Keywords
gestational diabetes - advanced maternal age - maternal obesity - preeclampsia - neonatal
outcomes
Palavras-chave
diabetes gestacional - idade materna avançada - obesidade materna - pré-eclâmpsia
- desfechos neonatais
Introduction
Gestational diabetes is a type of diabetes defined as any degree of glucose intolerance
with onset or first recognition during pregnancy, after excluding women with previous
diabetes. It usually constitutes ∼ 90% of all diabetes complicated pregnancies and
it is one of the most frequent complications during pregnancy. A gradual increase
in its prevalence has been observed worldwide. According to some authors, this increment
was due to increasing rates of maternal obesity, which is not consensual among others.
The global prevalence of gestational diabetes stands nowadays between 1 and 22% and
varies from country to country, depending on the genetic background, diagnostic methods
employed and environmental factors. [Box 1] shows some of the common risk factors that may contribute to this increase. There
is a higher risk of multiple maternal, fetal and neonatal adverse outcomes due to
gestational diabetes. Considering some studies, body mass index (BMI) and maternal
age showed to have the heaviest impact on pregnancy outcomes in women with gestational
diabetes.[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
Box 1
Common risk factors that may contribute to the increase of gestational diabetes
|
Common risk factors that may contribute to the increase of gestational diabetes
|
|
Previous diagnosis of gestational diabetes
Previous poor obstetric outcomes
Previous macrosomia
Advanced maternal age
Increasing prevalence of obesity
Polycystic ovarian syndrome
Family history of diabetes
Modern lifestyle with reduced physical activity and changed dietary habits
Smoking
|
Pregnancy at advanced maternal age has become more common in both developed and developing
countries over the last decades. Advanced maternal age is considered to be ≥ 35 years,
being very advanced maternal age considered to be ≥ 40 or 45 years. Advanced maternal
age is an independent risk factor for gestational diabetes and early onset pre-eclampsia
and is a known risk factor for other maternal and fetal adverse outcomes, such as
miscarriage and ectopic pregnancy. Nevertheless, the correlation between advanced
maternal age and adverse neonatal outcomes is still a matter of controversy in several
studies.[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
The number of obese pregnant women, individuals with BMI ≥ 30.0 kg/m2, is increasing
over time.[5]
[12]
[18] Pregestational BMI is a risk factor for the development of maternal and perinatal
complications.[24]
[27] In the clinical practice, obesity and gestational diabetes commonly coexist and
it is controversial which one the two conditions (gestational diabetes or maternal
obesity) is more strongly associated with risk for adverse maternal and neonatal outcomes.[10]
[13]
[19] Considering some authors, it seems that obese women with gestational diabetes have
an increased risk of adverse outcomes compared with diabetic nonobese women, but more
scientific evidence is necessary.[23]
[35]
[36]
Pre-eclampsia is one of the major pathologies in pregnancy and is a major health issue
for women and their descendants worldwide.[17]
[34] This disease is characterized by hypertension developing in pregnancy associated
with new-onset proteinuria or other end-organ dysfunctions.[34] According to some studies, pre-eclampsia complicates between 2 and 5% of all pregnancies.[34] This disease seems to raise the risk of some important adverse pregnancy outcomes,
raising morbidity and mortality not only in pregnant women but probably also in their
offspring.[17]
[34]
It remains unclear whether the combination of gestational diabetes and other pregnancy
risk factors and poor obstetric outcomes, such as advanced maternal age, maternal
obesity and pre-eclampsia, represents a synergic risk in pregnancy, and whether the
diagnosis and treatment of gestational diabetes among these women modifies this risk.
So, it seems crucial to examine the results of current clinical care and assess if
this care is sufficient or if it needs to be changed. The purpose of the present study
was to analyze adverse fetal or neonatal outcomes of women with gestational diabetes,
measured by fetal death, presence of preterm deliveries, birthweight, neonatal morbidity
and neonatal death, as well as the synergic effect of concomitant pregnancy risk factors
and poor obstetric outcomes, as advanced maternal age, maternal obesity and pre-eclampsia
in the worsening of these outcomes.
