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Improvement in perinatal mortality rate attributed to spontaneous preterm labor without use of tocolytic agents
Improvement in perinatal mortality rate attributed to spontaneous preterm labor without use of tocolytic agents PETER KIERAN Dublin,
BOYLAN,
M.R.C.P.I.,
O’DRISCOLL,
M.R.C.O.G.
F.R.C.P.I.,
F.R.C.O.G.
Irektnd
A retrospec0ve study of the influence of spontaneous preterm labor on perinatal mortality rate over a period of 15 years was conducted at the National Maternity Hospital, Dublin. As the perinatal mortality rate from all causes declined from 46 to 16 per 1,000 births, the rate attributed to spontaneous preterm labor declined in the same proportion, from 10 to three per 1,000 births. Review of the circumstances of death attributed to spontaneous preterm labor in each case indicates that improvement in this area was due mainly to a natural reduction in incidence and, to a lesser degree, to better care of the neonate. Pharmacologic agents recommended for the purpose of averting spontaneous preterm labor made no contribuGon, because none was used. Natural improvement in the evolution of a disease may lead to exaggerated claims for the benefits of treatment; experience with perinatal death attributed to spontaneous preterm labor in this large unit suggests that current enthusiasm for tocolytic agents may well be misplaced. (AM. J. OESTET. GYNECOL. 145781, 1983.)
IN RECENT ~~~~~,vigorousattemptshavebeenmade to avert spontaneous preterm labor on the grounds that prematurity is associated with a substantial proportion of perinatal deaths.‘. ’ Therapeutic agents recommended for this purpose include alcohol, prostaglandin synthetase inhibitors, and P-sympathomimetic agents.2 There now exists a wide measure of agreement in the United Kingdom,” as in Europe,” that suspected preterm labor should be treated with one or the other of these substances, usually p-sympathomimetic preparations, and favorable reaction to approval of ritodrine by the Food and Drug Administration’* ’ suggests that events are likely to follow a similar course in the United States. Tocolytic agents have never been used at the National Maternity Hospital, which is one of the largest obstetric units in Western Europe. With almost 9,000 births each year and no specific treatment directed toward averting preterm labor, results reflect the natural From the National Maternity Ohrtetrics and Gynaerology, Receimd
for publication
Accepted
November
Hospitnl University
September
and Department College Dublin.
IO, 1982.
Methods and definitions All perinatal deaths which occurred at the National Maternity Hospital during the years 1966 through 1980 were reviewed. By definition, a perinatal death occurred between 20 weeks’ (110 days’) gestation, or 500 gm birth weight, and 7 days (168 hours) after birth. A preterm birth occurred between 20 weeks and 37 weeks (259 days). A death was said to be nssocinted IL& pttprm birth when delivery occurred at less than 37 weeks, irrespective of’ the cause of death. There are four distinct clinical categories of perinatal death associated with preterm birth: fetal death before labor, congenital malformation, neonatal death after elective delivery, and death after onset ot’ spontaneous preterm labor: a death is nttributd to .+!~~nttnnsozcspiteym labor when the first three categories have been excluded.
Results
1, 1982.
Reprint requests: Dr. Peter Boyhn, National Hospital, Holles St., Dxblin 2, Ireland.
of
course of events. With this in mind, a Is-year period, which corresponds with the introduction of tocolytic agents in most other centers, was chosen fi)r review.
Maternity
During a 1 j-year period, 2,981 were either stillborn
104,892 infants were born: or did not survive 7 days 781
782
Boylan and O’Driscoll
April I, I 9x3 Am. J. Obstet.
