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Outcome of very low-birth weight infants born at a perinatal center
Outcome of very low- birth weight infants born at a perinatal center ELlZABETH M. HOSKINS, M.D., F.R.C.P.(C.) ELIZABETH ELLIOT, M.D. ANDREW T. SHENNAN, M.B., M.R.C.P.(U.K.), F.R.C.P.(C.) MARTIN B. SKIDMORE, M.B., M.R.C.P.(U.K.), F.R.C.P.(C.) EILEEN KEITH. PH.D. Toronto, Onta-rio, Caruuia One hundred six infants with birth weights s1,000 gm were born at a Perinatal Center in 1979 and 1980. Eighty-three (78%) were born to women transferred to the Center because of antenatal problems. The most common obstetric problem was premature labor with or without premature rupture of the membranes. Seventy-two infants (68%) survived. The following perinatal factors were associated with increased survival: increased birth weight and gestational age, intrauterine growth retardation, antenatal steroids, absence of hyaline membrane disease, and absence of setzures or clinical signs of intraventricular hemorrhage. Of the 72 survivors, two were lost to follow-up and one died (sudden infant death syndrome). The most common general health problem was recurrent middle ear infection. Growth was satisfactory. Significant neurological or developmental handicap was found in nine infants (13% of the 69 evaluated). (AM. J. Ossrer. GYNECOL. 145:135, 1983.)
THE cosT of supporting very immature infants, especially those with a birth weight < l ,500 gm at birth, is enormous in terms of money and manpower. 1• 2 The emotional impact of this prolonged mother-infant separation is difficult to measure and has only recently become an area of concern.3 By the late 1970s, there appeared to be enough favorable data referring to short- and long-term outcome of infants in the weight group from 1,000 to 1,500 gm to support such expenditure.4· ·' More current reports 6- 8 offer reassurance concerning the outcome of infants weighing <1,000 gm at birth. To date, most studies with large numbers of infants have involved a mixture of infants born in and out of the hospital, which makes interpretation difficult. This study was done to delineate the outcome of a group of infants with birth weights< 1,000 gm, born in a perinatal setting. From the Regional Perinatal Unit, Women's College Hospital. Pmenti!d at the Thirty-eighth. Annual Meeting of The Sodei}' of Obstetricians and Gynaecologists of Canada, Toronto, Ontario, Canada,June 15-19, 1982.
Reprint requests: Dr. Elizabeth M. Hoskins, Regional PeriMtal Unit, Women's College Hospital, 76 Grenville St., Toronto, Ontario, CaMda M5S 1B2. 0002-9378/83/020135+06$00.60/0
©
1983 The C. V. Mosby Co.
Patients and material
Between January l, 1979, and December 31, 1980. 106 infants weighing s 1,000 gm were admitted to the Neonatal Intensive Care Unit of Women's College Hospital. Although all were born in the hospital, 83 (78%) were born to women transferred to the Tertiary Care Perinatal Unit at Women's College Hospital because of antenatal problems. They ranged from 500 to l ,000 gm in weight and from 23 to 33 weeks in gestational age. Twenty-six were small for gestational age. Throughout this period, the perinatal approach to the high-risk antenatal patient was relatively consistent. In patients admitted in premature labor, labor was inhibited with isoxsuprine to allow administration ofbetamethasone, providing there was no evidence of fetal stress on monitoring. If labor could not be arrested, mode of delivery depended on fetal presentation, monitoring, and estimated gestational age. Beyond 25 weeks' gestation, cesarean section was performed for breech or transverse presentation, for evidence of fetal stress, or in multiple pregnancy. 9 At less than 25 weeks, the obstetric management was not as aggressive, and many patients were allowed to be delivered vaginally. Management of patients admitted with premature rupture of membranes with or without labor was similar if there was no evidence of chorioamnionitis. In 135
136 Hoskins et al.
January 15, 1983 Am. J. Obstet. Gynecol.
Tabie I. Primary causes of death Cause of death
No.
Severe immaturity: 23 to 24 weeks, limited resuscitation Intraventricular hemorrhage Hyaline membrane disease Congenital abnormalities Fetal crush syndrome (oligohydramnios) Clostridial infection Fetal hydrops
13 ll 2 3 3 1 1
addition, vaginal swab specimens were obtained, and the patients were started on a regimen of parenteral penicillin. The patient was then managed conservatively, as long as she was not in labor and showed no signs of chorioamnionitis. Patients admitted with preeclampsia were stabilized with fluids, magnesium sulfate, and sedation, as medically indicated. In most cases, delivery was by cesarean section. Antepartum hemorrhages were managed expectantly, depending on fetal and maternal well-being. Patients with growth-retarded _fetuses were monitored with nonstress testing and ultrasound to assess fetal well-being as well as to rule out congenital abnormalities. Neonatal resuscitation was very aggressive with intubation and assisted ventilation provided in the first few minutes if there was any evidence of respiratory distress, such as in-drawing or grunting. No transport of the infant was required as the resuscitation room was adjacent to the delivery room. There was always a staff neonatologist or senior fellow in attendance. Gestational age was based on maternal dates in association with physical and neurological assessment of the infant. Ventilation requirements were evaluated by measurement of arterial blood gas levels, transcutaneous Po 2 monitoring, and clinical symptomatology. Nasopharyngeal continuous positive airway pressure was frequently used in the weaning process. Particular emphasis was placed on fluid balance during the early course of any respiratory illness. Infants with patent ductus arteriosus complicating their respiratory course were treated initially with digoxin and fluid restriction. Indomethacin was used early and surgical ligation was considered if indomethacin was contraindicated or ineffective. The diagnosis of intraventricular hemorrhage was made on clinical grounds as a computerized tomographic scan was not readily available at Women's College Hospital, and ultrasonography was not used routinely until 1981. All infants were assessed by the same ophthalmologist at the time oxygen therapy was discontinued.