Methods
Identification of the Patients and Setting of Study
This is a retrospective cohort study focusing on adverse fetal and neonatal outcomes
of women with gestational diabetes whose pregnancy surveillance and childbirth took
place at the Hospital da Senhora da Oliveira (HSO, in the Portuguese acronym), a tertiary
center, during the years of 2017 and 2018. The data were collected from the medical
records registered in HSO's health informatic programs Sclinico and Obscare. These
programs contain data on all births in the mentioned hospital, including information
on diagnosis, procedures, interventions, deliveries and newborns, as well as hospital
outpatient care. Using these medical records, the following data were retrieved and
analyzed: the incidence of gestational diabetes among all the deliveries occurred
in 2018 in the HSO; as well as, among the women with gestational diabetes: maternal
age, coexistence of pre-eclampsia, maternal BMI, gestational age and preterm deliveries,
onset of labor (spontaneous or induced), mode of birth (normal birth, instrumental
birth or cesarean), gender of the newborn, birthweight, fetal death, admission in
a neonatal intensive care unit, neonatal morbidity and mortality.
Variables Description
Advanced maternal age was defined as maternal age ≥ 35 years old and maternal obesity
as a BMI ≥ 30 kg/m2, using the pregestational weight of each pregnant woman for the ratio between weight
and height squared. Preeclampsia was defined by hypertension (arterial pressure ≥
140/90 mmHg) developing in pregnancy associated with new-onset proteinuria (protein
to creatinine ratio in occasional urine ≥ 0,30 or proteinuria in 24h urine ≥ 300 mg)
or other end-organ dysfunctions. Fetal death was defined as death in the gestational
period. Neonatal mortality was defined as death in the neonatal period (from childbirth
up to 28 days postpartum), and neonatal morbidity included pathological diagnosis
in the same period, being them respiratory distress, metabolic acidosis, hypoxic-ischemic
encephalopathy, hypoglycemia, hyperbilirubinemia, low Apgar scores at the 1st and 5th minutes of life, and congenital anomalies in the neonatal period. Birthweight was
divided into 3 different categories: normal if ≥ 2500 g, low if < 2500 g but ≥ 1500 g,
and very low if <1500 g. Preterm deliveries were defined by the gestational age on
the moment of birth < 37 weeks of gestation.
Statistical Analysis
The data were analyzed using IBM SPSS Statistics for Windows, Version 26.0 (IBM Corp.,
Armonk, NY, USA). A descriptive statistic was used to describe some of the most important
variables, as maternal age, gestational age and birthweight. To verify the distribution
of each variable, the Shapiro-Wilk normality test was used, more appropriated for
the size of the studied sample. A simple analysis with linear regression was first
done to compare each one of the variables with the studied outcomes. The independent
sample t-test and the Mann-Whitney U-test were used to compare the means of continuous and
categoric variables. To analyze the influence of a categoric variable in another categoric
variable, the chi-squared test was used. Afterwards, a multivariate analysis was performed
to assess the concomitance of maternal risk factors in neonatal outcomes, using a
multiple regression. A p-value < 0.05 was considered statistically significant, and a 95% confidence interval (CI)
was used. Analysis of differences between groups, tables, circle charts and histograms
were also executed, all created in IBM SPSS for Windows, Version 26.0 (IBM Corp.,
Armonk, NY, USA). The results are expressed in percentages, and the means, ranges
and standard deviations (SDs) are reported when appropriate. The present investigation
was approved by the hospital's ethics committee and authorized by the Board of Directors
of the Hospital da Senhora da Oliveira.
Results
The present study included a total number of 301 unifetal pregnancies (146 from 2017
and 155 from 2018). It was decided to exclude the 8 cases of twin pregnancies (3 from
2018 and 5 from 2017) from these data, since twin pregnancies are from the beginning
associated with worse outcomes, which could interfere with our results.
The women had a mean maternal age of 33,37 ± 5,12 years old, with a minimum of 18
years old and a maximum of 47 years old, and their pregnancies had a median of gestational
age of 38,00 ± 2,00 weeks, with a minimum of 30 weeks and a maximum of 41 weeks of
gestation. They contributed to 301 childbirths within a total number of 4089 childbirths
that occurred in 2017 and 2018 (2036 in 2017 and 2053 in 2018) in the HSO, corresponding
to 7,36% of childbirths, and led to 31 cases (10,30%) of preterm births (< 37 weeks).
The onset of labor was mainly spontaneous (56.10%) and it was normal in about half
of the cases (54.15%). These 301 childibirths resulted in 300 live births (99.70%)
and 1 case of fetal death and stillbirth (0.30%). There were no cases of neonatal
mortality and 6.30% of cases of neonatal morbidity. The birthweight of the newborns
had a mean of 3,146.97 ± 500,66 g, with a minimum of 990 g and a maximum of 4,645 g,
and there were almost 8% of newborns with low and very low birthweight. The description
of the study participants and pregnancy and neonatal outcomes can be analyzed in [Table 1].
