if any) patients received insulin. This makes it unlikely that mild fasting
gestational diabetes was treated at all.
Considering these aspects and the data from previous studies performed in the USA and
Denmark, it is most likely that some forms of gestational diabetes do not translate
into adverse pregnancy outcome, although the HAPO study indicated that increasing
fasting glucose levels are linearly associated with adverse pregnancy outcomes
without apparent threshold [4]. This is
highly relevant, because diagnosing gestational diabetes puts a burden on pregnant
women (psychologically and economically in many societies) and on the healthcare
system and may result in an increased rate of cesarean sections [12]. On the other hand, even impaired
gestational fasting glycemia may be a risk factor for childhood obesity, but it is
unclear if treating this condition can prevent obesity and other metabolic
consequences in the offspring [18]. While
it is known that gestational diabetes is associated with an increased risk of type 2
diabetes and metabolic diseases later in life, it is unclear whether elevated
fasting glucose (which does not translate into adverse short-term pregnancy
outcomes) leads to metabolic consequences later in life (in the mother
and/or the offspring).
If our findings, that an elevated fasting glucose level does not translate into
adverse pregnancy outcomes, are confirmed by other studies, then a strategy that
propagates general screening using WHO criteria in countries such as Tajikistan,
where most pregnant women are young and slim, should be questioned. In that case,
different screening strategies may be more appropriate to identify women with
clinically significant gestational diabetes. Options include a two-step screening
[19], or only measuring 2-hour
glucose level after ingesting 75 g glucose in the non-fasting state as
suggested by the “Diabetes In Pregnancy Study group of India
(DIPSI)” [20], or using a
75 g glucose test in the fasting state but applying different cut-off values
as suggested by the International Federation of Obstetrics and Gynecology (FIGO)
[21]. Finally, screening only women
with risk factors could be a further option. However, these alternatives have
limitations, and none is validated for Tajikistan or any other central Asian country
[22]
[23]. Interestingly, a recent report by the
US Preventive Services Task Force indicates that many aspects of screening for
gestational diabetes, remain unclear also in developed countries [24].
Our study also shows that severe elevation of glucose levels during the OGTT is
associated with a very high rate of complications in the mother and the offspring.
This probably reflects the fact that gestational diabetes, even when diagnosed, is
not managed appropriately. Unfortunately, we could not collect data on diabetes
management in affected women.
In a previous study, we used a two-step approach to determine the prevalence of
gestational diabetes in Turkmenistan, revealing a rate of 6.3% [13]. This is more than double the
prevalence of impaired gestational glucose tolerance in Tajikistan described in this
study, although Turkmenistan and Tajikistan share many similarities. This difference
in prevalence is most likely because in Turkmenistan, our study was performed in a
private hospital with women coming from a privileged socio-economic background and
thus being older and more obese (age: 27.6±5.2 vs. 24.8±5.1 years;
BMI: 26.6±4.8 vs. 23.4±4.1 kg/m²).
The strengths of our study relate to the size of the cohort, the first study to
report data on the prevalence of gestational diabetes in Tajikistan in a
representative sample of women, and present the prevalence data in relation to
outcome.
Our study has some limitations. We did not collect data on diabetes management and
therefore cannot make any statement on why the outcome of those with impaired
gestational glucose tolerance is so poor. Similarly, as discussed above, we cannot
exclude that the excellent outcome of women with impaired gestational fasting
glycemia relates to a treatment effect.
Although we included data from several centers in Tajikistan, we cannot make any
statement on women living in more rural areas such as the Pamir mountains. In more
remote areas, women have to travel to get to their Reproductive Health Center, which
is challenging if a fasting glucose level is required. In addition, our results
refer only to the ethnic group of Tajiks, which represent approximately 84%
of the Tajik population. [https://en.wikipedia.org/wiki/Demographics_of_Tajikistan#Ethnic_groups]
Although we studied a large number of women, the absolute number of women with
impaired gestational glucose tolerance was low, preventing any further analysis of
this subgroup (for example, to show predictors for poor outcome).
In this study, we confirmed very high perinatal mortality, approximately 10-times
higher than in European countries. The project also highlights that many aspects of
the health sector, that can be taken for granted in Europe, are not widely available
in Tajikistan (such as easy-to-use and exact glucose measurement devices or
treatment options for gestational diabetes). This indicates that Tajikistan must
develop strategies to better manage high-risk pregnancies and decrease the high
perinatal mortality. This should include guideline-oriented management of women with
gestational diabetes. In that context, it would be interesting to repeat the
screening project after introducing diabetes education, self-measurement of glucose
levels, and insulin therapy for women with gestational diabetes, if necessary.
In our trial, we found a high rate of gestational diabetes in Tajikistan, of which,
however, only a minority were clinically relevant. This finding is compatible with
the fact that the women did not receive any therapy and that a small increase in
fasting glucose in this group did not lead to adverse outcomes even without therapy
under the local health care system.
