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Oxygen for intrauterine resuscitation: of unproved benefit and potentially harmful
Clinical Opinion
www.AJOG .org
OBSTETRICS
Oxygen for intrauterine resuscitation: of unproved benefit and potentially harmful Maureen S. Hamel, MD; Brenna L. Anderson, MD, MSc; Dwight J. Rouse, MD, MSPH
E
very day, on most labor and delivery units in the United States, laboring women receive inhaled oxygen in the hope that it will improve the metabolic condition of their fetuses, or at least alleviate nonreassuring fetal heart rate patterns. In fact, administration of oxygen for this purpose is sanctioned by the American Congress of Obstetricians and Gynecologists; the Association of Women’s Health, Obstetric, and Neonatal Nurses; and the American College of Nurse-Midwives.1 Although population-based data on the frequency of this practice are not available, in 1 randomized trial of fetal pulse oximetry,2 two-thirds of patients received oxygen at some point during their labor for a nonreassuring fetal heart rate tracing (written personal communication Steven Weiner, MS, April 8, 2013). Despite its frequent use, data to support that maternal oxygen supplementation benefits the fetus are limited. Fawole and Hofmeyr,3 in their Cochrane Review, conclude that there is insufficient evidence to support the notion that use of oxygen for prophylaxis in labor or for treatment of fetal distress is beneficial to the fetus. Indeed, it may even be harmful. Herein we review the physiology pertinent to maternal oxygen supplementation, and the available relevant animal From the Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI (all authors). Received Nov. 2, 2013; accepted Jan. 7, 2014. The authors report no conflict of interest. Reprints: Maureen S. Hamel, MD, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, 101 Dudley St., Providence, RI 02905. [email protected]. 0002-9378/$36.00 ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.01.004
Maternal oxygen is often given to laboring women to improve fetal metabolic status or in an attempt to alleviate nonreassuring fetal heart rate patterns. However, the only 2 randomized trials investigating the use of maternal oxygen supplementation in laboring women do not support that such supplementation is likely to be of benefit to the fetus. And by increasing free radical activity, maternal oxygen supplementation may even be harmful. Based on a review of the available literature, we conclude that until it is studied properly in a randomized clinical trial, maternal oxygen supplementation in labor should be reserved for maternal hypoxia, and should not be considered an indicated intervention for nonreassuring fetal status. Key words: fetal resuscitation, labor, maternal oxygen
and human data to summarize the potential benefits and risks of maternal oxygen administration during labor. To inform our review, we conducted a search of the electronic databases MEDLINE, PubMed, and the Cochrane Database of Systematic Reviews through September 2013 using the phrases or key words: “fetal resuscitation,” “maternal oxygen administration,” “maternal oxygen therapy,” “nonreassuring fetal heart tracing/patterns,” and “lipid peroxidation in labor.” Additionally, we reviewed the reference lists of the articles identified in our electronic search for pertinent studies.
Background Our understanding of maternal-fetal gas exchange comes primarily from animal experiments, specifically with sheep, and, to a lesser extent, from human observational data.4 At baseline, PO2 (oxygen dissolved in blood and unbound to hemoglobin) in maternal arterial blood is around 100 mm Hg, while the umbilical venous PO2 in the near term fetus is estimated to be approximately 28 mm Hg.4 Despite lower partial pressures within the umbilical vein, the fetus is able to adequately oxygenate its tissues. Oxygen saturation is the percentage of oxygen-binding sites on hemoglobin that are bound by oxygen. Normal
oxygen saturation in healthy women is 99-100% while in the near term fetus it is usually 60-70%.4 The fetus survives in this relatively hypoxic state because fetal hemoglobin more avidly binds oxygen than maternal hemoglobin, and the fetal hemoglobin concentration is higher than the maternal: 16.5 g/dL (range, 15e18.6 g/dL)5 vs 12.5 g/dL (range, 11.0e14.0 g/dL).6,7 Oxygen content in blood is the combination of dissolved oxygen and oxygen bound to hemoglobin. Despite lower partial pressure, because of increased binding capacity and higher hemoglobin, when compared with maternal arterial blood, umbilical venous blood has similar total oxygen content.4 Why give oxygen? Under normal physiologic conditions, oxygen supply to the fetus exceeds demand; fetal oxygen uptake is not affected until oxygen delivery is reduced by more than half.8 Work in nonhuman primates by James et al9 in 1972 indicates that fetal hypoxia is the principle cause of late decelerations and can be resolved by increasing fetal PO2. Additional primate work by Murata et al10 suggests that late decelerations are early signs of hypoxia that, without intervention, will be followed by the absence of accelerations, and, if the hypoxia is sustained, fetal
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acidemia. Thus, administration of supplemental maternal oxygen would appear to be a logical intervention in response to an abnormal fetal heart rate pattern. Will maternal oxygen supplementation alleviate abnormal fetal heart rate patterns? In fact, there is a significant body of animal and human data demonstrating that maternal oxygen administration increases fetal oxygen levels and can remediate abnormal fetal heart rate patterns. As early as 1967, Althabe et al11 reported human data showing that 100% oxygen via face mask corrected fetal tachycardia and reduced the frequency of late decelerations, or eliminated them altogether. The fetal heart rate effects correlated with changes in fetal muscle PO2 levels. Four years later, in 1971, Khazin et al12 also found that just a few minutes of giving oxygen to laboring women alleviated late decelerations. Does the alleviation of abnormal fetal heart rate patterns with oxygen translate into improved fetal metabolic status? Human observational data by Kubli et al13 demonstrate a relationship between late decelerations and abnormal fetal acid-base status. However, data on the relationship between maternal oxygen administration and fetal acid-base status are mixed, and limited for the most part to nonrandomized trials, or trials that do not exclusively involve laboring women. Newman et al14 administered either 50% or 100% oxygen to women during the first stage of labor and measured fetal scalp blood pH. During maternal hyperoxia, no significant change in fetal scalp pH was observed ([mean SD] baseline value 7.28 0.013 vs hyperoxia 7.30 0.01, P value not stated). In addition to alleviating late decelerations, Khazin et al12 also reported that maternal hyperoxia during labor was associated with an increase in fetal PO2 without concomitant acidosis; however, mean pH and P values were not reported. In a randomized trial by Ramanathan et al15 in 1982, 40 women undergoing elective cesarean
