Respiratory and hemodynamic effects of methadone in pregnant women

Respiration Physiolo,gy (1980) 42, 383 393 © Elsevier/North-Holland Biomedical Press

RESPIRATORY AND HEMODYNAMIC EFFECTS OF METHADONE IN PREGNANT WOMEN*

JAMES METCALFE, MARCIA J. DUNHAM, GEORGE D. OLSEN and MICHAEL A. KRALL Heart Researeh Laboratory, Department of Medicine and the Department o1"Pharmacology, University of Oregon Health Scienees Center, Porthmd, OR 97201, U.S.A.

Abstract. Minute ventilation, end-tidal Pco2, 02 and CO2 concentrations in expired air, pulse rate and arterial blood pressure were measured in the last half of pregnancy in eight women taking methadone daily. Measurements were made with the subjects seated at rest, during the steady state of 50-watt bicycle exercise, and during recovery. Calculations of 02 consumption, CO 2 production, alveolar ventilation and oxygen debt were made. Studies were repeated in five subjects postpartum. Methadone diminishes the normal hyperventilation of pregnancy and its effect persists for more than 24 h. When comparisons are made of pregnant and postpartum values, some respiratory stimulation during pregnancy is apparent. Maternal oxygen debt following standard exercise during pregnancy is diminished after the daily dose of methadone and the maternal heart rate response to exercise is diminished concurrently. The maternal hypoventilation induced by methadone and maintained during exercise may be relevant to the low birth weights and high incidence of sudden infant death syndrome observed by others in the ofl~pring of methadone-dependent women.

Hemodynamics Methadone Oxygen debt

Pregnancy Respiration

During pregnancy minute ventilation increases out of proportion to the simultaneous increase in resting oxygen consumption (Burwell and Metcalfe, 1958). In other words, the ventilatory equivalent for oxygen (the volume of air ventilated for each liter of oxygen utilized) increases during pregnancy (Knuttgen and Emerson, 1974). Furthermore, although physiologic dead space is increased during pregnancy Accepted./br publication 20 August 1980 * This work was supported in part by U.S. Public Health Service Program Project Grant HD 10034 and the Oregon Heart Association. 383

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J. M E T C A L F E e t a / .

(Pernoll et al., 1975b), the alveolar partial pressure (Goodland et al., 1954) and the arterial carbon dioxide tension (Lucius et al., 1970) decline progressively as gestation advances. Thus, the occurrence of alveolar hyperventilation is well established. This phenomenon appears to be due to the effect of progesterone (Lyons and Antonio, 1959) or to the combined effects of progesterone and estrogen (Wilbrand et al., 1959), presumably acting on the respiratory center (Loeschcke, 1954). The hyperventilation of pregnancy persists during exercise. Indeed, calculations of alveolar Pco~ during exercise suggest that it is held even closer to the low resting level of pregnant women than it is to the higher resting level of nonpregnant individuals doing the same exercise (Pernoll et al., 1975b). Methadone depresses resting respiration of pregnant women on daily doses of the drug (Olsen et al., 1977). The hemodynamic effects of methadone are not prominent. It occasionally produces a sinus bradycardia and this may be associated with orthostatic hypotension. It does not interfere with cardiovascular reflexes (Goodman and Gilman, 1975). Infants of methadone-addicted mothers are underweight at birth (Reddy et al., 1971 ; Zelson et al., 1971) and the incidence of sudden infant death syndrome is about five times higher in this group than in infants born to nonaddicted mothers of similar socio-economic backgrounds (Chavez et al., 1979). The handicap to fetal growth may be due to a direct effect of the drug upon growth, although we are unaware of any evidence to support this hypothesis. It may be due to fetal hypoxia secondary to blocking by methadone of cytochrome P-450 in the placenta (Gurtner and Burns, 1972). Another alternative explanation for the retardation of fetal growth is that maternal hypoventilation limits CO2 removal from the pregnant uterus and that hypercapnia retards fetal growth. Studies of ventilation and hemodynamics in pregnant methadone maintenance subjects have not included measurements during exercise. The present study was undertaken to assess the effects of chronic methadone ingestion on the respiratory and hemodynamic responses of pregnant women to exercise.