They were then followed up as indicated by retinal changes. Follow-up assessments were performed at 3, 6, 9, 12, and 18 months' corrected age. Interim histories were obtained regarding general health problems and developmental progress. Physical and neurological examinations were performed. Evidence of hydrocephalus, definite cerebral palsy, or minor changes in tone was noted. Psychometric assessment was performed by a psychologist at 12 to 18 months after term. She was unaware of the child's neonatal or subsequent clinical course. The test used was the Bayley Scale of Infant Development. 10 Audiometric and repeat ophthalmologic assessments were performed as indicated.
Results Overall results. In the two-year study period, 106 infants weighing 1,000 gm or less were born. There were 59 female and 4 7 male infants. The mean gestational age was 26.4 weeks and the mean birth weight was 801 gm. Twenty-six infants were small for gestational age. Twenty-four of the mothers involved had had obstetric complications in previous pregnancies. The present pregnancy was complicated by premature labor in 24%. Premature rupture of membranes with or without labor accounted for a further 31%. Preeclampsia alone or superimposed on preexisting hypertension led to early delivery in 15%. Other complications, including antepartum bleeding, growth retardation, or combinations of those factors, accounted for the rest of the cases. Maternal disease, such as diabetes, cardiovascular disease, or malignancy, were not presenting factors in any of these pregnancies. A full course of betamethasone was administered to 41 (39%) mothers. Delivery was by cesarean section in 57% of the patients, half by classical or vertical incision and the rest by lower segment incision. General anesthesia was induced in 93% of these procedures. Of the 45 infants delivered vaginally, only six were in the breech presentation; the others were in the vertex. An epidural anesthetic was used in 71% of the vaginal deliveries. Mortality. Thirty-four infants (32%) died in the first 28 days. There were no other infant deaths prior to discharge. All but seven deaths occurred in the first 3 days. Three ofthese infants lived more than 7 days: two lived 8 days and one died at 3 weeks. Thirteen infants were assessed to be 23 to 24 weeks' gestation by the neonatologist at the time of delivery and, on the basis of previous results at this gestational age, were not aggressively resuscitated. The other primary causes of death are presented in Table I.
Volume 145 Number 2
Many perinatal factors were examined to determine
Very low-birth weight infants born at perinatal center
137
Table II. Factors affecting survival
difference!: between tho,;;e who lived and those who
died. Seven factors (Table II) were found to be of significance. Survivors were more mature and larger. Intrauterine growth retardation and antenatal corticosteroids were associated with increased survival. The presence of hyaline membrane disease, seizures, and clinical signs of intraventricular hemorrhage resulted in increased mortality. Other factors were examined but found not to correlate with mortality: obstetric complications in previous pregnancies, presenting complication in present pregnancy. route of delivery, and sex of the infant. There was certainly a trend for infants delivered by cesarean section to do better but this trend did not reach statistical significance. Nineteen or 42% of infants delivered vaginally died, while only 25% of those delivered by cesarean section died. No comment can be made about vaginal delivery of infants in a breech presentation as the numbers were too small. Neonatal morbidity in survivors. Of the 72 survivors, 46 (64%) were delivered by cesarean section (with a general anesthetic used in 90%). Sixty-three infants (87%) were intubated soon after delivery, which reflects the aggressive approach to resuscitation at Women's College Hospital. The other nine infants required only suctioning or resuscitation with bag and mask. Only two infants had Apgar scores below 6 at 5 minutes. Seven infants required a volume expander in the first hour. Some form of respiratory distress was present in most infants. The primary diagnoses were wet lung in 52 and hyaline membrane disease in 15. Forty-five infants, including all those with hyaline membrane disease, required assisted ventilation for >24 hours. Five infants with hyaline membrane disease suffered pneumothoraces and two developed bronchopulmonary dysplasia. Neither of these infants required oxygen beyond their term date. Patent ductus arteriosus was a very common diagnosis, occurring in 42 infants. Diagnosis was based primarily on clinical findings and chest roentgenograms. Fifty percent of these infants were stabilized with digoxin, fluid restriction, and diuretics. Increasing ventilatory requirements associated with a patent ductus arteriosus led to use of indomethacin in 18 infants and surgical ligation in three infants. Necrotizing enterocolitis was documented in nine infants; three cases were complicated by intestinal perforation. Each of these perforations was treated conservatively with a local drain rather than laparotomy. Septicemia was confirmed by a positive blood culture in
p Gestational age (wk) Birth weight (gm) Small for gestatational age Betamethasone >36 hour H valine membrane disease Seizures Clinical intraventricular hemorrhage
25.2 ± 2.2
27 ± 2
731 ± 138 835 ± 101 3 (8.8%) 23 (32%)
<0.001 <0.001 <0.02
7 (20%)
34 (47%)
<0.02
16 (47%)
15 (21 %)
<0.02-<0.01
14 (41%) 17 (50%)
5 (7%)
2 (2.7%)
<0.00001 <0.00001
Values represent mean± 1 SD.
