Observational Study Medicine ®

Clinical analysis of diabetes in pregnancy with

stillbirth
Zhenyu Wang, MSa,b, Jia Chen, MSc, Tuhong Long, MSd, Lixuan Liang, MSe, Caijuan Zhong, MSf,
Yingtao Li, MSa,*

Abstract
We analyzed the clinical characteristics of patients with diabetes in pregnancy (DIP) associated with stillbirth and explored strategies
to reduce its incidence. We retrospectively analyzed 71 stillbirths associated with DIP (group A) and 150 normal pregnancies
(group B) during 2009 to 2018. The incidence of the following was higher in group A (P < .05): hypertensive disorders (38.03%
vs 6.00%), placenta previa (14.08% vs 2.67%), placental abruption (5.63% vs 0.67%), fetal malformation (8.45% vs 0.67%),
fasting plasma glucose (FPG) ≥ 7.0 mmol/L (46.48% vs 0.67%), 2-h postprandial plasma glucose ≥ 11.1 mmol/L (57.75% vs
6.00%), HbA1c ≥ 6.5% (63.38% vs 6.00%), and polyhydramnios (11.27% vs 4.67). The incidence of oligohydramnios (4.23%
vs 6.67%) was lower in group A than in group B (P < .05). According to the gestational age at the time of stillbirth, Group-A
cases were subgrouped into miscarriages (20–27+6 weeks), premature deliveries (28–36+6 weeks), and full-term deliveries (≥37
weeks). Age, parity, and DIP type did not differ among the subgroups (P > .05). Among patients with DIP, antenatal FPG, 2-h
postprandial plasma glucose, and HbA1c were significantly associated with stillbirth (P < .05). Stillbirth was first detected at
22 weeks and typically occurred at 28–36+6 weeks. DIP was associated with a higher incidence of stillbirth, and FPG, 2-h
postprandial plasma glucose, and HbA1c were potential indicators of stillbirth in DIP. Age (odds ratio [OR]: 2.21, 95% confidence
interval [CI]: 1.67–2.74), gestational hypertension (OR: 3.44, 95% CI: 2.21–4.67), body mass index (OR: 2.86, 95% CI: 1.95–3.76),
preeclampsia (OR: 2.29, 95% CI: 1.45–3.12), and diabetic ketoacidosis (OR: 3.99, 95% CI: 1.22–6.76) were positively correlated
with the occurrence of stillbirth in DIP. Controlling perinatal plasma glucose, accurately detecting and managing comorbidities/
complications, and timely termination of pregnancy can reduce the incidence of stillbirths associated with DIP.
Abbreviations: BMI = body mass index, CI = confidence interval, DIP = diabetes in pregnancy, FGR = fetal growth restriction,
FPG = fasting plasma glucose, GDM = gestational diabetes mellitus, HbA1c = glycohemoglobin, OR = odds ratio, PGDM =
pregestational diabetes mellitus.
Keywords: complications, diabetes in pregnancy, glucose, risk factors, stillbirth

1. Introduction
Diabetes is a common complication of pregnancy and is asso-
ciated with adverse maternal and fetal outcomes. The term
diabetes in pregnancy (DIP) refers to both pregestational dia-
betes mellitus (PGDM), which is preexisting diabetes that is
diagnosed before pregnancy, and gestational diabetes mellitus
(GDM), which is diabetes that first occurs during pregnancy.[1]
GDM can also be described as the occurrence of glucose intol-
erance during pregnancy that does not satisfy the diagnostic
criteria for PGDM.[2] Intrauterine fetal death after 20 weeks of
gestation is termed stillbirth. A stillborn fetus refers to a fetus
that dies during the process of childbirth, which is also a type
of stillbirth.[2] DIP is the most common clinical cause of embryo
demise, premature delivery, hypertensive disorders of pregnancy,
amniotic fluid abnormalities, fetal distress, fetal growth restric-
tion (FGR), macrosomia, and perinatal death.
Diabetes can significantly influence maternal and fetal out-
comes. The presence of diabetes can increase the risk of still-
birth and neonatal death. The incidence of GDM is high,
ranging from 26% during the second trimester[3] to 33% during
the third trimester of pregnancy.[4] To decrease the stillbirth
rate in DIP, various interventions have been adopted, includ-
ing early detection of diabetes and plasma glucose monitoring.

The datasets generated during and/or analyzed during the current study are
available from the corresponding author on reasonable request.
The authors have no conflicts of interest to disclose.
a
Department of Obstetrics and Gynecology, The Third Affiliated Hospital
of Guangzhou Medical University, Guangdong Provincial Key Laboratory of
Major Obstetric Diseases, Guangzhou, China, b Department of Obstetrics
and Gynecology, Sun Yat-Sen Memorial Hospital of Sun Yat-sen University,
Guangzhou, China, c Department of Obstetrics, Foshan Women and Children
Hospital, Foshan, China, d Department of Medical Affairs Section, The Third
Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,
e
Department of Obstetrics, Dongguan Songshan Lake Central Hospital,
Dongguan, China f Department of Obstetrics, Maternal and Child Health Hospital
of Guangdong, Guangzhou, China.
* Correspondence: Yingtao Li, Department of Obstetrics and Gynecology, The
Third Affiliated Hospital of Guangzhou Medical University, Guangdong Provincial
Key Laboratory of Major Obstetric Diseases, Guangzhou 510150, China (e-mail:
yingtao9777@163.com).
Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is
permissible to download, share, remix, transform, and buildup the work provided
it is properly cited. The work cannot be used commercially without permission
from the journal.
How to cite this article: Wang Z, Chen J, Long T, Liang L, Zhong C, Li Y. Clinical
analysis of diabetes in pregnancy with stillbirth. Medicine 2023;102:21(e33898).
Received: 20 July 2022 / Received in final form: 6 May 2023 / Accepted: 10 May
2023
http://dx.doi.org/10.1097/MD.0000000000033898

