Short-Term Implications and Management
Francis B. Mimouni, MD
Galit Mimouni Sheffer, MD
Dror Mandel, MD
One cool judgment is worth a dozen hasty councils. The thing to do is to supply light and not heat.
—Woodrow Wilson
Key Points
• Early growth delay, major congenital malformations, and abortions are related to periconceptional and first trimester poor glycemic control, while minor congenital malformations are related to poor second trimester glycemic control.
• Macrosomia may be associated with significant obstetrical morbidity such as shoulder dystocia, which may result in severe birth trauma.
• Poor glycemic control in late pregnancy is a significant risk factor for fetal distress and neonatal asphyxia; a team of professionals (physicians, neonatal nurse practitioners, midwives, and/or respiratory therapists) trained in the pediatric management of complicated deliveries should be present in the delivery room.
• Glucose monitoring should be initiated as soon as possible after birth, within 2 hours and before feeding, or at any time in which there are abnormal signs. Whenever possible, early enteral feeding should be instituted. Serum calcium and magnesium concentrations should be measured at their physiologic nadir (24 hours of age), while screening for polycythemia should be performed at 2-4 hours of age.
• The differential diagnosis of respiratory symptoms in an infant of diabetic mother should include transient tachypnea of the newborn, respiratory distress syndrome, and asymmetric septal hypertrophy.
INTRODUCTION
In spite of the tremendous improvements in prenatal care and the management of diabetes during pregnancy, the perinatal survival rate of infants of diabetic mothers (IDMs) is still not identical to that of infants of nondiabetic mothers and significant morbidities are still observed.1 Specifically, the perinatal complications can be traced to inadequate glycemic control during key periods of the pregnancy.1 For instance, poor glycemic control in the per- iconceptional period and the early first trimester are predictive of spontaneous abortions, early growth delay, and major congenital malformations.1 Poor glycemic control during the second trimester of pregnancy is highly predictive of the development of pregnancy-induced hypertension (PIH) and its complications, preterm labor, and all the complications of premature delivery as well as the development of minor congenital anomalies.1 Poor glycemic control during the third trimester of pregnancy is highly predictive of macrosomia and its associated complications of birth trauma, fetal dystocia, and maternal trauma and high cesarean delivery rate1 (Figure 9-1). It is also predictive of the complications linked to fetal hyperinsulinism such as neonatal hypoglycemia, respiratory distress, and cardiac septal hypertrophy1 (see Figure 9-1). Also, poor glycemic control during the third trimester of pregnancy is linked to disturbed fetal oxygenation that may express itself through neonatal depression, fetal distress in labor, and the worst cases of fetal or neonatal death2 (see Figure 9-1). Finally, hyperglycemia in labor aggravates the risk of neonatal hypoglycemia and is associated with lowered Apgar scores.2,3 Thus, there is no period during the diabetic pregnancy that allows for inadequate glycemic control, which in all cases bares the risk of being highly consequential. This chapter will review the aforementioned neonatal complications of pregnancy in diabetes and their management.
