Fetal breathing movements and lung hypoplasia: Preliminary human observations

Uterine electromyographic activity

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12.

13.

14.

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isodes of diminished uterine blood flow on breathing movements, sleep states and heart rate in fetal sheep. J Dev PhysioI1981;3:231-43. Nathanielsz PW, Jansen CAM, Yu HK, Cabalum T. Regulation of myometrial function and labor: effect on fetal development. In: Beard RW, Nathanielsz PW, eds. Fetal physiology and medicine. 2d ed, New York: Marcel Dekker, 1984:629-52. Sigger IN, Harding R, Jenkin G. Relationship between electrical activity of the uterus and surgically isolated myometrium in the pregnant and non-pregnant ewe. J Reprod FertiI1984;70:103-14. Nathanielsz PW, Abel MH, Bass FG, Krane EJ, Thomas AL, Liggins Gc. Pituitary stalk-section and some of its effects on endocrine function in the fetal lamb. Q J Exp Physiol 1978;63:221-9. Harding R, Poore ER. Techniques for the measurement and analysis of fetal breathing. In: Nathanielsz PW, ed. Animal models in fetal medicine. Ithaca, New York: Perinatology Press, 1982:219-58.

16. Nathanielsz PW, Yu HK, Cabalum TC. Effect of abolition of fetal movement on fetal intravascular P02and incidence of tonic myometrial contractu res in the pregnant ewe at 114 to 134 days' gestation. AM J OBSTET GYNECOL 1982;144:614-8. 17. Tarroux P, Rabilloud T. Complete computer system for processing chromatographic data. J. Chromatogr 1982; 248:249-62. 18. Snedecor GW, Cochran WG. Statistical methods. 7th ed. Ames, Iowa: The Iowa State University Press, 1980. 19. Brennecke SP, Turnbull AC. Maternal peripheral plasma prostaglandin E2 metabolite and F2a metabolite concentrations in the late pregnant ewe in relation to fetal vascular catheterisation surgery. J Physiol 1983;338:45P. 20. EI Badry A, Figueroa JP, Poore ER, et al. Effect of fetal intravascular 4-aminoantipyrine infusions on myometrial activity (contractures) at 125 to 143 days' gestation in the pregnant sheep. AMJ OBSTET GYNECOL 1984;150:474-9.

Fetal breathing movements and lung hypoplasia: Preliminary human observations Harold E. Fox, M.D., and Adrien C. Moessinger, M.D. New York, New York Hypoplasia of the fetal lung is found in association with long-standing Oligohydramnios. In animal models, interference with fetal breathing activity has led to lung hypoplasia. It has been suggested that lung hypoplasia associated with oligohydramnios is due to inhibition of fetal breathing. Observations of seven patients with prolonged oligohydramnios, three of whom had lung hypoplasia, indicate that fetal breathing does occur in these cases and that it is unlikely that lung hypoplasia is merely the result of absent fetal breathing activity. In fact, when compared to the four patients with oligohydramnios and presumably normal lungs, the three patients with oligohydramnios and lung hypoplasia spent more time breathing and did so at higher rates. (AM J OBSTET GYNECOL 1985;151 :531-3.)

Key words: Fetus, amniotic fluid, fetal breathing, oligohydramnios, lung hypoplasia Hypoplasia of the fetal lungs is found in association with long-standing oligohydramnios. Potter I first reported on a series of babies with renal agenesis and noted that lung hypoplasia was a constant feature. It was later recognized that the same phenotype, including lung hypoplasia, could be seen in newborn infants with posterior urethral valves, in the donors of severe and chronic twin-to-twin transfusion, or simply following prolonged leakage of amniotic fluid!" In all of these cases, oligohydramnios was present for an extended period of time. Nimrod et al. 5 have recently reported From the Perinatal Division, Department of Obstetrics and Gynecology, the Department ofPediatrics, and the Department ~f Pathology, College of Physicians and Surgeons of Columbza Umvemty. This study was supported by National Institutes of Health Grants HL14218 and RR-0645. Sponsored by the Society for Gynecologic Investigation. . Reprint requests: Harold E. Fox, M.D., Presbytman HospItal, 630 West 168th St., New York, NY 10032.

a 9% incidence of lung hypoplasia following very prolonged rupture of the membranes. Experimental production of oligohydramnios has led to lung hypoplasia in several animal species.6-9 The pathogenesis of the pulmonary hypoplasia associated with oligohydramnios is unclear. It has been speculated that hypoplasia of the lungs in this situation is the result of fetal compression (either thoracic or abdominal) leading to reduced space available for lung growth!' 10. II More specifically, it has been proposed that oligohydramnios could enhance the outflow of fetal lung liquid and thus interfere with lung expansion in utero. II . I ' Both experimental tracheal ligation and drainage of fetal lung liquid, by resulting, respectively, in hyperplasia and hypoplasia of the lung, support the concept that lung expansion in utero is an important determinant of fetal lung growth. 14 Fetal breathing movements, by intermittently raising 531

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February IS. 1985 Am J Obstet Gynecol

Table I. Clinical findings in three cases of lung hypoplasia Case No.