Table I. Perinatal deaths from all causes in infants born at all gestations and in infants born before 37 weeks (expressed as an absolute number and as a rate per 1,000 births)
1966 1967 1968 1970 1969
5,108 5,068 4,886 6,697 5,500
247 230 218 220 234
48.3 45.4 44.6 32.8 42.5
127 155 130 142 138
24.8 30.6 26.6 25.8 20.6
197 1 1972 1973 1974 1975 1976 1977 1978 1979 1980
7,129 7.296 7;370 7,687 7,444 7,580 7,630 8,151 8,497 8,874
218 219 228 164 171 149 188 193 178 149
30.5 30.0
129 131 137 101 99 93 106 93 116 87
18.1 17.9 18.5 13.1 13.3 12.2 13.8 11.4 13.6 9.8
30.9
21.3 22.9 19.7 24.6 23.7 20.9 16.7
Table II. Perinatal mortality preterm delivery, expressed its four component parts
rate associated with as a total figure with Component parts
Fetal Year
Total
1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980
24.8 30.6 26.6 25.8 20.6 18.1 17.9 18.5 13.1 13.3 12.2 13.8 11.4 13.6 9.8
death
9.5 11.6 13.1 11.4 8.2 8.8 7.8 9.4 6.2 5.3 5.0 5.2 3.8 6.1 4.7
Congenital malformation
3.3 3.9 3.1 3.4 3.1 2.9 3.2 3.1 2.9 2.0 1.3 2.8 1.8 2.0 1.2
Elective delivery
2.2 1.9 2. 2 2.9 2.6 1.8 0.9 0.4 0.8 1.3 0.8 0.9 0.8 1.4 0.8
Spontaneow lUb0r
*
9.8 13.2 8.2 8.1 6.7 4.6 6.0 5.6 3.2 4.7 5.1 4.9 5.0 4.1 3.1
*Deaths in this column were attributed to preterm labor.
past birth. The perinatal mortality rate declined from 48.3 in 1966 to 16.7 in 1980. The perinatal mortality rate associated with preterm birth declined from 24.8 to 9.8 over the same period of time (Table I). The rate of each of the four categories of perinatal death associated with preterm birth declined progressively over the 15 years (Table II). A 4.4% incidence of spontaneous preterm labor in 1966 had fallen to 2.9% in 1980, while the incidence of
Gvnecol.
low-birth-weight infants (<2,500 gm) had declined b) half, from 8% to 4%. in the same time. Notable changes occurred in the demographic features of women delivered of their infants at the hospital during the 15 years: The proportion ~35 years of age declined from 25%. to 12%‘: those younger than 20 years increased from -4% to 6%‘: mothers with five or more children decreased from 20% to 10%: primigravidas increased from 30% to 35%‘: there was a reduction from 2057 to IO%, in mothers of the lowest socioeconomic group; at the other end of the scale the highest socioeconomic group increased from 4%’ to 6%.
Comment These results show a progressive decline in perinatal deaths attributed to spontaneous preterm labor which could be explained in two possible ways: Spontaneous preterm labor may have occurred less frequently or care of’newborn infants may have improved. Tocolytic drug therapy is an influence which can be confidently excluded, because none was used. Before proceeding to discuss results it is necessary to recall the fundamental differences between perinatal death associated with preterm delivery and death attributed to spontaneous preterm labor. Although preterm delivery is associated with a disproportionate number of perinatal deaths, it is wrong to conclude that lack of maturity necessarily accounts for those deaths. This is clearly the case where the fetus is already dead or where death is due to lethal congenital malformation. Consideration of the value of tocolytic agents must be confined to events related to spontaneous labor: fetal death, congenital malformation, and elective deliveries must be rigorously excluded. Hence, this study is confined to infants who were alive when spontaneous labor began and who did not suffer from a serious congenital malformation. The purpose of this article is not to scrutinize each of the possible causes but simply to draw attention to a noteworthy improvement in perinatal mortality rate attributed to preterm labor, in which tocolytic drugs played no part. It is, nevertheless, of considerable interest to note that the other three causes of perinatal death associated with preterm delivery showed a similar decline (Table II). The incidence of spontaneous preterm labor did decrease slightly in frequency. from 4.4% of births in 1966 to 2.9% in 1980: and in addition, the rate of low-birth-weight infants fell by half, from 8rr in 1966 to 4% in 1980. Improved demographic features, with a reduction in age and parity, and improved socioeconomic circumstances may in large part account for these changes. Intensive neonatal care was introduced in the mid/late 197Os, but it is apparent that
Volume Number
145 7
Perinatal
the
decline
in perinatal
way
before
this.
