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Absence or impaired response of fetal breathing to intravenous glucose is associated with pulmonary hypoplasia in congenital myotonic dystrophy
Absence or impaired response of fetal breathing to intravenous glucose is associated with pulmonary hypoplasia in congenital myotonic dystrophy George A. Vilos, M.D., William J. McLeod, M.D., Lesley Carmichael, B.Sc., Carol Probert, B.Se., and Paul G. R. Harding, M.D. London, Ontario, Canada Two fetuses of a patient affected with myotonic dystrophy were studied ultrasonically from 28 to 34 weeks' gestation. After a 1-hour observation period, an intravenous injection of 25 gm of 50% glucose solution was given to the mother. Fetal breathing movements were 0% during the control period and increased to only 10% at 90 minutes after the injection of glucose; the episode lasted approximately 30 minutes. The infants, who were delivered at 33 and 35 weeks, had generalized hypotonia, normal arterial cord blood gases, and died shortly after birth from pulmonary insufficiency, in spite of maximum ventilatory support. Postmortem pulmonary hypoplasia was confirmed by a lung weight/body weight ratio of less than 0.019. We postulate that fetal breathing activity and its response to the injection of glucose may be a potential clinical test by which normal fetuses can be differentiated from fetuses affected by neuromuscular disorders, including myotonic dystrophy. (AM. J. OesTET. GVNECOL. 148:558, 1984.)
Fetal breathing movements and gross fetal body movements are normal physiologic events in all healthy fetuses. In the human, fetal breathing activity has been observed as early as 11 weeks' gestation,! and during the third trimester the fe us makes breathing movements approximately 30% of the time {range, 17% to 65%).2 Fetal breathing activity is significantly increased 10 minutes after the administration of an intravenous bolus of 25 gm of glucose to the motherl and is dramatically abolished for a period of up to 4 hours soon after 1 ounce of alcohol is taken orally by the mother. 4 Although fetal breathing movements have been observed for many years, the relationship of fetal breathing movement to lung development was not recognized until recently. When fetal breathing was abolished by transection of the fetal spinal cord at C 2- 3 in rabbits 5 and in sheep6 or by bilateral phrenectomy in sheep/' B the weight and volume of the lungs were more than 50% lower than in control animals. Furthermore, when the negative intrathoracic pressure generated by each breath was "blunted" by thoracoplasty to increase the compliance of the chest wall in fetal Iambs, the weight and volume of the lungs were also reduced by more than 50%.9
From the Department of Obstetrics and Gynecology, St. Joseph's Hospital, The University of Western Ontario. Presented at the Thirty-ninth Annual Meeting of The Society of Obstetricians and Gynaecologists of Canada, Vancouver, British Columbia, Canada, June 14-18,1983. Reprint requests: Dr. G. A. Vilos, Department of Obstetrics and Gynecology, SI.joseph's Hospital, 268 Grosvenor St., London, Ontario, Canada N6A 4V2.
558
Since fetal breathing movements of normal intensity are necessary for lung development, and since pulmonary hypoplasia has been observed in infants with neonatal myotonic dystrophy,1O it follows that breathing movements in fetuses affected with myotonic dystrophy would be absent or ofIow intensity. The present report describes patterns of breathing activity and gross fetal body movements in two fetuses from 28 to 35 weeks' gestation and the response of fetal breathing movements and gross fetal body movements to an intravenous injection of glucose in one fetus at 32 and 33 weeks' gestation of a mother with myotonic dystrophy. Case history A 22-year-old Caucasian woman was referred during her third pregnancy at 31 weeks' gestation with polyhydramnios and a poor prior obstetric history. The first pregnancy had been complicated by polyhydramnios, with spontaneous delivery of a stillborn female infant at 26 weeks' gestation. The second pregnancy had also been complicated by polyhydramnios, with spontaneous delivery at 35 weeks' gestation. In the latter case, the female infant (birth weight, 2,176 gm) was delivered vaginally as an assisted breech. The Apgar scores were 1 and 4 at 1 and 5 minutes, respectively. The infant was actively resuscitated and transferred to our neonatal intensive care unit. On arrival, the baby had a blood pH of 6.89, and in spite of further aggressive therapy and ventilatory support, she died within 24 hours. Postmortem findings are reported in Table I. The mother was Rh negative with no antibodies present. She was given Rh immune globulin. The results of an oral glucose tolerance test on the mother were within normal limits.
Response Of fetal breathing to Intravenous glucose
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Table I. Perinatal outcome in four infants delivered of a mother with myotonic dystrophy A rterial blood gases Infant No.
Delivery (wk)
Sex
Method of delivery
1
26 35 32 33
F F M M
Breech Assisted breech Cesarean breech Cesarean breech
2 3 4
Apgar score at 5 min
Umbilical pH
Po.
I
Peo.