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Wang et al. • Medicine (2023) 102:21Medicine
Understanding the factors involved in DIP and their impact
on stillbirth would help to reduce complications and improve
pregnancy outcomes.[5,6]
DIP is closely related to the occurrence of stillbirth. In this
study, we summarized the general information, plasma glucose
data, and other characteristics of cases of stillbirth at different
gestational weeks in women with DIP, and analyzed the risk
factors and potential indicators of the occurrence of stillbirth in
DIP to provide clinical guidance for its prevention.
2. Methods
2.1. Data source
We collected all data from a chart review and an electronic data-
base review on 71 women with DIP and stillbirth (group A)
and 150 pregnant women with normal obstetric examination
(group B) between January 1, 2009 and December 31, 2018,
who were admitted to the Department of Obstetrics, the Third
Affiliated Hospital of Guangzhou Medical University, which is a
referral center for cases in Guangdong Province and surround-
ing areas. DIP with stillbirth was diagnosed in accordance with
the International Classification of Diseases code. Their clinical
features were retrospectively analyzed.
2.2. Data collection
The medical records were screened by 2 independent investiga-
tors to collect the general information of the patients at the time
of admission, including the age of the pregnant woman, parity,
antenatal checkup status, body mass index (BMI), type of DIP
(PGDM vs GDM), gestational age at the time of stillbirth, fetal
condition, comorbidities or complications during pregnancy
(other than DIP), and auxiliary examination status. After admis-
sion, the fasting plasma glucose (FPG), 1-h postprandial and 2-h
postprandial plasma glucose, and glycosylated hemoglobin lev-
els of the patients were measured.
2.3. Diagnostic criteria
According to the WHO guidelines for diagnosis, early stillbirth
is characterized by a birth weight ≥ 500 g or gestational age of
22 weeks or a crown-to-heel length ≥ 25 cm; late stillbirth is
characterized by a birth weight ≥ 1000 g or gestational age > 28
weeks or a crown-to-heel length ≥ 35 cm.[7] Under this classifica-
tion, birth weight is given higher priority than gestational age.
In China, stillbirth is defined as an intrauterine death occurring
after 20 weeks of gestation.[2] The present study adopted the
diagnostic criteria for stillbirth used in China.
2.4. Diagnostic criteria for DIP
DIP may be diagnosed before pregnancy or first diagnosed
during pregnancy, according to the 9th edition of Obstetrics
and Gynecology, edited by Xie et al,[2] and the guidelines of the
American College of Obstetricians and Gynecologists[8,9] and
American Diabetes Association, 2018.[10]
Women who have been diagnosed with diabetes before preg-
nancy are considered to have PGDM. For pregnant women who
have not undergone plasma glucose testing before pregnancy,
especially those with high risk factors for diabetes, it is neces-
sary to test for diabetes at the first prenatal examination. In such
cases, the patient should be diagnosed with PGDM if any of the
following criteria are met during pregnancy: FPG ≥ 7.0 mmol/L
(126 mg/dL), plasma glucose level 2 hours after a 75-g oral glu-
cose tolerance test ≥ 11.1 mmol/L (200 mg/dL), typical symp-
toms of hyperglycemia or hyperglycemic crisis, random plasma
glucose level ≥ 11.1 mmol/L (200 mg/dL), and glycohemoglobin
(HbA1c) ≥ 6.5%.
2
2.5. Diagnostic criteria for GDM
The 75-g oral glucose tolerance test should be performed after
the patient has fasted for at least 8 hours. The fasting, 1-hour,
and 2-hour plasma glucose levels should be measured. Elevated
plasma glucose levels meeting any of the following criteria indi-
cate a diagnosis of GDM: FPG ≥ 5.1 mmol/L (92 mg/dL), 1-hour
plasma glucose ≥ 10.0 mmol/L (180 mg/dL), and 2-hour plasma
glucose ≥ 8.5 mmol/L (153 mg/dL).
2.6. Diagnostic criteria for fetal weight
The fetal/newborn weight distribution curve from a 2015 study
from China was adopted.[11]
2.7. Statistical analysis
The SPSS v22.0 software (IBM Corp, Armonk, NY) was used
for all statistical analyses. Measurement data were presented as
mean ± standard deviation. Analysis of variance was used for
comparisons between 3 groups. Percentages or frequencies were
used to express count data. Fisher exact test or χ2 test was used
to compare between-group differences. The multivariate logistic
regression technique was used to analyze high-risk factors.
2.8. Ethics approval and consent to participate
Our study had been approved by the Ethics Committee of the
Third Affiliated Hospital of Guangzhou Medical University.
All procedures were performed according to the Declaration of
Helsinki. All patients gave written informed consent.
3. Results
3.1. Incidence of DIP
The incidence of DIP in our hospital was 14.10% (8398/59,654);
the mean maternal age was 36.00 ± 8.00 years. The incidence of
DIP with stillbirth was 0.85% (71/8398); the mean maternal
age was 38.00 ± 5.00 years. The mean gestational age at still-
birth was 31.00 ± 8.00 weeks.
3.2. General information of pregnant women in Group A
and Group B
The incidence of hypertensive disorders (38.03% vs 6.00%),
placenta previa (14.08% vs 2.67%), placental abruption
(5.63% vs 0.67%), fetal malformation (8.45% vs 0.67%),
FPG ≥ 7.0 mmol/L (46.48% vs 0.67%), 2-h postprandial plasma
glucose ≥ 11.1 mmol/L (47.89% vs 6.00%), HbA1c ≥ 6.5%
(63.38% vs 6.00%), and polyhydramnios (11.27% vs 4.67%)
was significantly higher, while the incidence of oligohydram-
nios (4.23% vs 6.67%) was significantly lower in group A than
in group B (P < .05 for all; Table 1). We found that FPG, 2-h
postprandial plasma glucose, and HbA1c during pregnancy
were significantly associated with the occurrence of stillbirths
in patients with DIP (P < .05), and that stillbirth could first be
detected at 22 weeks.
3.3. Subgrouping of Group-A cases
According to the gestational age at the time of the stillbirth, the
cases in Group A were further divided into 3 subgroups: miscar-
riage (20–27+6 weeks), premature delivery (28–36+6 weeks), and
full-term (≥37 weeks).
The mean maternal age was 36.00 ± 8.00 years (range, 26–42
years; n = 20) in the miscarriage group, 36.5 ± 6 years (range,
23–40 years; n = 35) in the premature delivery group, and
38 ± 5 years (range, 22–39 years; n = 16) in the full-term group.
Wang et al. • Medicine (2023) 102:21www.md-journal.com