is that
tocolytic
outcome of
other
distract
attention
Tocolytic States
will
provement
in
method ron
and
birth
prevention
term
labors
note steady
in
suggests are viewed The
rate
labor,
and
in 1 year).
Maternity
in perinatal considerable
that
large
numbers
38
among
in
are
reactions.“-” attributed
further
mav to
agents,
the
cerning
preterm study
inthis period can
in
perinatal
mortality
rate
documented
The can
deaths, which
01
the
01’ niav
a~kd may
lead
inc.rease
in
de&m. preterm
to ad-
in pcarinaral labor,
introdllction to lalse
lack
iihwss
decisions
contributed
which
6 11‘ tocolytic cotlclllsions
c OII-
effect. is that
should
be shown
from could
in
doubrs
c~f’f~c ac.v
to llow
a concomitant
with
conclusion agents
111~
recrntlv
in making
and
\‘cars,
01‘ untreatc-tl
A progressive
have
n IIO
( JL’di tficult\
alxltlt
to spontaneous
cause
dr
OI ~\c~rnen
In recent
drawn
with
coincided
may
colvtic they
be
in perspective. fall
have
inI-
ativersc
because
course
physicians
a sI)ontancous
numbers
onlv
of’
Seenr-
.>‘. I”
been the
remedies,
deaths
study
results
has of
verse
variation;
a long
improvement
Attention
sattt\
as ‘i source
agai11s1
labor.g not
about
16 pre-
of
large
783
LIW 01 tocolvtic
against historv,
the
labor
arc- tlsed.
widespread
unnecessarilv
expressed
but
hamper
of
of preterm
been
ser\‘es
tocolvtics
natural
against
the diagnosis
drastic
It is interesting
annual and
in pre-
results
Hospital
deaths
of before
delivery,
treatment
knowledge
of a preterm
initial
and
receive hale
Her-
(a total
effects,
therapv
where
to be balanced in the
and preterm
Hospital
units results
need
provemenr
to this
a fall
the
small
the
an im-
related
report
while in
that
to be demonstrated.’
were
spite
essential
to stan-
and
Maternity for
beneficial
drugs
widespread
fallen
demonstrated
numbers
National
decline
fants
recently
likely
their
not
in a preliminary
resulting
the
ingly
serve into
National
comparison
further
could
Despite
mortality is yet
of preterm in
the
improved
and
it seems
have
program; the
episodes
suit.
perinatal
rates
in the labor
incorporated
’ and rates
associates”
delivery
impressive,
been
follow
of treatment
term
part
under
this.
have
delivery
no
well
investigation
explanations
in Europe”,
preterm
was
of this
preterm
from
practice
United
played
possible
drugs
rate
point
spontaneous
analysis
use,
central
agents
of
dard
mortality
The
mortality
current
be ternpercd to produce
sf~otctntwotr~ result from
prrtrrm natural
enthusiasm lvith
a reductic)ll
for
carltion
LOuntil
in perinatal
l&j,-, exceeding caust’h.