THE PATHOPHYSIOLOGY OF NEONATAL COMPLICATIONS IN THE IDM
Early Growth Delay, Major Congenital Malformations, and Abortions
Pedersen was the first to theorize that the fetus of the diabetic mother is hyperglycemic whenever the mother is hyperglycemic.4 His theory has been verified in both humans and multiple animal models. Interestingly, it appears that the consequences of embryonic or early fetal (<16-20 weeks) hyperglycemia are strikingly different from those of later hyperglycemia (>20 weeks).5 Indeed, prior to 16-20 weeks, while the fetal pancreas is capable of synthesizing and secreting insulin, it does not do so in response to glucose stimulus.6 Thus, during early pregnancy, fetal hyperglycemia is not accompanied by fetal hyperinsulinism.7 As shown by Freinkel et al.,8 elevated sugar concentration in the culture medium is highly toxic to cell growth, which may be a significant contributing factor for the early growth delay observed when poor glycemic control occurs early in pregnancy.5 When present, this early growth delay is highly predictive of congenital malforma- tions.9 In fact HbAlc values at 14 weeks gestation <7% indicate a low risk of congenital anomalies, but when HbAlc rises from 7%-8.5%, the risk increases to 5%, rising to 22% when HbAlc exceeds 10%.10,11 Malformations and abortions may be significantly linked in that severe major malformations may not be compatible with intrauterine life and may lead to embryonic or early fetal death.12 In the past few years, there has been a better understanding about the teratogenic effect of hyperglycemia. It appears that in the early stages of embryogenesis, embryonic structures express glucose transporters, but because the placenta is not yet present, they develop under relatively hypoxic conditions (8%- 12% oxygen compared to 21% in the maternal circulation).13 Hyperglycemia combined to environmental hypoxemia lead to increased production of reactive oxygen species (ROS) and subsequent AMP-dependent protein kinase (AMPK) activation.14 In turn, AMPK and ROS lead to decreased PAX3 gene expression.15 Decreased PAX3 gene expression leads to a loss of control of p53 protein with subsequent increase in apoptosis.15 Other factors than hyperglycemia that may also contribute to malformations include maternal-fetal hyperketonemia16 and maternal magnesium (Mg) depletion, also linked to poor glycemic control.17 The infant of the diabetic mother is at an increased risk for all known kinds of major malformations. However, some of them may be particularly suggestive of maternal diabetes. For instance, the caudal regression syndrome, an extremely rare malformation, is seen almost exclusively in these infants.18
It is unclear whether the so-called small left colon syndrome (SLCS) should be classified among the malformations found in IDMs.19,20 Clearly, in most cases, SLCS is transient and resolves on its own, precluding the true definition of malformation. In this entity, mostly seen in IDMs, the infants present with delayed evacuation of meconium, abdominal distension, and at times with vomiting. Abdominal X-rays are those of low intestinal obstruction, with nonspecific gaseous distention of the gut. If performed, barium enema reveals a uniformly narrowed colon from the splenic flexure.20
Minor congenital malformations are also more frequent in the IDM than in the general population.21 Interestingly, the presence of minor congenital malformations has been linked to poor glycemic control in the second trimester of pregnancy, that is at a time when major organs have already been formed, precluding the occurrence of a major malformation.21 Since gestational diabetes is mostly a disease of the second half of pregnancy, one should not expect an increase in the rate of malformations in the products of pregnancies complicated by gestational diabetes. Surprisingly, there is epidemiologic evidence that this may not hold true, and major congenital malformations in pregnancies complicated by gestational diabetes appear to be related to prepregnancy body mass index (BMI).22
MACROSOMIA AND ITS CONSEQUENCES
During the second half of pregnancy, maternal fetal hyperglycemia leads to pancreatic β-cell hyperplasia, which responds to hyperglycemia with an increased insulin production.4 The combination of hyperglycemia and hyperinsulinism has several consequences: the first one is enhanced growth, which may culminate in significant macrosomia.23 Both fetal weight and placental weight tend to increase.24 This macrosomia is not only due to increased fat stores but also is linked to significant visceromegaly, in particular that of the liver, the spleen,, and the heart. Visceromegaly is not only due to organ hypertrophy and may also be due to increased fat storage, such as evidenced in the liver of such infants.25 The head size is typically not increased, thus during vaginal deliveries a typical complication of maternal diabetes is shoulder dystocia, which may lead to significant fetal trauma (clavicular or humeral fracture and Erb’s palsy), maternal trauma, and high cesarean delivery rates.23-26 Consistent with Pedersen’s hypothesis, body composition is normal in term infants born to mothers with well-controlled gestational diabetes mellitus.27 Moreover, the risk for macrosomia is clearly increased with increasing maternal BMI.28 Importantly, the risk of macrosomia may not only be affected by the metabolic imbalance of diabetes but also appears to be affected by ethnic- ity29 (higher risk of macrosomia in African American and Asian neonates at any given level of maternal BMI) and by gender.30,31 Indeed, gender determines the actions of adiponectin