I
Base excess
Stillborn
During the third pregnancy the patient was referred to our tertiary care hospital at 31 weeks' gestation. Ultrasonic assessment at 28 weeks identified a normal fetus presenting as a breech, with a normal placenta but excessive amniotic fluid. The symphysis-to-fundus ?eight was 32 cm at 28 weeks' gestation and rapidly Increased to 46 cm by 32 weeks. At 32 weeks' gestation, because of the spontaneous onset of labor and a persistent breech presentation, the patient was delivered uneventfully by low-segment cesarean section of a male infant who weighed 1,760 gm. The baby was pale and extremely hypotonic with no spontaneous respiratory effort. The Apgar scores were 0, 2, and 4 at 1,5, and 10 minutes, respectively, and the arterial cord blood gases were as follows: pH 7.24, P02 16, Peo2 40, base excess -7.0. After immediate intubation, a peak airway pressure of 40 em H 20 was necessary to achieve adequate ventilation. A chest x-ray film revealed a complete "white out" appearance, with severe atelectasis and poor ~xpansion of the lungs compatible with respiratory distress syndrome, type I. Bilateral pleural effusion and hypoplastic ribs were also noted. The baby continued to need vigorous ventilatory support because of the respiratory distress syndrome, persistent fetal circulation, and generalized hypotonia. At 42 hours of age, he developed bilateral pneumothoraces, and in spite of the insertion of chest tubes, he died. Autopsy findings are summarized in Table II. The patient's poor obstetric performance, her physical appearance, including a receding hairline and myotonic facies, as well as the complete apnea and hypotonia of the latter infant at birth, with normal arterial cord blood gases, strongly suggested the presence of neuromuscular disorder. Myotonic dystrophy was subsequently confirmed in the mother and several relatives by electromyography and muscle biopsy. Despite genetic counseling, the patient was referred again at the beginning of her fourth pregnancy. At 29 weeks' gestation, she was hospitalized because of polyhydramnios. The symphysis-to-fundus height was 37 cm. At 33 weeks, she sustained spontaneous rupture of the membranes, and spontaneous labor commenced 1 week later. Because of a breech presentation and the previous history of cesarean delivery, a repeat cesarean section was carried out. The infant was a male who weighed 2,000 gm, with Apgar scores of 1 and 4 at 1 and 5 minutes, respectively, and with the following arterial cord blood gases: pH 7.24, Po, 22.9, Peo, 22.7, base excess -16.4. Despite immediate respiratory sup-
4
Not done
2
7.24 7.24
4
16.0 22.9
40.0
-7.0
22.7
-16.4
Table II. Body, lung, and diaphragmatic weights of infants with congenital myotonic dystrophy Infant No.
Birth weight (gm)
1
Not available
2 3 4
2,200 1,760 2,000
Lung weight (gm)
Lung/body weight ratio
38.0 22.1
0.017
17.5
0.012 0.009
Diaphragm (gm)
7.0 7.8
port and aggressive pulmonary assisted ventilation, the baby died 6 hours after delivery. Autopsy findings are summarized in Table II. Nonstress testing was performed daily in the last two fetuses throughout the period of hospitalization. Observations of fetal breathing movement and gross fetal body movements were also made in the last two fetuses twice a week with an ADR real-time ultrasonic scanner for at least 1 hour. During the fourth pregnancy, observations of fetal breathing movements and gross fetal body movements were made at 32 and 33 weeks' gestation after the mother had been given an intravenous injection of glucose. The patient fasted for 8 hours prior to each study. At 8 AM, the ADR scanner was connected to a PDPII computer for data analysis (Digital Equipment Corporation, Maynard, Massachusetts). Individual fetal breathing movements and gross fetal body movements were identified on a video monitor and coded on a chart recorder and the computer by an event marker. At 9 AM, the mother received an intravenous injection that contained 25 gm of 50% glucose solution, and the study was continued for an additional 3 hours. Details of the computer program and analysis have been reported. 2 Determinations of maternal glucose were performed by means of a glucose-oxidase oxygen rate meter (Beckman Instruments, Schiller Park, Illinois) (Fig. 1). The results presented in Figs. 2 and 3 represent the percentage of the time spent making fetal breathing movements and gross fetal body movements for each I5-minute interval before and after the administration of glucose at 32 and 33 weeks' gestation. Results
The maternal plasma glucose concentration increased from 73 mg/dl prior to injection, to more than 170 mg/dl in the first 30 minutes, and decreased
560
Vilos at aI.
March I, 1984 Am. J. Obstet. Gynecol.
terstitial hemorrhage, as well as marked atelectasis with severe hyaline membrane formation. The radial alveolar count was less than 3 in all lungs. The two diaphragms available for examination were thinner and wider than usual, with pale attenuated muscle fibers.