that
at
REFERENCES 1. Rush, R. W., Keirse, M. J, N. C., Howat, P., et al.: Contribution of’ preterm delivery to perinatal mortality, Br. Med. J. 2:965, 1976. 2. Fuchs, F.: Prevention of’ premature birth, Clin. Perinatol. 7:3, 19X0. 3. Lewis, P. J., de Sweit, M., Boylan, P., and Bulpitt, C. J.: How obstetricians in the United Kingdom manage preterm labor, Br. J. Obstet. Gynaecol. 87:574, 1980. 4. Kubli, F.: In Anderson, A., Beard, R., Brudenell, M. J., and Dunn, P., editors: Pre-term Labour, Proceedings of the Fifth Study Group of the Royal College of Obstetricians and Gynaecologists, London, 1977, Royal College of v Obstetricians and Ginaecolo ists, p. 2 18. ’ 5. Editorial: Ritodrine approve 2 for premature labor, FDA Drug Bull. 10:22, 1980. 6. Check. W. A.: FDA considers a first: ADDrOVd of drug for o inhibiiing preterm labor, JAMA 243:ii13, 1980. 7 Hendricks, C. H.: The case for non-intervention in preterm labor, in Eider, M. G., and Hendricks, C. H., edi-
8.
9. 10.
11. 12.
13.
tors: Preterm Labor, Obstetrics and Gynecology, Butterworth’s International Medical Reviews. London, 1981, vol. 1. Butterworth & Co., Ltd., p. 93. Herron, M. A., Katz, M., and Creasy, R. K.: Evaluation of a preterm birth prevention program: Preliminary report, Obstet. Gynecol. 59:452, 1982. Editorial: Drug treatment of prematltre lahotlr. Br. Med. J. 283:395, 1981. Hemminki, E., and Starfield, B.: Prevention and treatment of premature labour by drugs: Review of‘controlled clinical trials, Br. J. Obstet. Gynaecol. 85:,111. 1978. Myers, J. D.: Preventing iatrogenic complications, N. Engl. J. Med. 304:664, 1981. Couch, N. P.. Tilney, N. L., Rayner, A. :I., and Moore, F. D.: The high cosi of low-frequency events: The anatomy and economics ot‘ surgical mishaps. N Engl. J. Med. 304~634, 1981. Steel, K., Gertman, P. M., Crescenzi, C., and Anderson, J.: Iatrogenic illness on a general medical service at a university hospital, N. Engl. J. Med. 304:63&. 1981,
BOYLAN,
M.R.C.P.I.,
O’DRISCOLL,
M.R.C.O.G.
F.R.C.P.I.,
F.R.C.O.G.
Irektnd
A retrospec0ve study of the influence of spontaneous preterm labor on perinatal mortality rate over a period of 15 years was conducted at the National Maternity Hospital, Dublin. As the perinatal mortality rate from all causes declined from 46 to 16 per 1,000 births, the rate attributed to spontaneous preterm labor declined in the same proportion, from 10 to three per 1,000 births. Review of the circumstances of death attributed to spontaneous preterm labor in each case indicates that improvement in this area was due mainly to a natural reduction in incidence and, to a lesser degree, to better care of the neonate. Pharmacologic agents recommended for the purpose of averting spontaneous preterm labor made no contribuGon, because none was used. Natural improvement in the evolution of a disease may lead to exaggerated claims for the benefits of treatment; experience with perinatal death attributed to spontaneous preterm labor in this large unit suggests that current enthusiasm for tocolytic agents may well be misplaced. (AM. J. OESTET. GYNECOL. 145781, 1983.)
IN RECENT ~~~~~,vigorousattemptshavebeenmade to avert spontaneous preterm labor on the grounds that prematurity is associated with a substantial proportion of perinatal deaths.‘. ’ Therapeutic agents recommended for this purpose include alcohol, prostaglandin synthetase inhibitors, and P-sympathomimetic agents.2 There now exists a wide measure of agreement in the United Kingdom,” as in Europe,” that suspected preterm labor should be treated with one or the other of these substances, usually p-sympathomimetic preparations, and favorable reaction to approval of ritodrine by the Food and Drug Administration’* ’ suggests that events are likely to follow a similar course in the United States. Tocolytic agents have never been used at the National Maternity Hospital, which is one of the largest obstetric units in Western Europe. With almost 9,000 births each year and no specific treatment directed toward averting preterm labor, results reflect the natural From the National Maternity Ohrtetrics and Gynaerology, Receimd
for publication
Accepted
November
Hospitnl University
September
and Department College Dublin.