multimers on fetal growth and adiposity,30 and the magnitude of the reduction of a newborn’s birth weight percentile and neonatal fat mass related to the treatment of mild gestational diabetes mellitus appear greater for male neonates.31 An exception to Pedersen’s model is that a small subgroup of IDMs is affected by growth restriction. This group of small-for-gestational-age (SGA) infants generally belongs to mothers with advanced diabetic class, with significant vascular disease, often resulting in maternal hypertension, reduced uterine and placental blood flow, and compromised nutrient and oxygen delivery to the fetus.32 Importantly, in obese women who undergo bariatric surgery, fetal growth is affected in such a manner that the risk of macrosomia is lowered two to three times and the risk of SGA infants is two to three times higher than in a matched group of women without bariatric surgery.33 The impact on SGA infants is even higher in the subgroup with gastric bypass.33
IMPAIRED FETAL OXYGENATION: PATHOPHYSIOLOGY
In pregnancy complicated by poorly controlled diabetes, there is both decreased oxygen supply to the fetus and increased oxygen consumption by the feto-placental unit, and both may contribute to fetal hypoxemia. Indeed, fetal oxygen supply may be reduced by a decrease in placental blood flow by as much as 35%-50%,34 which may be aggravated by severe vascular disease.34 In diabetic ketoacidosis, maternal hypovolemia and acidosis may further reduce placental blood flow.35 In addition, the increased affinity of glycosylated hemoglobin (HbA1c) to O2 may be contributory to decreased O2 maternal-fetal transfer. It has been calculated that an increase in HbA1c of 1% of the total hemoglobin may cause a decrease in the P50 of approximately 0.3 mm Hg.36-38 Also, in ketoacidosis, the detrimental effect on oxygen release due to a decrease in 2,3-DPG is counteracted by a lower plasma pH (Bohr effect).38 However, during the recovery period, plasma pH is corrected within hours, while 2,3-DPG values remain low for days. A subsequent left shift of the oxygen dissociation curve occurs, which may have a significant, deleterious impact on oxygen release.38 Furthermore, in pregnancy complicated by diabetes, placental oxygen transfer may be affected by additional factors such as a reduction of the villous surface area due to an increase in incidence of fetal artery throm- bosis39 and an increase in the diffusion distance, due to thickened basement membrane (as demonstrated by electron microscopy40 or by the frequent appearance of villous edema39).
Enhanced placental-fetal oxygen consumption may also cause fetal hypoxemia. Several animal models have shown that chronic (1 week) fetal hyperglycemia,41-43 acute (within hours) maternal44 and fetal hyperketonemia,45 acute maternal ketoaci- demia,46 and fetal hyperinsulinemia47-49 or alloxan-induced maternal diabetes50 lead to fetal hypoxemia and acidosis. The prevalent theory behind these findings is that in the presence of extra fuels or of hyperinsulinemia, the metabolic rate of the placenta increases together with the oxygen consumption rate depriving the fetus of oxygen.51 Hay et al. demonstrated using the fetal lamb model that insulin promotes the entry of glucose, thereby increasing glucose utilization and oxidation rates.48,49 Finally, prolonged labor due to fetal dystocia,22,23 a consequence of fetal macrosomia,2,22 has the potential to create an additional hypoxic stress to the fetus, as well as the development of PIH.51
CLINICAL CONSEQUENCES OF FETAL HYPOXEMIA IN DIABETES
There is a wide range of clinical consequences, from the feared “sudden” intrauterine death, to mild neonatal depression at birth. After the introduction of insulin in 1921, diabetic women became pregnant at increasing rates, but perinatal mortality was very high and remained so until the 1950s, where it still was about 20%. Nearly half of the deaths occurred antenatally.52 Before 36 weeks gestation, most intrauterine fetal deaths (IUFDs) were associated with diabetic ketoacidosis, while after 36 weeks, IUFDs were often unexplained and somewhat sudden. The series by Kitzmiller et al. and Tyson and Hock, published in the late 1970s, still revealed evidence of intrapartum distress, low Apgar scores, or both in 25% and 28% of infants, respectively.52,53
A large study published by our group in the late 1980s concurred with the aforementioned findings (26.7%).2 However, in our study, intensive fetal monitoring in late pregnancy combined with relatively strict goals of glycemic control enabled us to limit fetal distress in time and/or intensity in most cases and to maintain low Apgar scores into the mild range of neonatal asphyxia.2 In our series of 162 deliveries, there were only 2 IUFDs, which were attributed to very poor glycemic control, the presence of preeclampsia, and the mother’s failure to comply with the prescribed tests of fetal surveillance.2 In our study, when the infants with low Apgar scores and/or fetal distress were compared to the control (“nonasphyxiated” infants), mothers in the “asphyxiated” group had new-onset nephropathy during pregnancy more often and were regularly affected by preterm labor.2 There were no significant differences between the two groups in “long-term” glycemic control (as assessed by measurements of hemoglobin A1c); however, mothers in the asphyxiated group had more frequent hyperglycemia (>150 mg/dL) in labor.2
POLYCYTHEMIA AND HYPERBILIRUBINEMIA
Chronic fetal hypoxia leads to an increase in the production of fetal erythropoietin43 and is probably the principal explanation for the increased rates of polycythemia in IDMs.
