EHD-03950; No of Pages 4 Early Human Development xxx (2014) xxx–xxx
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Does gestational diabetes mellitus affect respiratory outcome in late-preterm infants? G.P.G. Fung a,⁎, L.M. Chan a, Y.C. Ho a, W.K. To b, H.B. Chan a, T.T. Lao c a b c
Department of Paediatrics and Adolescent Medicine, United Christian Hospital, Hong Kong Department of Obstetrics and Gynaecology, United Christian Hospital, Hong Kong Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, Hong Kong
a r t i c l e
i n f o
Article history: Received 18 January 2014 Received in revised form 6 April 2014 Accepted 8 April 2014 Available online xxxx Keywords: Respiratory distress Neonatal outcome Diabetes mellitus Late preterm Preterm infant Chinese
a b s t r a c t Background: Both gestational diabetes mellitus (GDM) and late-preterm delivery at 34–36 weeks' gestation are independently associated with neonatal respiratory complications, but it is unknown whether their combination increases further its risk. We therefore appraised the independent effect of GDM on the respiratory outcome of late-preterm infants. Methods: In a retrospective cohort study, respiratory outcome of 911 infants delivered at 34–36 weeks' gestation between 1 January 2009 and 30 August 2012 from mothers with GDM (study group, n = 130) was compared with infants delivered at the same gestation by mothers without GDM (control group, n = 781). Results: The study group had significantly higher incidence of transient tachypnoea of newborn (TTN, p = 0.02) and air leak (p = 0.012), and required more respiratory support, including oxygen, continuous positive airway pressure (CPAP), mechanical ventilation and neonatal intensive care, with a longer length of hospital stay, but not duration on respiratory support. On logistic regression analysis, GDM is an independent risk factor for TTN (aOR = 1.5, 95% C.I.1.0–2.4), CPAP (aOR = 2.37, 95% C.I. 1.05–4.89), mechanical ventilation (aOR = 4.02 95% C.I. 1.57–10.32) and neonatal intensive care (aOR 1.83, 95% C.I. 1.05–3.87). Conclusions: Our results demonstrated an independent effect of GDM on the risk of severe respiratory complications in late-preterm infants. Additional close monitoring and timely intervention are necessary in the management of these infants. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Of all the perinatal complications associated with gestational diabetes mellitus (GDM), neonatal respiratory complications are one of the commonest and potentially the most serious and life-threatening morbidity that may be encountered [1,2]. Globally, the incidence of respiratory complications in infants of mothers with GDM is as high as 34%, with a 4–6% incidence of respiratory distress syndrome (RDS) [3]. The risk of transient tachypnoea of newborn (TTN) is also increased 2–3 times compared to infants delivered from non-diabetic pregnancies [3,4]. In the Chinese population in Hong Kong, there is a 3.4-fold overall increased risk of neonatal respiratory complications for infants from diabetic pregnancies compared to controls [5]. GDM is also associated with increased late-preterm delivery [6–8], with up to 22% infants from mothers with GDM delivering between 340/7–366/7 weeks' gestation [1,3]. There is now abundant evidence that neonates delivered at 34–36 weeks are at increased risk of neonatal complications, leading
⁎ Corresponding author. Tel.: +852 9469 8094. E-mail address: [email protected] (G.P.G. Fung).
to significant morbidity and mortality [9–14]. One large epidemiological study has shown that compared to term infants at 39 weeks, the adjusted odds ratio (aOR) for RDS at 34 weeks was 40.1 and that for TTN was 14.7; at 35 weeks, 21.9 and 11.1; and at 36 weeks, 9.1 and 6.1; respectively [15]. Therefore, an increase in late-preterm births could also have contributed to the higher rate of neonatal respiratory complications associated with GDM. Although it is well-established that both GDM and late-prematurity are risk factors for respiratory morbidity, no reported studies have targeted neonatal outcome of GDM in late-preterm deliveries. It is not known whether GDM confers any independent and additional risk for respiratory morbidity in late-preterm infants. A recent study [16] showed that maternal GDM and late-prematurity are independent risk factors for severe neonatal respiratory morbidities requiring neonatal intensive unit (NICU) care. However, the effect of GDM together with late-prematurity, and the risk of less severe morbidities which nevertheless required interventions, were not investigated. This retrospective cohort study was therefore conducted to examine the additional impact of GDM on respiratory outcome of late-preterm infants. Our results will provide information from the neonatal perspective to facilitate obstetric decision-making in pregnancies complicated by GDM, and to enhance
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Please cite this article as: Fung GPG, et al, Does gestational diabetes mellitus affect respiratory outcome in late-preterm infants? Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.006
