Maternal hyperoxygenation in the treatment of intrauterine growth retardation Cesare Battaglia, MD, Paolo G. Artini, MD, Gerardo D' Ambrogio, MD, Paolo A. Galli, MD, Alberto Segre, MD, and Andrea R. Genazzani Modena, Italy OBJECTIVE: In the current study the efficacy of maternal hyperoxygenation on growth-retarded fetuses was evaluated. STUDY DESIGN: Thirty-six pregnant women with intrauterine growth retardation were studied. The patients were divided in oxygen-treated (n = 17) and untreated (n = 19) groups. Doppler analysis of the fetal circulation was performed on the arrival to the hospital, after 12 hours, and thereafter on alternate days until delivery. Fetal blood was sampled by cordocentesis for immediate blood gas analysis at entrance to the study and the day of delivery. RESULTS: Significant improvement in Doppler flow patterns in treated patients were found when compared with untreated women. The Doppler variations were associated with complementary modifications in fetal blood gas. These differences resulted in a significant modification in perinatal mortality with an incidence of 29% and 68% (p < 0.01) in treated and untreated groups, respectively. CONCLUSION: Our data suggest a benefit of maternal hyperoxygenation in the treatment of fetal growth retardation. (AM J OBSTET GVNECOL 1992;167:430-5.)
Key words: Hyperoxygenation, growth retardation, Doppler, cordocentesis
Uteroplacental insufficiency leads to intrauterine growth retardation (IUGR), which is a major cause of perinatal mortality and postnatal morbidity. I. 2 IUGR and oligohydramnios in the second and early third trimesters of pregnancy indicate a poor prognosis for the fetus. These conditions may complicate about 1% of pregnancies." Arterial P02 in the fetus is 25% to 33% of the arterial P02 in the adult. Some authors referred to this as "physiologic hypoxia" even though it represents a normal state of fetal oxygenation.' However, in spite of the low Po 2 , fetal blood is capable of transporting large amounts of oxygen from the placenta to the fetus. This is possible because (1) the hemoglobin of fetal red blood cells has a high affinity for oxygen and (2) the rate of perfusion of fetal organs is high in comparison with oxygen requirements. Fetal hypoxia is induced by any decrease in fetal oxygenation below the normal level. Such a decrease may induce a reduction in the P02 of umbilical venous blood (hypoxic hypoxia). Chronic intrauterine hypoxia, hyFrom the Department of Obstetrics and Gynecology, University of Modena. Supported by the Italian Research Council targeted project "Prevention and Control DiseasesFactors," subproject"Maternal-Infant Diseases," contract No. 91-00219.PF41. Received for publication September 30,1991; revised January 31, 1992; accepted February 18, 1992. Reprint requests: Cesare Battaglia, MD, Department of Obstetrics and Gynecology, University of Modena, Via del Pozzo, 71,41100 Modena, Italy. 611137250
430
percapnia, acidosis, hyperlacticemia, and erythroblastosis occur in many growth-retarded fetuses." Current management includes early diagnosis, bed rest, and antenatal monitoring of fetal well-being until the fetus reaches a stage of viability that allows delivery. In the current prospective, randomized study the value of long-term maternal hyperoxygenation in comparison with the traditional management of bed rest was evaluated in the treatment of growth-retarded fetuses.
Patients and methods From October 1989 through August 1991 we studied 36 pregnant women at 26 to 34 weeks' gestation with IUGR. All the patients gave their informed consent to participate in the study. Patients included in the study fulfilled the following criteria: known last menstrual period, regular menses, absence of maternal diabetes, fetal ultrasonographic examination before 22 weeks with biometric data consistent with duration of amenorrhea, singleton fetus, no fetal malformation or chromosomal defects; reduced amount of amniotic fluid (oligohydramnios was defined by the absence of any amniotic fluid pocket measuring 2:2 em in a vertical axis), abnormal Doppler flow velocity waveforms in maternal-fetal circulation (± 2 SD of our reference ranges), ultrasonographic measurements' of fetal abdominal circumference 1 Time fro m d iagnosis to parturition (d ays) Estrio l (ng/ ml) Hu man placental lactogen (l1g/ ml) Hematocrit (%) Uric acid (mg/ d l) Mean platelet volu me
I
Delivery
Significance (p)
Admis sion
I
Delivery
28. 1 (25-35) 30.2 ± 0.5 31.7 ± 0.3
29.4 (29-36) 29.7 ± 1.6 30.9 ± 0.1
8 (47%) 8 (47%) 1 (6%)
10 (53%) 7 (37%) 2 (10%)
10. 1 ± 3.5
Significance between groups Significance (p)
Ad,(;;sion
NS
IDe~;;ery
NS
NS
NS NS NS NS
9 ± 3. 1
41.4 ± 7 3.4 ± 0.2
58.1 ± 8.4 7.3 ± 0.6
NS NS
39. 1 ± 6.3 2.9 ± 0.2
40 .3 ± 0.8 2.9 ± 0.6
NS NS
NS NS
NS NS
37.8 ± 1.3 4.8 ± 0.2 12.1 ± 0.3
37.5 ± 1.7 5.1 ± 0.1 13.3 ± 0.5
NS NS NS
38.4 ± 1.5 4.9 ± 0. 1 11.4 ± 0.2
38.6 ± I 5.5 ± 0.8 12.2 ± 0.5
NS NS NS
NS NS NS
NS NS NS
NS
NS
(A)
Platelets (lOOO /ml) Oligo hydramnios
Untreated (n = 19)
165 ± II 131 ± 10 17 (100%)
NS
189 ± 17 152 ± 8 19 (100%)
NS
NS
NS , Not significant.