In the study by Widness et al.,54 mean maternal HbA1c during the last month of pregnancy correlated significantly with fetal umbilical venous erythropoietin at delivery; amniotic fluid glucose and amniotic fluid insulin also correlated with umbilical venous erythropoietin.54 We showed that maternal concentrations of HbA1c at the time of delivery correlate with neonatal hematocrit at birth.55 Moreover, neonatal polycythemia is six times more recurrent in IDMs than in appropriately matched controls56 with circulating nucleated red blood cells strikingly elevated in IDMs compared to controls.56,57 The latter finding is also true in infants of gestational diabetic mothers58 and in large-for-gestational-age infants born to nondiabetic mothers.59 In our study of perinatal asphyxia in IDMs, “asphyxiated” infants had higher nucleated red blood cell values (an index of chronic hypoxia) than con- trols.2 However, even in infants born without perinatal asphyxia, the mean nucleated red blood cell number was still very high, in comparison with a group of normal infants born to mothers without diabetes.2 There is recent evidence that amniotic fluid oxidative and nitrosative stress biomarkers correlate with fetal chronic hypoxia in diabetic pregnancies.60
The fetal erythropoietic response to hypoxia may occur at the expense of other bone marrow line cells, since IDMs have decreased platelet counts that correlate inversely with the circulating nucleated red blood cell counts.61 Finally, the increased demands for erythropoiesis may deplete iron stores in the fetus of the diabetic mother who at birth has decreased blood iron and ferritin concentrations and elevated transferrin and free erythrocyte protoporphyrin concentrations.62-64 Moreover, it has been suggested that the increase in red blood cell mass and the increased erythropoietic rate (including ineffective erythropoiesis) may play a role in the neonatal hyperbilirubinemia frequently observed in IDMs.3,65 Conversely, we showed that IDMs delivered by cesarean section have lower hematocrits and rates of hyperbilirubinemia than those delivered vaginally.3
NEONATAL HYPOGLYCEMIA: PATHOPHYSIOLOGY
From clinical experience, neonatal hypoglycemia in IDMs is probably the most frequent complication of diabetes during pregnancy. The exact incidence of neonatal hypoglycemia is, however, extremely difficult to assess, in particular because of the multiple definitions used to describe it66 and because its occurrence is highly affected by the degree of maternal glycemic control.1 Nevertheless, IDMs often have a rapid fall in the concentration of blood sugar in the immediate postnatal period.3 This decline differs in its pattern, both in terms of speed and depth, from the physiologic decrease of blood sugar observed in normal infants.67-70 The pathophysiology of hypoglycemia in IDMs can be, for the most part, viewed in the general context of Pedersen’s hypothesis.4 Indeed, hyperinsulinemia (presumably caused by maternal hyperglycemia) has been reported in umbilical cord plasma of IDMs71 as well as in amniotic fluid obtained during diabetic pregnancies.72 Hyperinsulinism of IDMs is apparently linked to maternal hyperglycemia during the third trimester of pregnancy since the frequency of neonatal hypoglycemia, as well as the cord blood concentrations of C-peptide, correlate with maternal gly- cohemoglobin concentrations at delivery71 and is modulated by maternal glycemia in labor.3 The importance of the availability of alternate fuels in the hypoglycemia of IDMs should not be underestimated, as the gluconeogenetic response to hypoglycemia appears to be blunted. Their blood concentrations of fatty acids are reduced,73,74 plasma concentrations of ketones are no different than those of nonhypoglycemic controls,74 and blood concentrations of plasma amino acids are little, if any, affected by hypoglycemia.75,76 A reduced postnatal glucagon surge appears to accompany the hyperinsulinism.77 Thus, it appears that IDMs are, in terms of energy metabolism, in double jeopardy because of frequent decreases in plasma glucose and a relative lack of adequate gluconeogenetic response. Moreover, other risk factors for hypoglycemia exist in the IDM. First, neonatal asphyxia may aggravate hypoglycemia, due to increased glucose demands during anaerobic metabolism.77 Hypoglycemic IDMs have lower umbilical cord pH than their nonhypoglycemic counterpart.78 Also, neonatal polycythemia is a known cause of refractory hypoglycemia, presumably because of increased glucose utilization by the red blood cell mass.79 We showed that polycythemic IDMs have rates of hypoglycemia three times higher than nonpolycythemic IDMs.56
DEFINITION AND CLINICAL SIGNIFICANCE
The definition of neonatal hypoglycemia is a matter of great controversy. Many reports have arbitrarily defined it as being a serum, plasma, or whole blood sugar value below 30-50 mg/dL, while it is a known fact that blood sugar determined from the same blood sample will differ whether serum, plasma, or whole blood glucose are measured and will vary with the method of measurement. Furthermore, as pointed out by Cornblath and Scwartz, “normal values” may be defined using many different approaches.80 One definition describes hypoglycemia statistically as blood glucose concentration more than 2 standard deviations below the mean for a population of full-term well infants. This method is arbitrary and only defines a population at higher risk. Another method is to define hypoglycemia from a metabolic standpoint, that is, the blood glucose concentration at which the counter-regulatory response becomes activated. Other authors have proposed a neurophysiological definition to neonatal hypoglycemia, based on a threshold blood glucose concentration associated with disturbed neurophysiological function, such as auditory evoked response waveform. Finally, a neurodevelopmental definition has been proposed by Lucas et al.81 who found a threshold value of 2.5 mmol (47 mg/dL) to be more predictive of lower Bayley scores. Cornblath et al. have recently and extensively reviewed the controversies regarding the definition of neonatal hypoglycemia and have suggested operational thresholds66 for the purpose of defining and managing neonatal hypoglycemia in IDMs.
DISORDERS OF MINERAL METABOLISM IN IDMS
Similar to the results of animal studies, IDMs have decreased bone density at birth.82 Decreased bone density in IDMs correlates with decreased bone density in their mothers, but does not appear to be predictive of their serum Ca.82 Decreased bone density in IDMs appears to be due to increased bone resorption, rather than decreased bone formation.83 Indeed, indices of osteoclastic activity (such as cord blood telopeptide of type I collagen) are higher at birth in IDMs than in controls, while indices of bone formation (such as cord blood propeptide type I collagen) are similar.83 The clinical consequences of decreased bone density in IDMs have not been systematically studied, and it is not known whether these infants are at an increased risk for fractures, in particular, obstetrical ones.