170
INJECTION OF 2511 OF GLUCOSE INTRAVENOUSLY
70
• - 30
! o
+ 30
+60
+ 90
+ 120
TIME (MINUTES)
Fig. 1. Maternal plasma glucose concentrations before and after injection of 25 gm of glucose intravenously at 33 weeks' gestation. rapidly to approximately 110 mg/dl at 90 minutes after the intravenous injection of glucose (Fig. 1). Fetal breathing activity was noted to be absent during the control period prior to the administration of glucose in both studies. Only one short episode of hiccoughing activity was recorded at 33 weeks' gestation. The percentage of time spent breathing by the fetus after the injection of glucose increased from 0% to approximately 10% in both studies. The peak of breathing activity occurred approximately 90 minutes after the injection of glucose, and it lasted for approximately 30 minutes (Fig. 2). The mean percentage of time spent by the fetus making gross body movements was not significantly altered by the administration of glucose. During the period before the injection, the fetus made gross body movements approximately 9.7% ± 3.0% of the time, whereas during the 3-hour period subsequent to injection, the mean percentage of time was 11.9% ± 1.9% (mean ± SEM, NS). The clinical presentation and the outcome of all four pregnancies are summarized in Table I. Polyhydramnios with premature onset of labor and delivery was associated with all pregnancies. Regardless of the method of delivery, the 1- and 5-minute Apgar scores were less than 4 in the three live-born infants, although the umbilical artery blood gases were within normal limits in the latter two infants. All infants died from pulmonary insufficiency shortly after birth, in spite of maximum ventilatory support. The body, lung, and diaphragm weights are shown in Table II. Histologically, the lungs of the three infants showed marked interstitial edema with focal in-
Comment The nonstress test, defined as five or more accelerations in the fetal heart rate of '2: 15 bpm lasting '2: 15 seconds in association with fetal movement during any 20-minute interval, was reactive in the last two fetuses during the entire period of hospitalization. Gross fetal body movements, as perceived by the mother and observed with the real-time scanner, were within normal limits. In contrast, fetal breathing movements were not observed on any of the occasions on which the two fetuses were observed. Only small-amplitude diaphragmatic excursions were observed episodically, whereas hiccoughing was observed occasionally in both fetuses. The substitution of fetal breathing movements by diaphragmatic "quivering" added support to the suspicion that these fetuses were also affected by myotonic dystrophy that resulted in muscular weakness of the diaphragm. We elected to study the fourth fetus further. It has been demonstrated that the amount of time the human fetus spends making breathing movements is increased when the maternal plasma glucose concentration is increased. This increase can be achieved by the mother consuming a high-calorie mea!,2 taking a glucose drink,!! or receiving an intravenous injection of glucoseY Adamson and associates!2 used an ultrasonic tracking devise to measure changes in fetal rib cage and abdominal diameter in healthy fetuses at term. After a 2-hour observation period, an intravenous injection of either 25 gm of a 50% glucose solution or an equal volume of saline solution was given to the mother. They found that, during the first 80 minutes after the injection of glucose, there was a significant increase in the amplitude of the fetal breaths. The 25 gm bolus of glucose resulted in maternal plasma concentrations of approximately 75 to 200 mg/dl immediately after the injection, with a rapid decrease to preinjection levels by 90 minutes.o A similar pattern of rise and fall in glucose concentrations was also observed in our patient. Bocking and associates3 found that healthy fetuses at 38 to 40 weeks' gestation made breathing movements 17.5% of the time during the 2 hours before the injection of glucose. Ten minutes after the injection, there was a dramatic increase in fetal breathing activity, with a peak of 54.9% between 30 and 75 minutes after the injection. In contrast, our fetus at 32 and 33 weeks' gestation made no breathing movements prior to the injection of glucose, and the incidence rose only to approximately 10% at 90 minutes after the injection. It is
Response of fetal breathing to intravenous glucose
Volume 148 Number 5
INJECTION OF 25g OF INTRAVENOUSLY
~GLUCOSE
ot)l
(32 WEEKS)
________~n~______~~
,
HIC COUGHS
(33 WEEKS)
o 0830
0900
0930
1000
1030
CLOCK TI ME
1100
1130
1200
(HOURS)
Fig. 2. Fetal breathing activity before and after an injection of 25 gm of glucose intravenously, at 32 and 33 weeks' gestation, to a mother affected with myotonic dystrophy.
INJECTION OF 25g OF GLUCOSE INTRAVENOUSLY
40
J!!
z ~
( n WEEKS)
~
30
'">
0
"2
>-
20
0
0
'" ..J
~
10
'".... CI) CI)
0 Ir
0
" "z ...;;:::E ...z
30
0..
20
'"
CI)
'"
2
>=
~
10
0
0830
0900
0930
1000
1030
CLOCK TIME
1100
1130
1200
(HOURS)
Fig. 3. There was no difference in the mean percentage of time spent making gross fetal body movements before and after the intravenous injection of glucose to a mother affected with myotonic dystrophy.
not known why human fetal breathing movements increase in incidence and amplitude after an elevation in the level of maternal blood glucose. Regardless of the mechanism, the failure to observe significant changes in our fetus after the injection added further support to our hypothesis that this fetus was affected by myotonic dystrophy.
