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Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes
Journal Pre-proofs Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes Beatriz Barquiel, Lucrecia Herranz, Nuria Martínez-Sánchez, Cristina Montes, Natalia Hillman, José Luis Bartha PII: DOI: Reference:
S0168-8227(19)31372-5 https://doi.org/10.1016/j.diabres.2019.107971 DIAB 107971
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
23 September 2019 9 November 2019 29 November 2019
Please cite this article as: B. Barquiel, L. Herranz, N. Martínez-Sánchez, C. Montes, N. Hillman, J. Luis Bartha, Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes, Diabetes Research and Clinical Practice (2019), doi: https://doi.org/10.1016/j.diabres. 2019.107971
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© 2019 Published by Elsevier B.V.
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Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes
Beatriz Barquiela, Lucrecia Herranza, Nuria Martínez-Sánchezb, Cristina Montesa, Natalia Hillmana, José Luis Barthab aDivision
of Diabetes, bDepartment of Obstetrics, a,bDiabetes and Pregnancy Unit, La Paz
University Hospital, Madrid, Spain
Corresponding author: Beatriz Barquiel Unidad de Diabetes, Hospital Universitario La Paz Paseo de la Castellana 261, CP 28046, Madrid Tel: +34 657 652 337 Fax: +34 917 691 901 E-mail: [email protected]
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Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes Beatriz Barquiel, Lucrecia Herranz, Nuria Martínez-Sánchez, Cristina Montes, Natalia Hillman, José Luis Bartha
ABSTRACT Aims: To evaluate if neonatal complications or death were poorer for neonates born small for gestational age (SGA) than for those born with adequate weight or large for gestation age (LGA) to women with gestational diabetes mellitus (GDM). Methods: Retrospective analysis of the clinical outcomes of neonates born to 3413 women with GDM. The prevalence of neonatal hypoglycaemia, hypocalcaemia, hyperbilirubinemia, polycythaemia, and death was compared among three birthweight groups: SGA, adequate, and LGA. A two-sided chi-squared or Fisher’s exact test was used for between-group comparisons. A forward multiple logistic regression was performed to determine the odds ratio (OR) associated with SGA. Results: Neonatal complications were more frequent in the SGA group (20.1%) than in the adequate (9.9%) or LGA (15.2%) groups. There were four deaths (1.6%) in the SGA group compared to one in the LGA (0.4%) and six in the adequate (0.2%) groups (P=0.002). SGA was a risk factor for neonatal complications or death (OR. 2.122; 95% confidence interval, 1.552-2.899), independent of maternal age, weight gain, fasting glucose, glycaemic control, gestational hypertension, pre-eclampsia, smoking, or neonatal prematurity.
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Conclusion: SGA birthweight is an important risk factor for neonatal complications or death among neonates born to mothers with GDM.
Keywords: gestational diabetes, neonatal outcomes, small for gestational age, large for gestational age
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INTRODUCTION Maternal gestational diabetes mellitus (GDM) is associated with a number of neonatal complications, the majority being metabolic in nature, with the most frequent being hypoglycaemia (1). Foetal hypoglycaemia normally results from foetal hyperinsulinemia due to chronic exposure to elevated maternal glucose levels. Infants born to mothers who develop GDM are often born large for gestational age (LGA). LGA itself also increases the risk for hypocalcaemia (due to the relative immaturity of the parathyroid glands), polycythaemia, hyperbilirubinemia, and even death, partly due to the increased oxygen demand to organ tissues (2,3). However, neonates of mothers with GDM can also be born small for gestational age (SGA). In mothers with GDM, two recent studies found that delivery of SGA neonates is independently associated with long-term cardiovascular offspring hospitalizations (4), but not with endocrine disorders (5). In normal pregnancies, SGA has been identified as a specific risk factor for hypoglycaemia and jaundice (6). However, it is not known if SGA associated with GDM is a risk factor for other neonatal complications. Moreover, other risk factors for neonatal complications associated with GDM include severity of hyperglycaemia at the time of diagnosis, glycaemic control, and gestational weight gain (7–9). However, few studies have examined the prevalence of neonatal complications associated with GDM, including adverse foetal outcomes, as a function of birthweight (10–12). Therefore, our aim was to assess neonatal complications associated with GDM in SGA neonates, compared with those in neonates with a normal birthweight or LGA. We also investigated if glycaemic control, severity of diabetes, or
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other related factors, such as hypertension, prematurity, or congenital malformations, further negatively impacted neonatal outcomes.
MATERIAL AND METHODS Statement of ethics The study was approved by our Hospital’s Research Ethics Committee: Comité Ético de Investigación Clínica del Hospital Universitario La Paz, code PI-1066. Study design Our retrospective analysis included only singleton pregnancies in women with GDM who were followed prospectively at La Paz University Hospital (Madrid, Spain) between 1987 and 2017 (N=3,426). GDM screening (100 g oral glucose tolerance test) was completed in all women, with the criteria of the National Diabetes Data Group used for diagnosis: fasting glycaemia, 5.8 mM; 1 h, 10.6 mM; 2 h, 9.2 mM; and 3 h, 8.1 mM. Women with concomitant pathology that could affect birthweight (such as corticosteroid treatment, glomerulonephritis, tubular acidosis nephropathy, nervous anorexia, alcoholism, congenital cardiopathy, HIV infection, HCV infection, antiphospholipid syndrome, or previous bariatric surgery) were excluded. From this initial group of 3,426 prospective mothers, 13 were excluded based on these exclusion criteria. Therefore, our analysis was based on the complete data set for 3,413 mothers with GDM.