delivery under epidural anesthesia were assigned to breathe 1 of 4 different concentrations of oxygen via face mask. Mean duration of oxygen exposure was 36 4 minutes and fetal umbilical cord pH was measured at delivery. Fraction of inspired oxygen (FIO2) ranged from 0.21e1.00 and no differences in fetal pH were found between normoxic (FIO2 0.21, 7.33 0.09) and hyperoxic (FIO2 0.47, 7.33 0.01; FIO2 0.74, 7.34 0.07; FIO2 1.00, 7.32 0.005) groups. To date there have been only 2 randomized trials investigating the use of maternal oxygen supplementation in exclusively laboring women. Both were trials of oxygen as prophylaxis in labor and enrolled <200 patients. In 1995, Thorp et al16 investigated the effects of maternal oxygen on fetal cord pH. In all, 86 women with reassuring fetal heart tracings were randomly allocated during the second stage of labor to breathe oxygen at 10 L/min via face mask or to breathe room air. While there was no difference in mean umbilical artery pH between the 2 groups (7.258 0.069 vs 7.285 0.058, oxygen and control, respectively, P ¼ .06), neonates born to women in the oxygen group were significantly more likely to have umbilical artery pH values <7.20 (9/41 vs 2/44, P ¼ .02, Fisher exact test). In 1997, Sirimai et al17 randomized 160 women at term to breathe oxygen or room air throughout the entirety of the second stage of labor. As in the trial of Thorp et al,16 more neonates born to mothers in the oxygen group had umbilical artery cord pH values <7.2 (8/80 vs 3/80 in the room air group). However, this difference was not statistically significant (P ¼ .12). Information from this trial is quite limited as it is available only in abstract form.17 Animal trials have allowed researchers to simulate and observe fetal compromise in scenarios that would be impossible to study in human beings by allowing oxygen to be studied as a single intervention. As previously mentioned, James et al9 conducted observational research monitoring the cardiovascular and acid-base status of laboring nonhuman primates. As labor progressed, a group of fetuses was noted to become
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www.AJOG.org hypoxic, hypotensive, and acidotic. The initial response to fetal hypoxia was fetal tachycardia and then, as hypoxia worsened, late decelerations appeared. While 100% maternal oxygen was successful at improving or even resolving late decelerations, it had no effect on acid-base status or fetal hypotension.9 In additional work with primates, Morishima et al18 administered 100% oxygen for 30 minutes during labor (spontaneous or induced) to mothers of fetuses with and without signs of “fetal distress” (which they defined as late decelerations). In the 40 primates with signs of fetal distress they found that while maternal oxygen raised both fetal and maternal oxygen levels and reduced the frequency of late decelerations, it did not improve mean fetal pH (7.10 0.029 vs 7.07 0.034). In the 15 subjects for whom maternal oxygen had no beneficial effect on the frequency of decelerations, pH worsened significantly (6.97 0.035 vs baseline 7.11 0.028, P < .01).18 Therefore, the available human and animal data, which admittedly are not robust, suggest that at best, maternal oxygenation supplementation can alleviate abnormal fetal heart rate patterns but not improve fetal acid-base status. At worst, such oxygen supplementation may actually lower fetal pH. And while it might be postulated that the alleviation of abnormal fetal heart rate tracings by maternal oxygen supplementation will reduce the number of operative deliveries for that indication, in our review of the literature (described earlier), we found no human trials that directly address this issue. Other than possibly lowering fetal pH, how else might oxygen be detrimental? Maternal oxygen supplementation readily induces maternal hyperoxia. Polvi et al19 found that just 5 minutes of breathing 50% oxygen via face mask increased maternal PaO2 to >200 mm Hg, and an additional 5 minutes of 100% oxygen increased it to >300 mm Hg. Maternal hyperoxia, in turn, may lead to increased free radical activity in both mothers and neonates. In 2002, in a double-blinded trial, Khaw et al20 randomized women undergoing elective
www.AJOG.org cesarean delivery under spinal anesthesia to breath room air or 60% oxygen via face mask prior to delivery and then measured 3 markers of free radical activity in maternal and umbilical cord blood: malondialdehyde (MDA), isoprostane, and organic hydroperoxides. Mean exposure time to oxygen was approximately 50 minutes. Maternal blood levels of MDA were increased in oxygen-exposed women as compared to control women (1.26 0.22 vs 0.89 0.16 mmol/L1, P < .05). However, isoprostane and organic hydroperoxides levels were similar between groups. Likewise, compared to neonates in the room aireexposed group, MDA levels were increased in the arterial umbilical cord blood of neonates born to mothers in the oxygen group (0.48 0.10 vs 0.40 0.06 mmol/L1) as were levels of isoprostane (215.2 92.7 vs 122.1 73.4 mmol/L1) and organic hydroperoxides (0.39 0.10 vs 0.18 0.09 mmol/L1). All 3 comparisons were statistically significant at P < .001.20 In lambs, Suzuki et al21 studied maternal exposure to 100% oxygen vs room air before, during, and after 5 minutes of umbilical cord occlusion. Predictably, oxygen exposure increased fetal PaO2. However, it also resulted in persistently elevated fetal plasma levels of xanthine, a marker of free radical activity, 30 minutes after cord release,21 suggesting that after a period of asphyxia, oxygen therapy may contribute to free radical activity. Similarly, Yamada et al22 exposed goats to maternal oxygen before, during, and after a period cord occlusion. Markers of free radical activity were elevated in fetuses of oxygen-exposed mothers before, during, and after the period of asphyxia.22 In both trials, animals served as their own controls. In 2012, in a double-blinded trial, Nesterenko et al23 randomized 56 women at term to breathe 100% oxygen via nasal cannula or room air for a minimum of 30 minutes prior to delivery. Both groups included laboring women as well as women scheduled for elective cesarean delivery. Mean time of oxygen exposure was approximately 2 hours and while no differences in mixed umbilical cord pH (control 7.35 0.1 vs