Gross body movements in healthy fetuses at term were observed to be present approximately 14% of the time 2 hours prior to the injection of glucose, and there was no statistically significant change during the 3 hours after the injectionY It is of interest to note that the amount of time that our fetus spent making gross body movements was also approximately 10%, which is
ob~
VIIOS et aI.
within normal limits. This observation is in agreement with that of Harper,13 who reported that only 24 of 70 infants with congenital myotonic dystrophy had reduced fetal movements, as perceived by the mothers. We are unable to explain the normal amount of gross body movements in our two fetuses in the presence of severe generalized hypotonia at birth. The two infants did not suffer from intrapartum asphyxia, since their arterial cord blood gases were within normal limits. Hypotonia at birth was also a consistent presentation in 47 of 70 infants with congenital myotonic dystrophy in Harper's reportY The lack of diaphragmatic contractility in utero and the presence of body movements also imply differential involvement of various muscles. The diaphragm seems to be more severely affected, which accounts for the respiratory difficulties experienced by these infants at birth.13 The respiratory insufficiency at birth seems to be due to at least two components-diaphragmatic weakness and pulmonary hypoplasia. In animal experiments, it has been well demonstrated that fetal breathing that generates phasic intrathoracic pressures of normal intensity is essential for the development of the lungs. 9 Pulmonary hypoplasia has also been described in a number of neuromuscular disorders in human infants, including congenital myotonic dystrophy.lO Although the definition of pulmonary hypoplasia is inadequate, the weight and volume of the lungs, as well as radial alveolar counts, have been used by other investigators.14 Furthermore, data on lung weights and radial alveolar counts at different gestational ages are lacking in healthy human infants. In Table II, in the data on three infants, the lung weight/body weight ratio is below the mean reported by Askenazi and Perlman,14 and in the last two infants the ratio is even below the normal range of 0.012 to 0.025. Since the lungs of all three infants had histologic evidence of marked interstitial edema and focal hemorrhages (most likely due to resuscitative efforts), the weight and volume of these lungs were grossly overestimated. This would indicate that the lungs of all three infants were severely hypoplastic, which correlated with the severity of respiratory difficulty at birth. Polyhydramnios has been reported to be present in approximately 40% of the pregnancies in which the fetuses are affected with myotonic dystrophy.l:l The mechanism of polyhydramnios has been attributed to a neuromuscular failure in fetal swaliowing. 15 This study demonstrated that fetal breathing movements were absent in two fetuses affected with myotonic dystrophy. Furthermore, the response of fetal breathing activity was markedly impaired after the mother received an intravenous bolus of 25 gm of glucose at 32 and 33 weeks' gestation. The lack of fetal
March I, 1984 Am. J. Obstet. Gynecol.
breathing predicted that these fetuses would have underdeveloped lungs, and this was confirmed by the respiratory difficulties at birth and by postmortem evaluation of the lungs. We speculate that observations of fetal breathing activity and the response of such activity to an intravenous injection of glucose to the mother are a potential clinical test by which normal fetuses can be differentiated from fetuses who are affected by neuromuscular disorders, including myotonic dystrophy. REFERENCES I. Boddy, K., and Dawes, A. 5.: Fetal breathing, Br. Med. Bull. 31:3, 1975. 2. Patrick, j., Campbell, K., Carmichael, L., Natale, R., and Richardson, B.: Patterns of human fetal breathing during the last 10 weeks of pregnancy, Obstet. Gynecol. 56:24, 1980. 3. Bocking, A., Adamson, L., Cousin, A., Campbell, K., Carmichael, L., Natale, R., and Patrick, j.: Effects of intravenous glucose injections on human fetal breathing movements and gross fetal body movements at 38 to 40 weeks' gestational age, AM. j. OBSTET. GYNECOL. 142:606, 1982. 4. McLeod, W., Brien, j. Loomis, C., Carmichael, L., Probert, C., and Patrick, j.: Effect of maternal ethanol ingestion on fetal breathing movements, gross body movements, and heart rate at 37 to 40 weeks' gestational age, AM. j. OBSTET. GYNECOL. 145:251, 1983. 5. Wigglesworth,j. 5., and Desai, R.: Effects on lung growth of cervical cord section in the rabbit fetus, Early Hum. Dev. 3:51,1979. 6. Liggins, G. c., Vilos, G. A., Campos, G. A., Kitterman, j. A., and Lee, C. H.: The effect of spinal cord transection on lung development in fetal sheep, j. Dev. Physiol. 3: 267,1981. 7. Alcorn, D., Adamson, T. M., Maloney, j. E., and Robinson, P. M.: Morphological effects of either chronic bilateral phrenectomy or vagotomy in the fetal lamb lung, j. Anat. 130:683, 1980. 8. Fewell,]. E., Lee, C. H., and Kitterman,j. A.: The effects of phrenic nerve section on the respiratory system of fetal lambs,j. App!. Physio!. 220:119,1981. 9. Liggins, G. C., Vilos, G. A., Campos, G. A., Kitterman, j. A., and Lee, C. H.: The effect of bilateral thoracoplasty on lung development in fetal sheep, j. Dev. Physio!. 3: 275,198Ib. 10. Swischeck, L. E., Richardson, C. j., Nickols, M. N., and Ingman, j.: Bilateral pulmonary hypoplasia in the neonate (review), AJR 133:1057, 1979. 11. Natale, R., Patrick, j., and Richardson, B.: Effects of human maternal venous plasma glucose concentrations on fetal breathing movements, AM. j. OBSTET. GYNECOL. 132: 36, 1978. 12. Adamson, L. 5., Bocking, A., Cousin, A. j., Rapoport, I., and Patrick, j. E.: Ultrasonic measurement of rate and depth of human fetal breathing: Effect of glucose. Submitted for publication. 13. Harper, P. 5.: Congenital myotonic dystrophy in Britain. I. Clinical aspects, Arch. Dis. Child. 50:505, 1975. 14. Askenazi, S. 5., and Periman, M.: Pulmonary hypoplasia: Lung weight and radial alveolar count as criteria of diagnosis, Arch. Dis. Child. 54:614, 1979. 15. Dunn, L. j., and Dierker, L. j.: Recurrent hydramnios in association with myotonia dystrophia, Obstet. Gyneco!. 42:104, 1973.