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GDM treatment followed an established protocol (13) and remained unchanged over the study period. Treatment included implementation of a standard diet, with supportive education that included nutritional management and physical activity counselling from specialized nurses. Fasting, pre-prandial and the 2-h post-prandial capillary glucose measurements were registered every other day, from the time of GDM diagnosis to the time of delivery. Insulin treatment was initiated when two measurements of capillary fasting glycaemia were >5.3 mM and/or the 2-h post-prandial glycaemia was >6.7 mM, despite dietary treatment. Outcome and explanatory variables Our analysis included both characteristics of the neonate and of their mothers. SGA was defined by a birthweight <10th percentile, according to sex and gestational age birthweight customized percentile charts (14). LGA was defined by a birthweight >90th percentile. Blood glucose levels are monitored in neonates born to mothers with GDM at our hospital, using blood samples obtained from the heel. Neonatal glycaemia was measured if symptoms of hypoglycaemia developed within 2 h of birth. Neonatal hypoglycaemia was defined by blood glucose values <2.2 mM. Additional tests and examinations were performed, as needed, as per the standard protocol of our Pediatric Unit. Other measures obtained were defined as follows: hypocalcaemia, total serum calcium level <1.75 mM; hyperbilirubinemia, total bilirubin level >0.20 mM; polycythaemia, central venous haematocrit >65%, red blood cells >6 x 106/L, or haemoglobin >200 g/L. The presence of at least one neonatal complication (hypoglycaemia, hypocalcaemia,
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hyperbilirubinemia, polycythaemia, and/or neonatal death) was assessed. Prematurity was defined as gestational age at birth of <37 weeks. Statistical analyses Descriptive statistics were presented as percentages for categorical variables, the mean and standard deviation for continuous variables with a normal distribution, and the median and interquartile range (IQR) for continuous variables with a non-normal distribution. The incidence of maternal, neonatal complications and death were compared between the three different birthweight groups (SGA, adequate, and LGA) using ANOVA, Welch test for continuous variables and a two-sided chi-squared or Fisher’s exact test, as appropriate for the data type. Covariates that could plausibly be related to neonatal outcomes were entered into a forward stepwise multiple logistic regression model, with the effects of these factors measured using adjusted odds ratios (AORs) and related 95% confidence intervals (CIs). A P-value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS (version 20.0 for Windows; SPSS, Inc., Chicago, IL).
RESULTS Relevant characteristics of mothers and of their neonates are presented in Table 1. With regard to ethnicity, 3201 (93.8%) of the mothers were from Europe, 64 (1.9%) from North Africa, 116 (3.4%) from Latin America, and 33 (0.9%) from Indo Asia and the Pacific Islands.
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Neonates were grouped by birthweight as follows: SGA, adequate, and LGA. Neonatal complications and death were compared between these three groups; of note, 11 neonatal deaths were from unknown causes (Table 2). Forward multivariate regression analysis was performed to determine the effect of birthweight on the composite of metabolic complications (hypoglycaemia, hypocalcaemia, hyperbilirubinemia, and polycythaemia) and neonatal death, with models adjusted for maternal age, gestational weight gain, fasting glucose, glycaemic control (entered as the mean HbA1c level of monthly measurements), gestational hypertension, pre-eclampsia, and smoking, as well as for neonate prematurity (Table 3). The following factors were associated with SGA: smoking (AOR, 1.404; 95% CI, 1.0111.949; P=0.043); a pre-pregnancy body mass index <25 kg/m2 (AOR, 1.586; 95% CI, 1.1232.238; P=0.009); gestational weight gain <5 kg (AOR, 2.013; 95% CI, 1.376-2.943; P<0.001), and neonate prematurity (AOR, 3.726; 95% CI, 2.284-6.080; P<0.001). Overall, there were 180 (5.4%) premature births, with 43 (23.9%) of these being in the SGA group. On multivariate analysis, the AOR of SGA on the composite of neonatal complications or death was 2.154 (95% CI, 1.524-3.045; P<0.001) and was not significantly different when premature neonates were excluded from the SGA group. For SGA neonates, maternal gestational weight gain (kg) (AOR, 0.963; 95% CI, 0.943-0.983; P<0.001) and fasting glucose (mM; AOR, 1.008; 95% CI, 1.002-1.015; P=0.007) were also associated with the composite of neonatal complications or death. Congenital malformations were identified in 207 (6.1%) neonates, with this incidence not being greater in the SGA (13, 4.9%) than the adequate and LGA (182, 5.8%) groups (P=0.679).
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The composite of neonatal complications or death was not more frequent in neonates with congenital malformations (14, 7.2%) compared to those without malformations (368, 11.5%; P=0.065). Based on the guidelines for maternal gestational weight gain of the Institute of Medicine, maternal weight gain was dichotomized into two groups for analysis: <5 kg and ≥5 kg. One-third (30.0%) of our study sample were classified into the <5 kg group, with complications identified in 161 (15.0%) of these neonates, compared to 222 (9.4%) among those born to mothers with a gestational weight gain ≥5 kg (AOR for a gestational weight gain <5 kg, 1.599; 95% CI, 1.283-1.993; P<0.001). Regarding diabetes severity, the fasting glycaemia was ≥5.8 mM in 471 (13.7%) of women in our study group. Complications were identified in 78 (16.6%) neonates from mothers with a fasting glycaemia ≥5.8 mM, compared to 105 (10.3%) neonates from mothers with a fasting glycaemia <5.8 mM (AOR for a fasting glycaemia ≥5.8 mM, 1.644; 95% CI, 1.2492.163; P<0.001). There was an additive effect of SGA birthweight, gestational weight gain and fasting glycaemia on the occurrence of neonatal complications or death (Figure 1).