The mean gestational age was 30.8 weeks (median, 31 weeks).
There was no statistical difference in maternal age among the
groups (P > .05). The miscarriage group had 5 primiparas and
15 multiparas; the premature delivery group had 9 primipa-
ras and 26 multiparas; and the full-term group had 5 primi-
paras and 11 multiparas. No significant differences in parity
were found among the groups (P > .05). There were 41 cases of
PGDM and 30 cases of GDM among the 71 cases of stillbirth.
The type of DIP did not significantly differ among the groups
(P > .05; Table 2).
Age (odds ratio [OR]: 2.21, 95% confidence interval [CI]:
1.67–2.74), gestational hypertension (OR: 3.44, 95% CI:
2.21–4.67), BMI (OR: 2.86, 95% CI: 1.95–3.76), preeclamp-
sia (OR: 2.29, 95% CI: 1.45–3.12), and diabetic ketoacido-
sis (OR: 3.99, 95% CI: 1.22–6.76) were positively correlated
with the occurrence of stillbirth in DIP. Chorioamnionitis
(OR: 1.53, 95% CI: 0.96–2.10), fetal malformation (OR:
2.66, 95% CI: 0.55–4.77), amniotic fluid factors (OR: 1.15,
95% CI: 0.86–1.43), true knot of the umbilical cord (OR:
0.96, 95% CI: 0.33–1.58), torsion of the umbilical cord (OR:
3.10, 95% CI: 0.76–5.43), prolapse of the umbilical cord
(OR: 3.78, 95% CI: 0.65–7.56), umbilical cord entanglement
(OR: 3.74, 95% CI: 0.82–6.65), and FGR (OR: 1.54, 95% CI:
0.66–2.41) were not correlated with the occurrence of still-
birth in DIP (Fig. 1).
3.4. Comparison of FPG, 1-h and 2-h postprandial plasma
glucose, and HbA1c status among the 3 subgroups
1.3.4. FPG. Among the 71 women with DIP and stillbirth, 17
(23.94%) women had FPG < 5.1 mmol/L. In the remaining 54
women, the FPG level was above the reference range, including
21 (29.58%) women with FPG < 7.0 mmol/L and 33 (46.48%)
women with FPG ≥ 7.0 mmol/L. There was a significant difference
in FPG among the subgroups. The premature delivery group had
the highest number of stillbirths (53.52%, P < .05; Table 3).
3.5. Postprandial (1 h) plasma glucose
The 1-h postprandial plasma glucose level was measured in 71
women with DIP and stillbirth. The level was < 10 mmol/L in
27 (38.03%) women and ≥ 10 mmol/L in 44 (61.97%) women.

Table 1
Comparison of clinical characteristics between group A and group B.
Group A (n = 71) Percentage Group B (n = 150) Percentage χ2 P value

Hypertensive disorder 27 38.03 9 6.00 32.263 <.001

Preeclampsia 23 32.39 5 3.33 23.78 <.001
Placenta previa 10 14.08 4 2.67 10.588 .002
Placental abruption 4 5.63 1 0.67 5.377 .038
Chorioamnionitis 3 4.23 1 0.67 3.434 .099
Fetal malformation 6 8.45 1 0.67 6.997 .015
Oligohydramnios 3 4.23 10 6.67 6.843 .045
Polyhydramnios 8 11.27 7 4.67 5.876 .032
FPG (mmol/L)
 <5.1 17 23.94 100 66.67 25.178 <.001
 5.1 ≤ FPG < 7.0 21 29.58 49 32.66
 ≥7.0 33 46.48 1 0.67
1-h Plasma glucose (mmol/L)
 <10 27 38.03 62 41.33 1.878 .243
 ≥10 44 61.97 85 56.67
2-h Plasma glucose (mmol/L)
 <8.5 15 21.13 48 32.00 7.985 .021
 8.5 ≤ FPG < 11.1 22 30.99 82 54.67
 ≥11.1 34 47.89 9 6.00
HbA1c (%)
 <6.5 26 36.62 140 93.33 32.263 <.001
 ≥6.5 45 63.38 9 6.00
FPG = fasting plasma glucose, HbA1c = glycohemoglobin.

