CO and NO pulmonary diffusing capacity during pregnancy: Safety and diagnostic potential

Abstract

This paper reviews the scientific evidence for the safety of carbon monoxide (CO) and nitric oxide (NO) inhalation to measure pulmonary diffusing capacity (DL_CO and DL_NO) in pregnant women and their fetuses. In eight earlier studies, 650 pregnant women had DL_CO measurements performed at various times during pregnancy, with a minimum of two to four tests per session. Both pregnant subjects that were healthy and those with medical complications were tested. No study reported adverse maternal, fetal, or neonatal outcomes from the CO inhalation in association with measuring DL_CO. Eleven pregnant women, chiefly with pulmonary hypertension, and 1105 pre-term neonates, mostly with respiratory failure, were administered various dosages of NO (5–80 ppm for 4 weeks continuously in pregnant women, and 1–20 ppm for 15 min to 3 weeks for the neonates). NO treatment was found to be an effective therapy for pregnant women with pulmonary hypertension. In neonates with respiratory failure and pulmonary hypertension, NO therapy improved oxygenation and survival and has been associated with only minor, transient adverse effects. In conclusion, maternal carboxyhemoglobin ([Hb_CO]) levels can safely increase to 5% per testing session when the dose-exposure limit is 0.3% CO inhalation for ≤3 min, and for NO, 80 ppm for ≤3 min. The risk of late fetal or neonatal death from increased Hb_CO from diffusion testing is considerably less than the risk of death from all causes reported by the Centers for Disease Control, and is therefore considered “minimal risk”.

Introduction

The 2005 guidelines for standardizing pulmonary function tests have been jointly updated, approved, and published by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) (Macintyre et al., 2005, Miller et al., 2005a, Miller et al., 2005b, Pellegrino et al., 2005, Wanger et al., 2005). These guidelines reflect the current knowledge in the field, and establish measures of safe clinical practice in quantifying pulmonary function. According to the ATS/ERS guidelines, only a few circumstances exist in which lung function testing is contraindicated (Miller et al., 2005b). For lung function testing that includes measurements of pulmonary diffusing capacity, there are only four contraindications: (1) chest or abdominal pain, (2) oral or facial pain, (3) stress incontinence, (4) and dementia. Pregnancy is not considered a contraindication for the measurement of pulmonary diffusing capacity (Miller et al., 2005b).

Despite the ATS/ERS guidelines, the question of whether measurement of pulmonary diffusing capacity in pregnant women is “safe” and “warranted” for themselves and their fetuses has not been studied adequately. Concern with performing diffusing capacity measurements during pregnancy stems from carbon monoxide (CO) exposure, resulting in increases in carboxyhemoglobin (Hb_CO) in the blood of the mother and fetus with each test. Accumulation of Hb_CO in excess can diminish the oxygen-carrying capacity of maternal and fetal blood to unsafe levels.

Nonetheless, determination of pulmonary diffusing capacity can be an excellent prognostic indicator for maternal and fetal outcomes, fitness, and mortality. Since impaired lung function is associated with an increase and recurrence of cardiovascular disease (Coburn et al., 1963), measuring pulmonary function in a pregnant woman may be a valuable prognostic indicator of adverse maternal (e.g. preeclampsia, gestational diabetes, cesarean section) and fetal outcomes (e.g. large for gestational age, small for gestational age infants). In fact, a forced expiratory volume in 1 s that is <80% of predicted in women who are pregnant is related to higher incidence of pre-term births (<37 weeks gestation), a higher prevalence of gestational hypertension, and a higher risk for low birth weight babies (<2500 g) (Getahun et al., 2006, Getahun et al., 2007, Schatz et al., 2006). Most recently, a low maternal hemoglobin concentration (<10 g/dl) has been related to a higher risk for stillbirths, pre-term births, and small for gestational age babies (Gonzales et al., 2009). Because hemoglobin concentration is a determinant of pulmonary diffusing capacity, measurement of pulmonary diffusion may also relate to maternal and fetal outcomes, a possibility that has not yet been tested. Pulmonary diffusing capacity for carbon monoxide (DL_CO) and nitric oxide (DL_NO) at rest is also related to aerobic capacity (Zavorsky et al., 2009), a strong independent predictor of death in women (Gulati et al., 2003) and men (Myers et al., 2002). Thus, a measurement of pulmonary diffusion could be a prognostic marker for mortality in pregnancy. Low pulmonary diffusion in a pregnant woman may prompt a physician to recommend regular aerobic exercise to improve her fitness. Finally, DL_CO and DL_NO are sensitive indicators of the morphological changes assessed with computed tomography to detect emphysema and cystic fibrosis (Dressel et al., 2009, van der Lee et al., 2009).

What is the clinical significance of measuring alveolar membrane diffusing capacity (DM) in the pregnant female “diseased” lung? Well, the global measurement of DL_CO only provides a global indication of whether gas exchange is normal or not. It does not specify where the abnormal physiology lies, whether the issue is low (or high) hemoglobin concentration, or low (or high) pulmonary capillary blood volume, or whether the problem lies solely within the alveolar-capillary membrane. A measurement of both DL_CO and DL_NO together allows partitioning to obtain pulmonary capillary blood volume (Vc) and DM (DM is essentially DL_NO) so that there is a more precise determination of the location of the pathophysiology. Pregnant women who have a high DM/Vc ratio (which is equal to the DL_NO/DL_CO ratio) should be evaluated for high pulmonary artery pressure compatible with pulmonary hypertension (Bonay et al., 2004, van der Lee et al., 2006). Therefore, a disproportionate reduction in DM relative to Vc would decrease the DM/Vc ratio (and thus decrease the DL_NO/DL_CO ratio), which is related to a wide spectrum of pulmonary vascular diseases (Oppenheimer et al., 2006) and could apply to pregnant women. Diabetes, which can cause pulmonary microangiopathy, lowers DL_NO/DL_CO compared to controls (Chance et al., 2008). Thus, a DL_NO and DL_CO measurement could be a prognostic indicator for gestational diabetes.

Therefore, future direction of the measurements of DL_CO and DL_NO in pregnancy has promise as a screening tool for predicting aerobic capacity (as a determinant of mortality), and to help identify pulmonary hypertension, pulmonary vascular diseases, and gestational diabetes (including type II and possibly type I diabetes). With the goals of advancing knowledge of alveolar gas exchange during pregnancy and ensuring safe testing of lung function, the guidelines proposed herein should help to facilitate the use of pulmonary diffusing capacity measurement in the pregnant woman.