Materials and methods

Eight women taking methadone daily by mouth (16 to 40 mg in different subjects) were studied in the last half of pregnancy (after 20 weeks). When more than one study was performed on the same subject during pregnancy, the data for that subject were averaged so that each subject is weighted equally in the group average; the same procedure was followed with postpartum data. Five subjects returned for at least one postpartum study. Each subject was studied before and I 3 h after her daily dose of methadone. Except for their addiction, and mild obesity in one subject, these women were judged to be free of disease by routine health screening procedures.

RESPIRATION IN PREGNANT METHADONE SUBJECTS

385

At each session the patient was seated on a bicycle ergometer (Godart), breathing room air through a rubber mouthpiece connected to a two-chamber valve system with a dead space of 85 ml. The nares were occluded by a sponge rubber nose clip. For the measurement of end-tidal CO 2 concentration (FETco_~), air was continuously sampled from the expiratory chamber of the valve and drawn at a known rate through a Perkin-EImer mass spectrometer (MGA-II00) which was calibrated before each study with room air and two gas mixtures containing known concentrations of CO2 and 02. The output signals of both channels (02 and CO2) of the mass spectrometer were recorded on a Brush Mark 240 recorder with the patient seated on the bicycle during the last 3 min of a 6-rain rest period before exercise, throughout a 6-min period of exercise (50-watt intensity) and for 10 min following exercise. Expired air was collected in four separate neoprene aeronautical balloons for: (1)the last 3 rain of rest; (2)for the first 3 min of exercise; (3)for the second, 3 min of exercise; and (4)for the 10-min recovery period. Each balloon's contents were analyzed within 30 min of collection for CO2 and 02 concentrations on the mass spectrometer and expired gas volume was measured in a Tissot spirometer and corrected for sampling losses. Respiratory rate (f) and FETco2 were determined from the recording, the latter by averaging the end-expiratory values throughout the last 1.5 min of measurement in each period (rest, exercise and recovery). The volumes of collected air were corrected to BTPS conditions. The rates of CO2 production (~/co.,) and oxygen consumption (Vow) are expressed at STPD. Resting alveolar ventilation (';CAr) was calculated from the equation: QAr_

~/co2, FETco~,

(1)

and the volume of the physiologic dead space at rest (VDr) was calculated : VD~ - g g r -- ~/ar

fr

(2)

Alveolar ventilation during exercise (VAe) was calculated in three ways, which we have previously described (Pernoll et al., 1975b). The first method assumes that FETco2 represents mean alveolar Fco2 during exercise, so equation (1) is used, substituting values obtained during exercise. It is generally accepted that F E T c o e is higher than mean alveolar Fco2 during exercise, so this method tends to underestimate alveolar ventilation. Method # 2 assumes that the physiologic dead space does not change from its resting value during exercise, in which case: VA~ = g E ~ - fe(VDr).

(3)

The third method assumes that FAco, does not change during exercise, in which case :

9Ae- 9co2~ FETco,,

(4)

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J. M E T C A L F E et al.

In normal pregnant women, values calculated by methods # 2 and # 3 are not significantly different from one another, but as expected, both are significantly higher than calculations based on method # 1. Arterial blood pressure was measured by sphygmomanometer on the right arm at 1-min intervals during rest. The 'Rest' reading is the average for the last 3 rain of the 6-min rest period before exercise. In addition, one measurement was taken within 15 sec of the cessation of exercise and is considered as the 'Exercise' reading. Measurements made at 1-min intervals for the last 3 min of recovery were similar to those at rest before exercise. Pulse rate was counted from a continuous electrocardiogram for 15 sec of each min. The results from the last three minutes of rest, exercise, and recovery, respectively, were averaged to obtain the value for each period.