Table 2
Age, parity, and type of diabetes in pregnant women.
Gestational age at stillbirth (wk)
Miscarriage group Premature delivery group Full-term group Total χ2 P value

Age
 <35 yr 7 12 2 21 2.912 .283
 ≥35 yr 13 23 14 50
Parity
 Primipara 5 9 5 19 0.317 .883
 Multipara 15 26 11 52
Type of DIP
 PGDM 12 23 6 41 3.554 .178
 GDM 8 12 10 30
Total 20 35 16 71
DIP = diabetes in pregnancy, GDM = gestational diabetes mellitus, PGDM = pregestational diabetes mellitus.

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Wang et al. • Medicine (2023) 102:21Medicine

There was no significant difference in the 1-h postprandial (30.99%) women, and ≥ 11.1 mmol/L in 34 (47.89%) women.
plasma glucose level among the 3 subgroups (P > .05; Table 3). There was no significant difference in the 2-h postprandial
plasma glucose level among the 3 groups (P > .05; Table 3).

3.6. Postprandial (2 h) plasma glucose

3.7. Glycosylated hemoglobin
The 2-h postprandial plasma glucose level was measured in 71
women with DIP and stillbirth. The level was < 8.5 mmol/L Among the 71 women with DIP and stillbirth were tested for
in 15 (21.13%) women, 8.5 ≤ FPG < 11.1 mmol/L in 22 glycosylated hemoglobin. The HbA1c level was < 6.5% in 45

Figure 1. Analysis of high-risk factors in the stillbirth group. FGR = fetal growth restriction.

Table 3
FPG, 1-h, and 2-h postprandial plasma glucose, and glycosylated hemoglobin status among the 3 subgroups.
Gestational age at stillbirth (wk)
Miscarriage (20–27 wks)+6
Premature delivery (28–36+6 wks) Full-term delivery (>37 wks) Total χ2 P value

FPG (mmol/L)
 <5.1 10 4 3 17 13.576 .007
 5.1 ≤ FPG < 7.0 7 9 5 21
 ≥7.0 3 22 8 33
Total 20 35 16 71
1-h plasma glucose (mmol/L)
 <10 8 13 6 27 2.65 .238
 ≥10 12 22 10 44
Total 20 35 16 71
2-h plasma glucose (mmol/L)
 <8.5 6 6 3 15 3.562 .571
 8.5 ≤ FPG < 11.1 3 12 7 22
 ≥11.1 11 17 6 34
Total 20 35 16 71
HbA1c (%)
 <6.5 4 13 9 26 2.769 .262
 ≥6.5 16 22 7 45
Total 20 35 16 71
FPG = fasting plasma glucose, HbA1c = glycohemoglobin.

