Preterm Birth: A Cost Benefit Analysis
Susan Rushing, SB, and Laura R. Ment, MD
Advances in prenatal and perinatal treatment of preterm and VLBW infants have dramatically increased the survival rate of these infants. Some interventions decrease long term
sequelae associated with preterm birth, making them more cost-effective than other
treatments. This paper reviews the cost-effectiveness of therapies targeted to protect the
preterm brain. Birth in a center with a NICU improves survival and decreases the rate of
severe neurologic disability. Administration of antenatal steroids increases survival and
decreases rates of periventricular hemorrhage, periventricular leukomalacia, necrotizing
enterocolitis, respiratory distress syndrome, and severe disability. Administration of antenatal steroids decreases costs per additional survivor. Addition of surfactant to the treatment of PT infants has also decreased treatment costs. Administration of surfactant is
beneficial for symptomatic RDS but recognizes a greater benefit when given to infants
younger than 30 weeks gestation prophylactically. Treatment with prophylactic indomethacin decreases the rate of intraventricular hemorrhage and results in cost savings in
survivors. Postnatal administration of dexamethasone can lead to severe disability when
administered before 7 to 10 days of life. Postnatal dexamethasone does not increase
survival or decrease rates of chronic lung disease.
Semin Perinatol 28:444-450 © 2004 Elsevier Inc. All rights reserved.
KEYWORDS preterm birth, cost, intraventricular hemorrhage, surfactant, antenatal steroids
D
espite the development of sophisticated care techniques, the incidence of neurodevelopmental disability
among the survivors of newborn intensive care remains
high.1-7 As newborn special care enters its fifth decade, survival rates for very low birth weight (VLBW) infants have
steadily increased,8-11 but the incidence of cerebral palsy (CP)
has not changed over the past 10 years and, at age 8 years,
over 50% of VLBW preterm children require special educational services and 15% have repeated at least one grade in
school.12,13
These data suggest that the neurodevelopmental sequelae
of preterm birth now represent a major pediatric public
health problem. A recent analysis by the Center for Disease
Control suggests that the average lifetime costs per person
with mental retardation are $1,014,000; the average lifetime
costs for each individual with CP are $921,000.14 These 2003
dollar figures reflect only the medical, educational and other
support services used by persons with mental retardation or
CP; they do not address the hidden costs of care for children
with developmental issues, such as those associated with
Departments of Pediatrics and Neurology, Yale University School of Medicine, New Haven, CT.
Address reprint requests to: Laura R. Ment, MD, Department of Pediatrics,
Yale University School of Medicine, New Haven, CT 06510.E-mail:
laura.ment@yale.edu
444
0146-0005/04/$-see front matter © 2004 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2004.10.007
treating the psychosocial and family problems that may result.
As the gestational age at which perinatologists and neonatologists resuscitate VLBW and preterm infants decreases, the
concern for prevention of injury to the developing brain increases. Periventricular brain injury, severe respiratory failure, the absence of antenatal corticosteroid exposure and
delay in regaining birth weight are all strong predictors of
significant disability in survivors.15 A number of advances
have been made in the treatment of preterm infants that show
promising survival and outcome benefits. The long term
health sequelae of these therapies along with their significant
cost have made their use the object of considerable scrutiny,
however. We review the cost of treatments aimed at preventing severe disability in the VLBW preterm infant.
Neurodevelopmental
Outcome of Preterm Birth
The sequelae of preterm birth have been well described. At
age 8 years, more than 50% VLBW, preterm children require
special assistance in the classroom, 20% are in special education, and 15% have repeated at least one grade in
school.3,12,16-21 The incidence of those with CP ranges from 8
to 24%, depending on birth weight and birth year. Addition-
Preterm birth
ally, 10 to 20% of infants with CP are reported to suffer
significant cognitive handicaps. Several investigators have reported that prematurely born infants experience structural
delay in postnatal brain development when compared with
term neonates.22-30 Regions serving math and verbal skills
appear especially vulnerable in the developing preterm brain.