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neonatal management for infants from GDM pregnancies delivered at the 34–36 week period. 2. Materials and methods Our hospital is a tertiary referral centre with an annual delivery rate of N 5000. Gestational age was determined by the last menstrual period and verified by first trimester dating ultrasonography, with further confirmation by Ballad score assessment [17] by neonatologist after delivery. Universal screening for GDM has been adopted in our centre. Women with known risk factors for GDM would undergo the oral glucose tolerance test (OGTT) at 24 weeks and repeated 8 weeks later if the first test was normal. For normal risk women, a random venous blood glucose testing is performed at 24 weeks. Women with random glucose level of 6 mmol/L or above, irrespective of the time of last meal, would be further assessed by the WHO 75 g OGTT [18]. Those with results falling into either impaired glucose tolerance (IGT), or diabetes mellitus, are all managed as GDM. Monitoring of glycaemic control and subsequent management of these mothers conforms to internationally accepted guidelines. Paediatricians are called to standby at delivery for resuscitation of high risk infants. All late-preterm infants, irrespective of maternal diagnosis, are admitted to the neonatal unit for monitoring of vital signs and blood glucose. Appropriate treatment is given where necessary. The maternal and neonatal diagnoses are coded under the ICD system and entered into a computer database. Both obstetric and neonatal data such as maternal and neonatal demographics, maternal illnesses, pregnancy and intrapartum complications; neonatal diagnoses and procedures, neonatal unit admission, and length of hospital stay are captured and entered by obstetricians and neonatologists. This is a retrospective cohort study covering the period 1 January 2009 to 30 August 2012 and included all liveborn infants delivered at the gestation of 340/7 to 366/7 weeks. Infants born to mothers with a diagnosis of GDM or pre-existing DM constituted the study group. The control group consists of the late-preterm infants from all nondiabetic pregnancies. Infants with major congenital malformations, chromosomal abnormalities, anatomical defects affecting lung development, and stillbirths were excluded from the analysis. Both obstetric and neonatal data retrieved from the aforementioned electronic database, including the neonatal diagnoses coding (ICD-9), and electronic inpatient discharge summaries for each infant were reviewed by the principal investigator. Where there was discrepancy between coding and electronic discharge summary, or missing data, hard copies of the case notes were retrieved for verification to ensure accurate data collection. Ethics approval for the study was obtained from the local Ethics Committee. The period reviewed for each case was from the time of delivery until discharge from hospital or death. For analysis, respiratory complications were compared between the two groups. RDS, TTN and pneumonia are defined by characteristic chest radiographic changes together with typical clinical course for the condition. Air leak was defined as pneumothorax or pneumomediastinum on chest radiograph. Persistent pulmonary hypertension of newborn (PPHN) was defined as intrapulmonary shunting as evidenced by significant pre/post-ductal SpO2 difference and confirmed by echocardiogram. Apnoea was defined by cessation of respiration for N20 s associated with desaturation and/or bradycardia. Infants were also compared according to the intervention or treatment required, including oxygen therapy, defined as need for oxygen supplement for over 4 h; continuous positive airway pressure (CPAP); and mechanical ventilation, defined as need for intubation and any form of mechanical ventilation for over 4 h. Another measure of intervention included admission to neonatal intensive care unit (NICU) for over 12 h. The duration of each intervention as well as the length of stay was also examined. Statistical analysis was performed using the SPSS 20.0 software (SPSS Inc, Chicago, IL). Categorical data were compared using the
Chi-square test or Fisher Exact test (for cells less than 5), and odds ratio (OR) with 95% confidence interval (C.I.) was calculated. Continuous variables were compared using the independent t test or Mann–Whitney U test. Multivariate logistic regression was used to determine the effect of maternal GDM on neonatal outcome parameters. A two-sided p-value of ≤ 0.05 is considered significant. 3. Results During the study period, there were a total of 929 livebirths delivered between 340/7 to 366/7 weeks, giving an overall incidence of late preterm birth of 4.78%. Of the 929 infants, 18(1.9%) were excluded because of major congenital anomalies, chromosomal abnormalities, and incomplete data, including 3 neonatal deaths related to major congenital anomalies (one with diaphragmatic hernia, one with omphalocoele and one with pulmonary hypoplasia). Among the remaining 911 infants in the final cohort, 130 (14.3%) were in the study group. There was a significantly higher maternal age (33.8 ± 4.2 vs 30.4 ± 5.4 years, p b 0.001), and total Caesarean section rate (43.3% vs 32.7%, p = 0.02) as well as elective Caesarean rate (10.7% vs 4.8%, p = 0.006) in the study group (Table 1). It was not the hospital protocol to give antenatal steroids routinely after 34 weeks' gestation, but a significantly higher percentage of the mothers in the study group had received antenatal steroids (10% vs 4.6%, p = 0.001). As for respiratory complications, only TTN (OR 1.46, 95% C.I. 1.09– 1.97) and air leak (OR 18.3, 95% C.I. 1.89–177.1) were significantly increased in the study group, while the incidences of RDS, apnoea, pneumonia and PPHN were similar between the two groups (Table 2). Admission to NICU was increased in the study group (OR 2.11, 95% CI 1.28–3.49), together with a longer length of stay (4 days vs 2 days, p = 0.047). Significantly more infants in the study group required respiratory support in terms of oxygen therapy (OR 1.81, 95% CI 1.11– 2.25), CPAP (OR 2.18, 95% CI 1.45–3.29), and mechanical ventilation (OR 3.11, 95% CI 1.30–7.42), but the duration of intervention was similar between the two groups (Table 3). To determine the independent effect of maternal GDM on respiratory complications, multivariate logistic regression analysis was performed after adjustment for gender, advanced maternal age, SGA, Table 1 Maternal and neonatal demographic features of late-preterm infants with and without GDM.