010

Gestational age (at study session) (wk)

Membrane status (gestational age at rupture)

28-34 (5 studies)

Outcome

Autopsy findings

Intact

Respiratory failure. death <24 hr

Renal agenesis Lung hypoplasia* Amnion nodosum of placenta Permit not granted on religious grounds Polycystic kidneys with lung hypoplasia* Placenta not available Lung hypoplasia* Hyaline membrane disease Amnion nodosum of placenta

012

37

Intact

Respiratory failure. death <24 hr

020

27

24 wk

Respiratory failure. death <24 hr

*The diagnosis of lung hypoplasia was based on (I) lung weight <2 SD below the norm for Case 010; (2) clinical course and known pattern of associated malformations for Case 012; (3) biochemical (DNA) and histologic criteria for Case 020 (reference 9).

Table II. Fetal breathing activity: Infants with oligohydramnios versus control infants

Infants

Proportion of time spent breathing (mean ± SD)

Oligohydramnios ;;.3 wk (n = 7) Control (n = 7)

0.09 ± 0.10 0.14 ± 0.14

P 0.246

Rate of breathing, breaths/min (mean ± SD)

27.5 ± 15.1 34.3 ± 11.9

P 0.184

Table III. Fetal breathing activity following oligohydramnios: Comparison of fetuses with or without lung hypoplasia

Oligohydramnios and lung hypoplasia (n = 3) Oligohydramnios and normal lungs (n = 4)

Proportion of time spent breathing (mean ± SD)

0.18 ± 0.10 0.02 ± O.oI

airway distending pressure, have been held responsible for contributing to normal fetal lung growth. Experimental division of the neural pathways supplying the respiratory system (bilateral phrenectomy or cervical cord section) and fetal paralysis (induced with curare) have led to lung hypoplasia. l5017 Both Gruenwald lO and Wigglesworth IS have postulated that failure of lung growth in association with oligohydramnios could be due to inhibition of breathing movements. The purpose of this report is to present an analysis of fetal breathing movements in seven patients with oligohydramnios resulting in lung hypoplasia in three of the seven cases.

Patients and methods Seven patients with prolonged oligohydramnios (two with intact membranes and renal anomalies, five with prolonged spontaneous rupture of the membranes for ;;.3 weeks) were studied in a total of 14 I-hour sessions at gestational ages ranging from 27 to 38 weeks. Session by session, a gestational age-matched control subject with intact membranes and normal amniotic fluid vol-

P

Rate of breathing, breaths/min (mean ± SD)

P

0.014

36.5 ± 10.2

0.011

16.0 ±

6.4

Fetal breathing activity was recorded by longitudinal fetal axis linear-array B-mode sonography as previously described,19 and analyses of the proportion of observation time spent in fetal breathing activity and of breathing rate during breathing intervals (breaths per minute) were carried out. All sessions occurred at the same time of the day and approximately 2 hours after a meal of about 350 kcal. No patient smoked within 4 hours of the recording session, and none had evidence of hypertension, abnormal carbohydrate metabolism, or clinical amnionitis. Oligohydramnios was defined by ultrasound assessment at each study session and was confirmed at the time of delivery. Of the seven cases of oligohydramnios, four infants died in the early neonatal period. Three of those were considered to have lung hypoplasia and their clinical findings are summarized in Table I. At autopsy the lungs of the infant in the fourth case weighed less than expected for gestational age and body weight but did not meet the criteria for the diagnosis of lung hypoplasia." Placental tissue was available in four of the seven cases (one infant was delivered at another insti-

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light microscopy. Amnion nodosum, a lesion thought to be pathognomonic of prolonged oligohydramnios, was seen in three of the four placentas available for study.2 We recorded 14 study sessions in seven patients with oligohydramnios and 14 sessions in gestational agematched control subjects. When a patient was studied more than once, only the mean value of the results was used for comparison. We compared the incidence and the rate of fetal breathing movements in the seven patients with prolonged oligohydramnios and in their matched control subjects by paired sample analysis. We also compared the same parameters in two subsets of the oligohydramnios group by the two-sample t test, that is, the three patients with lung hypoplasia were compared to the four patients without lung hypoplasia. Results

Fetal breathing activity was present in all seven cases of prolonged oligohydramnios. When compared to the matched control fetuses with normal amniotic fluid volume, the fetuses with oligohydramnios, taken as a group, tended to spend less time breathing and did so at lower rates. These apparent differences in the means of results did not however reach a level of statistical significance (see Table II). When compared to fetuses with oligohydramnios but normal lung growth, fetuses with oligohydramnios and lung hypoplasia (at the time of delivery) spent significantly more time breathing and did so at significantly higher rates (see Table III). Comment