Assessment of Risk for
Injury to Developing Brain
Critical to the implementation of prevention strategies is the
identification of risk factors for injury to the developing
brain. Thus, although several early studies reported that cognitive outcome was directly related to gestational age at
birth,19,31 recent data suggest that medical risk factors may be
equally important predictors of neurologic outcome.13,32-38
Chief among the medical risk factors are grades 3 to 4 intraventricular hemorrhage (IVH), periventricular leukomalacia
(PVL), and posthemorrhagic hydrocephalus.35 The incidence
of IVH is inversely related to gestational age (GA), and parenchymal involvement of IVH (ie, Grade 4 IVH) is more common among infants with the lowest GAs.39 Current data suggest that 25% of infants born weighing 501 to 750 g and 11%
born between 741 and 1000 g still develop grade 4 IVH.40-42
In the newborn period, infants with IVH are at risk for seizures and posthemorrhagic hydrocephalus; 5 to 10% of preterm infants with IVH suffer seizures and as many as 25 to
50% of infants with Grade 4 IVH experience posthemorrhagic hydrocephalus. Finally, mortality is higher in those
infants with IVH compared with GA-matched subjects without IVH.43,44
Infants with parenchymal involvement of hemorrhage suffer high rates (45 to 86%) of mental retardation and cerebral
palsy.31,45-47 In Pinto-Martin’s study, grade 4 IVH was associated with CP [odds ratio (OR), 15.4; 95% CI 7.6 to 31.1].20
Perhaps more importantly, recent data demonstrate that
Grade 4 IVH is strongly associated with mental retardation at
2 to 9 years (OR ranging from 9.97 to 19.0).48 Further, even
children with low grade hemorrhages are at cognitive disability when compared with their non-IVH GA-matched peers.31
In Pinto-Martin’s study, any grade IVH alone was associated
with CP (OR 3.14; 95% CI, 1.5 to 6.5). These difficulties may
be attributable in part to the long-lasting alterations in cerebral blood flow following IVH and the secondary impact on
corticogenesis and connectivity in developing brain.49,50
The Cost of Care
Medical decisions made during pregnancy and at the time of
delivery can have great impact on the development of the
preterm infant’s brain. Treatments and accommodations offered to the mother and fetus are often costly. This section
reviews some of the key studies that have estimated both the
financial cost of care and the indirect social costs associated
with preterm birth.
Comparing costs requires familiarity with the methods
used to make such estimates. Many studies look at hospital
445
costs alone. However, a more rigorous analysis of cost will
include both direct costs (hospital fees, drug therapy, doctor’s visits, etc.) as well as indirect costs (lost earning potential of the patient, costs of care for the infants, parent’s lost
earning potential, travel for parents, child care for siblings,
etc.).51 While it is possible to assign a numerical value to the
cost of a given treatment, preferences for outcomes also depend on prevailing ethical and moral standards about life,
death and disability.52
Predictors of
Disability and Cost of Care
Gestational age at birth is the strongest predictor of medical
service costs during the first 5 years of an infant’s life. The
adjusted mean cost of hospital services in the first 5 years of
life for infants born between 1970 and 1993 and treated in
the British National Health Services were $22,798 for infants
born at less than 28 weeks and $18,654 for those born between 28 to 31 weeks measured in 1998 US dollars (as derived from data based on British sterling).53
Birth weight is also a strong predictor of hospital service
costs during the neonatal period. In Petrou’s review of studies
published since the 1970s, hospital service costs alone for
infants born weighing less than 1000 g were 75% higher, on
average, than those incurred by infants born weighing 1000
to 1499 g, and more than four times higher, on average, than
those incurred by infants born weighing at least 1500 g.52 In
addition, year of birth, sex, survival period, multiplicity, maternal age, and the number of days the mother was hospitalized before birth were also significant predictors of postnatal
in-hospital medical costs.15
Birth in a Facility with a
NICU Increases Survival and
Enhances Neurodevelopment
Infants born at a center with a perinatal unit are more likely to
survive and fair better neurodevelopmentally than infants
born elsewhere (Table 1). Yu studied the developmental outcome of extremely low birth weight (ELBW) infants born
between 1979 and 1980 (before the use of surfactant therapy). The group was assessed at ages 2, 5, and 8 years (corrected age). Yu found a direct correlation between increased