Obstetrics oxygen 7.33 0.1, P ¼ .38) or markers of oxygen free radical activity were found, 20% (6 of 30) of infants in the oxygen group required resuscitation in the delivery room vs 0% (0 of 26) in the control group (P ¼ .03).23 Although the long-term consequences of fetal exposure to hyperoxia have not been well studied, the consequences of neonatal exposure have been. Oxygeninduced cellular damage has been implicated in the pathogenesis of bronchopulmonary dysplasia and retinopathy of prematurity.24 And evidence regarding the role of oxygen in neonatal resuscitation suggests that even brief exposure to excessive oxygen can result in adverse outcomes. Two separate metaanalyses of randomized controlled trials comparing neonatal resuscitation with 100% oxygen vs room air have demonstrated decreased mortality with room air (relative risk, 0.71; 95% confidence interval, 0.54e0.9425; and odds ratio, 0.70; 95% confidence interval, 0.5e0.9826); currently the use of 100% oxygen in neonatal resuscitation is discouraged.27 Maternal hyperoxia is induced to correct fetal hypoxia, however it is during periods of hypoxia that the fetus may be most at risk from reactive oxygen species. During hypoxia fetal respiration converts from aerobic to anaerobic and adenosine triphosphate (ATP) is depleted. ATP breakdown products accumulate and there is a subsequent increase in cell permeability to ions. When reoxygenation occurs, calcium flows into cells, disrupts ATP production, facilitates the breakdown of cellular molecules, and results in generation of oxygen free radicals.28 Unstable molecules that damage cell membranes, free radicals have the potential to cause edema or hemorrhage in vital fetal organs, specifically the brain and the lungs.29 Wang et al30 demonstrated an association between umbilical cord blood levels of MDA and fetal acid-base status proposing it as a surrogate of hypoxia. Dede et al31 investigated cord blood levels of lipid peroxidation products (MDA) in patients delivered by cesarean section for nonreassuring fetal heart tracings. When compared to controls,
Clinical Opinion
patients with nonreassuring fetal status had elevated lipid peroxidation products in both umbilical cord and placental samples.31 After a period of hypoxia, free radical activity may contribute to ischemia-reperfusion injury; in theory, introducing additional reactive oxygen species via maternal oxygen administration may only exacerbate this process.
Conclusions Oxygen is frequently given to improve fetal status, however there is a paucity of outcome data to support its use and evidence of fetal benefit is lacking. Animal studies suggest that when fetal hypoxia is not the result of maternal hypoxia, maternal oxygen raises markers of free radical activity21,22 and the negative repercussions of free radicals are well described.24,29 Primate research demonstrates that while oxygen may correct hypoxia, it will not correct acidosis.9,18 Neonatal resuscitation with 100% oxygen is no longer recommended because of its demonstrated potential for harm.27 The limited data from pregnant women suggest that oxygen can lead to decreased umbilical cord pH,16 increase the need for neonatal resuscitation,23 and increase markers of free radical activity.20 Nor do the data suggest that maternal oxygen administration for the purpose of alleviating nonreassuring fetal heart patterns will translate into a lowered rate of cesarean delivery. A randomized trial of oxygen for intrauterine resuscitation is feasible, although the practice may be so ingrained as to make recruitment to such a trial difficult. The necessary sample size of the trial would of course depend on the primary outcome. For example, assuming a mean (SD) umbilical artery cord pH of 7.28 0.0732 to detect a 0.02 difference in umbilical artery cord pH with 80% power and a 2-tailed alpha of 0.05, would require as few as 400 participants randomly allocated to supplemental oxygen or no oxygen. But to definitively assess efficacy with a serious neonatal composite as the primary outcome might require as many as 11,000.33 Each year in the United States, approximately 4 million women give
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birth, and of those, approximately 80% labor. If even half receive supplemental oxygen, then approximately 1.5 million women and their fetuses annually are subjected to supraphysiologic oxygen concentrations. Both animal and human data demonstrate that oxygen can be harmful, as does actual clinical experience (eg, retinopathy of prematurity). Thus, the public health consequences of maternal oxygen supplementation are potentially large. Therefore, until it is studied properly in a randomized clinical trial, our review leads us to conclude that maternal oxygen supplementation in labor should be reserved for maternal hypoxia and should not be considered an indicated intervention for nonreassuring fetal status. REFERENCES 1. American College of Obstetricians and Gynecologists. Management of intrapartum fetal heart rate tracings. ACOG practice bulletin no. 116. Obstet Gynecol 2010;116:1232-40. 2. Bloom SL, Spong CY, Thom E, et al. Fetal pulse oximetry and cesarean delivery. N Engl J Med 2006;355:2195-202. 3. Fawole B, Hofmeyr GJ. Maternal oxygen administration for fetal distress. Cochrane Database Syst Rev 2012;12:CD0000136. 4. Meschia G. Fetal oxygenation and maternal ventilation. Clin Chest Med 2011;32:15-9. 5. Walker J, Turnbull EP. Hemoglobin and red cells in the human fetus and their relation to the oxygen content of the blood in the vessels of the umbilical cord. Lancet 1953;2:312-8. 6. Milman N, Bergholt T, Byg K, Eriksen L, Hvas A. Reference intervals for hematological variables during normal pregnancy and postpartum in 434 healthy Danish women. Eur J Haematol 2007;79:39-46. 7. Beaton GH. Iron needs during pregnancy: do we need to rethink our targets? Am J Clin Nutr 2000;72(Suppl):265-71S. 8. Wilkening RB, Meschia G. Fetal oxygen uptake, oxygenation and acid-base balance as a function of uterine blood flow. Am J Physiol Heart Circ Physiol 1983;244:H749-55. 9. James LS, Morishima HO, Daniel SS, Bowe ET, Cohen H, Niemann WH. Mechanism of late deceleration of the fetal heart rate. Am J Obstet Gynecol 1972;113:578-82.