Table 1
Description of study participants and pregnancy and neonatal outcomes
|
Characteristics
|
Number of cases - %
|
|
Maternal characteristics
|
|
Number of pregnant women (unifetal pregnancies) with gestational diabetes
|
30–100
|
|
Advanced maternal age: Presence versus Absence
|
136 versus 165–45.20 versus 54.80
|
|
Preeclampsia: Presence versus Absence
|
18 versus 283–6 versus 94
|
|
Maternal Obesity: Presence versus Absence (missings)
|
77 versus 223 (1)–25.60 versus 74.10 (0.30)
|
|
Pregnancy outcomes
|
|
Onset of labor: Spontaneous versus Induced versus Absence (missings)
|
169 versus 95 versus 35 (2)–56.10 versus 31.60 versus 11.60 (0–70)
|
|
Type of labor: Normal versus Instrumental versus Cesarean section (missings)
|
163 versus 45 versus 89 (4)–54.15 versus14.95 versus 29.57 (1.33)
|
|
Number of unifetal deliveries among all the 2017 and 2018 deliveries in the mentioned
hospital
|
301/4,089–7.36
|
|
Preterm deliveries versus Term deliveries (missings)
|
31 versus 269 (1)–10.30 versus 89.40 (0.30)
|
|
Perinatal and neonatal outcomes
|
|
Live births versus Fetal deaths and stillbirths
|
300 versus 1–99.70 versus 0.30
|
|
Male newborns versus Female newborns
|
165 versus 135–55 versus 45
|
|
Birthweight: Normal versus Low versus Very low
|
277 versus 20 versus 3–92.30 versus 6.70 versus 1
|
|
Neonatal mortality: Presence versus Absence
|
0 versus 300–0 versus 100
|
|
Neonatal morbidity: Presence versus Absence (missings)
|
19 versus 280 (1)–6.30 versus 93.30 (0.30)
|
|
Admission in a neonatal intensive care unit: Presence versus Absence
|
17 versus 283–5.70 versus 94.30
|
Regarding maternal age, there were 45.20% of cases of advanced maternal age and 54.80%
of maternal age < 35 years. The incidence of neonatal morbidity, newborns with low
and very low birthweight and of preterm deliveries was similar among both categories
(6.0%, 7.40% and 10.40% in pregnant women with advanced maternal age versus 6.70%,
7.90% and 10.30% in pregnant women without advanced maternal age, respectively). The
influence of the advanced maternal age in these three outcomes was analyzed (p = 0.806; p = 0.879; p = 0.985, respectively). It's possible to analyze the aforementioned results in [Table 2].
Table 2
Influence of coexistence of advanced maternal age with gestational diabetes in neonatal
morbidity, low and very low birthweight and incidence of preterm deliveries
|
Influence of coexistence of advanced maternal age with gestational diabetes
|
|
Pregnancy and Neonatal outcomes
|
Maternal Age < 35 years old
|
Maternal Age ≥35 years old
|
p-value
|
|
Neonatal Morbidity
Absence (%)
Presence (%)
|
154 (93.30)
11 (6.70)
|
126 (94.00)
8 (6.00)
|
0.806
|
|
Birthweight
≥2500 g (%)
< 2500 g (%)
|
152 (92.10)
13 (7.90)
|
125 (92.60)
10 (7.40)
|
0.879
|
|
Deliveries
Term (%)
Preterm (%)
|
148 (89.70)
17 (10.30)
|
121 (89.60)
14 (10.40)
|
0.985
|
Considering the coexistence of pre-eclampsia with gestational diabetes, there were
6% of cases in both conditions versus 94% with only gestational diabetes. The incidence
of neonatal morbidity, newborns with low and very low birthweight and of preterm deliveries
was higher in the first group (22.20%, 33.30% and 61.10% in pregnant women with pre-eclampsia
and gestational diabetes versus 5.30%, 6.00% and 7.10% in pregnant women with only
gestational diabetes, respectively). The influence of pre-eclampsia in these 3 outcomes
was analyzed (p = 0.004; p < 0.01; p < 0.01, respectively). It is possible to analyze the aforementioned results in [Table 3].