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Wang et al. • Medicine (2023) 102:21www.md-journal.com
(63.38%) women and ≥ 6.5% in 26 (36.62%) women. There
was no significant difference in the HbA1c status among the 3
subgroups (Table 3).
4. Discussion
The incidence of DIP with stillbirth in our hospital was 0.85%
(71/8398). The mean maternal age was 39.00 ± 5.00 years.
Most cases occurred in women aged > 35 years (70.4%), at
28 to 36+6 weeks of gestation (49.29%), among multiparous
women (73.2%), and among women with PGDM rather than
those with GDM (57.7% vs 42.3%). Compared to stillborn
fetuses with a birth weight that was appropriate for gestational
age, there were more fetal malformations (8.45%) among
small- or large-for-gestational age stillborn fetuses. The most
common comorbidity was hypertension (38.03%). Possible
causes of stillbirth included placental factors (19.71%) and
amniotic fluid factors (15.50%). The occurrence of stillbirth
was correlated with the FPG level and the glycosylated hemo-
globin level.
4.1. Epidemiological characteristics
The causes and incidence of stillbirth vary globally. As of
2015, the global stillbirth rate was 1.84%, and the incidence in
China was approximately 1% to 4%. The perinatal mortality
rate in developed countries and regions has dropped to below
0.7%[12,13] According to a study, about 1 in 160 pregnancies
results in a stillbirth in the United States.[14] The risk of stillbirth
among pregnant women with GDM is 4 to 5 times higher than
that among women with normal pregnancies.[6] In the present
study, the stillbirth rate due to DIP alone was 0.85%, which is
probably due to the fact that our hospital is a specialized treat-
ment center for severe diseases in pregnancy in Guangzhou, and
is responsible for the diagnosis and treatment of difficult cases
involving high-risk pregnancies from Guangdong Province and
the surrounding areas. Our center provides effective treatment
for critically ill pregnant women, thereby reducing the incidence
of stillbirth.
4.2. Risk factors for stillbirth in DIP
The risk of stillbirth and the overall perinatal mortality were
significantly higher among pregnant women with DIP than
among healthy pregnant women. DIP was also highly associ-
ated with adverse pregnancy outcomes, such as preeclamp-
sia, preterm birth, and surgical and midwifery-related trauma
during delivery.[15] Compared to the general population, the
risk of stillbirth is 3 to 5 times and 1.5 to 2.3 times higher in
women with PGDM and GDM, respectively.[16] The risk fac-
tors for stillbirth are related to education status, marital status,
age, perinatal care, race, social status,[17] comorbidities, autoim-
mune diseases,[18] and other characteristics of pregnant women.
The present study found that DIP with stillbirth was related to
maternal diseases, fetal malformations, and amniotic fluid fac-
tors. Among the maternal diseases related to stillbirth, hyperten-
sion and diabetes mellitus are the most common.[19] It has been
reported that fetal malformation rates are higher in diabetic
pregnancies than in normal pregnancies.[20] Lethal malforma-
tions, intrauterine growth retardation, and placental abnormal-
ities are the main causes of stillbirth associated with diabetes.[21]
In the present study, stillbirths were more common between 28
weeks and 36+6 weeks of gestation. This may be due to different
degrees of increases in insulin requirements in the second and
third trimesters of pregnancy, particularly at 32 to 36 weeks of
gestation,[22] due to poor plasma glucose control. This indicates
that without effective management of DIP, stillbirth may occur
at any gestational age.
5
Some studies have indicated that marginal or velamentous
cord insertion, umbilical hyper coiling, and umbilical cord
thrombosis are significant risk factors for stillbirth.[23] There
is a positive association between maternal BMI and fetal
weight.[24] Obesity might increase the levels of inflammatory
markers.[25] Chronic chorioamnionitis has been associated
with preterm stillbirth potentially caused by maternal anti-fe-
tal rejection, which may explain approximately 10% of the
effect of obesity on the risk of stillbirth.[26] In addition, mater-
nal obesity is associated with fetal hyperinsulinemia, which
is an independent risk factor for fetal hypoxia.[12,13] Defects
of placentation are related to the etiologies of preeclampsia,
FGR, and small-for-gestational age neonates. Many authors
have indicated that it is possible to predict significant vascu-
lar events during pregnancy through uterine artery Doppler
examination.[27] High maternal BMI might decrease the uter-
ine artery pulsatility index (UtA-PI).[28] The UtA-PI of the
placental side is lower than that of the non-placental side.[29]
Women with DIP showed higher maternal mean UtA-PI val-
ues, which might result in decreased uterine blood flow.[30]
Abnormal results on uterine artery Doppler examination are
associated with placental apoptosis, indicating that placental
dysplasia can be caused by late-onset preeclampsia in some
cases.[31]
4.3. Relationship between plasma glucose and stillbirth
The plasma glucose level during pregnancy is directly related to
the prognosis of the fetus, particularly in cases of undiagnosed
GDM and uncontrolled glucose levels. Severe dysregulation of
maternal homeostasis, placental vasculopathy, and fetal met-
abolic pathway changes caused by hyperglycemia can lead to
stillbirth in DIP.[32] The maternal-fetal transfer rate of glucose
can reach 5.9 mg/kg·min, and the fetal plasma glucose level can
reach 60% to 80% of the maternal plasma glucose level.[33] The
IADPSG recommends screening for diabetes at the first antena-
tal visit.[34]
Elevated FPG is an independent risk factor for stillbirth and
stillborn fetus. An increase in FPG before delivery has been