four infants, and meningitis was diagnosed in two others. Metabolic imbalances were not uncommon. Acidosis (pH< 7.20) occurred in 20 infants. Significant hyponatremia or hypernatremia occurred in eight infants and hypoglycemia (blood glucose level <20 mg/100 ml) occurred in five. Hypocalcemia (calcium level <6 mgilOO ml) occurred in two. Two infants required exchange transfusions for hyperbilirubinemia. Retrolental fibroplasia was demonstrated in I 0 infants. In eight, it was healing well at discharge but remained very active in two. Of the 72 survivors, five had clinical evidence of intraventricular hemorrhage in the nurserv and two had at least one seizure. One of these infants had a seizure associated with an episode of aspiration; subsequent neurological examination and electroencephalogram were normal. Follow-up. Two of the 72 survivor~ were lost to follow-up: One family was visiting from Poland at the time of the delivery of their 26-week infant and returned to their homeland following her discharge, and the other family left Ontario. Five other children have not been seen in our clinic, but contact has been maintained with family physicians and all five were fell to be progressing normally. These children have been included in the normal follow-up group. Of the survivors, one child died 10 days after discharge of sudden infant death syndrome. The other 64 infants were followed up for 12 to 24 months. The most common general health problem was recurrent middle ear infections. Ten children have required repeated courses of antibiotics, and three of them underwent myringotomy with good results. Recurrent wheezing, with or without lower respiratory tract infection, was a problem during the first year in four infants. This problem improved in each child during
138 Hoskins et al.
January 15. 1983
Am.
Table III. Correlation of results with perinatal events
Total No. Gestational age (wk) Birth weight (gm) Small for gestational age Delivery: Vaginal Cesarean section Initial low blood pressure Clinical intraventricular hemorrhage
60 27.1
9 26.2 782 3 (33%)
5 4 3 4
837
20 (33%)
(55%) (45%) (33%) (45%)
19 41 4 1
{32%) (68%) (7%) (1.6%)
Table IV. Outcome according to weight lvfean gesta-
Birth weight
751-1,000 ,;750
Handicap
tional age (wk)
(gm)
67 39
27.5 25.3
(%)
79
49
6 32
the second year. A number of children required surgical procedures: inguinal hernia repair (three), patent ductus arteriosus ligation (two), hypospadias repair (one), and tracheostomy for subglottic stenosis (one). Seven children had significant ophthalmologic problems: Two were legally blind secondary to retrolental fibroplasia and five had strabismus (one requiring corrective surgery). One child was deaf, but she had been small for gestational age and felt to fit an unusual syndrome including congenital deafness. Somatic growth in weight and height was still lagging at 12 to 18 months. Forty-nine percent were below the tenth percentile for weight at 12 to 18 months' corrected age and only 13% were greater than the fiftieth percentile. Proportionately they were slightly taller, as 26% exceeded the fiftieth percentile for height and only forty percent were below the tenth percentile. There seemed to be a trend for more catch-up growth after the first year, and only longer follow-up will show whether this trend continues through the toddler years. Head growth accelerated much earlier. At 12 to 18 months' corrected age, only 14% of children had a head circumference measured below the tenth percentile, while 48% showed head growth at or above the fiftieth percentile. At the most recent examination, significant neurological or developmental handicap was found in nine infants. Three children had hydrocephalus that had required shunting. Two of these infants showed evidence of spastic quadriparesis with severe mental retardation. The third child demonstrated a left hemiplegia with moderate retardation. Cerebral palsy was evident in three other children, one with spastic diplegia and two with hemiplegia. All three children were
J. Obstet. Gvneco!.
walking at 15 to 18 months' corrected age and had Bayley scores from 90 to 105. They were coping well in physiotherapy programs. The other three children showed no specific neurological abnormalities but had Bayley scores between 50 and 70 and significant behavioral abnormalities. All three have been referred to nursery schools for retarded children. Thus, 13% of the infants evaluated showed signs of significant handicap at l to 2 years. Correlation with perinatal events yielded little information of statistical significance (Table Ill). The abnormal children had been slightly smaller and more immature. More of them were delivered by the vaginal route. More numbers are needed to see if this trend is significant. As expected, clinical evidence of intraventricular hemorrhage correlated well with long-term sequelae. Although Apgar scores were not significantly different in the two groups, a large proportion of the abnormal survivors had required volume expansion as part of their resuscitation, suggesting a greater degree of perinatal asphyxia. Outcome of infants weighing s750 gm at birth. Table IV clearly shows that the outcome of the infant weighing <750 gm at delivery is very different from that in the infant weighing between 750 and l ,000 gm. Only 49% survived and 32% of the survivors showed significant handicap. The most severely handicapped infants were in this group: three infants with hydrocephalus, cerebral palsy, and mental retardation as well as two infants with Bayley scores below 80. Added to these infants with developmental handicaps are two children with major problems related to prematurity: One child is blind because of retrolental fibroplasia, and one child requires a permanent tracheostomy secondary to subglottic stenosis.