Fetal breathing movements and gross fetal body movements are normal physiologic events in all healthy fetuses. In the human, fetal breathing activity has been observed as early as 11 weeks' gestation,! and during the third trimester the fe us makes breathing movements approximately 30% of the time {range, 17% to 65%).2 Fetal breathing activity is significantly increased 10 minutes after the administration of an intravenous bolus of 25 gm of glucose to the motherl and is dramatically abolished for a period of up to 4 hours soon after 1 ounce of alcohol is taken orally by the mother. 4 Although fetal breathing movements have been observed for many years, the relationship of fetal breathing movement to lung development was not recognized until recently. When fetal breathing was abolished by transection of the fetal spinal cord at C 2- 3 in rabbits 5 and in sheep6 or by bilateral phrenectomy in sheep/' B the weight and volume of the lungs were more than 50% lower than in control animals. Furthermore, when the negative intrathoracic pressure generated by each breath was "blunted" by thoracoplasty to increase the compliance of the chest wall in fetal Iambs, the weight and volume of the lungs were also reduced by more than 50%.9
From the Department of Obstetrics and Gynecology, St. Joseph's Hospital, The University of Western Ontario. Presented at the Thirty-ninth Annual Meeting of The Society of Obstetricians and Gynaecologists of Canada, Vancouver, British Columbia, Canada, June 14-18,1983. Reprint requests: Dr. G. A. Vilos, Department of Obstetrics and Gynecology, SI.joseph's Hospital, 268 Grosvenor St., London, Ontario, Canada N6A 4V2.
558
Since fetal breathing movements of normal intensity are necessary for lung development, and since pulmonary hypoplasia has been observed in infants with neonatal myotonic dystrophy,1O it follows that breathing movements in fetuses affected with myotonic dystrophy would be absent or ofIow intensity. The present report describes patterns of breathing activity and gross fetal body movements in two fetuses from 28 to 35 weeks' gestation and the response of fetal breathing movements and gross fetal body movements to an intravenous injection of glucose in one fetus at 32 and 33 weeks' gestation of a mother with myotonic dystrophy. Case history A 22-year-old Caucasian woman was referred during her third pregnancy at 31 weeks' gestation with polyhydramnios and a poor prior obstetric history. The first pregnancy had been complicated by polyhydramnios, with spontaneous delivery of a stillborn female infant at 26 weeks' gestation. The second pregnancy had also been complicated by polyhydramnios, with spontaneous delivery at 35 weeks' gestation. In the latter case, the female infant (birth weight, 2,176 gm) was delivered vaginally as an assisted breech. The Apgar scores were 1 and 4 at 1 and 5 minutes, respectively. The infant was actively resuscitated and transferred to our neonatal intensive care unit. On arrival, the baby had a blood pH of 6.89, and in spite of further aggressive therapy and ventilatory support, she died within 24 hours. Postmortem findings are reported in Table I. The mother was Rh negative with no antibodies present. She was given Rh immune globulin. The results of an oral glucose tolerance test on the mother were within normal limits.
Response Of fetal breathing to Intravenous glucose
Volume 148 Number 5
OOl:l
Table I. Perinatal outcome in four infants delivered of a mother with myotonic dystrophy A rterial blood gases Infant No.
Delivery (wk)
Sex
Method of delivery
1
26 35 32 33
F F M M
Breech Assisted breech Cesarean breech Cesarean breech
2 3 4
Apgar score at 5 min
Umbilical pH
Po.
I
Peo.