10. Murata Y, Martine CB, Ikenoue T, et al. Fetal heart rate accelerations and late decelerations during the course of intrauterine death in chronically catheterized rhesus monkeys. Am J Obstet Gynecol 1982;144: 218-23. 11. Althabe O, Schwarcz RL, Pose SV, Escarcena L, Caldeyro-Barcia R. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol 1967;98: 858-70. 12. Khazin AF, Hon EH, Hehre FW. Effects of maternal hyperoxia on the fetus. Am J Obstet Gynecol 1971;109:628-37. 13. Kubli FW, Hon EH, Khazin AF, Takemura H. Observations on heart rate and pH in the human fetus during labor. Am J Obstet Gynecol 1969;107:1190-206. 14. Newman W, McKinnon L, Phillips L, Paterson P, Wood C. Oxygen transfer from mother to fetus during labor. Am J Obstet Gynecol 1967;99:61-9. 15. Ramanathan S, Gandhi S, Arismendy A, Chalon J, Turndoff H. Oxygen transfer from mother to fetus during cesarean section under epidural anesthesia. Anesth Analg 1982;61: 576-81. 16. Thorp JA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol 1995;172:465-74. 17. Sirimai K, Atisook R, Boriboonhirunsam D. The correlation of intrapartum maternal oxygen administration and umbilical cord blood gas values. Acta Obstet Gynecol Scand Suppl 1997;76:90. 18. Morishima HO, Daniel SS, Richards RT, James LS. The effect of increased maternal PaO2 upon the fetus during labor. Am J Obstet Gynecol 1975;123:257-64. 19. Polvi HJ, Pirhonen JP, Erkkola RU. The hemodynamic effects of maternal hypo- and hyperoxygenation in healthy term pregnancies. Obstet Gynecol 1995;86:795-9. 20. Khaw KS, Wang CC, Ngan Kee WD, Pang CP, Rogers MS. Effects of high inspired oxygen fraction during elective cesarean section under spinal anesthesia on maternal and fetal oxygenation and lipid peroxidation. Br J Anaesth 2002;88:18-23. 21. Suzuki S, Yoneyama Y, Sawa R, Murata T, Araki T, Power GG. Changes in fetal plasma adenosine and xanthine concentrations during fetal asphyxia with maternal oxygen administration in ewes. Tohoku J Exp Med 2000;192: 275-81.
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www.AJOG.org 22. Yamada T, Yoneyama Y, Sawa R, Araki T. Effects of maternal oxygen supplementation on fetal oxygenation and lipid peroxidation following a single umbilical cod occlusion in fetal goats. J Nippon Med Sch 2003;70:165-71. 23. Nesterenko TH, Acun C, Mohamed MA, et al. Is it a safe practice to administer oxygen during uncomplicated delivery? A randomized controlled trial. Early Human Dev 2012;88: 677-81. 24. Sola A, Saldeno YP, Favareto V. Clinical practices in neonatal oxygenation: where have we failed? What can we do? J Perinatol 2008;28:S28-34. 25. Davis PG, Tan A, O’Donnell CPR, Schulze A. Resuscitation of newborn infants with 100% oxygen or air: a systematic review and metaanalysis. Lancet 2004;364:1329-33. 26. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation 2007;72:353-63. 27. Kattwinkle J, Perlman JM, Aziz K, et al. Neonatal resuscitation: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics 2010;126:e1400-13. 28. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312:159-63. 29. Klinger G, Beyene J, Shah P, Perlman M. Do hyperoxemia and hypocapnia add to the risk of brain injury after intrapartum asphyxia? Arch Dis Child Fetal Neonatal Ed 2005;90:F49-52. 30. Wang W, Pang CCP, Rogers MS, Chang AMZ. Lipid peroxidation in cord blood at birth. Am J Obstet Gynecol 1996;174: 62-5. 31. Dede FS, Guney Y, Dede H, Koca C, Dilbaz B, Bilgihan A. Lipid peroxidation and antioxidant activity in patients in labor with nonreassuring fetal status. Eur J Obstet Gynecol Reprod Biol 2006;124:27-31. 32. Ramin SM, Gilstrap LC, Leveno KJ, Little BB. Umbilical artery acid-base status in the preterm infant. Obstet Gynecol 1989;74: 256-8. 33. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). A randomized trial of fetal ECG ST segment and T wave analysis as an adjunct to electronic fetal heart rate monitoring (STAN). ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). 2000-NLM Identifier: NCT01131260. Available at: http:// clinicaltrials.gov/ct2/show/NCT01131260?term¼ STAN&rank¼1. Accessed Dec. 23, 2013.