Table 3
Influence of pre-eclampsia coexistence with gestational diabetes in neonatal morbidity,
low and very low birthweight and incidence of preterm deliveries
|
Influence of coexistence of preeclampsia with gestational diabetes
|
|
Pregnancy and Neonatal outcomes
|
Without preeclampsia
|
With preeclampsia
|
p-value
|
|
Neonatal Morbidity
Absence (%)
Presence (%)
|
266 (94.70)
15 (5.30)
|
14 (77.80)
4 (22.20)
|
0.004
|
|
Birthweight
≥2500 g (%)
< 2500 g (%)
|
265 (94.00)
17 (6.00)
|
12 (66.70)
6 (33.30)
|
< 0.01
|
|
Deliveries
Term (%)
Preterm (%)
|
262 (92.90)
20 (7.10)
|
7 (38.90)
11 (61.10)
|
< 0.01
|
In respect to the coexistence of maternal obesity (BMI ≥ 30kg/m2) with gestational
diabetes, there were ∼ 26% of cases in these conditions versus 74% of cases with just
gestational diabetes. The incidence of neonatal morbidity and of preterm deliveries
was higher in the first group (9.00% and 11.50% versus 5.40% and 9.90%, respectively).
The incidence of newborns with low and very low birthweight was similar between both
categories (7.70% versus 7.70%, respectively). The influence of maternal obesity in
these three outcomes was analyzed (p = 0.270; p = 0.992; p = 0.684, respectively). It is possible to analyze the aforementioned results in [Table 4].
Table 4
Influence of maternal obesity coexistence with gestational diabetes in neonatal morbidity,
low and very low birthweight and incidence of preterm deliveries
|
Influence of coexistence of maternal obesity with gestational diabetes
|
|
Pregnancy and Neonatal outcomes
|
Without maternal obesity
|
With maternal obesity
|
p-value
|
|
Neonatal Morbidity
Absence (%)
Presence (%)
|
209 (94.60)
12 (5.40)
|
71 (91.00)
7 (9.00)
|
0.270
|
|
Birthweight
≥2500 g (%)
< 2500 g (%)
|
205 (92.30)
17 (7.70)
|
72 (92.30)
6 (7.70)
|
0.992
|
|
Deliveries
Term (%)
Preterm (%)
|
200 (90.10)
22 (9.90)
|
69 (88.50)
9 (11.50)
|
0.684
|
A multivariate analysis was performed to assess the concomitance of maternal risk
factors in neonatal outcomes, using a multiple regression. In what concerns to the
prevision of the outcome neonatal morbidity, the only model with statistic significance
was the model including only preeclampsia: [F (1.297) = 8.274; p < 0.004; r
2 = 0.28]. A p-value = 0.934 and p = 0.530 were obtained for models including 2 variables (pre-eclampsia and advanced
maternal age) and including 3 variables (pre-eclampsia, advanced maternal age and
maternal obesity), respectively. In what concerns to the prevision of newborns of
low and very low birthweight, the only model with statistic significance was the model
including only preeclampsia: [F (1.298) = 26.761; p < 0.01; r
2 = 0.084]. A p-value = 0.474 and p = 0.686 were obtained for models including two variables (pre-eclampsia and advanced
maternal age) and including 3 variables (pre-eclampsia, advanced maternal age and
maternal obesity), respectively. In what concerns to the prevision of the outcome
of preterm deliveries, the only model with statistic significance was the model including
only preeclampsia: [F (1.298) = 64.364; p < 0,01; r
2 = 0.183]. A p-value = 0.340 and p = 0.312 were obtained for models including two variables (pre-eclampsia and advanced
maternal age) and including 3 variables (pre-eclampsia, advanced maternal age and
maternal obesity), respectively.
Discussion
As our results showed, the current literature also demonstrated that women with gestational
diabetes are at risk of both maternal, fetal and neonatal adverse outcomes, including
pre-eclampsia and eclampsia (8-fold raise), increased risk of preterm birth, higher
need for labor induction, caesarean section, stillbirths, macrosomia, full term low
weight infants, newborns large for gestational age, neonatal morbidity (namely hyperbilirubinemia
and jaundice, respiratory distress and asphyxia, hypoglycemia and congenital malformations),
increased need to admission in neonatal intensive care unit and neonatal death (5-fold
raise).[2]
[11]
[16] However, there are also some studies that do not share the same scientific opinion.