manageme nt of bed rest (plus antihypertensive med icatio n, whe n necessar y) and (2) the same management plus humidified 55% oxygen at a rate of 8 Ll min administered contin uously (except d uring meal s, etc.) through an MC face mask for 24 hours a day.' Ultrasonogra phic assessment of amniotic fluid volume was performed on alternate da ys until partu rition. A weekly ult raso nographic measurement of feta l abdominal circ umference was performed . Both assessments were pe rfo rm ed with the pat ients in a semi recumbent position with a 3.5 MH z convex array realtime scanne r (Ansaldo AU 940, Ge nova, Italy). Doppler analysis of maternal-fetal circulation was performed on the arrival of patien ts to the hospital , after 12 hours (only on um bilical artery), and thereaft er on alternate days until pa rturition. Flow velocity waveforms were recorded with a d uplex pu lsed Doppler (Ansaldo AU 940) with a 3.5 MHz convex tr an sdu cer. Low-frequen cy Doppler signals originating from vessel wall motio n were eliminated by a 100 Hz low-frequency filter. No fetal breath ing or intervening fetal mot ion activity occurred during recording. Several arteries were ana lyzed transabdominally. We calculated the resistance index (Resistance index = Systolic - Diastolic/Systolic)" for the uterine and umbilical artery and the pulsati lity index (Pulsatility index = Systolic - Diastolic/Mean)' for the descending tho racic ao rta an d middle cerebral artery. The time-averaged mean velocity in the descending aorta was calculated" (the pu lsed sample volume was placed in the fetal de scending aorta j ust abo ve the level of diaphragm ; the angle of insonation was between 50 and 60 degrees ; and th e resu lts ex press the mean velocities over the cardiac cycle
of the max imum frequencies reco rded). For each exam ination we obtai ne d th e mea n value of th re e con secu tive waveforms. Feta l blood was samp led by cordocentesis'"" for immediate blood-gas ana lysis at entrance to the stud y while the mo ther was breathing air an d again on th e da y of delivery while the mother was breathi ng oxygen. Cordocentesis was perfor med by an aseptic tech nique without maternal fasting, sedation, and local anest hesia. The umbilical cord vessel sam pled was identified by ult rasonography as either vein or artery by turbulence produced after injection of 200 J.Ll of saline solut ion .'?: 11 The fetal origin of blood was subsequently confir med by the Kleihau er test . Fetal blood (100 J.LI) was collecte d into heparinized syringes, and blood- gas ana lysis was perform ed with a Radiometer AB-330 blood gas anlayzer (Radiometer, Copenhagen). On the day of delivery, after a further informed consent, cordocentesis was repeated , indicating to the pat ien ts that gas analysis would be useful to understand about fetal well-being. T he Dop ple r and cordocentesis indices were no t re vealed to the labor staff but were correlate d with pregnancy outcome. Duri ng the stud y all patients ha d the following matern al-fetal fu nctional indices measured every 3 days: human placental lactogen, estriol, hematocrit , platelet cou nt, mean platelet volume, and uric acid. The po ten tial harm of hyperoxygenation for the mother's lung was stud ied by seria l determinations of pu lmo nary vital cap acity." Statistical analysis. An un paired t test was used to calculate the significance of the di fferen ce among th e