www.AJOG .org
OBSTETRICS
Oxygen for intrauterine resuscitation: of unproved benefit and potentially harmful Maureen S. Hamel, MD; Brenna L. Anderson, MD, MSc; Dwight J. Rouse, MD, MSPH
E
very day, on most labor and delivery units in the United States, laboring women receive inhaled oxygen in the hope that it will improve the metabolic condition of their fetuses, or at least alleviate nonreassuring fetal heart rate patterns. In fact, administration of oxygen for this purpose is sanctioned by the American Congress of Obstetricians and Gynecologists; the Association of Women’s Health, Obstetric, and Neonatal Nurses; and the American College of Nurse-Midwives.1 Although population-based data on the frequency of this practice are not available, in 1 randomized trial of fetal pulse oximetry,2 two-thirds of patients received oxygen at some point during their labor for a nonreassuring fetal heart rate tracing (written personal communication Steven Weiner, MS, April 8, 2013). Despite its frequent use, data to support that maternal oxygen supplementation benefits the fetus are limited. Fawole and Hofmeyr,3 in their Cochrane Review, conclude that there is insufficient evidence to support the notion that use of oxygen for prophylaxis in labor or for treatment of fetal distress is beneficial to the fetus. Indeed, it may even be harmful. Herein we review the physiology pertinent to maternal oxygen supplementation, and the available relevant animal From the Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI (all authors). Received Nov. 2, 2013; accepted Jan. 7, 2014. The authors report no conflict of interest. Reprints: Maureen S. Hamel, MD, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, 101 Dudley St., Providence, RI 02905. [email protected]. 0002-9378/$36.00 ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.01.004
Maternal oxygen is often given to laboring women to improve fetal metabolic status or in an attempt to alleviate nonreassuring fetal heart rate patterns. However, the only 2 randomized trials investigating the use of maternal oxygen supplementation in laboring women do not support that such supplementation is likely to be of benefit to the fetus. And by increasing free radical activity, maternal oxygen supplementation may even be harmful. Based on a review of the available literature, we conclude that until it is studied properly in a randomized clinical trial, maternal oxygen supplementation in labor should be reserved for maternal hypoxia, and should not be considered an indicated intervention for nonreassuring fetal status. Key words: fetal resuscitation, labor, maternal oxygen
and human data to summarize the potential benefits and risks of maternal oxygen administration during labor. To inform our review, we conducted a search of the electronic databases MEDLINE, PubMed, and the Cochrane Database of Systematic Reviews through September 2013 using the phrases or key words: “fetal resuscitation,” “maternal oxygen administration,” “maternal oxygen therapy,” “nonreassuring fetal heart tracing/patterns,” and “lipid peroxidation in labor.” Additionally, we reviewed the reference lists of the articles identified in our electronic search for pertinent studies.
Background Our understanding of maternal-fetal gas exchange comes primarily from animal experiments, specifically with sheep, and, to a lesser extent, from human observational data.4 At baseline, PO2 (oxygen dissolved in blood and unbound to hemoglobin) in maternal arterial blood is around 100 mm Hg, while the umbilical venous PO2 in the near term fetus is estimated to be approximately 28 mm Hg.4 Despite lower partial pressures within the umbilical vein, the fetus is able to adequately oxygenate its tissues. Oxygen saturation is the percentage of oxygen-binding sites on hemoglobin that are bound by oxygen. Normal
oxygen saturation in healthy women is 99-100% while in the near term fetus it is usually 60-70%.4 The fetus survives in this relatively hypoxic state because fetal hemoglobin more avidly binds oxygen than maternal hemoglobin, and the fetal hemoglobin concentration is higher than the maternal: 16.5 g/dL (range, 15e18.6 g/dL)5 vs 12.5 g/dL (range, 11.0e14.0 g/dL).6,7 Oxygen content in blood is the combination of dissolved oxygen and oxygen bound to hemoglobin. Despite lower partial pressure, because of increased binding capacity and higher hemoglobin, when compared with maternal arterial blood, umbilical venous blood has similar total oxygen content.4 Why give oxygen? Under normal physiologic conditions, oxygen supply to the fetus exceeds demand; fetal oxygen uptake is not affected until oxygen delivery is reduced by more than half.8 Work in nonhuman primates by James et al9 in 1972 indicates that fetal hypoxia is the principle cause of late decelerations and can be resolved by increasing fetal PO2. Additional primate work by Murata et al10 suggests that late decelerations are early signs of hypoxia that, without intervention, will be followed by the absence of accelerations, and, if the hypoxia is sustained, fetal
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acidemia. Thus, administration of supplemental maternal oxygen would appear to be a logical intervention in response to an abnormal fetal heart rate pattern. Will maternal oxygen supplementation alleviate abnormal fetal heart rate patterns? In fact, there is a significant body of animal and human data demonstrating that maternal oxygen administration increases fetal oxygen levels and can remediate abnormal fetal heart rate patterns. As early as 1967, Althabe et al11 reported human data showing that 100% oxygen via face mask corrected fetal tachycardia and reduced the frequency of late decelerations, or eliminated them altogether. The fetal heart rate effects correlated with changes in fetal muscle PO2 levels. Four years later, in 1971, Khazin et al12 also found that just a few minutes of giving oxygen to laboring women alleviated late decelerations. Does the alleviation of abnormal fetal heart rate patterns with oxygen translate into improved fetal metabolic status? Human observational data by Kubli et al13 demonstrate a relationship between late decelerations and abnormal fetal acid-base status. However, data on the relationship between maternal oxygen administration and fetal acid-base status are mixed, and limited for the most part to nonrandomized trials, or trials that do not exclusively involve laboring women. Newman et al14 administered either 50% or 100% oxygen to women during the first stage of labor and measured fetal scalp blood pH. During maternal hyperoxia, no significant change in fetal scalp pH was observed ([mean SD] baseline value 7.28 0.013 vs hyperoxia 7.30 0.01, P value not stated). In addition to alleviating late decelerations, Khazin et al12 also reported that maternal hyperoxia during labor was associated with an increase in fetal PO2 without concomitant acidosis; however, mean pH and P values were not reported. In a randomized trial by Ramanathan et al15 in 1982, 40 women undergoing elective cesarean