Comment Prior to the early 1970s, the neonatal survival rate for infants weighing <1,001 gm was 10%.U The present study shows an overall survival rate of 68% for such infants born in a perinatal center. Seventy-nine percent of infants weighing >750 gm survived while 39% of those between 500 and 750 gm lived. These figures compared very favorably with those of recent reports.12· 13 Improving survival did not result in increasing numbers of handicapped children. The incidence of significant neurological sequelae was only 13%. Only 6% of the infants weighing 750 to 1,000 gm showed long-term sequelae while 32% of the lower-weight group demonstrated long-term handicap. Again, these figures compared favorably with those of other perinatal centers. 14 • 15 Not surprisingly, survivors were more mature and larger. The role of glucocorticoids in improving outcome
Volum(' 145
Number 2
must be looked at critically. This is a retrospective, uncontrolled analysis. Ability to complete a 36-hour course of betamethasone implies a more stable, non urgent sitUation with no evidence of fetal distress. The avoidance of stress associated with atraumatic delivery and aggressive resuscitation may be more important, as suggested by others. 1H 8 The specific complication leading to premature delivery did not affect outcome in this study. Paul and associates 19 found that antepartum bleeding results in increased mortality, regardless of mode of delivery. Delivery by cesarean section resulted in improved survival and a decreased number of long-term handicaps. although not at a statistically significant level. Similar trends have been shown by Stewart and associates.8 as well as by Paul and associates 19 and Bowes and associates. 13 This trend needs to be more adequately confirmed, as the absence of a well-defined lower uterine segment in women in premature labor often necessitates classical cesarean section. The added risk of such a procedure must be justified. Stewart and associates8 found that growth retardation correlated with improved survival, which our data confirmed. On the other hand, growth retardation did not alter long-term handicaps. Britton and associates 20 also showed no effect of this factor on handicap. The most significant factor related to mortality and
Very low-birth weight infants born at perinatal center
neurological sequelae was clinical evidence of intraventricular hemorrhage. As neither computerized tomographic scan nor ultrasound was available for diagnosis, probably only the most severe hemorrhages were diagnosed. Several studies have correlated severe intraventricular hemorrhage with increasing mortality and handicap. 21 ' 22 At present, a research study concerning intraventricular hemorrhage is underway at Women's College Hospital. The incidence of intraventricular hemorrhage, its evolution. and its possible association with specific perinatal and/or neonatal events are being examined. Hopefully. a better understanding of factors related to the occurrence of intraventricular hemorrhage will lead to therapeutic changes resulting in decreased mortality and morbidity. In conclusion, this study demonstrates that the outcome of infants weighing 750 to 1.000 gm, delivered in a perinatal center, certainly justifies the financial and emotional expenditure. The outcome of the infant weighing <750 gm causes more concun. The numbers in this group were small and the obstetric approach was less consistent; therefore, statistical analvsis was impossible. Ideally, prevention of prematurity is the answer, but in the meantime assessment of more tiny infants born in a perinatal center is required ro answer these concerns.
REFERENCES I. Pomerance, J. J., Ukrainski, C. T, Ukra, T., Henderson, D. H., Nash. A. H., and Meredith, J. I.: Cost of living for infants weighing I 000 grams or less at birth, Pediatrics 61:908, 1978. 2. Phibbs, C. S., Williams, R. L., and Phibbs, R. H.: Newborn risk factors and cost of neonatal intensive care, Pediatrics 68:313, 1981. 3. Klaus, M. H., and Kennell,]. H.: Maternal-Infant Bonding: The Impact of Early Separation or Loss on Family Development, St. Louis, 1976, The C. V. Mosby Co. 4. Hack, M., Fanaroff, A. A., and Merkatz, I. R.: The low birthweight infant-evolution of a changing outlook, N. Engl. J. Med. 301: ll62. 1979. 5. Shennan, A. T., and Milligan, J. E.: The growth and development of infants weighing 1,000 to 2,000 grams at birth and delivered in a perinatal unit, AM. J. 0BSTET. CYNECOL. 136:273, 1980. 6. Driscoll, J. M., Driscoll, Y. T., Steir, M. E., Stark, R. I., Dangman, B. C., Perez, A., Wung, J.-T., and Kritz, P.: Mortality and morbidity in infants less than I 00 I grams birthweight. Pediatrics 69:31, 1982. 7. Ruiz, M. P. D., LaFever, J. A., Hakanson, D. 0., Clark, D. A., and Williams, M. L.: Early development of infants of birthweights less than I 000 grams, with reference to mechanical ventilation in newborn period, Pediatrics 68:330. 1981. 8. Stewart, A. L., Turcan, D. M., Rawlings, G., and Reynolds, E. 0. R.: Prognosis of infants weighing 1000 grams or less at birth, Arch. Dis. Child. 52:97, 1977. 9. Milligan, J. E., and Shennan, A. T.: Perinatal manage-
139
10. I I.
12. 13.
14.
15.
16.
17.