Maternal age (yrs)* Nulliparas (%) Hypertensive diseases (%)a Antepartum haemorrhage (%) Other diseases (%)b Antenatal steroids (%) Tocolytics (%) Labour induction (%) Caesarean delivery (%) Elective Caesarean (%) Gestation (wks)* Male (%) Birth weight (g)* LGA (%) SGA (%) Congenital anomalies (%)c
GDM (n = 130)
Non-GDM (n = 781)
p-Value
33.8 ± 4.2 45.4 12.3 5.4 7.7 10 0.8 6.2 43.0 10.7 35.3 ± 0.8 47.7 2470 ± 524 4.6 10 5.4
30.4 ± 5.4 53.1 9.9 9.1 3.7 4.6 1.0 9.0 32.7 4.6 35.4 ± 0.8 56.2 2525 ± 429 3.8 9.2 4.5
b0.005 0.11 0.43 0.18 0.06 0.01 NS 0.32 0.02 0.006 0.36 0.09 0.25 0.81 0.87 0.32
Analysis by chi square test or t-test as indicated *. Key: LGA = large for gestation, defined as birth weight N 2 s.d. above mean for gestation. SGA = small for gestation, defined as birth weight b 2 s.d. below mean for gestation. APH = antepartum haemorrhage. a Includes maternal hypertensive disorders in pregnancy (pre-exisiting hypertension, pregnancy induced hypertension, PET and eclampsia). b Includes maternal co-existing diseases other than hypertension (eg cardiac, thyroid, autoimmune diseases). c Includes all minor congenital anomalies. Major congenital anomalies and chromosomal disorders are already excluded from the study.
Please cite this article as: Fung GPG, et al, Does gestational diabetes mellitus affect respiratory outcome in late-preterm infants? Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.006
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Table 2 Univariate analysis of respiratory outcome of late-preterm infants with GDM.
Diagnosis
TTN RDS Apnoea Pneumonia* PPHN* Air leak* NICU admission
Study group (n = 130)
Comparison group (n = 781)
p-Value
Odds ratio (95% C.I.)
30.0 0.8 6.9 0 0.8 2.3 18.3
20.0 1.4 4.2 0.6 0.1 0.4 9.6
0.02 0.56 0.18 0.36 0.15 0.012 0.003
1.46 (1.09–1.97) 0.55 (0.07–4.10) 1.63 (0.80–3.34) NS 6.0 (0.37–94.53) 18.3 (1.89–177.1) 2.11 (1.28–3.49)
Analysis by chi-square test and Fisher Exact test as indicated by *.
steroid in late-preterm pregnancies deemed at higher risk for RDS, but this did not appear to have any impact on logistic regression analysis. In the literature, no added benefit for antenatal steroids administered after 34 weeks' gestation was shown [29–33]. However, most studies have not examined specifically the impact of GDM in addition to prematurity, so that some investigators [16] have raised the question of whether steroids might still play a role in late-preterm delivery when GDM is present. Our finding that the incidence of RDS was not significantly different when the effect of antenatal steroid was adjusted for in late-preterm infants born to mothers with GDM supports the opinion that infants of diabetic mothers with good glycaemic control have similar lung maturation as infants from non-diabetic mothers [34,35]. However, because of small numbers, the impact of antenatal steroids in this particular group cannot be generalized. A significant increase in incidence of air leak for the study group was found in the univariate analysis but not supported in the multivariate analysis. Nevertheless, our study group had a significantly higher NICU admission rate, as well as increased requirement for respiratory support of all entities. Infants from the GDM group have longer length of stay compared to controls, which could have been due to a higher incidence of other coexisting complications (glycaemic control, infection, jaundice) thus requiring a longer period of observation or treatment. As this study concentrates mainly on respiratory aspects, other neonatal complications were not studied. As the need for intervention is a measure of disease severity, our results suggested that neonates from pregnancies complicated by GDM were more prone to increased severity rather than frequency of respiratory complications, thus warranting higher levels of support. However, when the duration of various respiratory support was compared, there was no difference between the two groups, which suggested that these neonates improved quickly with appropriate intervention, so prolonged support was usually not necessary. The result of this study helps to elucidate the hitherto unanswered but clinically important question of the impact of GDM on respiratory complications in late-preterm infants in a population with high prevalence of GDM. While the study is limited by its retrospective nature, all the mothers and infants were managed in one centre covering a large catchment area with population of over 1 million that is highly representative of the general population of the territory, with standard and uniform treatment protocols, so that bias due to differing practices was avoided. In addition, the major confounding effect of gestational age is limited as the study and comparison groups were of comparable
Caesarean section, and use of antenatal steroids. GDM is confirmed to be an independent risk factor for TTN (aOR 1.50, 95% C.I. 1.01–2.41), need for CPAP (aOR 2.37, 95% C.I. 1.19–4.89), mechanical ventilation (aOR 4.02, 95% C.I. 1.57–10.32) and NICU admission (aOR 1.83, 95% C.I. 1.05–3.19). (Table 4.) 4. Discussion Maternal GDM occurs in 4–14% of pregnancies [19], with higher prevalence in Asians [20,21]. In Hong Kong, the prevalence was 10.3% in the general obstetric population with universal screening [22]. Worldwide, the number of women with GDM is on a rising trend, due to increasing prevalence of obesity and Type II DM [23]. Meanwhile, the incidence of late-preterm birth has increased markedly over the past decade, accounting for up to 9% of deliveries in some countries [24]. In Hong Kong, the incidence of spontaneous labour between 35–36 weeks is 2.4% to 3.8% [25], and the incidence of late-preterm (34–36 weeks) delivery varied between 2.4% and 3.8% according to fetal gender [26]. As GDM would predispose to either spontaneous or iatrogenic preterm delivery, an increasing incidence of late-preterm deliveries from diabetic pregnancies is likely to be encountered in clinical practice. This leads to questions on the need or otherwise of delaying delivery or deferring obstetric intervention beyond 34–36 weeks, as well as the approach to management of these preterm infants, and implications on resources. Our study showed that maternal GDM accounted for 14.3% of our late-preterm live births, and increased the risk of TTN but not RDS in these infants. The pathophysiology of TTN is due to delayed reabsorption of pulmonary fluid by epithelial sodium channels [27,28] which is deficient in late-preterm infants [28]. Although most cases of TTN resolve spontaneously, the infant's condition may deteriorate with the development of respiratory failure if not intervened in time. In this study, no infant developed severe detrimental sequelae from TTN because of early, effective respiratory management. Close monitoring after delivery is thus necessary, as TTN is encountered in almost one third of the study group and one fifth of the control group. This should be taken into account in future NICU capacity planning. On the other hand, the incidence of RDS was very low (0.76% in the study group and 1.4% in the comparison group) in this study. A significantly higher proportion of infants from the GDM group received antenatal steroids, which may reflect lower thresholds in our obstetricians for prescribing Table 3 Univariate analysis of intervention and treatment duration of late preterm infants with GDM.