DISCUSSION Among pregnant women with GDM, the risk of hypoglycaemia, hyperbilirubinemia, polycythaemia, and neonatal death is higher in SGA neonates than in adequate weight or LGA neonates. These outcomes do not depend on glycaemic control, hypertension, or prematurity. Our results agree with those of Langer et al. (12) who reported an L-shaped
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association between birthweight and hyperbilirubinemia and a J-shaped association between birthweight and polycythaemia. A higher rate of morbidity has also been previously reported amount SGA neonates (8,9). Therefore, there is a need for specific medical attention and care for women who develop GDM in general and not only for those with LGA babies. With GDM, neonatal metabolic complications are related to foetal hyperinsulinemia and overgrowth. Foetal hyperinsulinemia causes neonatal hypoglycaemia, which is generally associated with LGA neonates (2). The metabolic demands for LGA neonates is also increased, leading to polycythaemia and subsequent hyperbilirubinemia due to an enhanced oxygen demand and the relative immaturity of the hepatic system. Of note, our study also identified a high frequency of these complications in SGA neonates. The effect of hyperglycaemia in SGA neonates is not surprising as baseline glucose has been widely associated with neonatal morbidity (9). Moreover, as foetal hyperglycaemia and insulin may alter the metabolism and gene expression in foetal tissues (15), insulin resistance would be increased in SGA foetuses, which may influence post-natal outcomes. In fact, SGA neonates are at risk for insulin resistance, obesity, metabolic syndrome, and prediabetes in early childhood (16). The frequency of SGA neonates was similar to that of LGA neonates in our study sample and was close to the estimated 11% in the general population (15). Customized birthweight curves can be useful to identify SGA neonates, with the prevalence otherwise being underestimated (17), particularly among women with GDM (6). The possibility of SGA should, therefore, be considered when making clinical decisions about GDM
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treatment, with regards to appropriate diet and the possibility of including insulin treatment (18). Our study presents novel information, not previously reported, as we considered SGA, glycaemic control, diabetes severity, maternal hypertension, and neonate prematurity simultaneously. We identified only one previous study (11) that reported a 4-fold higher rate of mortality among SGA than adequate and LGA neonates, with this risk of mortality not related to glycaemic control, prematurity, or maternal complications. In our study, we identified that maternal fasting glucose and low gestational weight gain were predicative of a higher composite of neonatal complications or death, indicating that diabetes severity and maternal malnutrition may increase the risk of neonatal death associated with SGA. This raises the possibility that SGA foetuses in women with GDM may need to be delivered early, although further studies are needed to fully clarify this issue. With regard to factors that might increase the impact of SGA on neonatal outcomes, we examined gestational weight gain, defined per the criterion of the Institute of Medicine, on the composite of neonatal complications or death (19). Low gestational weight gain has not previously been identified as a risk factor for neonatal complications among women with GDM. Lower gestational weight gain may be associated to a lower than expected neonatal growth and maturity, which is significant when we consider that maturity in these neonates is already delayed due to exposure to high levels of maternal glucose. Among women with GDM, SGA birthweight may be clinical evidence of maternal malnutrition (15) or nutritional restriction due to the diabetic condition. Specifically, maternal fasting glucose influences hyperinsulinemia and neonatal complications in
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women with GDM (7,9), particularly in those with SGA neonates. Of note, hyperinsulinemia may influence utero-placental insufficiency, which is the most common cause of an SGA birthweight. We did not find that maternal hypertension explained the composite of complications among SGA neonates born to mothers with GDM. It is possible that other factors might have influenced foetal growth restriction, including foetal, placental, and genetic factors. The main strength of our study is the large cohort of women with GDM who were prospectively followed and managed using a consistent prenatal dietary protocol, combined with insulin treatment as needed, as well as consistent post-natal care to infants. The sample size also allowed for strict selection criteria (including exclusion of known underlying diseases that can affect foetal growth) and multivariate analyses of factors that might affect foetal growth. The retrospective design also allowed us to adjust regression models for maternal characteristics that could influence neonatal outcomes. However, because of the retrospective design, effects of selection bias cannot be denied, even if data were prospectively collected; this was a limitation of this study. In conclusion, we present evidence that neonatal death or metabolic complications are more frequent among SGA neonates born to mothers with GDM than among adequate or LGA neonates. In fact, we identified a SGA birthweight as an independent factor of the composite of neonatal complications or death, regardless of maternal gestational weight gain, glucose level, and neonatal prematurity. A balanced maternal nutrition, with adequate energy supplementation and smoking cessation, may be crucial for the prevention of SGA birthweight. The prevalence of SGA should be added to the rate of LGS
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and caesarean section in future studies regarding GDM-related complications. In addition, programs for the early detection of diabetes should be implemented for mothers with a foetus experiencing a slowed growth rate. Once GDM is detected, dietary intervention and obstetric care should be implemented to lower the risk of complications associated with SGA.
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Acknowledgements We are indebted to nurses Lourdes Sáez de Ibarra, Ruth Gaspar, Montserrat Arévalo, and Silvia López who provided therapeutic education to women with gestational diabetes. No funding was received for this research. Conflicts of interest: The authors report no conflict of interests.
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Gardosi J, Mongelli M, Wilcox M, Chang A. An adjustable fetal weight standard.
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Ultrasound Obstet Gynecol 1995; 6: 168-74. 15.
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Kjos SL, Schaefer-Graf UM. Modified therapy for gestational diabetes using high-risk and low-risk fetal abdominal circumference growth to select strict versus relaxed maternal glycemic targets. Diabetes Care 2007; 30: S200-5.
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Siega-Riz AM, Viswanathan M, Moos M-K, et al. A systematic review of outcomes of maternal weight gain according to the Institute of Medicine recommendations: birthweight, fetal growth, and postpartum weight retention. Am J Obstet Gynecol 2009; 201: 339.e1-14.
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FIGURE LEGEND Figure 1. Perinatal complications or death in a cohort of women with gestational diabetes. The incidence of neonatal complications is presented as a function of birthweight, classified (from left to right) as: within normal limits (adequate, AGA), large for gestational age (LGA), and small for gestational age (SGA). Added risk factors are included in columns from left to right: there was an additive effect of low maternal gestational weight gain or high fasting glucose.