delivery under epidural anesthesia were assigned to breathe 1 of 4 different concentrations of oxygen via face mask. Mean duration of oxygen exposure was 36 4 minutes and fetal umbilical cord pH was measured at delivery. Fraction of inspired oxygen (FIO2) ranged from 0.21e1.00 and no differences in fetal pH were found between normoxic (FIO2 0.21, 7.33 0.09) and hyperoxic (FIO2 0.47, 7.33 0.01; FIO2 0.74, 7.34 0.07; FIO2 1.00, 7.32 0.005) groups. To date there have been only 2 randomized trials investigating the use of maternal oxygen supplementation in exclusively laboring women. Both were trials of oxygen as prophylaxis in labor and enrolled <200 patients. In 1995, Thorp et al16 investigated the effects of maternal oxygen on fetal cord pH. In all, 86 women with reassuring fetal heart tracings were randomly allocated during the second stage of labor to breathe oxygen at 10 L/min via face mask or to breathe room air. While there was no difference in mean umbilical artery pH between the 2 groups (7.258 0.069 vs 7.285 0.058, oxygen and control, respectively, P ¼ .06), neonates born to women in the oxygen group were significantly more likely to have umbilical artery pH values <7.20 (9/41 vs 2/44, P ¼ .02, Fisher exact test). In 1997, Sirimai et al17 randomized 160 women at term to breathe oxygen or room air throughout the entirety of the second stage of labor. As in the trial of Thorp et al,16 more neonates born to mothers in the oxygen group had umbilical artery cord pH values <7.2 (8/80 vs 3/80 in the room air group). However, this difference was not statistically significant (P ¼ .12). Information from this trial is quite limited as it is available only in abstract form.17 Animal trials have allowed researchers to simulate and observe fetal compromise in scenarios that would be impossible to study in human beings by allowing oxygen to be studied as a single intervention. As previously mentioned, James et al9 conducted observational research monitoring the cardiovascular and acid-base status of laboring nonhuman primates. As labor progressed, a group of fetuses was noted to become
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www.AJOG.org hypoxic, hypotensive, and acidotic. The initial response to fetal hypoxia was fetal tachycardia and then, as hypoxia worsened, late decelerations appeared. While 100% maternal oxygen was successful at improving or even resolving late decelerations, it had no effect on acid-base status or fetal hypotension.9 In additional work with primates, Morishima et al18 administered 100% oxygen for 30 minutes during labor (spontaneous or induced) to mothers of fetuses with and without signs of “fetal distress” (which they defined as late decelerations). In the 40 primates with signs of fetal distress they found that while maternal oxygen raised both fetal and maternal oxygen levels and reduced the frequency of late decelerations, it did not improve mean fetal pH (7.10 0.029 vs 7.07 0.034). In the 15 subjects for whom maternal oxygen had no beneficial effect on the frequency of decelerations, pH worsened significantly (6.97 0.035 vs baseline 7.11 0.028, P < .01).18 Therefore, the available human and animal data, which admittedly are not robust, suggest that at best, maternal oxygenation supplementation can alleviate abnormal fetal heart rate patterns but not improve fetal acid-base status. At worst, such oxygen supplementation may actually lower fetal pH. And while it might be postulated that the alleviation of abnormal fetal heart rate tracings by maternal oxygen supplementation will reduce the number of operative deliveries for that indication, in our review of the literature (described earlier), we found no human trials that directly address this issue. Other than possibly lowering fetal pH, how else might oxygen be detrimental? Maternal oxygen supplementation readily induces maternal hyperoxia. Polvi et al19 found that just 5 minutes of breathing 50% oxygen via face mask increased maternal PaO2 to >200 mm Hg, and an additional 5 minutes of 100% oxygen increased it to >300 mm Hg. Maternal hyperoxia, in turn, may lead to increased free radical activity in both mothers and neonates. In 2002, in a double-blinded trial, Khaw et al20 randomized women undergoing elective
www.AJOG.org cesarean delivery under spinal anesthesia to breath room air or 60% oxygen via face mask prior to delivery and then measured 3 markers of free radical activity in maternal and umbilical cord blood: malondialdehyde (MDA), isoprostane, and organic hydroperoxides. Mean exposure time to oxygen was approximately 50 minutes. Maternal blood levels of MDA were increased in oxygen-exposed women as compared to control women (1.26 0.22 vs 0.89 0.16 mmol/L1, P < .05). However, isoprostane and organic hydroperoxides levels were similar between groups. Likewise, compared to neonates in the room aireexposed group, MDA levels were increased in the arterial umbilical cord blood of neonates born to mothers in the oxygen group (0.48 0.10 vs 0.40 0.06 mmol/L1) as were levels of isoprostane (215.2 92.7 vs 122.1 73.4 mmol/L1) and organic hydroperoxides (0.39 0.10 vs 0.18 0.09 mmol/L1). All 3 comparisons were statistically significant at P < .001.20 In lambs, Suzuki et al21 studied maternal exposure to 100% oxygen vs room air before, during, and after 5 minutes of umbilical cord occlusion. Predictably, oxygen exposure increased fetal PaO2. However, it also resulted in persistently elevated fetal plasma levels of xanthine, a marker of free radical activity, 30 minutes after cord release,21 suggesting that after a period of asphyxia, oxygen therapy may contribute to free radical activity. Similarly, Yamada et al22 exposed goats to maternal oxygen before, during, and after a period cord occlusion. Markers of free radical activity were elevated in fetuses of oxygen-exposed mothers before, during, and after the period of asphyxia.22 In both trials, animals served as their own controls. In 2012, in a double-blinded trial, Nesterenko et al23 randomized 56 women at term to breathe 100% oxygen via nasal cannula or room air for a minimum of 30 minutes prior to delivery. Both groups included laboring women as well as women scheduled for elective cesarean delivery. Mean time of oxygen exposure was approximately 2 hours and while no differences in mixed umbilical cord pH (control 7.35 0.1 vs