Up to 50% of IDMs may develop neonatal hypocalcemia (NHC).82 Both rates and severity of NHC have been significantly lowered by modern management of glycemic control during pregnancy. Many studies of NHC in IDMs originated from the Program Project Grant of Diabetes in Pregnancy conducted by the authors and other investigators at the University of Cincinnati. Well-established risk factors of NHC are birth asphyxia and prematurity. These two factors play a dominant role in the NHC of IDMs.84-86
As previously mentioned, earlier IDMs are at a higher risk of developing birth asphyxia.2 The mechanisms of asphyxia-induced NHC are multiple and include increased intracellular phosphorus release, usage of sodium bicarbonate to buffer acidosis,86 and stress-induced calcitonin release.87 Furthermore, IDMs are at a higher risk of being born early, either because of iatrogenic prematurity (due to maternal or fetal reasons)2,3 or because of spontaneously occurring preterm labor.88 Preterm infants have high rates of NHC, due to a combination of factors: increased rate of birth asphyxia,89 decreased ability to secrete parathyroid hormone (PTH) in response to induced hypocalcemia,90,91 sustained calcitonin production in the presence of hypocalcemia,87 and possibly end-organ resistance to 1,25 (OH)2 cholecalciferol (the most active form of vitamin D).92
Independent of the asphyxia and the prematurity factor, it appears that Mg deficiency plays an important role in the pathogenesis of NHC in IDMs.93-104 In poorly controlled insulin- dependent diabetes mellitus (IDDM), glycosuria is accompanied by urinary Mg losses, in both nonpregnant and pregnant patients.93-95 Maternal Mg deficiency leads to fetal Mg deficiency, as evidenced by decreased amniotic fluid Mg concentrations95 and in lower cord blood or neonatal serum Mg concentrations in IDMs.94,95 It is known that Mg is necessary for the appropriate function of the Mg-dependent adenylate cyclase involved in the secretion of PTH, as well as in the Mg-dependent adenylate cyclase involved in the action of PTH on its target cells.98 Thus, in Mg deficiency, there is a state of functional hypoparathyroidism, combined to end-organ resistance to PTH. In infants, the PTH response to Mg administration correlates inversely with Mg status; in Mg-replete infants, Mg administration leads to an appropriate negative feedback, and a decrease in PTH production and in serum calcium concentrations. Paradoxically, in Mg-depleted infants, Mg administration leads to an increase in PTH production and in serum calcium concentra- tions.98 In IDMs, serum Ca concentrations correlate directly with serum Mg concentrations and inversely with maternal HbA1c.85 Also, IDMs have inadequate PTH elevation in response to hypoc- alcemia.84 Their calcitonin concentrations remain elevated at birth, as in every other normal newborn, but this does not appear to play a significant role in the pathogenesis of NHC.85
We demonstrated that a protocol of strict management of diabetes in pregnancy is associated with a reduction in the rate of hypocalcemia.103 Moreover, in a randomized, blinded, controlled clinical trial, we showed that prophylactic administration of intramuscular Mg at birth decreased the intensity of the physiologic drop in serum Ca that occurs after birth.104 However, in this group of very well-controlled diabetic mothers, as stated earlier, NHC is rare, and prophylactic Mg therapy did not prevent NHC.104
PREMATURITY AND RESPIRATORY DISTRESS SYNDROME
