Gladys A. Ramos, MD Thomas R. Moore, MD
Time is a dressmaker specializing in alterations.
—Faith Baldwin
Key Points
• Appearance of phosphatidylglycerol is delayed in diabetic pregnancies with and without adequate glucose control
• Normalization of maternal glucose values allows lung maturity to progress at a rate similar to nondiabetic pregnancies
• In the presence of accurate obstetrical dating and good maternal glucose control, amniotic fluid assessment for fetal lung maturity prior to elective delivery at term is not needed
• With uncertain obstetrical dates or poor glucose control, amniocentesis is recommended before elective term delivery prior to 39 weeks
Respiratory distress syndrome (RDS), a deficiency in surfactant in premature infants leading to increased surface tension within alveoli, subsequent alveolar collapse, and difficult gas exchange, which then leads to neonatal hypoxia, has been historically one of the major complications of neonates born to mothers with diabetes. In the 1970s, an estimated 31% of newborns from diabetic pregnancies were complicated by RDS; this rate has been reduced currently to less than 3% with improved glycemic control and improved understanding of fetal lung maturity.1
FETAL LUNG MATURATION
The pulmonary system begins development at approximately three weeks after conception, but it is at approximately 16-20 weeks of gestation that the development of early bronchioles and vascularization of pulmonary epithelium occurs.2 At 22-23 weeks of gestation, alveolar development occurs with proliferation of capillaries around these alveoli to allow for effective gas exchange. Alveoli are lined with type II pneumocytes that produce phospholipids packaged in lamellar bodies. Surfactants are a type of phospholipid that facilitates alveolar expansion upon neonatal respiratory efforts.3 These surface-active compounds reduce surface tension within the alveolar sacs, allowing them to expand with less pressure during the initial respirations following delivery. In the absence of surfactant, much higher ventilatory pressures are required to expand the alveoli. If the pressures required exceed what the newborn can generate, positive pressure ventilation may be required for initial alveolar inflation and adequate gas exchange.3 In the third trimester of pregnancy, owing to the outflux of fetal respiratory secretions, surfactant is found in the amniotic fluid, which can be assessed to determine lung maturity.
FETAL LUNG MATURITY TESTS
Currently, there are biochemical tests that measure concentrations of pulmonary surfactant or biophysical tests that measure surface-active effects of these phospholipids in the amniotic fluid.2
Fluorescence polarization is based on the ratio of surfactant to albumin in amniotic fluid to predict lung maturity.3,4 It is a simple automated technique with excellent validity that can be performed in less than an hour. The amount of sample needed is only 1 mL. In a retrospective study conducted by Fantz et al., 15 samples from women whose neonates developed RDS and 170 controls, a value of > 45 mg/g had a sensitivity of 100 (95% CI of 82-100) and specificity of 90% (95% CI of 78-89) for diagnosing surfactant-deficient RDS.4 Women who received corticosteroids were excluded.4 Since this test relies on a ratio of surfactant to albumin, interpretation of the results from fluorescence polarization is affected by both meconium and blood.3
Lecithin to sphingomyelin ratio measures these two surfactants in amniotic fluid. Gluck et al. subjected amniotic fluid from a spectrum of gestational ages to thin layer chromatography and found that sphingomyelin rose early in the third trimester, but returned to baseline as term approached.5-7 In contrast, lecithin began to rise at the same gestational age, but continued to rise throughout gestation with a sharper increase as term approached (Figure 36-1). In normal pregnancies, a cutoff ratio of twice as much lecithin as sphingomyelin was identified as an assurance of fetal maturity (lecithin-sphingomyelin [L/S] ratio >2:1).8,9 Reliability of predicting pulmonary maturity was found to be excellent for nondiabetic pregnancies using this cutoff.7 However, amniotic fluid and blood interfere with interpretation of the test. This test has fallen out of favor as newer tests have emerged, as trained personnel are needed to conduct the test, an average of five to six hours is required to run the test, and blood and meconium interfere with results.2
Soon after discovery and utilization of the L/S ratio, there was concern that a ratio of 2:1 may not be as predictive of maturity in pregnancies complicated by maternal diabetes. In one study, up to 28% of infants of diabetic mothers with an L/S ratio >2 were reported to have respiratory insufficiency.10 Cunningham et al. found RDS in 6 of 29 (20.7%) infants of diabetic mothers delivered at 34-37 weeks after a mature L/S ratio.11 In other populations, the L/S ratio was reported to be just as predictive in diabetic mothers as in nondiabetics.12 Regardless, a more predictive test was clearly needed to assure pulmonary maturity in pregnancies complicated by maternal diabetes.