linked to an increased risk of several adverse pregnancy out-
comes in DIP, including hypertension in pregnancy, polyhy-
dramnios, premature delivery, stillbirth, and stillborn fetus.[33]
The Nielsen study found that elevated glycosylated hemoglobin
was associated with pregnancy outcomes. For every 1% increase
in glycosylated hemoglobin, the risk of adverse pregnancy out-
comes increased by 3.8% to 7.3%.[35] Another result of poor
glycemic control is the risk of diabetic ketoacidosis. A UK pro-
spective case-control study showed that the risk of late stillbirth
among pregnant women with undiagnosed GDM and elevated
FPG levels was 4 times higher than that among pregnant women
with normal FPG. However, pregnant women diagnosed with
GDM did not have an increased risk despite having increased
FPG levels, indicating that screening and diagnosis of GDM
could reduce the risk of late stillbirth and stillborn fetus caused
by increased FPG or GDM.[36] The International Association
of Diabetes and Pregnancy Study Groups (IADPSG) note that
there is no clear consensus on whether FPG, random plasma
glucose, or HbA1c should be used for screening, and whether
routine screening should be used widely or only in people at
high risk for DIP.[34]
Our study found that FPG, 2-h postprandial plasma glucose,
and HbA1c during pregnancy were significantly correlated with
the occurrence of stillbirth in patients with DIP. This indicates
that it is particularly important for women with DIP to undergo
regular monitoring of FPG, 2-h postprandial plasma glucose,
and HbA1c levels. It is suggested that actively controlling the
plasma glucose level within the normal range during pregnancy
is an effective means to prevent and control perinatal complica-
tions and prevent stillbirth.
Wang et al. • Medicine (2023) 102:21Medicine
4.4. Health care during pregnancy
Poor plasma glucose control during pregnancy increases the risk
of complications such as preeclampsia, premature birth, and
polyhydramnios, and increases the risk of gestational hyperten-
sion by 3 to 5 times.[36] GDM patients have a 7-fold higher risk
of postpartum type 2 diabetes mellitus than the general popula-
tion.[37] DIP is a high-risk factor for preeclampsia. Treatment of
GDM with diet, insulin, and metformin could reduce the risk of
preeclampsia.[38] The use of low-dose aspirin starting from 10 to
12 weeks of gestation can improve pregnancy outcomes. Early
prevention can reduce the incidence of preeclampsia by 20% to
40%.[35,39] Aspirin can inhibit cyclooxygenases 1 and 2, and thus
inhibit the inflammatory pathway of arachidonic acid metabo-
lism. The first wave of trophoblast migration occurs at 10 to 14
weeks; the second wave of trophoblast migration in the deep
myometrium begins by 18 to 20 weeks and is completed only by
22 to 24 weeks.[24] Nonetheless, some studies have indicated that
aspirin started in the late second and third trimester could also
prevent eclampsia.[40,41] The American College of Obstetricians
and Gynecologists recommends low-dose aspirin (81 mg/d) for
prevention from 12 to 28 weeks of gestation until delivery. For
pre-pregnancy obesity, the 2019 Society of Obstetricians and
Gynaecologists of Canada Guidelines for the Management of
Obesity in Pregnancy state that compared to women with a nor-
mal BMI, the risk of stillbirth is 1.40 to 3.10 times higher in
women with a BMI ≥ 30 and 2.79 times higher in women with
BMI ≥ 40. Maternal risk factors such as obesity, gestational dia-
betes, hypertension, and preeclampsia are also high risk factors
for stillbirth.[42] Most studies consider that obesity predisposes
mainly to late-onset preeclampsia.[43] Gestational weight gain
(GWG) is an important factor affecting the risk of stillbirth.
Studies have reported that too much or too little GWG increases
the risk of stillbirth.[42] Therefore, it is recommended that GWG
be routinely monitored. For women with singleton pregnancies
and BMI ≥ 30, it is recommended that the GWG be controlled
within 5.0 to 9.0 kg.[42,44,45] For obese women, it is necessary to
check for common complications such as chronic hypertension,
type 2 diabetes, cardiovascular disease, blood dyslipidemia, and
endocrine diseases, and to control weight through medical treat-
ment, diet, and exercise before pregnancy. It was shown that yoga
can improve the functional indices of the uterine artery as well
as fetal development indices. Yoga might have a positive impact
on maternal stress, causing diminished sympathetic tone, which
in turn relaxes the uterine arteries and results in better blood
circulation.[46] Elevated FPG has been linked to an increased risk
of adverse pregnancy outcomes in women with GDM, such as
polyhydramnios, premature delivery, and stillbirth.[33] Therefore,
FPG may be a convenient and effective indicator to predict the
risk of adverse maternal and neonatal outcomes. Increasing FPG
testing during pregnancy has significant benefits for the prog-
nosis of high-risk groups. It is recommended that FPG levels be
measured in all women during the initial checkup. checkups in
the second and third trimester may be needed to avoid stillbirth.
For the high-risk group of women with DIP, FPG, 2-h postpran-
dial plasma glucose, and HbA1c testing should be performed
regularly. In addition, a large population-based study in the
United Kingdom found that women with DIP before 32 weeks
of gestation had an increased risk of stillbirth.[47] In Scotland, the
stillbirth rate for women giving birth in the first trimester has
remained the same despite an increase in preterm birth rates.[48]
Uterine artery Doppler scanning and timely medical intervention
may help to improve the pregnancy outcomes of women with
DIP. Further research is necessary to determine the optimal tim-
ing of delivery in women with DIP.
4.5. Limitations of study