Obstetrics oxygen 7.33 0.1, P ¼ .38) or markers of oxygen free radical activity were found, 20% (6 of 30) of infants in the oxygen group required resuscitation in the delivery room vs 0% (0 of 26) in the control group (P ¼ .03).23 Although the long-term consequences of fetal exposure to hyperoxia have not been well studied, the consequences of neonatal exposure have been. Oxygeninduced cellular damage has been implicated in the pathogenesis of bronchopulmonary dysplasia and retinopathy of prematurity.24 And evidence regarding the role of oxygen in neonatal resuscitation suggests that even brief exposure to excessive oxygen can result in adverse outcomes. Two separate metaanalyses of randomized controlled trials comparing neonatal resuscitation with 100% oxygen vs room air have demonstrated decreased mortality with room air (relative risk, 0.71; 95% confidence interval, 0.54e0.9425; and odds ratio, 0.70; 95% confidence interval, 0.5e0.9826); currently the use of 100% oxygen in neonatal resuscitation is discouraged.27 Maternal hyperoxia is induced to correct fetal hypoxia, however it is during periods of hypoxia that the fetus may be most at risk from reactive oxygen species. During hypoxia fetal respiration converts from aerobic to anaerobic and adenosine triphosphate (ATP) is depleted. ATP breakdown products accumulate and there is a subsequent increase in cell permeability to ions. When reoxygenation occurs, calcium flows into cells, disrupts ATP production, facilitates the breakdown of cellular molecules, and results in generation of oxygen free radicals.28 Unstable molecules that damage cell membranes, free radicals have the potential to cause edema or hemorrhage in vital fetal organs, specifically the brain and the lungs.29 Wang et al30 demonstrated an association between umbilical cord blood levels of MDA and fetal acid-base status proposing it as a surrogate of hypoxia. Dede et al31 investigated cord blood levels of lipid peroxidation products (MDA) in patients delivered by cesarean section for nonreassuring fetal heart tracings. When compared to controls,
Clinical Opinion
patients with nonreassuring fetal status had elevated lipid peroxidation products in both umbilical cord and placental samples.31 After a period of hypoxia, free radical activity may contribute to ischemia-reperfusion injury; in theory, introducing additional reactive oxygen species via maternal oxygen administration may only exacerbate this process.
Conclusions Oxygen is frequently given to improve fetal status, however there is a paucity of outcome data to support its use and evidence of fetal benefit is lacking. Animal studies suggest that when fetal hypoxia is not the result of maternal hypoxia, maternal oxygen raises markers of free radical activity21,22 and the negative repercussions of free radicals are well described.24,29 Primate research demonstrates that while oxygen may correct hypoxia, it will not correct acidosis.9,18 Neonatal resuscitation with 100% oxygen is no longer recommended because of its demonstrated potential for harm.27 The limited data from pregnant women suggest that oxygen can lead to decreased umbilical cord pH,16 increase the need for neonatal resuscitation,23 and increase markers of free radical activity.20 Nor do the data suggest that maternal oxygen administration for the purpose of alleviating nonreassuring fetal heart patterns will translate into a lowered rate of cesarean delivery. A randomized trial of oxygen for intrauterine resuscitation is feasible, although the practice may be so ingrained as to make recruitment to such a trial difficult. The necessary sample size of the trial would of course depend on the primary outcome. For example, assuming a mean (SD) umbilical artery cord pH of 7.28 0.0732 to detect a 0.02 difference in umbilical artery cord pH with 80% power and a 2-tailed alpha of 0.05, would require as few as 400 participants randomly allocated to supplemental oxygen or no oxygen. But to definitively assess efficacy with a serious neonatal composite as the primary outcome might require as many as 11,000.33 Each year in the United States, approximately 4 million women give
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Obstetrics
birth, and of those, approximately 80% labor. If even half receive supplemental oxygen, then approximately 1.5 million women and their fetuses annually are subjected to supraphysiologic oxygen concentrations. Both animal and human data demonstrate that oxygen can be harmful, as does actual clinical experience (eg, retinopathy of prematurity). Thus, the public health consequences of maternal oxygen supplementation are potentially large. Therefore, until it is studied properly in a randomized clinical trial, our review leads us to conclude that maternal oxygen supplementation in labor should be reserved for maternal hypoxia and should not be considered an indicated intervention for nonreassuring fetal status. REFERENCES 1. American College of Obstetricians and Gynecologists. Management of intrapartum fetal heart rate tracings. ACOG practice bulletin no. 116. Obstet Gynecol 2010;116:1232-40. 2. Bloom SL, Spong CY, Thom E, et al. Fetal pulse oximetry and cesarean delivery. N Engl J Med 2006;355:2195-202. 3. Fawole B, Hofmeyr GJ. Maternal oxygen administration for fetal distress. Cochrane Database Syst Rev 2012;12:CD0000136. 4. Meschia G. Fetal oxygenation and maternal ventilation. Clin Chest Med 2011;32:15-9. 5. Walker J, Turnbull EP. Hemoglobin and red cells in the human fetus and their relation to the oxygen content of the blood in the vessels of the umbilical cord. Lancet 1953;2:312-8. 6. Milman N, Bergholt T, Byg K, Eriksen L, Hvas A. Reference intervals for hematological variables during normal pregnancy and postpartum in 434 healthy Danish women. Eur J Haematol 2007;79:39-46. 7. Beaton GH. Iron needs during pregnancy: do we need to rethink our targets? Am J Clin Nutr 2000;72(Suppl):265-71S. 8. Wilkening RB, Meschia G. Fetal oxygen uptake, oxygenation and acid-base balance as a function of uterine blood flow. Am J Physiol Heart Circ Physiol 1983;244:H749-55. 9. James LS, Morishima HO, Daniel SS, Bowe ET, Cohen H, Niemann WH. Mechanism of late deceleration of the fetal heart rate. Am J Obstet Gynecol 1972;113:578-82.