18.
ment and outcome in the infant weighing 1,000 to 2,000 grams. AM. j. 0BSTET. GYNECOL. 136:269. 1980. Bayley, N.: Bayley &ales of Infant Development, New York, 1969, The Psychological Corporation. Behrman, R. E., Babson, G. S., and Lessel, R.: Fetal and neonatal mortality in white middle class infants, mortality risks by gestational age and weight, Am. J Dis. Child. 121:486, 1971. Haesslein, H. C., and Goodlin, R. C.: Delivery of the tiny newborn, AM.]. OBSTET. GYNECOL. 134:192, 1979. Bowes, W. A., Halgrimson, M., and Simmons, M.A.: Results of intensive perinatal management of very-lowbirthweight infants (501 to 1500 grams).J. Reprod. Med. 23:245. 1979. Kumar, S. P., Anday, E. K., Sacks, L. M., Ting, R. Y., and Delivoria-Papadopoulos, M.: Follow-up studies of very low birth weight infants ( 1250 grams or less) born and treated within a perinatal center, Pediatrics 66:438j 1980. Yu, V. Y. H., and Hollingsworth, E.: Improving prognosis for infants weighing 1000 grams or less at birth, Arch. Dis. Child. 55:422, 1980. Quirk, J. G., Raker, R. K., Petrie, R. H., and Williams, A. M.: The role of glucocorticoids, unstressfullabor, and atraumatic delivery in the prevention of respiratory distress syndrome, AM.J. 0BSTET. GvNECOL.l34:768, 1979. Caspi, E., &hreyer, P., Reif, R., and Goldberg, M.: An analysis of the factors associated with respiratory distress syndrome in premature infants whose mothers had been given dexamethasone therapy, Br. J. Obstf'l. Gynaecol. 87:808, 1980. Robson, E .. and Hev, E.: Resuscitation of prf'term babies
140 Hoskins et al.
January 15, 19H3 Am.
at birth reduces their risk of death from hyaline membrane disease, Arch. Dis. Child. 57:184, 1982. 19. Paul, R. H., Koh, K. S., and Monfared, A. H.: Obstetric factors influencing outcome in infants weighing from 1,001 to 1,500 grams, AM.]. 0BSTET. GYNECOL. 133:503, 1979. 20. Britton, S. B., Fitzhardinge, P. M., and Ashby, S.: Is intensive care justified for infants weighing less than 801 grams at birth? J. Pediatr. 99:937, 1981.
J. Obstet. Gynecol.
21. Krishnamoorthy, S., Shannon, D. C., Delong, G. R., Todores, I. D., and Davis, K. R.: Neurologic sequelae in the survivors of neonatal intraventricular hemorrhage, Pediatrics 64:233, 1979. 22. Papile, L.A., Burstein,]., Burstein, R., and Koffler, H.: Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 grams,J. Pediatr. 92:529, 1978.
THE cosT of supporting very immature infants, especially those with a birth weight < l ,500 gm at birth, is enormous in terms of money and manpower. 1• 2 The emotional impact of this prolonged mother-infant separation is difficult to measure and has only recently become an area of concern.3 By the late 1970s, there appeared to be enough favorable data referring to short- and long-term outcome of infants in the weight group from 1,000 to 1,500 gm to support such expenditure.4· ·' More current reports 6- 8 offer reassurance concerning the outcome of infants weighing <1,000 gm at birth. To date, most studies with large numbers of infants have involved a mixture of infants born in and out of the hospital, which makes interpretation difficult. This study was done to delineate the outcome of a group of infants with birth weights< 1,000 gm, born in a perinatal setting. From the Regional Perinatal Unit, Women's College Hospital. Pmenti!d at the Thirty-eighth. Annual Meeting of The Sodei}' of Obstetricians and Gynaecologists of Canada, Toronto, Ontario, Canada,June 15-19, 1982.
Reprint requests: Dr. Elizabeth M. Hoskins, Regional PeriMtal Unit, Women's College Hospital, 76 Grenville St., Toronto, Ontario, CaMda M5S 1B2. 0002-9378/83/020135+06$00.60/0
©
1983 The C. V. Mosby Co.
Patients and material
Between January l, 1979, and December 31, 1980. 106 infants weighing s 1,000 gm were admitted to the Neonatal Intensive Care Unit of Women's College Hospital. Although all were born in the hospital, 83 (78%) were born to women transferred to the Tertiary Care Perinatal Unit at Women's College Hospital because of antenatal problems. They ranged from 500 to l ,000 gm in weight and from 23 to 33 weeks in gestational age. Twenty-six were small for gestational age. Throughout this period, the perinatal approach to the high-risk antenatal patient was relatively consistent. In patients admitted in premature labor, labor was inhibited with isoxsuprine to allow administration ofbetamethasone, providing there was no evidence of fetal stress on monitoring. If labor could not be arrested, mode of delivery depended on fetal presentation, monitoring, and estimated gestational age. Beyond 25 weeks' gestation, cesarean section was performed for breech or transverse presentation, for evidence of fetal stress, or in multiple pregnancy. 9 At less than 25 weeks, the obstetric management was not as aggressive, and many patients were allowed to be delivered vaginally. Management of patients admitted with premature rupture of membranes with or without labor was similar if there was no evidence of chorioamnionitis. In 135
136 Hoskins et al.
January 15, 1983 Am. J. Obstet. Gynecol.
Tabie I. Primary causes of death Cause of death
No.