TABLE 1

Comparison of data obtained from pregnant women (20M-I weeks) before and after the daily methadone dose. Values are reported as mean_+ standard deviation Before daily dose I (n=8)

After daily dose 2 (n=8)

Exercise Recovery

I 1,131 -+ 1888 34,922 +_ 3115 14,599 -+ 2205

I0,346 -+ 1956 31,247 +_ 2582 b 12,953 + 1949 d

O x y g e n consumption

Rest

271 _+ 27

274 ± 33

(~¢o2) (SlPD) (ml/min)

Exercise Recovery

919_+ 51 343 _+ 29

898 _+ 64 330 + 33

Ventilatory equivalent

Rest

~/E (BTPS)/Vo2(STPD)

Exercise

41.3 _+ 5. I 38.2 _+ 2.9 42.7 + 4.5

37.8 _+ 4. I a 35.0 _+ 2.5 c 39.7 + 4.9 b

32.3 -+ 3.6 34.2 -+ 3. I 31.1 _+ 3.0

35.4_+ 3.2 c 37.1 -+ 2.3 b 34.1 + 2.6 e

697_+ 217

528 _+ 155 d

5,741 _+ 1077

5,354

25,117 _+ 2258 28,264_+ 2390 26,784_+ 3238

22,870 _+ 2363 b 24,807_+ 1817 d 24,030_+ 2596 c

247_+ 17

263 _+ 33

E x p i r a t o r y minute volume (VE) (BTPS) (ml/min)

Rest

Recovery End-tidal CO2 partial pressure (P~Tc, o~)

Rest

(mm Hg)

Recovery

Exercise

O x y g e n debt (ml O2) (STPO)

Alveolar ventilation (~¢A) (ml/min)

Rest Exercise Method 1 Method 2 Method 3

1019

Physiologic dead space VD r (ml)

Rest

I 24-26 h after previous daily dose of methadone, 2 I 3 h after previous daily dose of methadone.

Paired t-test (comparison of values before and after daily dose): a = P < 0.05: b = P < 0.025; c = P < 0.01 ; d = P < 0.005; e = P < 0.001.

RESPIRATION IN P R E G N A N T M E T H A D O N E SUBJECTS

387

Statistical analyses were made using a paired t-test of the data obtained before and after methadone in each subject. An unpaired t-test was made of the group data obtained during pregnancy with the group data after pregnancy, separating data before from data after methadone in both pregnant and nonpregnant groups. A two-tailed table was used for evaluation of t.

Results R E S P I R A T I O N BEFORE A N D A F T E R THE DAILY DOSE OF M E T H A D O N E IN P R E G N A N C Y

The results of this comparison are shown in table 1. Expiratory minute volume decreases after the daily maintenance dose and the decrease is significant under the stress of exercise and during recovery. Oxygen consumption, CO2 production, and respiratory exchange ratio do not change significantly. The ventilatory equivalent for oxygen declines significantly after the daily dose of methadone during rest, exercise and recovery and there is a significant increase in the PEXco_, in all three periods of observation. The oxygen debt incurred by the 6-min period of 50-watt exercise is significantly lower after the daily dose than before it. Calculated alveolar ventilation declines in all three periods. The decrease at rest is not statistically significant, but it did occur in 7 of the 8 subjects. Calculated alveolar ventilation during exercise declines significantly according to calculations by all three methods. The calculated value for physiologic dead space is not significantly altered after the daily dose of methadone.

RESPIRATION BEFORE A N D A F T E R THE DAILY DOSE OF M E T H A D O N E 1N THE POSTPARTUM PERIOD

Data derived from studies of the postpartum subjects are shown in table 2. Only five subjects returned for postpartum studies and one of those was unwilling to be studied before her daily maintenance dose. As a result, there is great variability in the values, and there are no significant differences when comparisons are made of data obtained before the daily dose with data obtained 1 to 3 h after the daily dose. However, PETco, rises at rest, with exercise and during recovery, and the ventilatory equivalent for oxygen declines after the daily dose in all three periods. Additionally, alveolar ventilation during exercise declines according to all three methods of calculation.