survival and delivery in a hospital with a NICU. Eighteen
percent of all 1979 cohort survivors had a severe disability
(nonambulatory cerebral palsy, IQ score ⬍2 SD below the
mean, or bilateral blindness). However, infants that were
born in a center with a NICU had a significantly lower severe
disability rate than those born in centers without a NICU: 15
versus 50% at 2 years, 15 versus 38% at 5 years, and 13
versus 39% at 8 years.54
Cost of treatment in the NICU has primarily been assessed
according to birth weight (Table 2). Petrou compared the
studies in this area and concluded that for babies born at less
than 1000 g, there was a cost per additional survivor of between £84,490 and £174,040 (1998 £ sterling). When mea-
S. Rushing and L.R. Ment
446
Table 1 Risk Factors Associated with Adverse Outcomes
Mortality
Risk of
IVH
Birth in NICU
Antenatal
Corticosteroids
Reduced
Reduced
Surfactant
Reduced
Indomethacin
Unchanged
Reduced
Reduces risk
of PVH
[OR .38]
Data not
available
Reduced
Postnatal
Dexamethasone
Unchanged
Unchanged
Risk of RDS
and/or CLD
Risk of
NEC
Severe
Disability
Rate
PVL
Reduced
Reduced RDS
Reduced
Reduces risk
[OR .32]
Reduced
Reduced
Reduced
Reduced with
Betamethasone
Reduced
Data not
available
Unchanged
Unchanged
Data not
available
Unchanged
Increased GI
perforation
Increased if
given with
96 hours
of birth
Unchanged risk of
BPD
Unchanged rate of
CLD except in
high dose early
administration
Unchanged
Unchanged
Note. Data derived from Mugford65, Yu54, Fowlie82,83,74, Moya73, Halliday79,84, Ment85, and Hohlagschwandtner.86
sured in terms of additional life year gained the cost effectiveness ratio fell to between £4440 and £15,790. When the
outcome was measured in terms of an additional quality adjusted life year (QALY) gained, the cost-effectiveness ratio fell
to between £4190 and £38,030 Higher birth weight infants
are on average less costly, to treat in the NICU and incur less
cost per additional life year gained and less cost per additional QALY.55,56
Antenatal Steroids:
Better Outcome, Low Cost
Many studies have examined antenatal treatment with steroids and it is well accepted that antenatal steroids improve
mortality and morbidity for VLBW preterm infants (Tables 1
and 2). When two injections of corticosteroids are given to
the mother before a preterm delivery, instances of respiratory
distress syndrome, neonatal mortality, and intraventricular
hemorrhage are reduced.57 However, in some pregnancies it
is common for women to receive multiple doses of antenatal
steroids; currently, there are no human study data suggesting
neurodevelopmental harm associated with such treatment.58,59
In a meta-analysis of corticosteroid trials from 1972 to
1994, in utero exposure to corticosteroids has resulted in a
50% reduction in neonatal respiratory distress syndrome
(RDS).60 Crowley found that eight clinical trials show a clear
benefit of antenatal steroids to even the highest risk preterm
infants born at less than 31 weeks (OR 0.41, 95% CI).60 More
recent data suggests that only betamethasone and not dexamethasone is associated with reduced neonatal mortality and
reduced periventricular leukomalacia (PVL).61,62
Table 2 Cost of Specific Treatments
Cost per Additional
Survivor
Measurement
Birth in NICU
<1000 g
1000-1499 g
All less than 35 weeks GA
Ante-Natal
Steroids
All less than 31 weeks GA
1992 in NICU cost
including surfactant
Surfactant
Indomethacin
Post-Natal
Dexamethasone
Prophylactic Indomethacin
compared to standard
NICU treatment
Within 96 h of birth
After 7-10 day of birth
Note. Derived from
Petrou52,
Mugford65,
Yu54,
and
Additional
Cost per
Additional
Life Year Gained
Additional
Cost per
Additional
QALY Gained
£84,490-£174,040 (1998 £
sterling)
£56,080-£89,680
14% reduction
£4,440-£15,790
£4,190 and £38,030
£4,920
NA
£5,430
NA
9% reduction
$66,800 (1992 US dollar)
(decreased from $72,800
in pre-surfactant era)
NA
NA
NA
$585 savings
NA
$3,800 (decreased
from $4,700 in
pre-surfactant era)
$725 savings
NA
NA
NA
NA
Negative cost-benefit b/c
of increase rate of
severe disability
Positive cost benefit
Halliday.87
Preterm birth
Use of antenatal corticosteroids can lead to a net savings in
cost per life saved for infants younger than 31 weeks63-65 and
for infants under 2000 g.66 In 1991, Mugford estimated the
cost savings of antenatal corticosteroids in eligible patients
based on the cost of caring for infants with and without
respiratory distress.65 Mugford estimated administering antenatal corticosteroids to expectant mothers of less than 35
weeks gestation would reduce the average cost per baby by
10%, with a 14% reduction in the average cost per survivor.