IO, 1982.
Methods and definitions All perinatal deaths which occurred at the National Maternity Hospital during the years 1966 through 1980 were reviewed. By definition, a perinatal death occurred between 20 weeks’ (110 days’) gestation, or 500 gm birth weight, and 7 days (168 hours) after birth. A preterm birth occurred between 20 weeks and 37 weeks (259 days). A death was said to be nssocinted IL& pttprm birth when delivery occurred at less than 37 weeks, irrespective of’ the cause of death. There are four distinct clinical categories of perinatal death associated with preterm birth: fetal death before labor, congenital malformation, neonatal death after elective delivery, and death after onset ot’ spontaneous preterm labor: a death is nttributd to .+!~~nttnnsozcspiteym labor when the first three categories have been excluded.
Results
1, 1982.
Reprint requests: Dr. Peter Boyhn, National Hospital, Holles St., Dxblin 2, Ireland.
of
course of events. With this in mind, a Is-year period, which corresponds with the introduction of tocolytic agents in most other centers, was chosen fi)r review.
Maternity
During a 1 j-year period, 2,981 were either stillborn
104,892 infants were born: or did not survive 7 days 781
782
Boylan and O’Driscoll
April I, I 9x3 Am. J. Obstet.
Table I. Perinatal deaths from all causes in infants born at all gestations and in infants born before 37 weeks (expressed as an absolute number and as a rate per 1,000 births)
1966 1967 1968 1970 1969
5,108 5,068 4,886 6,697 5,500
247 230 218 220 234
48.3 45.4 44.6 32.8 42.5
127 155 130 142 138
24.8 30.6 26.6 25.8 20.6
197 1 1972 1973 1974 1975 1976 1977 1978 1979 1980
7,129 7.296 7;370 7,687 7,444 7,580 7,630 8,151 8,497 8,874
218 219 228 164 171 149 188 193 178 149
30.5 30.0
129 131 137 101 99 93 106 93 116 87
18.1 17.9 18.5 13.1 13.3 12.2 13.8 11.4 13.6 9.8
30.9
21.3 22.9 19.7 24.6 23.7 20.9 16.7
Table II. Perinatal mortality preterm delivery, expressed its four component parts
rate associated with as a total figure with Component parts
Fetal Year
Total
1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980
24.8 30.6 26.6 25.8 20.6 18.1 17.9 18.5 13.1 13.3 12.2 13.8 11.4 13.6 9.8
death
9.5 11.6 13.1 11.4 8.2 8.8 7.8 9.4 6.2 5.3 5.0 5.2 3.8 6.1 4.7
Congenital malformation
3.3 3.9 3.1 3.4 3.1 2.9 3.2 3.1 2.9 2.0 1.3 2.8 1.8 2.0 1.2
Elective delivery
2.2 1.9 2. 2 2.9 2.6 1.8 0.9 0.4 0.8 1.3 0.8 0.9 0.8 1.4 0.8
Spontaneow lUb0r
*
9.8 13.2 8.2 8.1 6.7 4.6 6.0 5.6 3.2 4.7 5.1 4.9 5.0 4.1 3.1
*Deaths in this column were attributed to preterm labor.
past birth. The perinatal mortality rate declined from 48.3 in 1966 to 16.7 in 1980. The perinatal mortality rate associated with preterm birth declined from 24.8 to 9.8 over the same period of time (Table I). The rate of each of the four categories of perinatal death associated with preterm birth declined progressively over the 15 years (Table II). A 4.4% incidence of spontaneous preterm labor in 1966 had fallen to 2.9% in 1980, while the incidence of
Gvnecol.
low-birth-weight infants (<2,500 gm) had declined b) half, from 8% to 4%. in the same time. Notable changes occurred in the demographic features of women delivered of their infants at the hospital during the 15 years: The proportion ~35 years of age declined from 25%. to 12%‘: those younger than 20 years increased from -4% to 6%‘: mothers with five or more children decreased from 20% to 10%: primigravidas increased from 30% to 35%‘: there was a reduction from 2057 to IO%, in mothers of the lowest socioeconomic group; at the other end of the scale the highest socioeconomic group increased from 4%’ to 6%.