Several epidemiologic studies, including the one we performed in the framework of the Program Project Grant at the University of Cincinnati, have revealed that the incidence of spontaneously occurring preterm labor is nearly twice greater in a population of insulin-dependent diabetic pregnant women than in a control pop- ulation.88 Moreover, preterm labor in insulin-dependent pregnant women is highly predicted by both poor glycemic control in the second trimester of pregnancy (as evidenced by high glycohemo- globin A1 concentrations) and by the presence of urogenital infec- tions.88 These two risk factors act in combination and independently. Whether poor glycemic control favors the development of urogenital infection or urogenital infection precipitates the loss of glycemic control is unknown.88 Nevertheless, the IDM is at risk for prematurity, either due to spontaneously occurring preterm labor or due to iatrogenic prematurity. Indeed, because of intense fetal surveillance in the modern management of maternal diabetes mellitus, iatrogenic prematurity is at times required to prevent IUFD.2,3
IDMs appear to be at a particular risk for respiratory distress syndrome (RDS), even when they are not delivered prematurely.105 This risk may be amplified by the fact that in poorly controlled diabetes, fetal hyperinsulinism causes a delay in surfactant production, placing the IDM at a higher risk of RDS than non-IDMs, at any given gestational age.105,106 However, we demonstrated that adequate glycemic control reduces the risk of RDS to that of the nondiabetic population.107 Moreover, we also have shown that with modern management and adequate prenatal care, IDM born very low birthweight do not seem to be at an excess risk of developing RDS or other major complications of prematurity compared with non-IDM.108 Nevertheless, the presence of respiratory distress in IDMs is not necessarily indicative of RDS. Indeed, such patients are at a higher risk for transient tachypnea of the newborn (TTN), probably due to a much higher rate of cesarean deliveries. Also, respiratory symptoms may be very well linked to the development of asymmetric septal hypertrophy (ASH), a kind of cardiomyopathy specific to hyperinsulinism, which leads to systolic left outflow obstruction.109 Elevated cardiac troponin 1 concentration in IDMs with RDS appear to be excellent predictors of ASH.110 This entity is best diagnosed by echocardiography and is particular because inotropic agents are specifically contraindicated in its management, as they may increase the strength of cardiac contractions and aggravate the left outflow obstruction.109
NEONATAL MANAGEMENT OF THE IDDM
Delivery Room Management
We believe that in view of the risk of significant dystocia and that of neonatal depression due to fetal acidemia, a team of professionals trained in the pediatric management of complicated deliveries should be present in the delivery room. This team may be composed of physicians, neonatal nurse practitioners, midwives, or respiratory therapists with formal training and experience in neonatal resuscitation. These professionals should apply all standards and techniques described in the Neonatal Resuscitation Program, program developed as a joint effort of the American Heart Association, and the American Academy of Pediatrics.111
Nursery Management
The IDM that required respiratory assistance at delivery should be evaluated and monitored at least in a level II or III facility. Otherwise, its management may be well conducted in a well baby nursery, provided that the following steps guidelines are addressed and facilities are available:
1. Vital signs examination and monitoring, including heart rate, respiratory rate, and blood pressure, at least hourly for the next four hours during which signs and symptoms of complications such as hypoglycemia or RDS may develop.