C O M P A R I S O N OF RESPIRATION D U R I N G P R E G N A N C Y A N D POSTPARTUM

Resting expiratory minute volume declines following delivery both before and after the daily maintenance dose of methadone, but the decrease is not statistically

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J. M E T C A L F E et al.

TABLE 2 Comparison of data obtained from postpartum women before and after the daily methadone dose*

Before daily dose (n = 4)

After daily dose (n = 5)

Rest Exercise Recovery

8639_+ 2129 27769 _+ 2853 12187 _+ 2725

8916+_ 2094 25765 +_ 4758 10655 _+ 1675

Rest Exercise Recovery

274+- 51 947_+ 141 310+- 92

261_+ 42 923_+ 102 335-+ 47

Ventilatory equivalent ~¢E (uvPS}/Vo, {STPD)

Rest Exercise Recovery

35.0_+ 6.3 29.7+- 4.5 41.9+_ 15.9

34.4+- 7.9 27.8_+ 3.8 31.8_+ 2.0

End-tidal CO2 partial pressure {PET('o~) {ram Hg)

Rest Exercise Recovery

35.6_+ 4.2 42.9 +- 3.0 35.3 +_ 5.0

42.8+- 6.3 48.7+- 4.2 44.3 _+ 1.7

640 _+ 813

743 _+ 207

Expiratory minute volume

(~/E) (BTPS) {ml/min) Oxygen consumption

{~/O2) (STPD) (ml/min}

Oxygen debt (STPD) (ml O2} Alveolar ventilation (~¢A) (ml/min)

Physiologic dead space VD (ml)

Rest Exercise Method I Method 2 Method 3

5468+_ 1550

5537_+ 1482

20444 +_ 2164 22385 _+ 2429 23555 +_ 4769

18605 ± 33 l0 20112 +_ 3999 21402 _+ 4347

Rest

223+_ 14

242_+ 27

* There are no significant differences between data obtained before and after methadone.

significant. Neither is the fall in minute ventilation which occurred during recovery. However, minute ventilation during exercise is significantly lower postpartum than during pregnancy, both before (P < 0.005) and after the daily dose (P < 0.025). Oxygen consumption, CO2 production, and respiratory exchange ratio are not significantly different when postpartum values are compared with the corresponding values during pregnancy. However, the ventilatory equivalent for oxygen is significantly smaller postpartum than during pregnancy, before (P < 0.005) and after (P < 0.005) the daily maintenance dose of methadone. Resting end-tidal P(:o: increases significantly after delivery, before ( P < 0.05) and after (P < 0.025) the daily dose of methadone. During exercise the difference is more striking (P < 0.005 before methadone, P < 0.001 after methadone). There are no significant changes attributable to pregnancy in oxygen debt, tidal volume or respiratory frequency. The decline in alveolar ventilation after delivery is not significant for resting values. Alveolar ventilation calculated on the assumption that PETcQ, represents

RESPIRATION IN PREGNANT METHADONE SUBJECTS

389

alveolar air (Method 1) is significantly smaller in the postpartum period, both before ( P < 0 . 0 1 ) and after ( P < 0.025) the methadone dose. When calculated assuming that respiratory dead space does not change during exercise (Method 2), the fall after delivery is also significant before ( P < 0.005) and after (P < 0.025) the daily dose of methadone. Calculation of alveolar ventilation during exercise on the assumption that end-tidal CO2 does not increase with exercise (Method 3) shows no significant change when post partum values are compared with data obtained during pregnancy.

ALVEOLAR VENTILATION IN METHADONE MAINTENANCE SUBJECTS COMPARED WITH NORMAL INDIVIDUALS Values obtained in methadone maintenance subjects are compared in table 3 with data which we have previously reported from normal women (Pernoll et al., 1975b). All three methods which we have used to calculate alveolar ventilation during exercise show that pregnant methadone maintenance subjects hypoventilate in comparison with normal pregnant women before their daily methadone dose (26 h after their previous dose) and that the hypoventilation becomes more marked after the daily dose.