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Table 1. Characteristics of a cohort of singleton pregnant women with gestational diabetes as a function of birthweight, as follows: adequate for gestational age (AGA), large for gestational age (LGA) and small for gestational age (SGA) Characteristics
All groups
AGA
LGA
SGA
P value
Mean ± SD or N (%)
(N=3,413)
(Reference)
(N=736)
(N=287)
Age (years)
33 ± 5
33 ± 4
34 ± 5
33 ± 5
0.049
Height (m)
1.60 ± 0.06
1.60 ± 0.06
1.61 ± 0.06
1.58 ± 0.06
<0.001
Parity prior-to-index
1.0 (0.0-1.0)
1.0 (0.0-1.0)
1.0 (0.0-1.5) 1.0 (0.0-1.0)
<0.001
83 (2.4)
48 (2.0)
22 (3.0)
13 (4.5)
0.004
202 (5.9)
121 (5.1)
54 (7.3)
27 (9.4)
0.002
Pre-eclampsia
31 (0.9)
21 (0.9)
7 (1.0)
3 (1.0)
N/v
Smoking (any)
664 (19.5)
496 (20.8)
106 (14.4)
62 (21.6)
<0.001
Pre-pregnancy body
24.8 ± 4.7
24.5 ± 4.4
26.1 ± 5.6
24.7 ± 4.9
<0.001
804 (23.6)
572 (23.9)
172 (23.4)
60 (20.9)
0.549
pregnancy (N) Chronic arterial hypertension Gestational hypertension
mass index (kg/m2) Pre-pregnancy overweight (25.0-29.9 kg/m2)
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Pre-pregnancy
249 (7.3)
161 (6.7)
73 (9.9)
15 (5.2)
0.005
136 (4.0)
74 (3.1)
47 (6.4)
15 (5.2)
<0.001
27 ± 5
27 ± 5
26 ± 6
26 ± 5
0.030
5.0 ± 0.8
5.0 ± 0.8
5.2 ± 0.9
4.9 ± 0.7
<0.001
11.5 ± 1.6
11.4 ± 1.6
11.6 ± 1.6
11.6 ± 1.6
0.004
10.5 ± 1.5
10.4 ± 1.4
10.6 ± 1.7
10.6 ± 1.5
0.012
8.1 ± 1.9
8.1 ± 1.9
8.1 ± 1.9
7.9 ± 2.0
0.258
Average of 3rd
5.1 ± 0.4,
5.1 ± 0.4,
5.2 ± 0.5
5.1 ± 0.4,
<0.001
trimester HbA1cc
32 ± 3
32 ± 3
33 ± 3
32 ± 3
Gestational weight
8
8.1
8.5
7
gaind
(2-11.5)
(3-11.4)
(0-12)
(0-10.5)
obesity class I (≥30.0-34.9 kg/m2) Obesity class II (≥35 kg/m2) Gestational age at diagnosis (weeks) 100 g OGTTa fasting glycaemia (mmol/l) 100 g OGTT 1 h glycaemia 100 g OGTT 2 h glycaemia 100 g OGTT 3 h glycaemia
measures (%, mmol/mol) 0.004
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Gestational age at
39 ± 1
39 ± 1
38 ± 1
39 ± 2
<0.001
3,104 ± 534
3,055 ± 504
3633 ± 353
2,0149 ± 805
<0.001
delivery (weeks) Neonatal birthweight (g) Data are expressed as the mean ±SD, median (IQ Range) or number (%). a100 g OGTT: 100 g oral glucose tolerance test. cglycated haemoglobin A1c. P-value for the comparison of the SGA group to the AGA and LGA groups. N/v, non-valid comparison. Table 2. Neonatal complications or death in a cohort of women with gestational diabetes as a function of birthweight, as follows: adequate for gestational age (AGA), large for gestational age (LGA) and small for gestational age (SGA)
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Perinatal
All groups
AGA
LGA
SGA
P value
complicationsa
(N=3,413)
(Reference)
Hypoglycaemia
153 (4.9)
106 (4.0)
29 (10.9)
18 (7.4)
<0.001
Hypocalcaemia
13 (0.4)
10 (0.4)
1 (0.4)
2 (0.8)
N/v
Hyperbilirubinemia
221 (7.1)
167 (6.4)
21 (7.9)
33 (13.5)
<0.001
Polycythaemia
49 (1.6)
34 (1.3)
6 (2.3)
9 (3.7)
0.010
Respiratory distress
106 (3.4)
84 (3.2)
13 (4.9)
9 (3.7)
0.330
Trauma
458 (1.5)
36 (1.4)
11 (4.2)
1 (0.4)
0.001
Perinatal death
11 (0.4)
6 (0.2)
1 (0.4)
4 (1.6)
0.002
Composite of
383 (11.2)
281 (9.9)
44 (15.2)
58 (20.1)
<0.001
N (%)
complications aAt
least one of the following perinatal complications: hypoglycaemia, hypocalcaemia,
hyperbilirubinemia, polycythaemia, or perinatal death. P-value for the comparison of the SGA group to the AGA and LGA groups. N, number. N/v, non-valid comparison.
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Table 3. Stepwise forward multivariate logistic regression analyses for a composite of metabolic complications (hypoglycaemia, hypocalcaemia, hyperbilirubinemia and polycythaemia) or perinatal death in a cohort of women with gestational diabetes Risk factors
Adjusted Odds Ratioc
95% Confidence interval
P value
SGAa
2.122
1.552-2.899
<0.001
Gestational weight
0.959
0.941-0.978
0.001
1.008
1.002-1.014
0.005
gain Fasting glucoseb aSGA,
small for gestational age. bFasting glucose with the 100 g oral glucose tolerance
test used for the diagnosis of gestational diabetes. cOdds ratio adjusted for maternal age, glycaemic control (mean HbA1c level of monthly measurements), gestational hypertension, pre-eclampsia, smoking and neonate prematurity. Statistical significance if P <0.050.
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25 Highlights
The present study was conducted to examine the perinatal complications and mortality of small for gestational age (SGA) in women with gestational diabetes (GDM). Higher rates of hypoglycemia, polycythemia, hyperbilirubinemia and perinatal death were found in SGA neonates compared to large for gestational age (LGA) and normal weight neonates.
The outcomes remained similar after excluding prematurity and adjustment for age, weight gain, glycemic control, gestational hypertension, preeclampsia and tabaquism.
These results suggest a need of careful follow-up of women with GDM and SGA babies.
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Author Contributions: Author Contributions: B.B., L.H., N.M-S., C.M., N.H., and JL.B. had substantial involvement in the design of the study and critically revising the paper for important intellectual content. B.B., L.H., N.M-S., and JL.B. had substantial involvement in the drafting of the article. All authors had substantial involvement in either acquisition of data, analysis of data, or
26 interpretation of data. All authors critically revised the article for important intellectual content. All authors gave approval of this final version of the article.