Severe immaturity: 23 to 24 weeks, limited resuscitation Intraventricular hemorrhage Hyaline membrane disease Congenital abnormalities Fetal crush syndrome (oligohydramnios) Clostridial infection Fetal hydrops
13 ll 2 3 3 1 1
addition, vaginal swab specimens were obtained, and the patients were started on a regimen of parenteral penicillin. The patient was then managed conservatively, as long as she was not in labor and showed no signs of chorioamnionitis. Patients admitted with preeclampsia were stabilized with fluids, magnesium sulfate, and sedation, as medically indicated. In most cases, delivery was by cesarean section. Antepartum hemorrhages were managed expectantly, depending on fetal and maternal well-being. Patients with growth-retarded _fetuses were monitored with nonstress testing and ultrasound to assess fetal well-being as well as to rule out congenital abnormalities. Neonatal resuscitation was very aggressive with intubation and assisted ventilation provided in the first few minutes if there was any evidence of respiratory distress, such as in-drawing or grunting. No transport of the infant was required as the resuscitation room was adjacent to the delivery room. There was always a staff neonatologist or senior fellow in attendance. Gestational age was based on maternal dates in association with physical and neurological assessment of the infant. Ventilation requirements were evaluated by measurement of arterial blood gas levels, transcutaneous Po 2 monitoring, and clinical symptomatology. Nasopharyngeal continuous positive airway pressure was frequently used in the weaning process. Particular emphasis was placed on fluid balance during the early course of any respiratory illness. Infants with patent ductus arteriosus complicating their respiratory course were treated initially with digoxin and fluid restriction. Indomethacin was used early and surgical ligation was considered if indomethacin was contraindicated or ineffective. The diagnosis of intraventricular hemorrhage was made on clinical grounds as a computerized tomographic scan was not readily available at Women's College Hospital, and ultrasonography was not used routinely until 1981. All infants were assessed by the same ophthalmologist at the time oxygen therapy was discontinued.
They were then followed up as indicated by retinal changes. Follow-up assessments were performed at 3, 6, 9, 12, and 18 months' corrected age. Interim histories were obtained regarding general health problems and developmental progress. Physical and neurological examinations were performed. Evidence of hydrocephalus, definite cerebral palsy, or minor changes in tone was noted. Psychometric assessment was performed by a psychologist at 12 to 18 months after term. She was unaware of the child's neonatal or subsequent clinical course. The test used was the Bayley Scale of Infant Development. 10 Audiometric and repeat ophthalmologic assessments were performed as indicated.
Results Overall results. In the two-year study period, 106 infants weighing 1,000 gm or less were born. There were 59 female and 4 7 male infants. The mean gestational age was 26.4 weeks and the mean birth weight was 801 gm. Twenty-six infants were small for gestational age. Twenty-four of the mothers involved had had obstetric complications in previous pregnancies. The present pregnancy was complicated by premature labor in 24%. Premature rupture of membranes with or without labor accounted for a further 31%. Preeclampsia alone or superimposed on preexisting hypertension led to early delivery in 15%. Other complications, including antepartum bleeding, growth retardation, or combinations of those factors, accounted for the rest of the cases. Maternal disease, such as diabetes, cardiovascular disease, or malignancy, were not presenting factors in any of these pregnancies. A full course of betamethasone was administered to 41 (39%) mothers. Delivery was by cesarean section in 57% of the patients, half by classical or vertical incision and the rest by lower segment incision. General anesthesia was induced in 93% of these procedures. Of the 45 infants delivered vaginally, only six were in the breech presentation; the others were in the vertex. An epidural anesthetic was used in 71% of the vaginal deliveries. Mortality. Thirty-four infants (32%) died in the first 28 days. There were no other infant deaths prior to discharge. All but seven deaths occurred in the first 3 days. Three ofthese infants lived more than 7 days: two lived 8 days and one died at 3 weeks. Thirteen infants were assessed to be 23 to 24 weeks' gestation by the neonatologist at the time of delivery and, on the basis of previous results at this gestational age, were not aggressively resuscitated. The other primary causes of death are presented in Table I.