HEMODYNAMIC DATA Table 4 presents the hemodynamic data obtained in this study. During pregnancy the heart rate was significantly slower after methadone, both during exercise and also during the last 3 min of recovery. Systolic and diastolic levels of blood pressure usually fell after methadone, but the fall was not significant either at rest or during exercise. Neither are postpartum values significantly different than those obtained under the same conditions during pregnancy. When hemodynamic data from these methadone maintenance subjects are compared with those from 12 normal women studied under the same conditions (Pernoll et al., 1975b) the only significant difference (P < 0.05) is the lower resting pulse rate during pregnancy in the methadone subjects (87+ 11, n = 8 vs. 103+ 15, n = 12) while sitting on the bicycle ergometer prior to exercise.

Discussion

Figure 1 is a graphic description of the relationship between PETco2 and minute ventilation at rest and with exercise. The lightly stippled area overlies the range of values found throughout pregnancy in normal women (Pernoll et al., 1975b) and the darker stippled area overlies the postpartum range. Mean values obtained

390

J. M E T C A L F E

et al.

TABLE 3 C o m p a r i s o n of a l v e o l a r ventilation at rest ('kArl a n d during exercise (~¢Ae) in m e t h a d o n e m a i n t e n a n c e subjects and n o r m a l w o m e n C o m p a r i s o n of VA r (1/min) Pregnant

Postpartum

N o r m a l w o m e n , n = 12

7.4-+ 1.0

5.1+_0.9

Methadone subjects Before daily dose After daily dose

5.7-+ I.I, n = 8 5.4 -+ 1.0, n = 8

5.4-+ 1.5, n = 4 5.5-+ 1.5, n = 5

P for n o r m a l w o m e n c o m p a r e d with methadone subjects Pregnant Before dose : P < 0.005 After dose: P < 0.001 Postpartum: no significant differences C o m p a r i s o n of c a l c u l a t e d 'kA e (l/min)*

Method 1

Method 2

Method 3

N o r m a l p r e g n a n t w o m e n , n = 12

27.0-+ 3.3

30.0-+ 4.0

30.6-+ 3.2

Pregnant methadone subjects Before daily dose. n = 8 After daily dose. n = 8

25. I _+ 2.3 22.9 + 2.4

28.3 _+ 2.4 24.8 _+ 1.8

26.8 -+ 3.2 24.0 -+ 2.6

N o r m a l w o m e n p o s t p a r t u m , n = 12

19.9-+ 3.1

22.8_+ 3.7

24.2-+ 3.2

Methadone subjects postpartum. Before daily dose. n = 4 After daily dose, n = 5

20.4--+ 2.1 18.6_+ 3.3

22.4-+ 2.4 20.1 +_ 4.0

23.6-+ 4.8 21.4-+ 4.3

NS P < 0.005

NS P < 0.025

P for n o r m a l w o m e n c o m p a r e d with methadone subjects Pregnant Before dose NS After dose P < 0.01 Postpartum : no significant differences * See text for methods of calculating ~¢Ac.

before and after the daily dose of methadone in the subjects of the present study are shown for comparison. Compared to normal pregnant women, before the daily dose of methadone, PETco~ is high at rest, but not during exercise. After the daily dose of methadone the addicts show further respiratory depression, both at rest and during exercise. Postpartum values in methadone subjects are all out of the range observed in normal postpartum women. Our data confirm previous reports that depression of respiration by methadone is not corrected by the stimulating effects of steroid hormones during pregnancy (Olsen et al., 1977). In addition, we have demonstrated that the respiratory depression persists during exercise. However, the respiratory response to exercise is more

391

R E S P I R A T I O N IN P R E G N A N T M E T H A D O N E SUBJECTS TABLE 4 Comparison of hemodynamic measurements before and after the daily methadone dose Pregnant (n = 8)

Postpartum

Belbre

After

Before (n = 4)

After (n = 5)

Heart rate (beats/rain)