Some authors stated that the prevalence of newborns large for gestational age, cesarean
section and preterm deliveries in gestational diabetes was not elevated.[1]
The statistically significant influence of pre-eclampsia coexistence in women with
gestational diabetes in the ocurrence of neonatal morbidity, newborns of low and very
low birthweight and preterm deliveries was at some point expected, since pre-eclampsia
is per se a severe obstetric pathology with severe well-known pregnancy outcomes in
the literature revision, as mentioned by many investigators: newborns small for gestational
age, preterm birth and 5 minute Apgar score < 7.[17]
[34] Nevertheless, the verified absence of influence of maternal obesity and advanced
maternal age in the same group of women in these 3 outcomes, was instead against most
of the authors, who do not only point them as risk factors for gestational diabetes,
but also in most studies as aggravating factors of its outcomes. Considering the findings
of some authors, an increased maternal insulin resistance in pregnancies with obesity
and gestational diabetes promote the placental growth and inhibit its efficiency,
being this pathophysiological mechanism responsible for the adverse outcomes in pregnant
obese women with gestational diabetes.[26]
[35] According to other investigators, prepregnancy obesity increased the likelihood
of neonatal hypoglycemia among infants of mothers with gestational diabetes.[13] In certain studies, the mentioned association will increase the risk for obstetric
and neonatal complications, in particular preterm birth and infant birth weight above
the 90th percentile.[23]
[36] Nevertheless, according to some other studies, obesity (without gestational diabetes)
is more frequently associated with adverse perinatal outcomes (including births at < 33
weeks of gestation, birthweight > 4000 g and low 5-minute Apgar scores) than the association
of obesity and gestational diabetes or than gestational diabetes in nonobese mothers,
and, so, it's at least so crucial to treat prepregancy obesity as to prevent gestational
diabetes in future mothers.[35] This same finding is concordant with the results of the present study, which showed
that maternal obesity doesn't seem to be an aggravating factor of gestational diabetes,
which could be explained by the greater number of prenatal visits and strict vigilance
of women with gestational diabetes that should be enough to achieve a more rigorous
diet and weight control, as already mentioned in the recent literature.[2]
[4]
[11] In the same way, other authors considered advanced maternal age as a potential risk
factor of gestational diabetes, as well as an aggravating factor of it, capable to
raise the incidence of adverse outcomes for mothers, newborns and infants, as spontaneous
late preterm deliveries, fetal growth restriction, small for gestational age infants
and birthweight < 2500 g.[3]
[14]
[21] However, according to some authors, maternal age does not significantly influence
birthweight.[25] Despite the findings in the literature, the present study did not find advanced
maternal age as an aggravating factor of gestational diabetes, which could be explained
also by a more rigorous vigilance of these pregnant women.
It is proven by the findings of many studies that early screening, high utilization
of prenatal visits and subsequent treatment of gestational diabetes to promote maternal–fetal
health allows the adhesion to a more balanced diet and to a regular exercise program,
which leads to a more strict weight reduction and better glycemic control in the 3
months prior to birth, with a consequent improvement of some known adverse outcomes,
such as preterm deliveries, neonatal morbidity, infants requiring neonatal intensive
care unit (NICU) admission or maternal risk for diabetes later in life.[2]
[4]
[30] Therefore, the verification of maternal obesity and advanced maternal age as nonaggravating
factors of gestational diabetes in the present study may be a proof of an adequate
obstetric vigilance and strict metabolic control of the pregnant women with gestational
diabetes in the present tertiary center.
Using the multivariate analysis, it was shown that only pre-eclampsia in women with
gestational diabetes can be used to predict the three studied outcomes (neonatal morbidity,
newborns of low and very low birthweight and preterm deliveries). Neither maternal
obesity nor advanced maternal age are predictors of these neonatal outcomes in women
with gestational diabetes. As mentioned above, the severity of this obstetric pathology
can be a reasonable explanation.
As strengths of the study itself, it could be mentioned the good amount of information
of the participants, as well as the outcomes evaluated. Moreover, the majority of
the variables in the present study (maternal age, BMI, fetal death, birthweight, neonatal
mortality) were objective parameters, not influenced by inter or intraobserver variability
in their measurement. As limitations of the present study, it could be enumerated
the retrospective character of the study instead of a prospective one and the selection
of the study population from one single hospital, and not from many, which could be
resolved by a multicenter study, possibly more representative, not only in respect
to the number of pregnant women involved but also considering different settings and
backgrounds of the population analyzed.
Conclusion
Although the coexistence of pre-eclampsia and gestational diabetes showed a statistically
significant association with adverse neonatal outcomes, neither the association of
advanced maternal age nor maternal obesity with gestational diabetes had a negative
influence on these outcomes. Moreover, in a multivariate analysis, it was shown that
only pre-eclampsia can be used to predict the neonatal outcomes (neonatal morbidity,
newborns of low and very low birthweight and preterm deliveries) in women with gestational
diabetes.