2. Complete physical examination by a trained physician as soon as possible after birth. The physical examination will be meticulous in searching for birth trauma (long bones, clavicular fractures, and peripheral neurological deficits), major and minor congenital malformations, and for the determination of the neurologic status of the infant that may have been affected by acid-base status, hypoglycemia, or polycythemia. The time at which meconium is first passed should be noted; SLCS is usually suspected when there is a delayed evacuation of meconium.
3. Screening for and management of neonatal hypoglycemia. We base the following recommendations upon those suggested by an expert committee who published on the top- ic.66 Glucose monitoring should be initiated as soon as possible after birth, within two hours and before feeding, or at any time there are abnormal signs. Glucose reagent strips are commonly used in the newborn nurseries to screen for low blood glucose concentration. These methods should only be considered as a screen or an estimate because they may not be reliable and should not be used as the basis of a diagnosis.66,112 At least one reliable laboratory value that is significantly low should be obtained when one considers the diagnosis of hypoglycemia in the newborn infant; however, awaiting laboratory confirmation should not delay treatment in a symptomatic infant. However, the final diagnosis should depend on the laboratory plasma glucose values. If the plasma glucose concentration is less than 36 mg/dL (2.0 mmol/L), a close surveillance should be maintained, and intervention is recommended if plasma glucose remains below this level, if the level does not increase after a feed, or if abnormal clinical signs develop. At very low glucose concentrations (<20-25 mg/dL, 1.1-1.4 mmol/L), intravenous (IV) glucose infusion aimed at raising the plasma glucose levels above 45 mg/dL (2.5 mmol/L) is indicated. This therapeutic objective (plasma glucose > 45 mg/dL, 2.5 mmol/L) is different from the operational threshold for intervention (36 mg/dL, <2.0 mmol/L). The higher therapeutic goal includes a significant margin of safety in the absence of any data evaluating the correlation between glucose levels in this range and long-term outcome in full-term infants.66 As noted by Cornblath et al.,66 the recommendation for maintaining therapeutic levels in excess of 60 mg/dL (3.3 mmol/L) may be indicated in the symptomatic infant with documented profound, recurrent, or persistent hyperinsulinemic hypoglycemia,113 but it should not be the therapeutic goal for the majority of newborns with transient or brief episodes of low plasma glucose concentrations that are less than the operational thresholds recommended here.