Admission to neonatal unit (NICU and SCBU) Intervention (may have N1 for each infant)
Duration of treatment
Length of stay in NICU (days)* Total length of hospital stay (days)* O2 therapy (%) CPAP (%) Mech ventilation (%) O2 * CPAP* Ventilation*
Study group (n = 130)
Comparison group (n = 781)
p-Value
2.5 (10.0–27.0) 4.0 0–132.0) 19.1 15.4 6.1 1.0 (0.5–30.0) 1.0(0.5–10.0) 1.5 (0.5–6.0)
1.0 (0.5–78.0) 2.0 (0–150.0) 11.5 6.4 2.0 1.0 (0.5–14.0) 1.0 (0.5–6.0) 1.0 (0.5–10.0)
0.45 0.047 0.016 0.003 0.007 0.29 0.53 0.67
Odds ratio (95% C.I.)
1.81 (1.11–2.25) 2.18 (1.45–3.29) 3.11 (1.30–7.42)
Analysis by Chi square test and Mann–Whitney U test as indicated by *.
Please cite this article as: Fung GPG, et al, Does gestational diabetes mellitus affect respiratory outcome in late-preterm infants? Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.006
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Table 4 Multiple logistic regression analysis on the independent effect of GDM with adverse respiratory outcome.
TTNa RDSa Air leaka NICU admissionb Mechanical ventilationb CPAPb O2 therapyb
p value
aOR (95% C.I.)
0.05 0.86 0.10 0.04 0.004 0.02 0.30
1.50 (1.01–2.41) 0.83 (0.10–6.87) 12.01 (0.61–238.47) 1.83 (1.05–3.19) 4.02 (1.57–10.32) 2.37 (1.15–4.89) 1.42 (0.72–2.8)
a Adjusted for gender, advanced maternal age, mode of delivery (Caesarean section), small-for-gestation and antenatal steroids. b Adjusted for gender, advanced maternal age, mode of delivery (Caesarean section), small-for-gestation, antenatal steroids, TTN, RDS and air leak.
gestation. Our results concur with the latest (2013) guideline from the American College of Obstetrics and Gynecology [36], which recommends that late-preterm delivery is not indicated in GDM pregnancies if good glycaemic control is achieved, and that the pregnancy is otherwise uncomplicated. For complicated cases, management should be individualized. Therefore, obstetricians need to consider the risks and benefits of delivery for every individual case in order to avoid unnecessary preterm birth, whilst ensuring optimal maternal and fetal outcome. In view of the increased incidences of respiratory complications, latepreterm neonates from GDM pregnancies need to be closely monitored. Early recognition and timely intervention of respiratory problems is essential to prevent the neonate from going into a vicious cycle of deterioration which may lead to significant morbidity. As a significantly higher proportion of these neonates require assisted ventilation, facilities and manpower for respiratory support should be available at the delivery hospital. Otherwise, stabilization and transitional care in preparation for transferal to a higher level centre should be considered. Good communication between obstetricians and neonatologists; and between perinatal centres, plays a key role in the eventual provision of optimal care to these infants. 5. Conclusion In conclusion, our results have shown that GDM increases not only the risk of TTN, but also the requirement of O2, CPAP, mechanical ventilation and NICU care in late-preterm infants. Nevertheless, satisfactory neonatal outcome can be expected with timely and appropriate intervention. For pregnancies complicated by GDM, preterm delivery should be avoided in uncomplicated cases, while careful evaluation should be given for medically-indicated deliveries at 340/7 to 366/7. The infant needs to be closely monitored in a centre with readily available facilities for stabilization, respiratory and NICU support. The resource implications of the neonatal management of late-preterm infants from mothers with GDM, and decisions on use of antenatal steroids, timing and mode of delivery, warrant further studies. Conflict of interest The authors declare no conflict of interest. References [1] Weindling AM. Offspring of diabetic pregnancy: short-term outcome. Semin Fetal Neonatal Med 2009;14:111–8. [2] The HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002.