I
Base excess
Stillborn
During the third pregnancy the patient was referred to our tertiary care hospital at 31 weeks' gestation. Ultrasonic assessment at 28 weeks identified a normal fetus presenting as a breech, with a normal placenta but excessive amniotic fluid. The symphysis-to-fundus ?eight was 32 cm at 28 weeks' gestation and rapidly Increased to 46 cm by 32 weeks. At 32 weeks' gestation, because of the spontaneous onset of labor and a persistent breech presentation, the patient was delivered uneventfully by low-segment cesarean section of a male infant who weighed 1,760 gm. The baby was pale and extremely hypotonic with no spontaneous respiratory effort. The Apgar scores were 0, 2, and 4 at 1,5, and 10 minutes, respectively, and the arterial cord blood gases were as follows: pH 7.24, P02 16, Peo2 40, base excess -7.0. After immediate intubation, a peak airway pressure of 40 em H 20 was necessary to achieve adequate ventilation. A chest x-ray film revealed a complete "white out" appearance, with severe atelectasis and poor ~xpansion of the lungs compatible with respiratory distress syndrome, type I. Bilateral pleural effusion and hypoplastic ribs were also noted. The baby continued to need vigorous ventilatory support because of the respiratory distress syndrome, persistent fetal circulation, and generalized hypotonia. At 42 hours of age, he developed bilateral pneumothoraces, and in spite of the insertion of chest tubes, he died. Autopsy findings are summarized in Table II. The patient's poor obstetric performance, her physical appearance, including a receding hairline and myotonic facies, as well as the complete apnea and hypotonia of the latter infant at birth, with normal arterial cord blood gases, strongly suggested the presence of neuromuscular disorder. Myotonic dystrophy was subsequently confirmed in the mother and several relatives by electromyography and muscle biopsy. Despite genetic counseling, the patient was referred again at the beginning of her fourth pregnancy. At 29 weeks' gestation, she was hospitalized because of polyhydramnios. The symphysis-to-fundus height was 37 cm. At 33 weeks, she sustained spontaneous rupture of the membranes, and spontaneous labor commenced 1 week later. Because of a breech presentation and the previous history of cesarean delivery, a repeat cesarean section was carried out. The infant was a male who weighed 2,000 gm, with Apgar scores of 1 and 4 at 1 and 5 minutes, respectively, and with the following arterial cord blood gases: pH 7.24, Po, 22.9, Peo, 22.7, base excess -16.4. Despite immediate respiratory sup-
4
Not done
2
7.24 7.24
4
16.0 22.9
40.0
-7.0
22.7
-16.4
Table II. Body, lung, and diaphragmatic weights of infants with congenital myotonic dystrophy Infant No.
Birth weight (gm)
1
Not available
2 3 4
2,200 1,760 2,000
Lung weight (gm)
Lung/body weight ratio
38.0 22.1
0.017
17.5
0.012 0.009
Diaphragm (gm)
7.0 7.8
port and aggressive pulmonary assisted ventilation, the baby died 6 hours after delivery. Autopsy findings are summarized in Table II. Nonstress testing was performed daily in the last two fetuses throughout the period of hospitalization. Observations of fetal breathing movement and gross fetal body movements were also made in the last two fetuses twice a week with an ADR real-time ultrasonic scanner for at least 1 hour. During the fourth pregnancy, observations of fetal breathing movements and gross fetal body movements were made at 32 and 33 weeks' gestation after the mother had been given an intravenous injection of glucose. The patient fasted for 8 hours prior to each study. At 8 AM, the ADR scanner was connected to a PDPII computer for data analysis (Digital Equipment Corporation, Maynard, Massachusetts). Individual fetal breathing movements and gross fetal body movements were identified on a video monitor and coded on a chart recorder and the computer by an event marker. At 9 AM, the mother received an intravenous injection that contained 25 gm of 50% glucose solution, and the study was continued for an additional 3 hours. Details of the computer program and analysis have been reported. 2 Determinations of maternal glucose were performed by means of a glucose-oxidase oxygen rate meter (Beckman Instruments, Schiller Park, Illinois) (Fig. 1). The results presented in Figs. 2 and 3 represent the percentage of the time spent making fetal breathing movements and gross fetal body movements for each I5-minute interval before and after the administration of glucose at 32 and 33 weeks' gestation. Results
The maternal plasma glucose concentration increased from 73 mg/dl prior to injection, to more than 170 mg/dl in the first 30 minutes, and decreased
560
Vilos at aI.
March I, 1984 Am. J. Obstet. Gynecol.
terstitial hemorrhage, as well as marked atelectasis with severe hyaline membrane formation. The radial alveolar count was less than 3 in all lungs. The two diaphragms available for examination were thinner and wider than usual, with pale attenuated muscle fibers.