Phosphatidylglycerol (PG) is one of the last surfactant components to appear in pulmonary secretions because it enhances spread of phospholipids in the alveolar surface.2 An absolute concentration cutoff (0.5 μg/mL) using chromatography was established to predict pulmonary maturity (PG+). The presence of PG was found to be an excellent predictor of pulmonary maturity in both normal and diabetic pregnancies.11-13 The predictive value of a positive PG was reported as 98%-100% in both diabetic and nondiabetic pregnancies.14,15 Unfortunately, the absence of PG was even less predictive of RDS than an immature L/S ratio. Indeed, most pregnancies without detectable PG near term had no evidence of clinical pulmonary immaturity. Rates of RDS with negative PG were only 16.7% in diabetic and 14.4% in nondiabetic pregnancies.14 Currently, PG can be assessed with a slide agglutination test using antisera specific for PG and this test is not affected by blood or meconium.2
Lastly, recently there has been a new test, lamellar body count, that has been used to identify lung maturity. In type II pneumocytes, surfactant is stored in lamellar bodies. These are then secreted into the alveolar space and, therefore, found in amniotic fluid. A standard hematologic counter can be used to measure lamellar bodies as they have similar size to platelets. In a prospective trial of 80 patients ranging in gestational age from 28 to 40 weeks of gestation, a lamellar body count of 50,000 uL predicted fetal lung maturity with a sensitivity of 85% and specificity of 70% for the prediction of RDS.16 In 90 pregnancies complicated by type 1 diabetes, a lamellar count of >37,000/uL had a sensitivity of 80% and specifity of 100% in the prediction of fetal lung maturity when compared to PG and L/S ratio and there were no cases of RDS.17
FACTORS INFLUENCING FETAL LUNG MATURATION IN DIABETIC PREGNANCIES
The increased risk of RDS in diabetic pregnancies could be due to delay in production of alveolar phospholipids or abnormal pulmonary function. As mentioned above, the proportion of diabetic pregnancies with delayed appearance of a mature L/S ratio or a positive PG varied greatly between populations studied. Ojomo and Coustan reported that PG was absent in a significant proportion of pregnancies complicated by diabetes at term gestations (26% at 37 weeks, 20% at 38 weeks, and 4% at 39 weeks).18 The highest percentage with absent PG occurred in overt diabetes as compared to gestational diabetes. Tsai et al. likewise found delayed appearance of PG in their pregestational diabetics (Class B-RF) but not in gestational diabetic pregnancies at term; they did identify a delay in PG positivity in gestational diabetics below 37 weeks as compared to controls.19 Glycemic control has also been implicated to play a role. Kulovich and Gluck also found a clear delay in the onset of PG presence in poorly controlled gestational diabetics but not in other classes of diabetes.13 Landon et al. found that regardless of diabetes type, fetal lung maturity occurred later in pregnancies with poor glycemic control (mean plasma glucose level >110 mg/dL) and when infants were stratified by maternal plasma glucose levels.20 Similarly, Moore in a case-control study involving 295 pregnancies complicated by diabetes demonstrated no differences in the rate of rise of the amniotic fluid L/S ratio among types of diabetes or degree of glucose control.21 However, amniotic fluid PG was delayed approximately 1.5 weeks among women with diabetes (either pregestational or gestational diabetes mellitus [GDM]) compared to controls (Figure 36-2) and was associated with earlier and higher peak in phosphatidyl inositol.21 It may be that elevated maternal plasma levels of myoinositol in pregnancies complicated by diabetes may inhibit or delay the production of PG in their fetuses.21
IMPACT OF MATERNAL DIABETES ON NEONATAL RESPIRATORY DISTRESS SYNDROME
Although biochemical changes appear to play an important role in the development of RDS in pregnancies complicated by diabetes, there may also be physiologic etiologies. Kjos et al. reviewed 526 diabetic pregnancies delivered within five days of amniotic fluid assessment for lung maturity. RDS was noted in 3.4% of infants, and (1%) had surfactant deficient RDS. All five infants with surfactant-deficient RDS were delivered prior to 34 weeks and had immature PG and L/S results.22 Transient tachypnea, hypertrophic cardiomyopathy, and pneumonia led to RDS in majority of infants all of which were delivered by cesarean section and had mature L/S ratios.22 They concluded that surfactant-deficient RDS is not a problem in well-managed diabetic pregnancies beyond 34 weeks and thus amniotic fluid testing for fetal lung maturity is unnecessary.22
In a follow-up study, Kjos et al. compared a cohort of 1457 diabetic women with well-dated pregnancies, who were delivered at term without pulmonary maturity testing to a historical comparison group of 713 women delivered after the assessment of pulmonary maturity.23 There were no differences in rates of surfactant-deficient RDS between those delivered without amniocentesis and those delivered after amniocentesis (0.8% vs. 1.0%). Transient tachypnea likewise did not differ between groups (1.3% vs. 0.8%). The main risk factor for respiratory compromise was cesarean delivery (OR 2.21 [2.04-2.27]). They concluded that routine fetal lung maturity testing is unnecessary in well-dated diabetic pregnancies and should be abandoned. Furthermore, the study conducted by Moore demonstrated that the average gestational age that a nondiabetic fetus achieves pulmonary maturity is 34-35 weeks of gestation, furthermore more than 99% of normal newborns have a mature phospholipid profile by 37 weeks. In pregnancies complicated by diabetes, however, lung maturity occurs approximately 10 days after the nondiabetic pregnancies (38.5 gestational weeks). Delivery prior to 38.5 weeks of gestation, unless indicated by urgent fetal and maternal indications, should be preceded by documentation of pulmonary maturity by amniocentesis.
SUMMARY
The near-term infant of a mother with poorly controlled diabetes is more likely to have neonatal respiratory dysfunction than is the baby of a nondiabetic mother. In general, the same thresholds and tests used for fetal lung maturation can be used to predict a low risk of RDS in pregnancies with gestational and pregestational diabetes. The combination of accurate dates and more strict glucose control has led to a recent decline in the use of amniotic fluid assessment for fetal lung maturity. In well-dated term diabetic pregnancies with adequate glucose control, there is no need for amniocentesis for fetal lung maturity testing. In the absence of either early confirmation of dates or adequate glucose control, amniocentesis for lung maturity testing is still indicated if delivery is planned before 39 weeks.
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