Rest Exercise Recovery

87_+ l 1 123+ 8 a 97+- 13 b

87+_ 14 119+_ 8 90+_ 15

80+_ 12 116_+ 13 89+_ 14

81+ 9 117+- 9 83+ 8

Systolic blood pressure (ram Hg)

Rest Exercise

110-+ 13 136-+ II

108-+ 11 138-+ 5

111+_ 12 150-+ 6

108-+ 11 137-+ l0

Diastolic blood pressure (ram Hg)

Rest Exercise

63-+ 15 70-+ 1l

62-+ 17 69-+ 12

68-+ 15 73-+ 12

63-+ 8 67-+ 12

Paired t-test, comparison values before and after daily dose: a = P < 0.05; b = P < 0.01.

Range of meons for normal pregnant women Range of means for normal postpartum women o Pregnant, before methadone A Pregnant, after methadone • Postpartum, before methadone • Postpartum, after methadone

1

40

3o

o::::b 2O

10

k__//

I

I

I

I

I

I

25

:30

:35

40

45

50

PETco 2 (mmHg) Fig. I. The relationship between PETco: and minute ventilation at rest (symbol at lower end of each line) and during exercise (symbol at upper end of each line) in women taking methadone daily. Stippled areas indicate ranges obtained in normal women (Pernoll et al., 1975b).

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J. M E T C A L F E et al.

vigorous during pregnancy than in the postpartum period~ suggesting that the respiratory center is stimulated to some degree by the steroid hormones of pregnancy. Respiratory depression from methadone lasts longer than 24 h. A subject taking a daily maintenance dose during pregnancy, therefore, has higher tensions of CO2 in her arterial blood than do normal pregnant women. Unless a compensatory increase in uterine blood flow occurs or its distribution changes, fetal CO: tensions must also exceed normal. This is one possible basis for the handicap to fetal development which others have demonstrated in methadone maintenance subjects (Reddy et al., 1971). Fetal hypercapnia may also play a role in the delayed maturation of the ventilatory response to carbon dioxide seen in the congenitally addicted neonate (Olsen and Lees, 1980). The decrease after methadone in oxygen debt incurred by mild bicycle exercise during pregnancy is statistically highly significant, but its physiologic basis is unclear. During pregnancy normal women develop a larger oxygen debt with standard bicycle exercise than they do in the postpartum period (Pernoll et al., 1975a). If the magnitude of the oxygen debt indicates the magnitude of anaerobic metabolism during exercise the site of increased anaerobiosis during pregnancy may lie within the pregnant uterus. In sheep, Emmanouilides et al. (1972) found that the oxygen tension in blood from the descending aorta of the fetus decreased in association with maternal exercise. Orr et al. (1972) and Curet et al. (1976) could not document a significant change in uterine blood flow during or following exercise in pregnant sheep, but Longo et al. (1978) reported that pregnant sheep showed a reduction in uterine blood flow of nearly 50% while exercising at 46 m/min on a treadmill inclined at 10!!Jg. In humans, Morris et al. (1956) used the rate of disappearance of radioactively labeled saline injected into uterine muscle as an index of uterine blood flow. In patients with pre-eclampsia, the clearance rate was reduced by 250J~,during supine exercise. We know of no reason why methadone ingestion should improve fetal oxygenation during exercise. One hypothesis is that the release of epinephrine by the maternal organism is diminished after methadone administration. Epinephrine has a powerful vasoconstrictor effect upon the uterine vasculature (Clapp, 1979). This hypothesis derives some support from our observation that maternal heart rate during exercise is significantly lower in pregnant subjects after their daily methadone dose.

Acknowledgements The authors wish to thank Ann S. Mertl, J. Eugene Welch, Jean A. Matsumoto, Jack E. Wilson and Gene Robertson for their technical assistance.