27 Highlights
The present study was conducted to examine the perinatal complications and mortality of small for gestational age (SGA) in women with gestational diabetes (GDM). Higher rates of hypoglycemia, polycythemia, hyperbilirubinemia and perinatal death were found in SGA neonates compared to large for gestational age (LGA) and normal weight neonates.
The outcomes remained similar after excluding prematurity and adjustment for age, weight gain, glycemic control, gestational hypertension, preeclampsia and tabaquism.
These results suggest a need of careful follow-up of women with GDM and SGA babies.
S0168-8227(19)31372-5 https://doi.org/10.1016/j.diabres.2019.107971 DIAB 107971
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
23 September 2019 9 November 2019 29 November 2019
Please cite this article as: B. Barquiel, L. Herranz, N. Martínez-Sánchez, C. Montes, N. Hillman, J. Luis Bartha, Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes, Diabetes Research and Clinical Practice (2019), doi: https://doi.org/10.1016/j.diabres. 2019.107971
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Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes
Beatriz Barquiela, Lucrecia Herranza, Nuria Martínez-Sánchezb, Cristina Montesa, Natalia Hillmana, José Luis Barthab aDivision
of Diabetes, bDepartment of Obstetrics, a,bDiabetes and Pregnancy Unit, La Paz
University Hospital, Madrid, Spain
Corresponding author: Beatriz Barquiel Unidad de Diabetes, Hospital Universitario La Paz Paseo de la Castellana 261, CP 28046, Madrid Tel: +34 657 652 337 Fax: +34 917 691 901 E-mail: [email protected]
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Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes Beatriz Barquiel, Lucrecia Herranz, Nuria Martínez-Sánchez, Cristina Montes, Natalia Hillman, José Luis Bartha
ABSTRACT Aims: To evaluate if neonatal complications or death were poorer for neonates born small for gestational age (SGA) than for those born with adequate weight or large for gestation age (LGA) to women with gestational diabetes mellitus (GDM). Methods: Retrospective analysis of the clinical outcomes of neonates born to 3413 women with GDM. The prevalence of neonatal hypoglycaemia, hypocalcaemia, hyperbilirubinemia, polycythaemia, and death was compared among three birthweight groups: SGA, adequate, and LGA. A two-sided chi-squared or Fisher’s exact test was used for between-group comparisons. A forward multiple logistic regression was performed to determine the odds ratio (OR) associated with SGA. Results: Neonatal complications were more frequent in the SGA group (20.1%) than in the adequate (9.9%) or LGA (15.2%) groups. There were four deaths (1.6%) in the SGA group compared to one in the LGA (0.4%) and six in the adequate (0.2%) groups (P=0.002). SGA was a risk factor for neonatal complications or death (OR. 2.122; 95% confidence interval, 1.552-2.899), independent of maternal age, weight gain, fasting glucose, glycaemic control, gestational hypertension, pre-eclampsia, smoking, or neonatal prematurity.
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Conclusion: SGA birthweight is an important risk factor for neonatal complications or death among neonates born to mothers with GDM.
Keywords: gestational diabetes, neonatal outcomes, small for gestational age, large for gestational age
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INTRODUCTION Maternal gestational diabetes mellitus (GDM) is associated with a number of neonatal complications, the majority being metabolic in nature, with the most frequent being hypoglycaemia (1). Foetal hypoglycaemia normally results from foetal hyperinsulinemia due to chronic exposure to elevated maternal glucose levels. Infants born to mothers who develop GDM are often born large for gestational age (LGA). LGA itself also increases the risk for hypocalcaemia (due to the relative immaturity of the parathyroid glands), polycythaemia, hyperbilirubinemia, and even death, partly due to the increased oxygen demand to organ tissues (2,3). However, neonates of mothers with GDM can also be born small for gestational age (SGA). In mothers with GDM, two recent studies found that delivery of SGA neonates is independently associated with long-term cardiovascular offspring hospitalizations (4), but not with endocrine disorders (5). In normal pregnancies, SGA has been identified as a specific risk factor for hypoglycaemia and jaundice (6). However, it is not known if SGA associated with GDM is a risk factor for other neonatal complications. Moreover, other risk factors for neonatal complications associated with GDM include severity of hyperglycaemia at the time of diagnosis, glycaemic control, and gestational weight gain (7–9). However, few studies have examined the prevalence of neonatal complications associated with GDM, including adverse foetal outcomes, as a function of birthweight (10–12). Therefore, our aim was to assess neonatal complications associated with GDM in SGA neonates, compared with those in neonates with a normal birthweight or LGA. We also investigated if glycaemic control, severity of diabetes, or
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other related factors, such as hypertension, prematurity, or congenital malformations, further negatively impacted neonatal outcomes.
MATERIAL AND METHODS Statement of ethics The study was approved by our Hospital’s Research Ethics Committee: Comité Ético de Investigación Clínica del Hospital Universitario La Paz, code PI-1066. Study design Our retrospective analysis included only singleton pregnancies in women with GDM who were followed prospectively at La Paz University Hospital (Madrid, Spain) between 1987 and 2017 (N=3,426). GDM screening (100 g oral glucose tolerance test) was completed in all women, with the criteria of the National Diabetes Data Group used for diagnosis: fasting glycaemia, 5.8 mM; 1 h, 10.6 mM; 2 h, 9.2 mM; and 3 h, 8.1 mM. Women with concomitant pathology that could affect birthweight (such as corticosteroid treatment, glomerulonephritis, tubular acidosis nephropathy, nervous anorexia, alcoholism, congenital cardiopathy, HIV infection, HCV infection, antiphospholipid syndrome, or previous bariatric surgery) were excluded. From this initial group of 3,426 prospective mothers, 13 were excluded based on these exclusion criteria. Therefore, our analysis was based on the complete data set for 3,413 mothers with GDM.