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Please cite this article as: Fung GPG, et al, Does gestational diabetes mellitus affect respiratory outcome in late-preterm infants? Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.006
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Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Does gestational diabetes mellitus affect respiratory outcome in late-preterm infants? G.P.G. Fung a,⁎, L.M. Chan a, Y.C. Ho a, W.K. To b, H.B. Chan a, T.T. Lao c a b c
Department of Paediatrics and Adolescent Medicine, United Christian Hospital, Hong Kong Department of Obstetrics and Gynaecology, United Christian Hospital, Hong Kong Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, Hong Kong
a r t i c l e
i n f o
Article history: Received 18 January 2014 Received in revised form 6 April 2014 Accepted 8 April 2014 Available online xxxx Keywords: Respiratory distress Neonatal outcome Diabetes mellitus Late preterm Preterm infant Chinese
a b s t r a c t Background: Both gestational diabetes mellitus (GDM) and late-preterm delivery at 34–36 weeks' gestation are independently associated with neonatal respiratory complications, but it is unknown whether their combination increases further its risk. We therefore appraised the independent effect of GDM on the respiratory outcome of late-preterm infants. Methods: In a retrospective cohort study, respiratory outcome of 911 infants delivered at 34–36 weeks' gestation between 1 January 2009 and 30 August 2012 from mothers with GDM (study group, n = 130) was compared with infants delivered at the same gestation by mothers without GDM (control group, n = 781). Results: The study group had significantly higher incidence of transient tachypnoea of newborn (TTN, p = 0.02) and air leak (p = 0.012), and required more respiratory support, including oxygen, continuous positive airway pressure (CPAP), mechanical ventilation and neonatal intensive care, with a longer length of hospital stay, but not duration on respiratory support. On logistic regression analysis, GDM is an independent risk factor for TTN (aOR = 1.5, 95% C.I.1.0–2.4), CPAP (aOR = 2.37, 95% C.I. 1.05–4.89), mechanical ventilation (aOR = 4.02 95% C.I. 1.57–10.32) and neonatal intensive care (aOR 1.83, 95% C.I. 1.05–3.87). Conclusions: Our results demonstrated an independent effect of GDM on the risk of severe respiratory complications in late-preterm infants. Additional close monitoring and timely intervention are necessary in the management of these infants. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Of all the perinatal complications associated with gestational diabetes mellitus (GDM), neonatal respiratory complications are one of the commonest and potentially the most serious and life-threatening morbidity that may be encountered [1,2]. Globally, the incidence of respiratory complications in infants of mothers with GDM is as high as 34%, with a 4–6% incidence of respiratory distress syndrome (RDS) [3]. The risk of transient tachypnoea of newborn (TTN) is also increased 2–3 times compared to infants delivered from non-diabetic pregnancies [3,4]. In the Chinese population in Hong Kong, there is a 3.4-fold overall increased risk of neonatal respiratory complications for infants from diabetic pregnancies compared to controls [5]. GDM is also associated with increased late-preterm delivery [6–8], with up to 22% infants from mothers with GDM delivering between 340/7–366/7 weeks' gestation [1,3]. There is now abundant evidence that neonates delivered at 34–36 weeks are at increased risk of neonatal complications, leading
⁎ Corresponding author. Tel.: +852 9469 8094. E-mail address: [email protected] (G.P.G. Fung).
to significant morbidity and mortality [9–14]. One large epidemiological study has shown that compared to term infants at 39 weeks, the adjusted odds ratio (aOR) for RDS at 34 weeks was 40.1 and that for TTN was 14.7; at 35 weeks, 21.9 and 11.1; and at 36 weeks, 9.1 and 6.1; respectively [15]. Therefore, an increase in late-preterm births could also have contributed to the higher rate of neonatal respiratory complications associated with GDM. Although it is well-established that both GDM and late-prematurity are risk factors for respiratory morbidity, no reported studies have targeted neonatal outcome of GDM in late-preterm deliveries. It is not known whether GDM confers any independent and additional risk for respiratory morbidity in late-preterm infants. A recent study [16] showed that maternal GDM and late-prematurity are independent risk factors for severe neonatal respiratory morbidities requiring neonatal intensive unit (NICU) care. However, the effect of GDM together with late-prematurity, and the risk of less severe morbidities which nevertheless required interventions, were not investigated. This retrospective cohort study was therefore conducted to examine the additional impact of GDM on respiratory outcome of late-preterm infants. Our results will provide information from the neonatal perspective to facilitate obstetric decision-making in pregnancies complicated by GDM, and to enhance
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Please cite this article as: Fung GPG, et al, Does gestational diabetes mellitus affect respiratory outcome in late-preterm infants? Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.006