432 Battaglia et al.
August 1992 Am J Obstet Gynecol
Table II. Fetal transabdominal Doppler velocimetry in oxygen-treated and untreated patients (mean ± SE) Treated (N = 17)
Resistance index Uterine artery Umbilical artery Pulsatility index Thoracic aorta Middle cerebral artery Time-averaged mean velocity (ern/ sec) Thoracic aorta
N = II N = 2
N=4
Significance
After 12 hours
Admission
0.78 ± 0.06 EDF negative RF 0.84 ± 0.04
N = II
N=2 N=4
Delivery
EDF negative RF 0.83 ± 0.01
N = 10 N= I
N=6
0.78 ± 0.08 EDF negative RF 0.78 ± 0.06
5.8 ± 0.4 2.4 ± 0.2
5.0 ± 0.1 3.1 ± 0.1
16 ± 2
20.7 ± I
(P)
NS NC NC NS
Key words: Hyperoxygenation, growth retardation, Doppler, cordocentesis
Uteroplacental insufficiency leads to intrauterine growth retardation (IUGR), which is a major cause of perinatal mortality and postnatal morbidity. I. 2 IUGR and oligohydramnios in the second and early third trimesters of pregnancy indicate a poor prognosis for the fetus. These conditions may complicate about 1% of pregnancies." Arterial P02 in the fetus is 25% to 33% of the arterial P02 in the adult. Some authors referred to this as "physiologic hypoxia" even though it represents a normal state of fetal oxygenation.' However, in spite of the low Po 2 , fetal blood is capable of transporting large amounts of oxygen from the placenta to the fetus. This is possible because (1) the hemoglobin of fetal red blood cells has a high affinity for oxygen and (2) the rate of perfusion of fetal organs is high in comparison with oxygen requirements. Fetal hypoxia is induced by any decrease in fetal oxygenation below the normal level. Such a decrease may induce a reduction in the P02 of umbilical venous blood (hypoxic hypoxia). Chronic intrauterine hypoxia, hyFrom the Department of Obstetrics and Gynecology, University of Modena. Supported by the Italian Research Council targeted project "Prevention and Control DiseasesFactors," subproject"Maternal-Infant Diseases," contract No. 91-00219.PF41. Received for publication September 30,1991; revised January 31, 1992; accepted February 18, 1992. Reprint requests: Cesare Battaglia, MD, Department of Obstetrics and Gynecology, University of Modena, Via del Pozzo, 71,41100 Modena, Italy. 611137250
430
percapnia, acidosis, hyperlacticemia, and erythroblastosis occur in many growth-retarded fetuses." Current management includes early diagnosis, bed rest, and antenatal monitoring of fetal well-being until the fetus reaches a stage of viability that allows delivery. In the current prospective, randomized study the value of long-term maternal hyperoxygenation in comparison with the traditional management of bed rest was evaluated in the treatment of growth-retarded fetuses.
Patients and methods From October 1989 through August 1991 we studied 36 pregnant women at 26 to 34 weeks' gestation with IUGR. All the patients gave their informed consent to participate in the study. Patients included in the study fulfilled the following criteria: known last menstrual period, regular menses, absence of maternal diabetes, fetal ultrasonographic examination before 22 weeks with biometric data consistent with duration of amenorrhea, singleton fetus, no fetal malformation or chromosomal defects; reduced amount of amniotic fluid (oligohydramnios was defined by the absence of any amniotic fluid pocket measuring 2:2 em in a vertical axis), abnormal Doppler flow velocity waveforms in maternal-fetal circulation (± 2 SD of our reference ranges), ultrasonographic measurements' of fetal abdominal circumference 1 Time fro m d iagnosis to parturition (d ays) Estrio l (ng/ ml) Hu man placental lactogen (l1g/ ml) Hematocrit (%) Uric acid (mg/ d l) Mean platelet volu me
I
Delivery
Significance (p)
Admis sion
I
Delivery
28. 1 (25-35) 30.2 ± 0.5 31.7 ± 0.3
29.4 (29-36) 29.7 ± 1.6 30.9 ± 0.1
8 (47%) 8 (47%) 1 (6%)
10 (53%) 7 (37%) 2 (10%)
10. 1 ± 3.5
Significance between groups Significance (p)
Ad,(;;sion
NS
IDe~;;ery
NS
NS
NS NS NS NS
9 ± 3. 1
41.4 ± 7 3.4 ± 0.2
58.1 ± 8.4 7.3 ± 0.6
NS NS
39. 1 ± 6.3 2.9 ± 0.2
40 .3 ± 0.8 2.9 ± 0.6
NS NS
NS NS
NS NS
37.8 ± 1.3 4.8 ± 0.2 12.1 ± 0.3
37.5 ± 1.7 5.1 ± 0.1 13.3 ± 0.5
NS NS NS
38.4 ± 1.5 4.9 ± 0. 1 11.4 ± 0.2
38.6 ± I 5.5 ± 0.8 12.2 ± 0.5
NS NS NS
NS NS NS
NS NS NS
NS
NS
(A)
Platelets (lOOO /ml) Oligo hydramnios
Untreated (n = 19)
165 ± II 131 ± 10 17 (100%)
NS
189 ± 17 152 ± 8 19 (100%)
NS
NS
NS , Not significant.