Volume 145 Number 2
Many perinatal factors were examined to determine
Very low-birth weight infants born at perinatal center
137
Table II. Factors affecting survival
difference!: between tho,;;e who lived and those who
died. Seven factors (Table II) were found to be of significance. Survivors were more mature and larger. Intrauterine growth retardation and antenatal corticosteroids were associated with increased survival. The presence of hyaline membrane disease, seizures, and clinical signs of intraventricular hemorrhage resulted in increased mortality. Other factors were examined but found not to correlate with mortality: obstetric complications in previous pregnancies, presenting complication in present pregnancy. route of delivery, and sex of the infant. There was certainly a trend for infants delivered by cesarean section to do better but this trend did not reach statistical significance. Nineteen or 42% of infants delivered vaginally died, while only 25% of those delivered by cesarean section died. No comment can be made about vaginal delivery of infants in a breech presentation as the numbers were too small. Neonatal morbidity in survivors. Of the 72 survivors, 46 (64%) were delivered by cesarean section (with a general anesthetic used in 90%). Sixty-three infants (87%) were intubated soon after delivery, which reflects the aggressive approach to resuscitation at Women's College Hospital. The other nine infants required only suctioning or resuscitation with bag and mask. Only two infants had Apgar scores below 6 at 5 minutes. Seven infants required a volume expander in the first hour. Some form of respiratory distress was present in most infants. The primary diagnoses were wet lung in 52 and hyaline membrane disease in 15. Forty-five infants, including all those with hyaline membrane disease, required assisted ventilation for >24 hours. Five infants with hyaline membrane disease suffered pneumothoraces and two developed bronchopulmonary dysplasia. Neither of these infants required oxygen beyond their term date. Patent ductus arteriosus was a very common diagnosis, occurring in 42 infants. Diagnosis was based primarily on clinical findings and chest roentgenograms. Fifty percent of these infants were stabilized with digoxin, fluid restriction, and diuretics. Increasing ventilatory requirements associated with a patent ductus arteriosus led to use of indomethacin in 18 infants and surgical ligation in three infants. Necrotizing enterocolitis was documented in nine infants; three cases were complicated by intestinal perforation. Each of these perforations was treated conservatively with a local drain rather than laparotomy. Septicemia was confirmed by a positive blood culture in
p Gestational age (wk) Birth weight (gm) Small for gestatational age Betamethasone >36 hour H valine membrane disease Seizures Clinical intraventricular hemorrhage
25.2 ± 2.2
27 ± 2
731 ± 138 835 ± 101 3 (8.8%) 23 (32%)
<0.001 <0.001 <0.02
7 (20%)
34 (47%)
<0.02
16 (47%)
15 (21 %)
<0.02-<0.01
14 (41%) 17 (50%)
5 (7%)
2 (2.7%)
<0.00001 <0.00001
Values represent mean± 1 SD.
four infants, and meningitis was diagnosed in two others. Metabolic imbalances were not uncommon. Acidosis (pH< 7.20) occurred in 20 infants. Significant hyponatremia or hypernatremia occurred in eight infants and hypoglycemia (blood glucose level <20 mg/100 ml) occurred in five. Hypocalcemia (calcium level <6 mgilOO ml) occurred in two. Two infants required exchange transfusions for hyperbilirubinemia. Retrolental fibroplasia was demonstrated in I 0 infants. In eight, it was healing well at discharge but remained very active in two. Of the 72 survivors, five had clinical evidence of intraventricular hemorrhage in the nurserv and two had at least one seizure. One of these infants had a seizure associated with an episode of aspiration; subsequent neurological examination and electroencephalogram were normal. Follow-up. Two of the 72 survivor~ were lost to follow-up: One family was visiting from Poland at the time of the delivery of their 26-week infant and returned to their homeland following her discharge, and the other family left Ontario. Five other children have not been seen in our clinic, but contact has been maintained with family physicians and all five were fell to be progressing normally. These children have been included in the normal follow-up group. Of the survivors, one child died 10 days after discharge of sudden infant death syndrome. The other 64 infants were followed up for 12 to 24 months. The most common general health problem was recurrent middle ear infections. Ten children have required repeated courses of antibiotics, and three of them underwent myringotomy with good results. Recurrent wheezing, with or without lower respiratory tract infection, was a problem during the first year in four infants. This problem improved in each child during
138 Hoskins et al.
January 15. 1983
Am.
Table III. Correlation of results with perinatal events
Total No. Gestational age (wk) Birth weight (gm) Small for gestational age Delivery: Vaginal Cesarean section Initial low blood pressure Clinical intraventricular hemorrhage
60 27.1
9 26.2 782 3 (33%)
5 4 3 4
837
20 (33%)
(55%) (45%) (33%) (45%)
19 41 4 1
{32%) (68%) (7%) (1.6%)
Table IV. Outcome according to weight lvfean gesta-
Birth weight
751-1,000 ,;750
Handicap
tional age (wk)
(gm)
67 39
27.5 25.3
(%)
79
49
6 32
the second year. A number of children required surgical procedures: inguinal hernia repair (three), patent ductus arteriosus ligation (two), hypospadias repair (one), and tracheostomy for subglottic stenosis (one). Seven children had significant ophthalmologic problems: Two were legally blind secondary to retrolental fibroplasia and five had strabismus (one requiring corrective surgery). One child was deaf, but she had been small for gestational age and felt to fit an unusual syndrome including congenital deafness. Somatic growth in weight and height was still lagging at 12 to 18 months. Forty-nine percent were below the tenth percentile for weight at 12 to 18 months' corrected age and only 13% were greater than the fiftieth percentile. Proportionately they were slightly taller, as 26% exceeded the fiftieth percentile for height and only forty percent were below the tenth percentile. There seemed to be a trend for more catch-up growth after the first year, and only longer follow-up will show whether this trend continues through the toddler years. Head growth accelerated much earlier. At 12 to 18 months' corrected age, only 14% of children had a head circumference measured below the tenth percentile, while 48% showed head growth at or above the fiftieth percentile. At the most recent examination, significant neurological or developmental handicap was found in nine infants. Three children had hydrocephalus that had required shunting. Two of these infants showed evidence of spastic quadriparesis with severe mental retardation. The third child demonstrated a left hemiplegia with moderate retardation. Cerebral palsy was evident in three other children, one with spastic diplegia and two with hemiplegia. All three children were