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GDM treatment followed an established protocol (13) and remained unchanged over the study period. Treatment included implementation of a standard diet, with supportive education that included nutritional management and physical activity counselling from specialized nurses. Fasting, pre-prandial and the 2-h post-prandial capillary glucose measurements were registered every other day, from the time of GDM diagnosis to the time of delivery. Insulin treatment was initiated when two measurements of capillary fasting glycaemia were >5.3 mM and/or the 2-h post-prandial glycaemia was >6.7 mM, despite dietary treatment. Outcome and explanatory variables Our analysis included both characteristics of the neonate and of their mothers. SGA was defined by a birthweight <10th percentile, according to sex and gestational age birthweight customized percentile charts (14). LGA was defined by a birthweight >90th percentile. Blood glucose levels are monitored in neonates born to mothers with GDM at our hospital, using blood samples obtained from the heel. Neonatal glycaemia was measured if symptoms of hypoglycaemia developed within 2 h of birth. Neonatal hypoglycaemia was defined by blood glucose values <2.2 mM. Additional tests and examinations were performed, as needed, as per the standard protocol of our Pediatric Unit. Other measures obtained were defined as follows: hypocalcaemia, total serum calcium level <1.75 mM; hyperbilirubinemia, total bilirubin level >0.20 mM; polycythaemia, central venous haematocrit >65%, red blood cells >6 x 106/L, or haemoglobin >200 g/L. The presence of at least one neonatal complication (hypoglycaemia, hypocalcaemia,
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hyperbilirubinemia, polycythaemia, and/or neonatal death) was assessed. Prematurity was defined as gestational age at birth of <37 weeks. Statistical analyses Descriptive statistics were presented as percentages for categorical variables, the mean and standard deviation for continuous variables with a normal distribution, and the median and interquartile range (IQR) for continuous variables with a non-normal distribution. The incidence of maternal, neonatal complications and death were compared between the three different birthweight groups (SGA, adequate, and LGA) using ANOVA, Welch test for continuous variables and a two-sided chi-squared or Fisher’s exact test, as appropriate for the data type. Covariates that could plausibly be related to neonatal outcomes were entered into a forward stepwise multiple logistic regression model, with the effects of these factors measured using adjusted odds ratios (AORs) and related 95% confidence intervals (CIs). A P-value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS (version 20.0 for Windows; SPSS, Inc., Chicago, IL).
RESULTS Relevant characteristics of mothers and of their neonates are presented in Table 1. With regard to ethnicity, 3201 (93.8%) of the mothers were from Europe, 64 (1.9%) from North Africa, 116 (3.4%) from Latin America, and 33 (0.9%) from Indo Asia and the Pacific Islands.
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Neonates were grouped by birthweight as follows: SGA, adequate, and LGA. Neonatal complications and death were compared between these three groups; of note, 11 neonatal deaths were from unknown causes (Table 2). Forward multivariate regression analysis was performed to determine the effect of birthweight on the composite of metabolic complications (hypoglycaemia, hypocalcaemia, hyperbilirubinemia, and polycythaemia) and neonatal death, with models adjusted for maternal age, gestational weight gain, fasting glucose, glycaemic control (entered as the mean HbA1c level of monthly measurements), gestational hypertension, pre-eclampsia, and smoking, as well as for neonate prematurity (Table 3). The following factors were associated with SGA: smoking (AOR, 1.404; 95% CI, 1.0111.949; P=0.043); a pre-pregnancy body mass index <25 kg/m2 (AOR, 1.586; 95% CI, 1.1232.238; P=0.009); gestational weight gain <5 kg (AOR, 2.013; 95% CI, 1.376-2.943; P<0.001), and neonate prematurity (AOR, 3.726; 95% CI, 2.284-6.080; P<0.001). Overall, there were 180 (5.4%) premature births, with 43 (23.9%) of these being in the SGA group. On multivariate analysis, the AOR of SGA on the composite of neonatal complications or death was 2.154 (95% CI, 1.524-3.045; P<0.001) and was not significantly different when premature neonates were excluded from the SGA group. For SGA neonates, maternal gestational weight gain (kg) (AOR, 0.963; 95% CI, 0.943-0.983; P<0.001) and fasting glucose (mM; AOR, 1.008; 95% CI, 1.002-1.015; P=0.007) were also associated with the composite of neonatal complications or death. Congenital malformations were identified in 207 (6.1%) neonates, with this incidence not being greater in the SGA (13, 4.9%) than the adequate and LGA (182, 5.8%) groups (P=0.679).
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The composite of neonatal complications or death was not more frequent in neonates with congenital malformations (14, 7.2%) compared to those without malformations (368, 11.5%; P=0.065). Based on the guidelines for maternal gestational weight gain of the Institute of Medicine, maternal weight gain was dichotomized into two groups for analysis: <5 kg and ≥5 kg. One-third (30.0%) of our study sample were classified into the <5 kg group, with complications identified in 161 (15.0%) of these neonates, compared to 222 (9.4%) among those born to mothers with a gestational weight gain ≥5 kg (AOR for a gestational weight gain <5 kg, 1.599; 95% CI, 1.283-1.993; P<0.001). Regarding diabetes severity, the fasting glycaemia was ≥5.8 mM in 471 (13.7%) of women in our study group. Complications were identified in 78 (16.6%) neonates from mothers with a fasting glycaemia ≥5.8 mM, compared to 105 (10.3%) neonates from mothers with a fasting glycaemia <5.8 mM (AOR for a fasting glycaemia ≥5.8 mM, 1.644; 95% CI, 1.2492.163; P<0.001). There was an additive effect of SGA birthweight, gestational weight gain and fasting glycaemia on the occurrence of neonatal complications or death (Figure 1).