170
INJECTION OF 2511 OF GLUCOSE INTRAVENOUSLY
70
• - 30
! o
+ 30
+60
+ 90
+ 120
TIME (MINUTES)
Fig. 1. Maternal plasma glucose concentrations before and after injection of 25 gm of glucose intravenously at 33 weeks' gestation. rapidly to approximately 110 mg/dl at 90 minutes after the intravenous injection of glucose (Fig. 1). Fetal breathing activity was noted to be absent during the control period prior to the administration of glucose in both studies. Only one short episode of hiccoughing activity was recorded at 33 weeks' gestation. The percentage of time spent breathing by the fetus after the injection of glucose increased from 0% to approximately 10% in both studies. The peak of breathing activity occurred approximately 90 minutes after the injection of glucose, and it lasted for approximately 30 minutes (Fig. 2). The mean percentage of time spent by the fetus making gross body movements was not significantly altered by the administration of glucose. During the period before the injection, the fetus made gross body movements approximately 9.7% ± 3.0% of the time, whereas during the 3-hour period subsequent to injection, the mean percentage of time was 11.9% ± 1.9% (mean ± SEM, NS). The clinical presentation and the outcome of all four pregnancies are summarized in Table I. Polyhydramnios with premature onset of labor and delivery was associated with all pregnancies. Regardless of the method of delivery, the 1- and 5-minute Apgar scores were less than 4 in the three live-born infants, although the umbilical artery blood gases were within normal limits in the latter two infants. All infants died from pulmonary insufficiency shortly after birth, in spite of maximum ventilatory support. The body, lung, and diaphragm weights are shown in Table II. Histologically, the lungs of the three infants showed marked interstitial edema with focal in-
Comment The nonstress test, defined as five or more accelerations in the fetal heart rate of '2: 15 bpm lasting '2: 15 seconds in association with fetal movement during any 20-minute interval, was reactive in the last two fetuses during the entire period of hospitalization. Gross fetal body movements, as perceived by the mother and observed with the real-time scanner, were within normal limits. In contrast, fetal breathing movements were not observed on any of the occasions on which the two fetuses were observed. Only small-amplitude diaphragmatic excursions were observed episodically, whereas hiccoughing was observed occasionally in both fetuses. The substitution of fetal breathing movements by diaphragmatic "quivering" added support to the suspicion that these fetuses were also affected by myotonic dystrophy that resulted in muscular weakness of the diaphragm. We elected to study the fourth fetus further. It has been demonstrated that the amount of time the human fetus spends making breathing movements is increased when the maternal plasma glucose concentration is increased. This increase can be achieved by the mother consuming a high-calorie mea!,2 taking a glucose drink,!! or receiving an intravenous injection of glucoseY Adamson and associates!2 used an ultrasonic tracking devise to measure changes in fetal rib cage and abdominal diameter in healthy fetuses at term. After a 2-hour observation period, an intravenous injection of either 25 gm of a 50% glucose solution or an equal volume of saline solution was given to the mother. They found that, during the first 80 minutes after the injection of glucose, there was a significant increase in the amplitude of the fetal breaths. The 25 gm bolus of glucose resulted in maternal plasma concentrations of approximately 75 to 200 mg/dl immediately after the injection, with a rapid decrease to preinjection levels by 90 minutes.o A similar pattern of rise and fall in glucose concentrations was also observed in our patient. Bocking and associates3 found that healthy fetuses at 38 to 40 weeks' gestation made breathing movements 17.5% of the time during the 2 hours before the injection of glucose. Ten minutes after the injection, there was a dramatic increase in fetal breathing activity, with a peak of 54.9% between 30 and 75 minutes after the injection. In contrast, our fetus at 32 and 33 weeks' gestation made no breathing movements prior to the injection of glucose, and the incidence rose only to approximately 10% at 90 minutes after the injection. It is
Response of fetal breathing to intravenous glucose
Volume 148 Number 5
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Fig. 2. Fetal breathing activity before and after an injection of 25 gm of glucose intravenously, at 32 and 33 weeks' gestation, to a mother affected with myotonic dystrophy.
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Fig. 3. There was no difference in the mean percentage of time spent making gross fetal body movements before and after the intravenous injection of glucose to a mother affected with myotonic dystrophy.
not known why human fetal breathing movements increase in incidence and amplitude after an elevation in the level of maternal blood glucose. Regardless of the mechanism, the failure to observe significant changes in our fetus after the injection added further support to our hypothesis that this fetus was affected by myotonic dystrophy.