10. Murata Y, Martine CB, Ikenoue T, et al. Fetal heart rate accelerations and late decelerations during the course of intrauterine death in chronically catheterized rhesus monkeys. Am J Obstet Gynecol 1982;144: 218-23. 11. Althabe O, Schwarcz RL, Pose SV, Escarcena L, Caldeyro-Barcia R. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol 1967;98: 858-70. 12. Khazin AF, Hon EH, Hehre FW. Effects of maternal hyperoxia on the fetus. Am J Obstet Gynecol 1971;109:628-37. 13. Kubli FW, Hon EH, Khazin AF, Takemura H. Observations on heart rate and pH in the human fetus during labor. Am J Obstet Gynecol 1969;107:1190-206. 14. Newman W, McKinnon L, Phillips L, Paterson P, Wood C. Oxygen transfer from mother to fetus during labor. Am J Obstet Gynecol 1967;99:61-9. 15. Ramanathan S, Gandhi S, Arismendy A, Chalon J, Turndoff H. Oxygen transfer from mother to fetus during cesarean section under epidural anesthesia. Anesth Analg 1982;61: 576-81. 16. Thorp JA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol 1995;172:465-74. 17. Sirimai K, Atisook R, Boriboonhirunsam D. The correlation of intrapartum maternal oxygen administration and umbilical cord blood gas values. Acta Obstet Gynecol Scand Suppl 1997;76:90. 18. Morishima HO, Daniel SS, Richards RT, James LS. The effect of increased maternal PaO2 upon the fetus during labor. Am J Obstet Gynecol 1975;123:257-64. 19. Polvi HJ, Pirhonen JP, Erkkola RU. The hemodynamic effects of maternal hypo- and hyperoxygenation in healthy term pregnancies. Obstet Gynecol 1995;86:795-9. 20. Khaw KS, Wang CC, Ngan Kee WD, Pang CP, Rogers MS. Effects of high inspired oxygen fraction during elective cesarean section under spinal anesthesia on maternal and fetal oxygenation and lipid peroxidation. Br J Anaesth 2002;88:18-23. 21. Suzuki S, Yoneyama Y, Sawa R, Murata T, Araki T, Power GG. Changes in fetal plasma adenosine and xanthine concentrations during fetal asphyxia with maternal oxygen administration in ewes. Tohoku J Exp Med 2000;192: 275-81.
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www.AJOG.org 22. Yamada T, Yoneyama Y, Sawa R, Araki T. Effects of maternal oxygen supplementation on fetal oxygenation and lipid peroxidation following a single umbilical cod occlusion in fetal goats. J Nippon Med Sch 2003;70:165-71. 23. Nesterenko TH, Acun C, Mohamed MA, et al. Is it a safe practice to administer oxygen during uncomplicated delivery? A randomized controlled trial. Early Human Dev 2012;88: 677-81. 24. Sola A, Saldeno YP, Favareto V. Clinical practices in neonatal oxygenation: where have we failed? What can we do? J Perinatol 2008;28:S28-34. 25. Davis PG, Tan A, O’Donnell CPR, Schulze A. Resuscitation of newborn infants with 100% oxygen or air: a systematic review and metaanalysis. Lancet 2004;364:1329-33. 26. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation 2007;72:353-63. 27. Kattwinkle J, Perlman JM, Aziz K, et al. Neonatal resuscitation: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics 2010;126:e1400-13. 28. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312:159-63. 29. Klinger G, Beyene J, Shah P, Perlman M. Do hyperoxemia and hypocapnia add to the risk of brain injury after intrapartum asphyxia? Arch Dis Child Fetal Neonatal Ed 2005;90:F49-52. 30. Wang W, Pang CCP, Rogers MS, Chang AMZ. Lipid peroxidation in cord blood at birth. Am J Obstet Gynecol 1996;174: 62-5. 31. Dede FS, Guney Y, Dede H, Koca C, Dilbaz B, Bilgihan A. Lipid peroxidation and antioxidant activity in patients in labor with nonreassuring fetal status. Eur J Obstet Gynecol Reprod Biol 2006;124:27-31. 32. Ramin SM, Gilstrap LC, Leveno KJ, Little BB. Umbilical artery acid-base status in the preterm infant. Obstet Gynecol 1989;74: 256-8. 33. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). A randomized trial of fetal ECG ST segment and T wave analysis as an adjunct to electronic fetal heart rate monitoring (STAN). ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). 2000-NLM Identifier: NCT01131260. Available at: http:// clinicaltrials.gov/ct2/show/NCT01131260?term¼ STAN&rank¼1. Accessed Dec. 23, 2013.