Due to the small number of cases, we selected cases from the
past 10 years for analysis in this study in order to minimize
6
bias. The selection of case sources complied with WHO guide-
lines, and the clinical data were complete. In addition, we used
a 1:2 matching ratio for this case–control study, and the data
were complete. All outcomes, exposures, predictors, potential
confounders, and effect modifiers were clarified. The diagnostic
criteria were clarified in the article. Logistic regression was used
to analyze high-risk factors.
Our study has several limitations. First, since this was a sin-
gle-center study, the sample size was not large, so we could not
analyze the difference between PGDM and GDM in each sub-
group. Second, no analysis of stillbirth weight and gender was
performed. This may miss some meaningful data. Third, there
was no detailed division of the gestational age at stillbirth, and
it is impossible to draw a more precise gestational age range for
stillbirth. Future studies may include a larger size sample or use
a multicenter study design.
5. Conclusion
For perinatal health care in DIP, periodic obstetric checkups
should be jointly conducted by specialists from multiple dis-
ciplines, appropriate intervention plans should be formulated,
and the maternal-fetal condition should be closely monitored.
Treatment plans based on medical nutrition and exercise ther-
apy should be individualized. Early rational use of insulin inter-
vention is required to maintain a steady glucose level 24 hours a
day to enable ideal growth of maternal and fetal weight during
pregnancy. Comorbidities and complications should be detected
in time and promptly managed, and the pregnancy should be
terminated in a timely manner.
This work was supported by Basic and Applied Basic Research
Fund Project of Guangdong Province (2020A1515011347) and
University Innovation and Entrepreneurship (Employment) Ed-
ucation Project of Guangzhou (2020PT105).The funding agen-
cy was not involved in the following tasks: research design and
conduct; data collection, management, analysis and interpreta-
tion; article preparation, review or approval. The corresponding
author had full access to all the data in the study and had final
responsibility for the decision to submit for publication.
Author contributions
Conceptualization: Zhenyu Wang, Jia Chen, Yingtao Li.
Data curation: Zhenyu Wang, Jia Chen, Tuhong Long.
Formal analysis: Zhenyu Wang, Jia Chen, Yingtao Li.
Funding acquisition: Zhenyu Wang, Jia Chen, Yingtao Li.
Investigation: Zhenyu Wang, Lixuan Liang, Caijuan Zhong.
Methodology: Zhenyu Wang, Lixuan Liang, Caijuan Zhong,
Yingtao Li.
Project administration: Zhenyu Wang, Jia Chen, Yingtao Li.
Resources: Zhenyu Wang, Jia Chen, Yingtao Li.
Software: Zhenyu Wang, Jia Chen, Tuhong Long.
Supervision: Zhenyu Wang, Jia Chen, Yingtao Li.
Validation: Zhenyu Wang, Jia Chen, Tuhong Long.
Visualization: Zhenyu Wang, Jia Chen, Tuhong Long.
Writing – original draft: Zhenyu Wang, Jia Chen.
Writing – review & editing: Zhenyu Wang, Jia Chen, Tuhong
Long, Yingtao Li.
References
[1] Colagiuri S, Falavigna M, Agarwal MM, et al. Strategies for implement-
ing the WHO diagnostic criteria and classification of hyperglycaemia
first detected in pregnancy. Diabetes Res Clin Pract. 2014;103:364–72.
[2] Xie X, Kong B, Duan T, et al. Obstetrics and gynecology, 9th Edition (in
Chinese). 2018.
[3] Perovic M, Gojnic M, Arsic B, et al. Relationship between mid-trimes-
ter ultrasound fetal liver length measurements and gestational diabetes
mellitus. J Diabetes. 2015;7:497–505.
Wang et al. • Medicine (2023) 102:21www.md-journal.com
[4] Gojnic M, Stefanovic T, Perovic M, et al. Prediction of fetal mac-
rosomia with ultrasound parameters and maternal glycemic con-
trols in gestational diabetes mellitus. Clin Exp Obstet Gynecol.
2012;39:512–5.
[5] Syed M, Javed H, Yakoob MY, et al. Effect of screening and manage-
ment of diabetes during pregnancy on stillbirths. BMC Public Health.
2011;11(Suppl 3):S2.
[6] Mackin ST, Nelson SM, Wild SH, et al.; SDRN Epidemiology
Group and Scottish Diabetes Group Pregnancy subgroup. Factors
associated with stillbirth in women with diabetes. Diabetologia.
2019;62:1938–47.
[7] Lakew D, Tesfaye D, Mekonnen H. Determinants of stillbirth among
women deliveries at Amhara region, Ethiopia. BMC Pregnancy
Childbirth. 2017;17:375.
[8] American College of Obstetricians and Gynecologists’ Committee on
Practice Bulletins—Obstetrics. ACOG practice bulletin no. 201: preges-
tational diabetes mellitus. Obstet Gynecol. 2018;132:e228–48. PMID:
30461693.
[9] ACOG practice bulletin no. 190: gestational diabetes mellitus. Obstet
Gynecol. 2018;131:e49–64. PMID: 29370047.
[10] American Diabetes Association. 14. Management of diabetes in preg-
nancy: standards of medical care in diabetes-2021. Diabetes Care.
2021;44(Suppl 1):S200–10. PMID: 33298425.
[11] Zhu L, Zhang R, Zhang S, et al.; Chinese Neonatal Network. Chinese
neonatal birth weight curve for different gestational age. Zhonghua Er
Ke Za Zhi. 2015;53:97–103.
[12] Lawn JE, Blencowe H, Waiswa P, et al.; Lancet Ending Preventable
Stillbirths Series Study Group. Stillbirths: rates, risk factors, and accel-
eration towards 2030. Lancet. 2016;387:587–603.
[13] Chen D, Cui S, Liu C, et al. Stillbirth in China. Lancet. 2016;387:1995–6.
[14] MacDorman MF, Gregory EC. Fetal and perinatal mortality: United
States, 2013. Natl Vital Stat Rep. 2015;64:1–24.
[15] Alesi S, Ghelani D, Rassie K, et al. Metabolomic biomarkers in ges-
tational diabetes mellitus: a review of the evidence. Int J Mol Sci.
2021;22:5512. PMCID: PMC8197243.
[16] Akolekar R, Machuca M, Mendes M, et al. Prediction of stillbirth from
placental growth factor at 11-13 weeks. Ultrasound Obstet Gynecol.
2016;48:618–23.
[17] Åmark H, Westgren M, Persson M. Prediction of stillbirth in women
with overweight or obesity-A register-based cohort study. PLoS One.