Gross body movements in healthy fetuses at term were observed to be present approximately 14% of the time 2 hours prior to the injection of glucose, and there was no statistically significant change during the 3 hours after the injectionY It is of interest to note that the amount of time that our fetus spent making gross body movements was also approximately 10%, which is
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within normal limits. This observation is in agreement with that of Harper,13 who reported that only 24 of 70 infants with congenital myotonic dystrophy had reduced fetal movements, as perceived by the mothers. We are unable to explain the normal amount of gross body movements in our two fetuses in the presence of severe generalized hypotonia at birth. The two infants did not suffer from intrapartum asphyxia, since their arterial cord blood gases were within normal limits. Hypotonia at birth was also a consistent presentation in 47 of 70 infants with congenital myotonic dystrophy in Harper's reportY The lack of diaphragmatic contractility in utero and the presence of body movements also imply differential involvement of various muscles. The diaphragm seems to be more severely affected, which accounts for the respiratory difficulties experienced by these infants at birth.13 The respiratory insufficiency at birth seems to be due to at least two components-diaphragmatic weakness and pulmonary hypoplasia. In animal experiments, it has been well demonstrated that fetal breathing that generates phasic intrathoracic pressures of normal intensity is essential for the development of the lungs. 9 Pulmonary hypoplasia has also been described in a number of neuromuscular disorders in human infants, including congenital myotonic dystrophy.lO Although the definition of pulmonary hypoplasia is inadequate, the weight and volume of the lungs, as well as radial alveolar counts, have been used by other investigators.14 Furthermore, data on lung weights and radial alveolar counts at different gestational ages are lacking in healthy human infants. In Table II, in the data on three infants, the lung weight/body weight ratio is below the mean reported by Askenazi and Perlman,14 and in the last two infants the ratio is even below the normal range of 0.012 to 0.025. Since the lungs of all three infants had histologic evidence of marked interstitial edema and focal hemorrhages (most likely due to resuscitative efforts), the weight and volume of these lungs were grossly overestimated. This would indicate that the lungs of all three infants were severely hypoplastic, which correlated with the severity of respiratory difficulty at birth. Polyhydramnios has been reported to be present in approximately 40% of the pregnancies in which the fetuses are affected with myotonic dystrophy.l:l The mechanism of polyhydramnios has been attributed to a neuromuscular failure in fetal swaliowing. 15 This study demonstrated that fetal breathing movements were absent in two fetuses affected with myotonic dystrophy. Furthermore, the response of fetal breathing activity was markedly impaired after the mother received an intravenous bolus of 25 gm of glucose at 32 and 33 weeks' gestation. The lack of fetal
March I, 1984 Am. J. Obstet. Gynecol.
breathing predicted that these fetuses would have underdeveloped lungs, and this was confirmed by the respiratory difficulties at birth and by postmortem evaluation of the lungs. We speculate that observations of fetal breathing activity and the response of such activity to an intravenous injection of glucose to the mother are a potential clinical test by which normal fetuses can be differentiated from fetuses who are affected by neuromuscular disorders, including myotonic dystrophy. REFERENCES I. Boddy, K., and Dawes, A. 5.: Fetal breathing, Br. Med. Bull. 31:3, 1975. 2. Patrick, j., Campbell, K., Carmichael, L., Natale, R., and Richardson, B.: Patterns of human fetal breathing during the last 10 weeks of pregnancy, Obstet. Gynecol. 56:24, 1980. 3. Bocking, A., Adamson, L., Cousin, A., Campbell, K., Carmichael, L., Natale, R., and Patrick, j.: Effects of intravenous glucose injections on human fetal breathing movements and gross fetal body movements at 38 to 40 weeks' gestational age, AM. j. OBSTET. GYNECOL. 142:606, 1982. 4. McLeod, W., Brien, j. Loomis, C., Carmichael, L., Probert, C., and Patrick, j.: Effect of maternal ethanol ingestion on fetal breathing movements, gross body movements, and heart rate at 37 to 40 weeks' gestational age, AM. j. OBSTET. GYNECOL. 145:251, 1983. 5. Wigglesworth,j. 5., and Desai, R.: Effects on lung growth of cervical cord section in the rabbit fetus, Early Hum. Dev. 3:51,1979. 6. Liggins, G. c., Vilos, G. A., Campos, G. A., Kitterman, j. A., and Lee, C. H.: The effect of spinal cord transection on lung development in fetal sheep, j. Dev. Physiol. 3: 267,1981. 7. Alcorn, D., Adamson, T. M., Maloney, j. E., and Robinson, P. M.: Morphological effects of either chronic bilateral phrenectomy or vagotomy in the fetal lamb lung, j. Anat. 130:683, 1980. 8. Fewell,]. E., Lee, C. H., and Kitterman,j. A.: The effects of phrenic nerve section on the respiratory system of fetal lambs,j. App!. Physio!. 220:119,1981. 9. Liggins, G. C., Vilos, G. A., Campos, G. A., Kitterman, j. A., and Lee, C. H.: The effect of bilateral thoracoplasty on lung development in fetal sheep, j. Dev. Physio!. 3: 275,198Ib. 10. Swischeck, L. E., Richardson, C. j., Nickols, M. N., and Ingman, j.: Bilateral pulmonary hypoplasia in the neonate (review), AJR 133:1057, 1979. 11. Natale, R., Patrick, j., and Richardson, B.: Effects of human maternal venous plasma glucose concentrations on fetal breathing movements, AM. j. OBSTET. GYNECOL. 132: 36, 1978. 12. Adamson, L. 5., Bocking, A., Cousin, A. j., Rapoport, I., and Patrick, j. E.: Ultrasonic measurement of rate and depth of human fetal breathing: Effect of glucose. Submitted for publication. 13. Harper, P. 5.: Congenital myotonic dystrophy in Britain. I. Clinical aspects, Arch. Dis. Child. 50:505, 1975. 14. Askenazi, S. 5., and Periman, M.: Pulmonary hypoplasia: Lung weight and radial alveolar count as criteria of diagnosis, Arch. Dis. Child. 54:614, 1979. 15. Dunn, L. j., and Dierker, L. j.: Recurrent hydramnios in association with myotonia dystrophia, Obstet. Gyneco!. 42:104, 1973.