Gestational Diabetes and Perinatal Outcomes: 5-Year Neonatal Intensive Care Experience

GDM is a disturbance of glucose tolerance that manifests or is diagnosed during pregnancy for the first time. Although the actual incidence is unknown, the reported rates vary between 1% and 14% in the literature [1,2]. Although there are limited number of studies on GDM in Turkey, the prevalence has been reported between 1, 2% and 30, 8% [3,4]. It is one of the most important causes of increased morbidity and perinatal mortality for both mother and baby. It is responsible for 1, 1-14, 3% of serious complications observed in the fetus and the newborn [5].

The diagnosis of GDM was made based on the results of oral glucose tolerance test, according to the recommendations of National Diabetes Data Group (NDDG) [6]. Premature rupture of membranes (PROM) was defined as rupture of chorioamniotic membranes and release of amniotic fluid prior to initiation of labor, regardless of the gestational age.
Regardless of their birth weight, babies who were born before 37th gestational age was defined as premature infants. Classification for LGA was made using the Lubchenko growth curve [7]. Those who were over the 90th percentile according to the gestational week were classified as LGA babies. Birth weight above 4000 g was defined as macrosomia [8].
Transient tachypnea of the newborn (TTN) was defined as respiratory distress occurring in term or near-term babies, emerging within 4-6 hours of delivery, which generally resolved within 3 days. Respiratory Distress Syndrome (RDS) was defined as tachypnea, chest wall retractions and cyanosis with room air, showing persistence or progression for the initial 48-96 hours, together with characteristic reticulogranular appearance and air bronchograms in the chest X-ray. Hypoglycemia was defined as blood glucose level below 47mg/dL [9]. Patients' bilirubin levels were evaluated according to Bhutani nomogram, and hyperbilirubinemia was defined as an indirect bilirubin level that required treatment according to recommendations of American Academy of Pediatrics [10,11].
Hypocalcemia was defined as total calcium level below 7 mg/ dL in the blood sample. Those mothers and infants who were detected to have hypocalcemia were tested for 25 (OH) vitamin D levels. 25(OH)D level below 20 ng/mL was accepted as vitamin D deficiency, while levels below 5 ng/mL was accepted as severe vitamin D deficiency. CRP level above 0.5 mg/dL was accepted as pathological. Frequency and descriptive statistics were expressed as mean±standard deviation and percentage.

Results
Totally 3263 patients were admitted to NICU between July, 31st 2012 and July, 31st 2017. Among these, 180 (5.5%) were born to mothers with GDM. Of these babies, 119 (66.1%) were male, and 61 (33.9%) were female. 151 (83.8%) were term-infants, while 29 (16.2%) were preterm infants. Mean hospital stay length was 8.6±1.4 days, and mean Apgar score at 5 th minute was 8.7±1. 9   The most frequent indication for admission of the newborns to NICU was TTN in 114 (63.3%) patients, followed by TTN+sepsis in 27 (15%) patients, and sepsis in 19 (10.5%) patients. Other indications for admission were RDS in 5 (2.7%) patients, feeding problem in 3 (1.6%) patients, hyperbilirubineia in 3 (1.6%) patients, asphyxia in 2 (1.1%) patients, meconium aspiration in 1 (0.5%) patient, congenital malformation in 1 (0.5%) patient, convulsion in 1 (0.5%) patient, and bilateral choanal atresia in 1 (0.5%) patient. In terms of complications associated with birth trauma, 1 case had Erb's palsy, and 1 patient had Klumpke's paralysis. Three patients had pes equinovarus, and 1 patient had spina bifida. Forty six patients required mechanical ventilation. develop any complications. The case who had spina bifida was referred to neurosurery. The patient who was admitted due to TTN was detected to have Down syndrome after chromosomal analysis. The case with multiple congenital anomalies had atrial septal defect (ASD) detected in echocardiography, and died on the 24 th day (Table 3). The most common metabolic disorder was hypocalcemia, which was observed in 49 (27.2%) patients. A total of 42 (23.3%) patients had 25 (OH) vitamin D deficiencies, and 25 (OH) vitamin D deficiency was severe in 18 of them. Other metabolic disorders were hypoglycemia detected in 21 patients, hyponatremia in 9 patients, hyperbilirubinemia in 8 patients, hyperkalemia in 7 patients, hyperglycemia in 3 patients, thrombocytopenia in 2 patients, and polycytemia in 1 patient. Totally 51 patients were examined with echocardiography. Eight of these patients had normal echocardioagraphic findings. The most common cardiac defect observed in echocardiography was PFO in 23 (12.7%) patients, followed by ASD in 11 (6.1%) patients, thin PDA (patent ductus arteriosus) in 3 (1.6%) patients, ASD±VSD (ventricular septal defect) in 2 (1.1%) patients, persistent pulmonary hypertension (PPH) in 2 (1.1%) patients, and PDA in 1 (0.5%) patient. The patient with PPH showed improvement with sildenafil treatment. One of the twins with RDS+PDA, who was born premature at 30th gestational week was administered ibuprofen treatment, and PDA was closed, but the case was referred to an external center due to development of intracranial hemorrhage on the 3 rd day. The case died in the external center on 10 th day (Table 4).
USG examination of the cases showed renal pelviectasis in 13 patients (bilateral in 4, left in 7, and right in 2 patients), hydronephrosis in 10 patients (left in 9 patients, and right in 1 patient), multiple renal cysts in 1 patient, sponge kidney in 1 patient, left hepatic cystic lesion in 1 patient, gallbladder stone in 1 patient, and ectopic kidney in 1 patient.