2018;13:e0206940.
[18] American Diabetes Association. Standards of medical care in diabe-
tes--2010. Diabetes Care. 2010;33 Suppl 1(Suppl 1):S11–61. Erratum
in: Diabetes Care. 2010 Mar;33(3):692. PMID: 20042772; PMCID:
PMC2797382.
[19] Simpson LL. Maternal medical disease: risk of antepartum fetal death.
Semin Perinatol. 2002;26:42–50.
[20] Mills JL. Malformations in infants of diabetic mothers. Teratology
25:385-94. 1982. Birth Defects Res A Clin Mol Teratol. 2010;88:769–78.
[21] Wang M, Athayde N, Padmanabhan S, et al. Causes of stillbirths in
diabetic and gestational diabetes pregnancies at a NSW tertiary referral
hospital. Aust N Z J Obstet Gynaecol. 2019;59:561–6.
[22] Chinese Medical Association Obstetrics and Gynecology Branch
Obstetrics Group/Perinatal Medicine Branch Pregnancy and Diabetes
Collaborative Group. Guidelines for the diagnosis and treatment of
gestational diabetes mellitus. Diabetes World. 2014;8:489–98.
[23] Åmark H, Westgren M, Sirotkina M, et al. Maternal obesity and still-
birth at term; placental pathology – a case control study. PLoS One.
2021;16:e0250983.
[24] Sharma N, Srinivasan S, Srinivasan KJ, et al. Role of aspirin in high
pulsatility index of uterine artery: a consort study. J Obstet Gynaecol
India. 2018;68:382–8.
[25] Shah TJ, Leik CE, Walsh SW. Neutrophil infiltration and systemic vas-
cular inflammation in obese women. Reprod Sci. 2010;17:116–24.
[26] Harrison MS, Thorsten VR, Dudley DJ, et al. Stillbirth, inflammatory
markers, and obesity: results from the stillbirth collaborative research
network. Am J Perinatol. 2018;35:1071–8.
[27] Tian Y, Yang X. A review of roles of uterine artery doppler in pregnancy
complications. Front Med (Lausanne). 2022;9:813343.
[28] Khong SL, Kane SC, Brennecke SP, et al. First-trimester uterine artery
Doppler analysis in the prediction of later pregnancy complications.
Dis Markers. 2015;2015:679730.
[29] Song WL, Zhao YH, Shi SJ, et al. First trimester Doppler velocimetry of
the uterine artery ipsilateral to the placenta improves ability to predict
early-onset preeclampsia. Medicine (Baltimore). 2019;98:e15193.
[30] Pérez-Martín SM, Quintero-Prado R, Lara-Barea A, et al. Fetal
cerebral three-dimensional power Doppler vascularization indi-
ces and their relationships with maternal glucose levels in preg-
nancies complicated with gestational diabetes. Diab Vasc Dis Res.
2022;19:14791641221078109.
[31] Rodríguez M, Couve-Pérez C, San Martín S, et al. Perinatal outcome
and placental apoptosis in patients with late-onset pre-eclampsia and
abnormal uterine artery Doppler at diagnosis. Ultrasound Obstet
Gynecol. 2018;51:775–82.
[32] Lauenborg J, Mathiesen E, Ovesen P, et al. Audit on stillbirths in women
with pregestational type 1 diabetes. Diabetes Care. 2003;26:1385–9.
[33] Feng R, Liu L, Zhang YY, et al. Unsatisfactory glucose management
and adverse pregnancy outcomes of gestational diabetes mellitus in the
real world of clinical practice: a retrospective study. Chin Med J (Engl).
2018;131:1079–85.
[34] Metzger BE, Gabbe SG, Persson B, et al.; International Association of
Diabetes and Pregnancy Study Groups Consensus Panel. International
association of diabetes and pregnancy study groups recommendations
on the diagnosis and classification of hyperglycemia in pregnancy.
Diabetes Care. 2010;33:676–82.
[35] Nielsen GL, Møller M, Sørensen HT. HbA1c in early diabetic preg-
nancy and pregnancy outcomes: a Danish population-based cohort
study of 573 pregnancies in women with type 1 diabetes. Diabetes
Care. 2006;29:2612–6.
[36] Stacey T, Tennant P, McCowan L, et al. Gestational diabetes and the
risk of late stillbirth: a case-control study from England, UK. BJOG.
2019;126:973–82.
[37] Yang H. New criteria of gestational diabetes mellitus and its enlighten-
ment (in Chinese). Chin J Diabetes. 2011;19:711–3.
[38] Jung E, Romero R, Yeo L, et al. The etiology of preeclampsia. Am J
Obstet Gynecol. 2022;226:S844–66.
[39] Ringholm L, Damm JA, Vestgaard M, et al. Diabetic nephropathy in
women with preexisting diabetes: from pregnancy planning to breast-
feeding. Curr Diab Rep. 2016;16:12.
[40] Cantu JA, Jauk VR, Owen J, et al. Is low-dose aspirin therapy to prevent
preeclampsia more efficacious in non-obese women or when initiated
early in pregnancy? J Matern Fetal Neonatal Med. 2015;28:1128–32.
[41] Meher S, Alfirevic Z. Aspirin for pre-eclampsia: beware of subgroup
meta-analysis. Ultrasound Obstet Gynecol. 2013;41:479–85.
[42] Maxwell C, Gaudet L, Cassir G, et al. Guideline No. 391-pregnancy
and maternal obesity part 1: pre-conception and prenatal care. J Obstet
Gynaecol Can. 2019;41:1623–40.
[43] Bodnar LM, Catov JM, Klebanoff MA, et al. Prepregnancy body mass
index and the occurrence of severe hypertensive disorders of pregnancy.
Epidemiology. 2007;18:234–9.
[44] Maxwell C, Gaudet L, Cassir G, et al. Guideline No. 392-pregnancy
and maternal obesity part 2: team planning for delivery and postpar-
tum care. J Obstet Gynaecol Can. 2019;41:1660–75.
[45] Institute of Medicine (US) and National Research Council (US)
Committee to Reexamine IOM Pregnancy Weight Guidelines. Weight
gain during pregnancy: reexamining the guidelines. Rasmussen KM,
Yaktine AL, editors. Washington (DC): National Academies Press (US);
2009. PMID: 20669500.
[46] Bouya S, Rezaie Keikhaie L, Hosseini S, et al. The effect of yoga on
uterine artery Doppler indices, maternal and fetal complications in
pregnant women: a quasi-experimental study. J Ayurveda Integr Med.
2021;12:70–4.
[47] Holman N, Bell R, Murphy H, et al. Women with pre-gestational dia-
betes have a higher risk of stillbirth at all gestations after 32 weeks.
Diabet Med. 2014;31:1129–32.
[48] Mackin ST, Nelson SM, Kerssens JJ, et al.; SDRN Epidemiology
Group. Diabetes and pregnancy: national trends over a 15 year period.
Diabetologia. 2018;61:1081–8.