Comment These results show a progressive decline in perinatal deaths attributed to spontaneous preterm labor which could be explained in two possible ways: Spontaneous preterm labor may have occurred less frequently or care of’newborn infants may have improved. Tocolytic drug therapy is an influence which can be confidently excluded, because none was used. Before proceeding to discuss results it is necessary to recall the fundamental differences between perinatal death associated with preterm delivery and death attributed to spontaneous preterm labor. Although preterm delivery is associated with a disproportionate number of perinatal deaths, it is wrong to conclude that lack of maturity necessarily accounts for those deaths. This is clearly the case where the fetus is already dead or where death is due to lethal congenital malformation. Consideration of the value of tocolytic agents must be confined to events related to spontaneous labor: fetal death, congenital malformation, and elective deliveries must be rigorously excluded. Hence, this study is confined to infants who were alive when spontaneous labor began and who did not suffer from a serious congenital malformation. The purpose of this article is not to scrutinize each of the possible causes but simply to draw attention to a noteworthy improvement in perinatal mortality rate attributed to preterm labor, in which tocolytic drugs played no part. It is, nevertheless, of considerable interest to note that the other three causes of perinatal death associated with preterm delivery showed a similar decline (Table II). The incidence of spontaneous preterm labor did decrease slightly in frequency. from 4.4% of births in 1966 to 2.9% in 1980: and in addition, the rate of low-birth-weight infants fell by half, from 8rr in 1966 to 4% in 1980. Improved demographic features, with a reduction in age and parity, and improved socioeconomic circumstances may in large part account for these changes. Intensive neonatal care was introduced in the mid/late 197Os, but it is apparent that
Volume Number
145 7
Perinatal
the
decline
in perinatal
way
before
this.
is that
tocolytic
outcome of
other
distract
attention
Tocolytic States
will
provement
in
method ron
and
birth
prevention
term
labors
note steady
in
suggests are viewed The
rate
labor,
and
in 1 year).
Maternity
in perinatal considerable
that
large
numbers
38
among
in
are
reactions.“-” attributed
further
mav to
agents,
the
cerning
preterm study
inthis period can
in
perinatal
mortality
rate
documented
The can
deaths, which
01
the
01’ niav
a~kd may
lead
inc.rease
in
de&m. preterm
to ad-
in pcarinaral labor,
introdllction to lalse
lack
iihwss
decisions
contributed
which
6 11‘ tocolytic cotlclllsions
c OII-
effect. is that
should
be shown
from could
in
doubrs
c~f’f~c ac.v
to llow
a concomitant
with
conclusion agents
111~
recrntlv
in making
and
\‘cars,
01‘ untreatc-tl
A progressive
have
n IIO
( JL’di tficult\
alxltlt
to spontaneous
cause
dr
OI ~\c~rnen
In recent
drawn
with
coincided
may
colvtic they
be
in perspective. fall
have
inI-
ativersc
because
course
physicians
a sI)ontancous
numbers
onlv
of’
Seenr-
.>‘. I”
been the
remedies,
deaths
study
results
has of
verse
variation;
a long
improvement
Attention
sattt\
as ‘i source
agai11s1
labor.g not
about
16 pre-
of
large
783
LIW 01 tocolvtic
against historv,
the
labor
arc- tlsed.