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neonatal management for infants from GDM pregnancies delivered at the 34–36 week period. 2. Materials and methods Our hospital is a tertiary referral centre with an annual delivery rate of N 5000. Gestational age was determined by the last menstrual period and verified by first trimester dating ultrasonography, with further confirmation by Ballad score assessment [17] by neonatologist after delivery. Universal screening for GDM has been adopted in our centre. Women with known risk factors for GDM would undergo the oral glucose tolerance test (OGTT) at 24 weeks and repeated 8 weeks later if the first test was normal. For normal risk women, a random venous blood glucose testing is performed at 24 weeks. Women with random glucose level of 6 mmol/L or above, irrespective of the time of last meal, would be further assessed by the WHO 75 g OGTT [18]. Those with results falling into either impaired glucose tolerance (IGT), or diabetes mellitus, are all managed as GDM. Monitoring of glycaemic control and subsequent management of these mothers conforms to internationally accepted guidelines. Paediatricians are called to standby at delivery for resuscitation of high risk infants. All late-preterm infants, irrespective of maternal diagnosis, are admitted to the neonatal unit for monitoring of vital signs and blood glucose. Appropriate treatment is given where necessary. The maternal and neonatal diagnoses are coded under the ICD system and entered into a computer database. Both obstetric and neonatal data such as maternal and neonatal demographics, maternal illnesses, pregnancy and intrapartum complications; neonatal diagnoses and procedures, neonatal unit admission, and length of hospital stay are captured and entered by obstetricians and neonatologists. This is a retrospective cohort study covering the period 1 January 2009 to 30 August 2012 and included all liveborn infants delivered at the gestation of 340/7 to 366/7 weeks. Infants born to mothers with a diagnosis of GDM or pre-existing DM constituted the study group. The control group consists of the late-preterm infants from all nondiabetic pregnancies. Infants with major congenital malformations, chromosomal abnormalities, anatomical defects affecting lung development, and stillbirths were excluded from the analysis. Both obstetric and neonatal data retrieved from the aforementioned electronic database, including the neonatal diagnoses coding (ICD-9), and electronic inpatient discharge summaries for each infant were reviewed by the principal investigator. Where there was discrepancy between coding and electronic discharge summary, or missing data, hard copies of the case notes were retrieved for verification to ensure accurate data collection. Ethics approval for the study was obtained from the local Ethics Committee. The period reviewed for each case was from the time of delivery until discharge from hospital or death. For analysis, respiratory complications were compared between the two groups. RDS, TTN and pneumonia are defined by characteristic chest radiographic changes together with typical clinical course for the condition. Air leak was defined as pneumothorax or pneumomediastinum on chest radiograph. Persistent pulmonary hypertension of newborn (PPHN) was defined as intrapulmonary shunting as evidenced by significant pre/post-ductal SpO2 difference and confirmed by echocardiogram. Apnoea was defined by cessation of respiration for N20 s associated with desaturation and/or bradycardia. Infants were also compared according to the intervention or treatment required, including oxygen therapy, defined as need for oxygen supplement for over 4 h; continuous positive airway pressure (CPAP); and mechanical ventilation, defined as need for intubation and any form of mechanical ventilation for over 4 h. Another measure of intervention included admission to neonatal intensive care unit (NICU) for over 12 h. The duration of each intervention as well as the length of stay was also examined. Statistical analysis was performed using the SPSS 20.0 software (SPSS Inc, Chicago, IL). Categorical data were compared using the
Chi-square test or Fisher Exact test (for cells less than 5), and odds ratio (OR) with 95% confidence interval (C.I.) was calculated. Continuous variables were compared using the independent t test or Mann–Whitney U test. Multivariate logistic regression was used to determine the effect of maternal GDM on neonatal outcome parameters. A two-sided p-value of ≤ 0.05 is considered significant. 3. Results During the study period, there were a total of 929 livebirths delivered between 340/7 to 366/7 weeks, giving an overall incidence of late preterm birth of 4.78%. Of the 929 infants, 18(1.9%) were excluded because of major congenital anomalies, chromosomal abnormalities, and incomplete data, including 3 neonatal deaths related to major congenital anomalies (one with diaphragmatic hernia, one with omphalocoele and one with pulmonary hypoplasia). Among the remaining 911 infants in the final cohort, 130 (14.3%) were in the study group. There was a significantly higher maternal age (33.8 ± 4.2 vs 30.4 ± 5.4 years, p b 0.001), and total Caesarean section rate (43.3% vs 32.7%, p = 0.02) as well as elective Caesarean rate (10.7% vs 4.8%, p = 0.006) in the study group (Table 1). It was not the hospital protocol to give antenatal steroids routinely after 34 weeks' gestation, but a significantly higher percentage of the mothers in the study group had received antenatal steroids (10% vs 4.6%, p = 0.001). As for respiratory complications, only TTN (OR 1.46, 95% C.I. 1.09– 1.97) and air leak (OR 18.3, 95% C.I. 1.89–177.1) were significantly increased in the study group, while the incidences of RDS, apnoea, pneumonia and PPHN were similar between the two groups (Table 2). Admission to NICU was increased in the study group (OR 2.11, 95% CI 1.28–3.49), together with a longer length of stay (4 days vs 2 days, p = 0.047). Significantly more infants in the study group required respiratory support in terms of oxygen therapy (OR 1.81, 95% CI 1.11– 2.25), CPAP (OR 2.18, 95% CI 1.45–3.29), and mechanical ventilation (OR 3.11, 95% CI 1.30–7.42), but the duration of intervention was similar between the two groups (Table 3). To determine the independent effect of maternal GDM on respiratory complications, multivariate logistic regression analysis was performed after adjustment for gender, advanced maternal age, SGA, Table 1 Maternal and neonatal demographic features of late-preterm infants with and without GDM.