Discussion
According to the 1979 definition by NDDG, GDM is a disturbance of glucose tolerance that manifests or is diagnosed during pregnancy for the first time [6]. Human placental lactogen (HPL) hormone, which is released from the placenta in response to insulin densitization caused by the physiological increase in blood glucose level particularly in the second and third trimester of pregnancy, plays role in development of GDM. In addition, increased estrogen, progesterone, growth hormone, and cortisone also contribute in the insulin resistance [12,13]. Insulin sensitivity is decreased by 50%, while insulin release is increased by 50% [14].
Among the complications of GDM, macrosomia is the most renowned. The high amounts of maternal glucose passing through the placenta stimulates fetal insulin secretion, leading to increased growth factors and macrosomia. Macrosomia is particularly responsible for increased frequency of Caesarean section or difficult labor, and for predisposing to clavicular fracture, Erb's palys and asphyxia. Because of all these complications, Caesarean section is preferred in women with GDM even though blood glucose level was well-regulated. The prevalence of macrosomia is 7-9% in the non-diabetic population, whereas this rate has been reported up to 16-45% in case of GDM [15][16][17][18]. A study from Switzerland including 3322 mothers with GDM reported macrosomia as the most important cause of morbidity associated with birth trauma and asphyxia, and found 1.6 folds increase in the rate of emergency Cesarean sections and 2 folds increase in preeclampsia rate. The same study reported that macrosomia, asphyxia and TTN rates were 2 to 3 times higher than the rate of Erb's paralysis [19]. Ghosh studied 58 mothers with GDM, and found the rate of Cesarean section as 60.3% [20].
In our study, 145 patients (80.5%) were born with Cesarean section, and the rate was higher than the rates reported in literature. The numbers were high due to macrosomia+ elective Cesarean sections, since the study was conducted in a private hospital. Since the elective Cesarean section deliveries were not recorded properly, we could not obtain the exact number of elective Caesarean sections, but we specified the total number of Cesarean sections instead.
Babies born to mothers with GDM have increased risk of hyperbilirubinemia, neonatal hypoglycemia, hyperglycemia, intrauterine sudden fetal death, intrauterine growth retardation (IUGR), preterm delivery, RDS, polycytemia, hypomagnesemia, learning disabilities, obesity at childhood, and future type II diabetes development [21]. In their study from a tertiary hospital including 136 patients with an average gestational age of 37 weeks (29% GDM, 40% type 2 diabetes), Watson et al. found hypocalcemia in 51% of patients, and respiratory distress in 40% of patients [22]. In their study including 91 cases, of which 78 were born to mothers with GDM and 13 were born to diabetic mothers, Turkmen et al. Among babies born to diabetic mothers, cardiovascular malformations were observed in a rate of 3%, and obstructive and shunted cardiac defects were detected in a rate of 1.4% [25,26]. In our study, 43 of a total of 51 patients were detected to have cardiac defects. The most frequently detected cardiac defect was PFO observed in 23 (12.7%) patients, followed by ASD observed in 11 (6.1%) patients. Turkmen et al. found congenital heart defects in 12.8% of babies born to mothers with GDM, most common of which was ASD [23].
Maternal complications of GDM include preeclampsia, type II diabetes, urinary tract-vaginal infections, metabolic disturbances, progression of diabetic vasculopathies, spontaneous abortion, preterm labor, polyhydramniosis, postpartum endometritis, wound site infection and increased maternal mortality risk [21]. A study including 220 Saudian mothers with GDM found hypertension in 18.2%, preterm delivery in 11.4%, polyhydramniosis in 3.2%, and oligohydramniosis in 2,7% of women [27]. In the present study, we detected preterm delivery in 29 (16.1%) patients, urinary tract infections in 10 (5.5%) patients, hypertension in 6 (3.3%) patients, PROM in 3 (1.6%) patients, oligohydramniosis in 4 (2.2%) patients, and polyhydramniosis in 2 (1.1%) patients. Congenital malformations are also related with maternal age, number of deliveries, history of GDM, and glycemic parameters as well. The prevalence of minor and major congenital malformations among babies born to mothers with GDM were reported as 6%, and 3.8%, respectively [28,29]. We detected congenital malformations in 5.5% of our patients (pes equinovarus in 3 patients, bilateral choanal atresia in 1 patient, spina bifida in 1 patient, Down syndrome in 1 patient, multiple anomalies in 1 patient, multiple renal cysts in 1 patient, sponge kidney in 1 patient, and hepatic cystic lesion at left in 1 patient).
The rate of admission to NICU among babies born to mothers with GDM was 5, 5%. Mean hospital stay length was 8.6±1.4 days, and mean 5 th minute Apgar score was 8.7±1.9. The study including 220 Saudian mothers with GDM found the rate of admission for longer than 24 hours as 16.4%, and did not find significant difference regarding Apgar 5 th minute score. The authors attributed the high admission rates to their routine policies, which required monitoring of babies even though there were no problems detected [27]. Another study reported NICU admission rate as 28.7% [21]. The reason why we had lower admission rate in the present study was that admissions were not for the purpose of monitoring, but only in case of a medical indication.

Conclusion
In conclusion, due to its fetal and maternal complications, GDM is a metabolic disturbance which should be given as much importance as diabetes. The rate of fetal loss and morbidity is 2-4 times higher compared to normal pregnancies. In addition to the associated increase in the risk of GDM, vitamin D deficiency also poses risk for the newborn. For this reason, in addition to metabolic follow-up, we recommend assessment of vitamin D status particularly before pregnancy.