DISCUSSION Among pregnant women with GDM, the risk of hypoglycaemia, hyperbilirubinemia, polycythaemia, and neonatal death is higher in SGA neonates than in adequate weight or LGA neonates. These outcomes do not depend on glycaemic control, hypertension, or prematurity. Our results agree with those of Langer et al. (12) who reported an L-shaped
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association between birthweight and hyperbilirubinemia and a J-shaped association between birthweight and polycythaemia. A higher rate of morbidity has also been previously reported amount SGA neonates (8,9). Therefore, there is a need for specific medical attention and care for women who develop GDM in general and not only for those with LGA babies. With GDM, neonatal metabolic complications are related to foetal hyperinsulinemia and overgrowth. Foetal hyperinsulinemia causes neonatal hypoglycaemia, which is generally associated with LGA neonates (2). The metabolic demands for LGA neonates is also increased, leading to polycythaemia and subsequent hyperbilirubinemia due to an enhanced oxygen demand and the relative immaturity of the hepatic system. Of note, our study also identified a high frequency of these complications in SGA neonates. The effect of hyperglycaemia in SGA neonates is not surprising as baseline glucose has been widely associated with neonatal morbidity (9). Moreover, as foetal hyperglycaemia and insulin may alter the metabolism and gene expression in foetal tissues (15), insulin resistance would be increased in SGA foetuses, which may influence post-natal outcomes. In fact, SGA neonates are at risk for insulin resistance, obesity, metabolic syndrome, and prediabetes in early childhood (16). The frequency of SGA neonates was similar to that of LGA neonates in our study sample and was close to the estimated 11% in the general population (15). Customized birthweight curves can be useful to identify SGA neonates, with the prevalence otherwise being underestimated (17), particularly among women with GDM (6). The possibility of SGA should, therefore, be considered when making clinical decisions about GDM
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treatment, with regards to appropriate diet and the possibility of including insulin treatment (18). Our study presents novel information, not previously reported, as we considered SGA, glycaemic control, diabetes severity, maternal hypertension, and neonate prematurity simultaneously. We identified only one previous study (11) that reported a 4-fold higher rate of mortality among SGA than adequate and LGA neonates, with this risk of mortality not related to glycaemic control, prematurity, or maternal complications. In our study, we identified that maternal fasting glucose and low gestational weight gain were predicative of a higher composite of neonatal complications or death, indicating that diabetes severity and maternal malnutrition may increase the risk of neonatal death associated with SGA. This raises the possibility that SGA foetuses in women with GDM may need to be delivered early, although further studies are needed to fully clarify this issue. With regard to factors that might increase the impact of SGA on neonatal outcomes, we examined gestational weight gain, defined per the criterion of the Institute of Medicine, on the composite of neonatal complications or death (19). Low gestational weight gain has not previously been identified as a risk factor for neonatal complications among women with GDM. Lower gestational weight gain may be associated to a lower than expected neonatal growth and maturity, which is significant when we consider that maturity in these neonates is already delayed due to exposure to high levels of maternal glucose. Among women with GDM, SGA birthweight may be clinical evidence of maternal malnutrition (15) or nutritional restriction due to the diabetic condition. Specifically, maternal fasting glucose influences hyperinsulinemia and neonatal complications in
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women with GDM (7,9), particularly in those with SGA neonates. Of note, hyperinsulinemia may influence utero-placental insufficiency, which is the most common cause of an SGA birthweight. We did not find that maternal hypertension explained the composite of complications among SGA neonates born to mothers with GDM. It is possible that other factors might have influenced foetal growth restriction, including foetal, placental, and genetic factors. The main strength of our study is the large cohort of women with GDM who were prospectively followed and managed using a consistent prenatal dietary protocol, combined with insulin treatment as needed, as well as consistent post-natal care to infants. The sample size also allowed for strict selection criteria (including exclusion of known underlying diseases that can affect foetal growth) and multivariate analyses of factors that might affect foetal growth. The retrospective design also allowed us to adjust regression models for maternal characteristics that could influence neonatal outcomes. However, because of the retrospective design, effects of selection bias cannot be denied, even if data were prospectively collected; this was a limitation of this study. In conclusion, we present evidence that neonatal death or metabolic complications are more frequent among SGA neonates born to mothers with GDM than among adequate or LGA neonates. In fact, we identified a SGA birthweight as an independent factor of the composite of neonatal complications or death, regardless of maternal gestational weight gain, glucose level, and neonatal prematurity. A balanced maternal nutrition, with adequate energy supplementation and smoking cessation, may be crucial for the prevention of SGA birthweight. The prevalence of SGA should be added to the rate of LGS
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and caesarean section in future studies regarding GDM-related complications. In addition, programs for the early detection of diabetes should be implemented for mothers with a foetus experiencing a slowed growth rate. Once GDM is detected, dietary intervention and obstetric care should be implemented to lower the risk of complications associated with SGA.
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Acknowledgements We are indebted to nurses Lourdes Sáez de Ibarra, Ruth Gaspar, Montserrat Arévalo, and Silvia López who provided therapeutic education to women with gestational diabetes. No funding was received for this research. Conflicts of interest: The authors report no conflict of interests.
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Gardosi J, Mongelli M, Wilcox M, Chang A. An adjustable fetal weight standard.
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Ultrasound Obstet Gynecol 1995; 6: 168-74. 15.
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FIGURE LEGEND Figure 1. Perinatal complications or death in a cohort of women with gestational diabetes. The incidence of neonatal complications is presented as a function of birthweight, classified (from left to right) as: within normal limits (adequate, AGA), large for gestational age (LGA), and small for gestational age (SGA). Added risk factors are included in columns from left to right: there was an additive effect of low maternal gestational weight gain or high fasting glucose.