4. Management of respiratory distress. The presence of respiratory distress in an IDM represents a particular challenge for the neonatologist. While respiratory distress may be indicative of congenital pneumonia, or spontaneous pneumothorax as in any other infant, the IDM may be more prone to TTN, due to a higher rate of cesarean deliveries, RDS, a higher rate of prematurity and delayed production of surfactant, and heart failure caused by ASH, than any other infant. The management of each condition is strikingly different. While all may require a similar symptomatic approach, such as administration of oxygen and ventilator support as needed, RDS may require administration of surfactant, ASH, the use of β-blockers,114,115 and TTN only time to improve. Thus, for every IDM with respiratory distress, careful evaluation of the history and pattern of the respiratory distress is fundamental. Maternal fever in labor and prolonged rupture of membranes may point out to potential pneumonia or sepsis and justify the use of antibiotics; rapidly improving respiratory distress supports the diagnosis of TTN, while rapidly deteriorating distress may indicate the development of RDS or the presence of ASH. All IDMs with respiratory symptoms should undergo (1) an urgent chest X-ray, which may help distinguish between RDS, pneumonia, and TTN, or that will reveal another cause; and (2) an echocardiogram, to verify the presence or absence of an anatomic heart disease or ASH. If present, ASH should be managed with β-blockers (propranolol, starting oral dose: 0.25 mg/kg per dose Q6 hours, increased as needed to maximum of 3.5 mg/kg per dose Q6 hours; starting IV dose: 0.01 mg/kg Q6 hours over 10 minutes, increased as needed to maximum of 0.15 mg/kg per dose Q6 hours) only when symptomatic, and under careful monitoring of the blood pressure.114,115
5. Imaging. We do not advocate routine imaging studies for the screening of malformations. These studies were probably conducted, in most cases, prenatally (using ultrasonography), and the majority of malformations in the IDM should not be a “surprise” at the time of delivery. However, some malformations may not be detected by antenatal ultrasonography, such as a small ventriculoseptal defect; thus, we advise performing echocardiography only when signs or symptoms pointing to a possible cardiac problem are present. Similarly, the documentation of ASH, if asymptomatic, is relevant only from an academic standpoint.
6. Blood testing. We believe that a routine hematocrit value should be obtained, preferably from a venous sample, to screen for neonatal polycythemia at the time of peak hematocrit, that is at two to four hours of life.56 Polycythemia (venous hematocrit > 65%) should be treated by a dilutional exchange transfusion only if symptomatic, or if accompanied by significant or persistent hypoglycemia or if the venous hematocrit exceeds 70%.116 Although the efficacy of dilutional exchange transfusion in preventing the late neurologic complications of polycythemia is controversial, we believe that in IDMs, it should be performed for the aforementioned indications because of the contribution of polycythemia to refractory hypoglycemia, and because of the high incidence of neurologic complications of polycythemia when hypoglycemia is concomitant.117-118
NHC and hypomagnesemia should be screened routinely at the age of 24 hours (i.e., at the nadir of postnatal values of serum calcium).118 Due to the potential effect of NHC on the central nervous system and on the heart, there is little controversy on the need for treatment if there is symptomatic hypocalcemia with arrhythmia, pump failure, or seizures.119 IV administration of Ca salts is the preferred, most rapid means of correction. Acute correction may be achieved by IV bolus infusion, over 10 minutes, with electrocardiographic monitoring of 18 mg elements Ca/Kg, followed by continuous infusion at 75 mg/kg/24 h.120 Stepwise reduction of calcium dose over a period of 3 days usually prevents rebound hypocalcemia.118 Calcium gluconate is usually preferred to Ca chloride, which may cause significant metabolic acidosis.118 Continuous infusion is preferred to bolus, since the latter will acutely increase serum osmolality, decrease serum pH by competition of Ca++ with H+ at the bone,118 be excreted in greater quantity,118 and may depress parathyroid function.118 In addition, boluses are more likely to cause arrhythmia, especially bradycardia, and possibly, cardiac standstill. Both bolus and continuous infusion of IV calcium may have the following complications: extravasation of calcium into soft tissue with Ca deposition or sloughing of the skin, and sometimes, severe cutaneous necrosis.119,120 Intraarterial infusion is prohibited as organ necrosis such as intestinal necrosis121 may result from it. In the cases where enteral Ca treatment is possible, a recognized side effect of enteral Ca salts is an increased frequency of bowel movement.103
In cases of refractory or relapsing hypocalcemia, it is advised to correct the often associated Mg deficiency. A single dose of 0.12 mL/kg of intramuscular 50% solution of magnesium sulfate (6 mg/kg of elemental magnesium) will, on average, increase within six hours the serum Mg concentration by 1 mg/dL, and correct the hypocalcemia.118,119 Rarely is a repeat dose administered.
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