All seven fetuses with prolonged oligohydramnios studied by linear-array B-mode sonography did show evidence of fetal breathing activity. Neither the incidence nor the rate of fetal breathing differed between these patients and their matched control subjects with normal amniotic fluid volume. Our recent experience with an animal model of amniotic fluid drainage led to similar findings. We found no difference in the incidence of fetal breathing movements in fetal lambs when comparing a 24-hour period preceding and a same period immediately following amniotic fluid drainage. 9 We conclude that it is unlikely that the lung hypoplasia seen with oligohydramnios is merely the result of the absence of fetal breathing movements. Whether other characteristics of fetal breathing, such as the transient alterations in lung volume,2o.21 are modified by oligohydramnios is unknown at this point. The observation that fetuses with both oligohydramnios and lung hypoplasia, when compared to fetuses with oligohydramnios and normal lungs, actually spent more time breathing and did so at higher rates was unexpected and is challenging. Whether this phenomenon relates to lung hypoplasia as a cause or as a con-

Fetal breathing movements and lung hypoplasia 533

sequence is unclear. However, and beyond that last question, it would be interesting to evaluate prospectively whether high rates and/or incidences of fetal breathing could become useful clinical indicators of lung hypoplasia in association with oligohydramnios. REFERENCES 1. Potter EL. Bilateral renal agenesis. 1 Pediatr 1946;29: 68-76. 2. Blanc WA, Apperson 1W, McNally J. Pathology of the newborn and of the placenta in oligohydramnios. Bull Sloane Hosp Women 1962;8:51-64. 3. Bain AD, Scott 1S. Renal agenesis and severe urinary tract dysplasia. A review of 50 cases with particular reference to the associated anomalies. Br Med11960;1:841-6. 4. Bain AD, Smith 11, Gauld IK. Newborns after prolonged leakage of liquor amni. Br Med 1 1964;2:598-9. 5. Nimrod C, Varela-Gittings F, Machin G, Campbell D, Wesenberg R. The effect of very prolonged membrane rupture on fetal development. AM 1 OBSTET GYNECOL 1984; 148:540-3. 6. Moessinger AC, Bassi 1A, Ballantyne G, Collins MH, 1ames LS, Blanc WA. Experimental production of pulmonary hypoplasia following amniocentesis and oligohydramnios. Early Hum Dev 1983;8:343-50. 7. Nakayama DK, Glick PL, Harrison MR, Villa RL, Noall R. Experimental pulmonary hypoplasia due to oligohydramnios and its reversal by relieving thoracic compression.1 Pediatr Surg 1983;18:347-53. 8. Moessinger AC, Collins MH, Blanc WA, Kleinerman 1, 1ames LS. Oligohydramnios-induced lung hypoplasia: influence of timing and duration. Pediatr Res 1984; 18: 336A. 9. Moessinger AC, Fewe1l1E, Stark RI, etal. Lung hypoplasia and breathing movements following oligohydramnios in fetal Iambs. In: 10nes CT, Nathanielsz PW, eds. The physiological development of the fetus and newborn. New York: Academic Press, 1984. 10. Gruenwald P. Hypoplasia of the lungs. J Mount Sinai Hosp 1957;24:913-21. II. Wigglesworth 1S, Desai R, Guerrini P. Fetal lung hypoplasia: biochemical and structural variations and their possible significance. Arch Dis Child 1981;56:606-15. 12. Perlman M, Willims H, Hirsch M. Neonatal pulmonary hypoplasia after prolonged leakage of amniotic fluid. Arch Dis Child 1976;52:349-53. 13. Thomas IT, Smith DW. Oligohydramnios, cause of the nonrenal features of Potter's syndrome, including pulmonary hypoplasia. 1 Pediatr 1974;84:811-4. 14. Alcorn P, Adamson TM, Lambert TF, et al. Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung. 1 Anat 1977; 123:649-60. 15. Wigglesworth 1 S, Desai R. Effects on lung growth of cervical cord section in the rabbit fetus. Early Hum Dev 1979;3:51-65. 16. Fewe1l1E, Chu CL, Kitterman1A. Effects of phrenic nerve section on the respiratory system of fetal lambs. J Appl Physiol 1981;51:293. 17. Moessinger AC. Fetal akinesia deformation sequence, an animal model. Pediatrics 1983;72:857. 18. Wigglesworth JS. The effects of placental insufficiency on the fetal lung. 1 Clin Pathol 1976;29(suppl 10):27-30. 19. Fox HE, Inglis 1, Steinbrecher M. Fetal breathing movements in uncomplicated pregnancies: relationship to gestational age. AM1 OBSTET GYNECOL 1979;134:544-6. 20. Murai DT, Lee CH, Wallen LD, KittermanJA. Breathing movements transiently increase lung volumes in fetal sheep. Pediatr Res 1984; 18:400A. 21. Harding R, Sigger 1N, Wickham P1D, Bocking AD. The regulation of flow of pulmonary fluid in fetal sheep. Respir PhysioI1984;57:47-59.