manageme nt of bed rest (plus antihypertensive med icatio n, whe n necessar y) and (2) the same management plus humidified 55% oxygen at a rate of 8 Ll min administered contin uously (except d uring meal s, etc.) through an MC face mask for 24 hours a day.' Ultrasonogra phic assessment of amniotic fluid volume was performed on alternate da ys until partu rition. A weekly ult raso nographic measurement of feta l abdominal circ umference was performed . Both assessments were pe rfo rm ed with the pat ients in a semi recumbent position with a 3.5 MH z convex array realtime scanne r (Ansaldo AU 940, Ge nova, Italy). Doppler analysis of maternal-fetal circulation was performed on the arrival of patien ts to the hospital , after 12 hours (only on um bilical artery), and thereaft er on alternate days until pa rturition. Flow velocity waveforms were recorded with a d uplex pu lsed Doppler (Ansaldo AU 940) with a 3.5 MHz convex tr an sdu cer. Low-frequen cy Doppler signals originating from vessel wall motio n were eliminated by a 100 Hz low-frequency filter. No fetal breath ing or intervening fetal mot ion activity occurred during recording. Several arteries were ana lyzed transabdominally. We calculated the resistance index (Resistance index = Systolic - Diastolic/Systolic)" for the uterine and umbilical artery and the pulsati lity index (Pulsatility index = Systolic - Diastolic/Mean)' for the descending tho racic ao rta an d middle cerebral artery. The time-averaged mean velocity in the descending aorta was calculated" (the pu lsed sample volume was placed in the fetal de scending aorta j ust abo ve the level of diaphragm ; the angle of insonation was between 50 and 60 degrees ; and th e resu lts ex press the mean velocities over the cardiac cycle
of the max imum frequencies reco rded). For each exam ination we obtai ne d th e mea n value of th re e con secu tive waveforms. Feta l blood was samp led by cordocentesis'"" for immediate blood-gas ana lysis at entrance to the stud y while the mo ther was breathing air an d again on th e da y of delivery while the mother was breathi ng oxygen. Cordocentesis was perfor med by an aseptic tech nique without maternal fasting, sedation, and local anest hesia. The umbilical cord vessel sam pled was identified by ult rasonography as either vein or artery by turbulence produced after injection of 200 J.Ll of saline solut ion .'?: 11 The fetal origin of blood was subsequently confir med by the Kleihau er test . Fetal blood (100 J.LI) was collecte d into heparinized syringes, and blood- gas ana lysis was perform ed with a Radiometer AB-330 blood gas anlayzer (Radiometer, Copenhagen). On the day of delivery, after a further informed consent, cordocentesis was repeated , indicating to the pat ien ts that gas analysis would be useful to understand about fetal well-being. T he Dop ple r and cordocentesis indices were no t re vealed to the labor staff but were correlate d with pregnancy outcome. Duri ng the stud y all patients ha d the following matern al-fetal fu nctional indices measured every 3 days: human placental lactogen, estriol, hematocrit , platelet cou nt, mean platelet volume, and uric acid. The po ten tial harm of hyperoxygenation for the mother's lung was stud ied by seria l determinations of pu lmo nary vital cap acity." Statistical analysis. An un paired t test was used to calculate the significance of the di fferen ce among th e
432 Battaglia et al.
August 1992 Am J Obstet Gynecol
Table II. Fetal transabdominal Doppler velocimetry in oxygen-treated and untreated patients (mean ± SE) Treated (N = 17)
Resistance index Uterine artery Umbilical artery Pulsatility index Thoracic aorta Middle cerebral artery Time-averaged mean velocity (ern/ sec) Thoracic aorta
N = II N = 2
N=4
Significance
After 12 hours
Admission
0.78 ± 0.06 EDF negative RF 0.84 ± 0.04
N = II
N=2 N=4
Delivery
EDF negative RF 0.83 ± 0.01
N = 10 N= I
N=6
0.78 ± 0.08 EDF negative RF 0.78 ± 0.06
5.8 ± 0.4 2.4 ± 0.2
5.0 ± 0.1 3.1 ± 0.1
16 ± 2
20.7 ± I
(P)
NS NC NC NS