Maternal age (yrs)* Nulliparas (%) Hypertensive diseases (%)a Antepartum haemorrhage (%) Other diseases (%)b Antenatal steroids (%) Tocolytics (%) Labour induction (%) Caesarean delivery (%) Elective Caesarean (%) Gestation (wks)* Male (%) Birth weight (g)* LGA (%) SGA (%) Congenital anomalies (%)c
GDM (n = 130)
Non-GDM (n = 781)
p-Value
33.8 ± 4.2 45.4 12.3 5.4 7.7 10 0.8 6.2 43.0 10.7 35.3 ± 0.8 47.7 2470 ± 524 4.6 10 5.4
30.4 ± 5.4 53.1 9.9 9.1 3.7 4.6 1.0 9.0 32.7 4.6 35.4 ± 0.8 56.2 2525 ± 429 3.8 9.2 4.5
b0.005 0.11 0.43 0.18 0.06 0.01 NS 0.32 0.02 0.006 0.36 0.09 0.25 0.81 0.87 0.32
Analysis by chi square test or t-test as indicated *. Key: LGA = large for gestation, defined as birth weight N 2 s.d. above mean for gestation. SGA = small for gestation, defined as birth weight b 2 s.d. below mean for gestation. APH = antepartum haemorrhage. a Includes maternal hypertensive disorders in pregnancy (pre-exisiting hypertension, pregnancy induced hypertension, PET and eclampsia). b Includes maternal co-existing diseases other than hypertension (eg cardiac, thyroid, autoimmune diseases). c Includes all minor congenital anomalies. Major congenital anomalies and chromosomal disorders are already excluded from the study.
Please cite this article as: Fung GPG, et al, Does gestational diabetes mellitus affect respiratory outcome in late-preterm infants? Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.006
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Table 2 Univariate analysis of respiratory outcome of late-preterm infants with GDM.
Diagnosis
TTN RDS Apnoea Pneumonia* PPHN* Air leak* NICU admission
Study group (n = 130)
Comparison group (n = 781)
p-Value
Odds ratio (95% C.I.)
30.0 0.8 6.9 0 0.8 2.3 18.3
20.0 1.4 4.2 0.6 0.1 0.4 9.6
0.02 0.56 0.18 0.36 0.15 0.012 0.003
1.46 (1.09–1.97) 0.55 (0.07–4.10) 1.63 (0.80–3.34) NS 6.0 (0.37–94.53) 18.3 (1.89–177.1) 2.11 (1.28–3.49)
Analysis by chi-square test and Fisher Exact test as indicated by *.
steroid in late-preterm pregnancies deemed at higher risk for RDS, but this did not appear to have any impact on logistic regression analysis. In the literature, no added benefit for antenatal steroids administered after 34 weeks' gestation was shown [29–33]. However, most studies have not examined specifically the impact of GDM in addition to prematurity, so that some investigators [16] have raised the question of whether steroids might still play a role in late-preterm delivery when GDM is present. Our finding that the incidence of RDS was not significantly different when the effect of antenatal steroid was adjusted for in late-preterm infants born to mothers with GDM supports the opinion that infants of diabetic mothers with good glycaemic control have similar lung maturation as infants from non-diabetic mothers [34,35]. However, because of small numbers, the impact of antenatal steroids in this particular group cannot be generalized. A significant increase in incidence of air leak for the study group was found in the univariate analysis but not supported in the multivariate analysis. Nevertheless, our study group had a significantly higher NICU admission rate, as well as increased requirement for respiratory support of all entities. Infants from the GDM group have longer length of stay compared to controls, which could have been due to a higher incidence of other coexisting complications (glycaemic control, infection, jaundice) thus requiring a longer period of observation or treatment. As this study concentrates mainly on respiratory aspects, other neonatal complications were not studied. As the need for intervention is a measure of disease severity, our results suggested that neonates from pregnancies complicated by GDM were more prone to increased severity rather than frequency of respiratory complications, thus warranting higher levels of support. However, when the duration of various respiratory support was compared, there was no difference between the two groups, which suggested that these neonates improved quickly with appropriate intervention, so prolonged support was usually not necessary. The result of this study helps to elucidate the hitherto unanswered but clinically important question of the impact of GDM on respiratory complications in late-preterm infants in a population with high prevalence of GDM. While the study is limited by its retrospective nature, all the mothers and infants were managed in one centre covering a large catchment area with population of over 1 million that is highly representative of the general population of the territory, with standard and uniform treatment protocols, so that bias due to differing practices was avoided. In addition, the major confounding effect of gestational age is limited as the study and comparison groups were of comparable
Caesarean section, and use of antenatal steroids. GDM is confirmed to be an independent risk factor for TTN (aOR 1.50, 95% C.I. 1.01–2.41), need for CPAP (aOR 2.37, 95% C.I. 1.19–4.89), mechanical ventilation (aOR 4.02, 95% C.I. 1.57–10.32) and NICU admission (aOR 1.83, 95% C.I. 1.05–3.19). (Table 4.) 4. Discussion Maternal GDM occurs in 4–14% of pregnancies [19], with higher prevalence in Asians [20,21]. In Hong Kong, the prevalence was 10.3% in the general obstetric population with universal screening [22]. Worldwide, the number of women with GDM is on a rising trend, due to increasing prevalence of obesity and Type II DM [23]. Meanwhile, the incidence of late-preterm birth has increased markedly over the past decade, accounting for up to 9% of deliveries in some countries [24]. In Hong Kong, the incidence of spontaneous labour between 35–36 weeks is 2.4% to 3.8% [25], and the incidence of late-preterm (34–36 weeks) delivery varied between 2.4% and 3.8% according to fetal gender [26]. As GDM would predispose to either spontaneous or iatrogenic preterm delivery, an increasing incidence of late-preterm deliveries from diabetic pregnancies is likely to be encountered in clinical practice. This leads to questions on the need or otherwise of delaying delivery or deferring obstetric intervention beyond 34–36 weeks, as well as the approach to management of these preterm infants, and implications on resources. Our study showed that maternal GDM accounted for 14.3% of our late-preterm live births, and increased the risk of TTN but not RDS in these infants. The pathophysiology of TTN is due to delayed reabsorption of pulmonary fluid by epithelial sodium channels [27,28] which is deficient in late-preterm infants [28]. Although most cases of TTN resolve spontaneously, the infant's condition may deteriorate with the development of respiratory failure if not intervened in time. In this study, no infant developed severe detrimental sequelae from TTN because of early, effective respiratory management. Close monitoring after delivery is thus necessary, as TTN is encountered in almost one third of the study group and one fifth of the control group. This should be taken into account in future NICU capacity planning. On the other hand, the incidence of RDS was very low (0.76% in the study group and 1.4% in the comparison group) in this study. A significantly higher proportion of infants from the GDM group received antenatal steroids, which may reflect lower thresholds in our obstetricians for prescribing Table 3 Univariate analysis of intervention and treatment duration of late preterm infants with GDM.