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References Burwell, C.S. and J. Metcalfe (1958). Heart Disease and Pregnancy: Physiology and Management. Boston, Little, Brown and Company, page 31. Chavez. C.J., E.M. Ostrea, Jr., J.C. Stryker and Z. Smialek (1979). Sudden infant death syndrome a m o n g infants of drug-dependent mothers. J. Pediatr. 95 : 407-409. Clapp, J.F. III (1979). Effect of epinephrine infusion on maternal and uterine oxygen uptake in the pregnant ewe. Am. J. Ohstet. Gynecol. 133: 208-212. Curet, L.B., J.A. Orr, J . H . G . Rankin and T. Ungerer (1976). Effect of exercise on cardiac output and distribution of uterine blood flow in pregnant ewes. J. Appl. Physiol. 4 0 : 7 2 5 728. Emmanouilides, G . C . , C.J. Hobel, K. Yashiro and G. Klyman (1972). Fetal responses to maternal exercise in the sheep. Am. J. Obstet. Gynecol. 112:130 137. Goodland, R. L., J. G. Reynolds and W.T. Pommerenke (1954). Alveolar carbon dioxide tension levels during pregnancy and early puerperium. J. Clin. Endocrinol. 14:522 530. G o o d m a n , L.S. and A. Gilman (1975). The Pharmacological Basis of Therapeutics, 5th ed. New York, MacMillan Publishing Company, page 269. Gurtner, G . H . and B. Burns (1972). Possible facilitated transport of oxygen across the placenta. Nature 240:473 475. Knuttgen, H . G . and K. Emerson, Jr. (1974). Physiological response to pregnancy at rest and during exercise. J. Appl. Physiol. 36: 549-553. Loeschcke, H . H . (1954). I~ber die Wirkung von Steroidhormonen a u f die Lungen-bel/iftung. Kiln. Wochenschr. 32: 441-445. Longo, L.D., C.W. Hewitt, R. H . W . Lorijn and R . D . Gilbert (1978). To what extent does maternal exercise affect fetal oxygenation and uterine blood flow'? Fed. Proc. 37: 905. Lucius. H., H. Gahlenbeck, H.-O. Kleine, H. Fabel and H. Bartels (1970). Respiratory functions, buffer system, and electrolyte concentrations of blood during h u m a n pregnancy. Respir. Physiol. 9:311 317. Lyons, H.A. and R. Antonio (1959). The sensitivity of the respiratory center in pregnancy and after the administration of progesterone. Trans. Assoc, Am. Physicians. LXXII: 173 180. Morris, N., S. B. Osborn and H. P. Wright (1956). Effective uterine blood-flow during exercise in normal and pre-eclamptic pregnancies. Lance1 2: 481-484. Olsen, G . D . , A.S. Mertl and H.A. Wendel (1977), Control of ventilation in pregnant methadone maintenance subjects. Proc. West. Pharmacol. Soc. 20: 48% 492. Olsen, G. D. and M. H. Lees (19803. Ventilatory response to carbon dioxide of infants following chronic prenatal methadone exposure. J. Pediatr. (In press). Orr, J., T. Ungerer, J. Will, K. Wernicke and L.B. Curet (1972). Efl'ect of exercise stress on carotid, uterine, and iliac blood flow in pregnant and nonpregnant ewes. Am. J. Obstet. Gynecol. l 14:213-217. Pernoll, M.L., J. Metcalfe, T.L. Schlenker, J.E. Welch and J.A. M a t s u m o t o (1975a). Oxygen consumption at rest and during exercise in pregnancy. Respir. Physiol. 25:285 293. PernolL M. L., J. Metcalfe, P.A. Kovach, R. Wachtel and M, J. D u n h a m (1975b). Ventilation during rest and exercise in pregnancy and postpartum. Re~pir. Physiol. 25:295 310. Reddy, A. M., R . G . Harper and G. Stern (1971). Observations on heroin and methadone withdrawal in the newborn. Pediatrics 48:353 358. Wilbrand, U., C. Porath, P. Matthaes and R. Jaster (1959). Der Einfluss der Ovarialsteroide auf die Funktion des Atemzentrums. Arch. Gvniik. 191 : 507-531. Zelson, C., E. Rubio and E. Wasserman (1971). Neonatal narcotic addiction: Ten-year observation. Pediatrics 48 : 178 189,