J. Obstet. Gvneco!.
walking at 15 to 18 months' corrected age and had Bayley scores from 90 to 105. They were coping well in physiotherapy programs. The other three children showed no specific neurological abnormalities but had Bayley scores between 50 and 70 and significant behavioral abnormalities. All three have been referred to nursery schools for retarded children. Thus, 13% of the infants evaluated showed signs of significant handicap at l to 2 years. Correlation with perinatal events yielded little information of statistical significance (Table Ill). The abnormal children had been slightly smaller and more immature. More of them were delivered by the vaginal route. More numbers are needed to see if this trend is significant. As expected, clinical evidence of intraventricular hemorrhage correlated well with long-term sequelae. Although Apgar scores were not significantly different in the two groups, a large proportion of the abnormal survivors had required volume expansion as part of their resuscitation, suggesting a greater degree of perinatal asphyxia. Outcome of infants weighing s750 gm at birth. Table IV clearly shows that the outcome of the infant weighing <750 gm at delivery is very different from that in the infant weighing between 750 and l ,000 gm. Only 49% survived and 32% of the survivors showed significant handicap. The most severely handicapped infants were in this group: three infants with hydrocephalus, cerebral palsy, and mental retardation as well as two infants with Bayley scores below 80. Added to these infants with developmental handicaps are two children with major problems related to prematurity: One child is blind because of retrolental fibroplasia, and one child requires a permanent tracheostomy secondary to subglottic stenosis.
Comment Prior to the early 1970s, the neonatal survival rate for infants weighing <1,001 gm was 10%.U The present study shows an overall survival rate of 68% for such infants born in a perinatal center. Seventy-nine percent of infants weighing >750 gm survived while 39% of those between 500 and 750 gm lived. These figures compared very favorably with those of recent reports.12· 13 Improving survival did not result in increasing numbers of handicapped children. The incidence of significant neurological sequelae was only 13%. Only 6% of the infants weighing 750 to 1,000 gm showed long-term sequelae while 32% of the lower-weight group demonstrated long-term handicap. Again, these figures compared favorably with those of other perinatal centers. 14 • 15 Not surprisingly, survivors were more mature and larger. The role of glucocorticoids in improving outcome
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Number 2
must be looked at critically. This is a retrospective, uncontrolled analysis. Ability to complete a 36-hour course of betamethasone implies a more stable, non urgent sitUation with no evidence of fetal distress. The avoidance of stress associated with atraumatic delivery and aggressive resuscitation may be more important, as suggested by others. 1H 8 The specific complication leading to premature delivery did not affect outcome in this study. Paul and associates 19 found that antepartum bleeding results in increased mortality, regardless of mode of delivery. Delivery by cesarean section resulted in improved survival and a decreased number of long-term handicaps. although not at a statistically significant level. Similar trends have been shown by Stewart and associates.8 as well as by Paul and associates 19 and Bowes and associates. 13 This trend needs to be more adequately confirmed, as the absence of a well-defined lower uterine segment in women in premature labor often necessitates classical cesarean section. The added risk of such a procedure must be justified. Stewart and associates8 found that growth retardation correlated with improved survival, which our data confirmed. On the other hand, growth retardation did not alter long-term handicaps. Britton and associates 20 also showed no effect of this factor on handicap. The most significant factor related to mortality and
Very low-birth weight infants born at perinatal center
neurological sequelae was clinical evidence of intraventricular hemorrhage. As neither computerized tomographic scan nor ultrasound was available for diagnosis, probably only the most severe hemorrhages were diagnosed. Several studies have correlated severe intraventricular hemorrhage with increasing mortality and handicap. 21 ' 22 At present, a research study concerning intraventricular hemorrhage is underway at Women's College Hospital. The incidence of intraventricular hemorrhage, its evolution. and its possible association with specific perinatal and/or neonatal events are being examined. Hopefully. a better understanding of factors related to the occurrence of intraventricular hemorrhage will lead to therapeutic changes resulting in decreased mortality and morbidity. In conclusion, this study demonstrates that the outcome of infants weighing 750 to 1.000 gm, delivered in a perinatal center, certainly justifies the financial and emotional expenditure. The outcome of the infant weighing <750 gm causes more concun. The numbers in this group were small and the obstetric approach was less consistent; therefore, statistical analvsis was impossible. Ideally, prevention of prematurity is the answer, but in the meantime assessment of more tiny infants born in a perinatal center is required ro answer these concerns.
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January 15, 19H3 Am.
at birth reduces their risk of death from hyaline membrane disease, Arch. Dis. Child. 57:184, 1982. 19. Paul, R. H., Koh, K. S., and Monfared, A. H.: Obstetric factors influencing outcome in infants weighing from 1,001 to 1,500 grams, AM.]. 0BSTET. GYNECOL. 133:503, 1979. 20. Britton, S. B., Fitzhardinge, P. M., and Ashby, S.: Is intensive care justified for infants weighing less than 801 grams at birth? J. Pediatr. 99:937, 1981.
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21. Krishnamoorthy, S., Shannon, D. C., Delong, G. R., Todores, I. D., and Davis, K. R.: Neurologic sequelae in the survivors of neonatal intraventricular hemorrhage, Pediatrics 64:233, 1979. 22. Papile, L.A., Burstein,]., Burstein, R., and Koffler, H.: Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 grams,J. Pediatr. 92:529, 1978.