Admission to neonatal unit (NICU and SCBU) Intervention (may have N1 for each infant)
Duration of treatment
Length of stay in NICU (days)* Total length of hospital stay (days)* O2 therapy (%) CPAP (%) Mech ventilation (%) O2 * CPAP* Ventilation*
Study group (n = 130)
Comparison group (n = 781)
p-Value
2.5 (10.0–27.0) 4.0 0–132.0) 19.1 15.4 6.1 1.0 (0.5–30.0) 1.0(0.5–10.0) 1.5 (0.5–6.0)
1.0 (0.5–78.0) 2.0 (0–150.0) 11.5 6.4 2.0 1.0 (0.5–14.0) 1.0 (0.5–6.0) 1.0 (0.5–10.0)
0.45 0.047 0.016 0.003 0.007 0.29 0.53 0.67
Odds ratio (95% C.I.)
1.81 (1.11–2.25) 2.18 (1.45–3.29) 3.11 (1.30–7.42)
Analysis by Chi square test and Mann–Whitney U test as indicated by *.
Please cite this article as: Fung GPG, et al, Does gestational diabetes mellitus affect respiratory outcome in late-preterm infants? Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.006
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Table 4 Multiple logistic regression analysis on the independent effect of GDM with adverse respiratory outcome.
TTNa RDSa Air leaka NICU admissionb Mechanical ventilationb CPAPb O2 therapyb
p value
aOR (95% C.I.)
0.05 0.86 0.10 0.04 0.004 0.02 0.30
1.50 (1.01–2.41) 0.83 (0.10–6.87) 12.01 (0.61–238.47) 1.83 (1.05–3.19) 4.02 (1.57–10.32) 2.37 (1.15–4.89) 1.42 (0.72–2.8)
a Adjusted for gender, advanced maternal age, mode of delivery (Caesarean section), small-for-gestation and antenatal steroids. b Adjusted for gender, advanced maternal age, mode of delivery (Caesarean section), small-for-gestation, antenatal steroids, TTN, RDS and air leak.
gestation. Our results concur with the latest (2013) guideline from the American College of Obstetrics and Gynecology [36], which recommends that late-preterm delivery is not indicated in GDM pregnancies if good glycaemic control is achieved, and that the pregnancy is otherwise uncomplicated. For complicated cases, management should be individualized. Therefore, obstetricians need to consider the risks and benefits of delivery for every individual case in order to avoid unnecessary preterm birth, whilst ensuring optimal maternal and fetal outcome. In view of the increased incidences of respiratory complications, latepreterm neonates from GDM pregnancies need to be closely monitored. Early recognition and timely intervention of respiratory problems is essential to prevent the neonate from going into a vicious cycle of deterioration which may lead to significant morbidity. As a significantly higher proportion of these neonates require assisted ventilation, facilities and manpower for respiratory support should be available at the delivery hospital. Otherwise, stabilization and transitional care in preparation for transferal to a higher level centre should be considered. Good communication between obstetricians and neonatologists; and between perinatal centres, plays a key role in the eventual provision of optimal care to these infants. 5. Conclusion In conclusion, our results have shown that GDM increases not only the risk of TTN, but also the requirement of O2, CPAP, mechanical ventilation and NICU care in late-preterm infants. Nevertheless, satisfactory neonatal outcome can be expected with timely and appropriate intervention. For pregnancies complicated by GDM, preterm delivery should be avoided in uncomplicated cases, while careful evaluation should be given for medically-indicated deliveries at 340/7 to 366/7. The infant needs to be closely monitored in a centre with readily available facilities for stabilization, respiratory and NICU support. The resource implications of the neonatal management of late-preterm infants from mothers with GDM, and decisions on use of antenatal steroids, timing and mode of delivery, warrant further studies. Conflict of interest The authors declare no conflict of interest. References [1] Weindling AM. Offspring of diabetic pregnancy: short-term outcome. Semin Fetal Neonatal Med 2009;14:111–8. [2] The HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002.
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