widespread
unnecessarilv
expressed
but
hamper
of
of preterm
been
ser\‘es
tocolvtics
natural
against
the diagnosis
drastic
It is interesting
annual and
in pre-
results
Hospital
deaths
of before
delivery,
treatment
knowledge
of a preterm
initial
and
receive hale
Her-
(a total
effects,
therapv
where
to be balanced in the
and preterm
Hospital
units results
need
provemenr
to this
a fall
the
small
the
an im-
related
report
while in
that
to be demonstrated.’
were
spite
essential
to stan-
and
Maternity for
beneficial
drugs
widespread
fallen
demonstrated
numbers
National
decline
fants
recently
likely
their
not
in a preliminary
resulting
the
ingly
serve into
National
comparison
further
could
Despite
mortality is yet
of preterm in
the
improved
and
it seems
have
program; the
episodes
suit.
perinatal
rates
in the labor
incorporated
’ and rates
associates”
delivery
impressive,
been
follow
of treatment
term
part
under
this.
have
delivery
no
well
investigation
explanations
in Europe”,
preterm
was
of this
preterm
from
practice
United
played
possible
drugs
rate
point
spontaneous
analysis
use,
central
agents
of
dard
mortality
The
mortality
current
be ternpercd to produce
sf~otctntwotr~ result from
prrtrrm natural
enthusiasm lvith
a reductic)ll
for
carltion
LOuntil
in perinatal
l&j,-, exceeding caust’h.
that
at
REFERENCES 1. Rush, R. W., Keirse, M. J, N. C., Howat, P., et al.: Contribution of’ preterm delivery to perinatal mortality, Br. Med. J. 2:965, 1976. 2. Fuchs, F.: Prevention of’ premature birth, Clin. Perinatol. 7:3, 19X0. 3. Lewis, P. J., de Sweit, M., Boylan, P., and Bulpitt, C. J.: How obstetricians in the United Kingdom manage preterm labor, Br. J. Obstet. Gynaecol. 87:574, 1980. 4. Kubli, F.: In Anderson, A., Beard, R., Brudenell, M. J., and Dunn, P., editors: Pre-term Labour, Proceedings of the Fifth Study Group of the Royal College of Obstetricians and Gynaecologists, London, 1977, Royal College of v Obstetricians and Ginaecolo ists, p. 2 18. ’ 5. Editorial: Ritodrine approve 2 for premature labor, FDA Drug Bull. 10:22, 1980. 6. Check. W. A.: FDA considers a first: ADDrOVd of drug for o inhibiiing preterm labor, JAMA 243:ii13, 1980. 7 Hendricks, C. H.: The case for non-intervention in preterm labor, in Eider, M. G., and Hendricks, C. H., edi-
8.
9. 10.
11. 12.
13.
tors: Preterm Labor, Obstetrics and Gynecology, Butterworth’s International Medical Reviews. London, 1981, vol. 1. Butterworth & Co., Ltd., p. 93. Herron, M. A., Katz, M., and Creasy, R. K.: Evaluation of a preterm birth prevention program: Preliminary report, Obstet. Gynecol. 59:452, 1982. Editorial: Drug treatment of prematltre lahotlr. Br. Med. J. 283:395, 1981. Hemminki, E., and Starfield, B.: Prevention and treatment of premature labour by drugs: Review of‘controlled clinical trials, Br. J. Obstet. Gynaecol. 85:,111. 1978. Myers, J. D.: Preventing iatrogenic complications, N. Engl. J. Med. 304:664, 1981. Couch, N. P.. Tilney, N. L., Rayner, A. :I., and Moore, F. D.: The high cosi of low-frequency events: The anatomy and economics ot‘ surgical mishaps. N Engl. J. Med. 304~634, 1981. Steel, K., Gertman, P. M., Crescenzi, C., and Anderson, J.: Iatrogenic illness on a general medical service at a university hospital, N. Engl. J. Med. 304:63&. 1981,