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Table 1. Characteristics of a cohort of singleton pregnant women with gestational diabetes as a function of birthweight, as follows: adequate for gestational age (AGA), large for gestational age (LGA) and small for gestational age (SGA) Characteristics
All groups
AGA
LGA
SGA
P value
Mean ± SD or N (%)
(N=3,413)
(Reference)
(N=736)
(N=287)
Age (years)
33 ± 5
33 ± 4
34 ± 5
33 ± 5
0.049
Height (m)
1.60 ± 0.06
1.60 ± 0.06
1.61 ± 0.06
1.58 ± 0.06
<0.001
Parity prior-to-index
1.0 (0.0-1.0)
1.0 (0.0-1.0)
1.0 (0.0-1.5) 1.0 (0.0-1.0)
<0.001
83 (2.4)
48 (2.0)
22 (3.0)
13 (4.5)
0.004
202 (5.9)
121 (5.1)
54 (7.3)
27 (9.4)
0.002
Pre-eclampsia
31 (0.9)
21 (0.9)
7 (1.0)
3 (1.0)
N/v
Smoking (any)
664 (19.5)
496 (20.8)
106 (14.4)
62 (21.6)
<0.001
Pre-pregnancy body
24.8 ± 4.7
24.5 ± 4.4
26.1 ± 5.6
24.7 ± 4.9
<0.001
804 (23.6)
572 (23.9)
172 (23.4)
60 (20.9)
0.549
pregnancy (N) Chronic arterial hypertension Gestational hypertension
mass index (kg/m2) Pre-pregnancy overweight (25.0-29.9 kg/m2)
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Pre-pregnancy
249 (7.3)
161 (6.7)
73 (9.9)
15 (5.2)
0.005
136 (4.0)
74 (3.1)
47 (6.4)
15 (5.2)
<0.001
27 ± 5
27 ± 5
26 ± 6
26 ± 5
0.030
5.0 ± 0.8
5.0 ± 0.8
5.2 ± 0.9
4.9 ± 0.7
<0.001
11.5 ± 1.6
11.4 ± 1.6
11.6 ± 1.6
11.6 ± 1.6
0.004
10.5 ± 1.5
10.4 ± 1.4
10.6 ± 1.7
10.6 ± 1.5
0.012
8.1 ± 1.9
8.1 ± 1.9
8.1 ± 1.9
7.9 ± 2.0
0.258
Average of 3rd
5.1 ± 0.4,
5.1 ± 0.4,
5.2 ± 0.5
5.1 ± 0.4,
<0.001
trimester HbA1cc
32 ± 3
32 ± 3
33 ± 3
32 ± 3
Gestational weight
8
8.1
8.5
7
gaind
(2-11.5)
(3-11.4)
(0-12)
(0-10.5)
obesity class I (≥30.0-34.9 kg/m2) Obesity class II (≥35 kg/m2) Gestational age at diagnosis (weeks) 100 g OGTTa fasting glycaemia (mmol/l) 100 g OGTT 1 h glycaemia 100 g OGTT 2 h glycaemia 100 g OGTT 3 h glycaemia
measures (%, mmol/mol) 0.004
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Gestational age at
39 ± 1
39 ± 1
38 ± 1
39 ± 2
<0.001
3,104 ± 534
3,055 ± 504
3633 ± 353
2,0149 ± 805
<0.001
delivery (weeks) Neonatal birthweight (g) Data are expressed as the mean ±SD, median (IQ Range) or number (%). a100 g OGTT: 100 g oral glucose tolerance test. cglycated haemoglobin A1c. P-value for the comparison of the SGA group to the AGA and LGA groups. N/v, non-valid comparison. Table 2. Neonatal complications or death in a cohort of women with gestational diabetes as a function of birthweight, as follows: adequate for gestational age (AGA), large for gestational age (LGA) and small for gestational age (SGA)
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Perinatal
All groups
AGA
LGA
SGA
P value
complicationsa
(N=3,413)
(Reference)
Hypoglycaemia
153 (4.9)
106 (4.0)
29 (10.9)
18 (7.4)
<0.001
Hypocalcaemia
13 (0.4)
10 (0.4)
1 (0.4)
2 (0.8)
N/v
Hyperbilirubinemia
221 (7.1)
167 (6.4)
21 (7.9)
33 (13.5)
<0.001
Polycythaemia
49 (1.6)
34 (1.3)
6 (2.3)
9 (3.7)
0.010
Respiratory distress
106 (3.4)
84 (3.2)
13 (4.9)
9 (3.7)
0.330
Trauma
458 (1.5)
36 (1.4)
11 (4.2)
1 (0.4)
0.001
Perinatal death
11 (0.4)
6 (0.2)
1 (0.4)
4 (1.6)
0.002
Composite of
383 (11.2)
281 (9.9)
44 (15.2)
58 (20.1)
<0.001
N (%)
complications aAt
least one of the following perinatal complications: hypoglycaemia, hypocalcaemia,
hyperbilirubinemia, polycythaemia, or perinatal death. P-value for the comparison of the SGA group to the AGA and LGA groups. N, number. N/v, non-valid comparison.
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Table 3. Stepwise forward multivariate logistic regression analyses for a composite of metabolic complications (hypoglycaemia, hypocalcaemia, hyperbilirubinemia and polycythaemia) or perinatal death in a cohort of women with gestational diabetes Risk factors
Adjusted Odds Ratioc
95% Confidence interval
P value
SGAa
2.122
1.552-2.899
<0.001
Gestational weight
0.959
0.941-0.978
0.001
1.008
1.002-1.014
0.005
gain Fasting glucoseb aSGA,
small for gestational age. bFasting glucose with the 100 g oral glucose tolerance
test used for the diagnosis of gestational diabetes. cOdds ratio adjusted for maternal age, glycaemic control (mean HbA1c level of monthly measurements), gestational hypertension, pre-eclampsia, smoking and neonate prematurity. Statistical significance if P <0.050.
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25 Highlights
The present study was conducted to examine the perinatal complications and mortality of small for gestational age (SGA) in women with gestational diabetes (GDM). Higher rates of hypoglycemia, polycythemia, hyperbilirubinemia and perinatal death were found in SGA neonates compared to large for gestational age (LGA) and normal weight neonates.
The outcomes remained similar after excluding prematurity and adjustment for age, weight gain, glycemic control, gestational hypertension, preeclampsia and tabaquism.
These results suggest a need of careful follow-up of women with GDM and SGA babies.
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Author Contributions: Author Contributions: B.B., L.H., N.M-S., C.M., N.H., and JL.B. had substantial involvement in the design of the study and critically revising the paper for important intellectual content. B.B., L.H., N.M-S., and JL.B. had substantial involvement in the drafting of the article. All authors had substantial involvement in either acquisition of data, analysis of data, or
26 interpretation of data. All authors critically revised the article for important intellectual content. All authors gave approval of this final version of the article.
27 Highlights
The present study was conducted to examine the perinatal complications and mortality of small for gestational age (SGA) in women with gestational diabetes (GDM). Higher rates of hypoglycemia, polycythemia, hyperbilirubinemia and perinatal death were found in SGA neonates compared to large for gestational age (LGA) and normal weight neonates.
The outcomes remained similar after excluding prematurity and adjustment for age, weight gain, glycemic control, gestational hypertension, preeclampsia and tabaquism.
These results suggest a need of careful follow-up of women with GDM and SGA babies.