However, if antenatal steroids were only administered to expectant mothers of less than 31 weeks gestation, prenatal
administration of corticosteroids would increase total costs
by 7% and reduce the cost per survivor by 9%.65
The use of antenatal corticosteroids appears to reduce
overall health care costs. In Crowley’s review, the odds of
both periventricular hemorrhage and necrotizing enterocolitis were reduced in infants exposed to antenatal steroids.60
Additionally, studies have not found long term developmental sequelae in infants exposed to corticosteroids.67 The reduction in neonatal care cost for surviving infants outweighs
the relatively low cost of the medication, its administration,
and monitoring of the mother, making antenatal corticosteroid use very cost-effective.
Surfactant: High
Cost but High Benefit
Surfactant is used to treat Respiratory Distress Syndrome
(RDS). The phospholipid reduces the surface tension in the
lungs and prevents the alveoli from collapsing. Until the infant is able to breathe on its own, a mechanical ventilator is
needed. Although surfactant and mechanical ventilation are
expensive therapies, they are cost effective.
Traditionally, surfactant was administered once signs of
RDS were clinically observed. Surfactant treatment for symptomatic RDS did not increase cost per survivor.52 For heavier
babies with symptomatic RDS, surfactant treatment actually
led to decreased costs.68 Heavier babies are more likely to
survive. In these infants, the decrease in cost resulted from
prevention of severe, chronic disease.
Early use of surfactant increases survival.69 Use of surfactant before signs of RDS emerge is cost effective in infants
born at less than 30 weeks gestation.63,70 Egbert found that
for infants weighing 800 to 1000 g prophylactic surfactant
treatment resulted in a net additional cost per additional
survivor.71 When prenatal steroids and prophylactic surfactant were given to all preterm infants less than 30 weeks
gestation more infants survived and the number of necessary
hospital days decreased, making combination therapy more
cost effective than either alone.63
In infants born as early as 24 to 26 weeks gestation,
surfactant has helped to double the survival rate in the
surviving population, without increasing the rate of severe
disability, which remained below 10%.54 These data are
shown in Table 3.
Surfactant coupled with ventilation therapy leads to a decrease in cost per additional quality-adjusted life-year gained
447
Table 3 Survival Pre-and Post-Surfactant
GA of Infant
at Time of
Birth
23
24
25
26
27
weeks
weeks
weeks
weeks
weeks
Survival
Rate PreSurfactanti
Survival
Rate PostSurfactantii
Severe
Disability
Rate
7%
30%
31%
55%
67%
10%
33%
58%
72%
77%
20%
14%
6%
9%
1%
Note. Derived from Yu et al.88,89
for infants born at gestational age 24 to 26 weeks.54 Expressed in terms of 1992 U.S. dollars, the cost per ELBW
survivor was $61,900 in 1979 to 1980, $72,800 in 1985 to
1987, and $66,800 in 1991 to 1992. Comparing 1985 to
1987 with 1979 to 1980, the cost per additional qualityadjusted ELBW survivor was $90,700, and the cost per additional quality-adjusted life-year gained was $4700. Comparing 1991 to 1992 with 1985 to 1987, the equivalent costs
were $72,500 and $3800, respectively, showing that the incremental cost during primary hospitalization had actually
fallen in the postsurfactant era.
Kilpatrick found that the survival rates of infants treated
with prenatal corticosteroids and postnatal surfactant born at
24 weeks gestation was 53% compared with 80% in infants
born at 25 or 26 weeks. The cost to produce a survivor was
63% higher for infants born at 24 weeks gestation, and only
35% of these infants were free from severe disability.72
Though therapies like antenatal corticosteroids and surfactant can be used to rescue even very young infants, physicians
and parents should recognize the higher risk of severe disability and increased cost associated with saving infants of 24
weeks gestation and younger. If possible, a delay in delivery
by even 1 week (from 24 to 25 weeks gestation) may lead to
cost savings and increase a neonate’s chance of survival and
life without severe disability.
Indomethacin
Indomethacin is a prostaglandin inhibitor, which has traditionally been used to close a patent ductus arteriosus (PDA)
in preterm infants. Recent trials have used Indomethacin in
an attempt to prevent intraventricular hemorrhage (IVH), a
brain injury highly correlated to poor neurodevelopmental
outcome.
Indomethacin is given after birth in three doses. The cost
of this therapy is approximately $70, whereas the cost to
surgically repair a PDA is more than $11,000.73 Indomethacin used prophylactically in VLBW infants is a cost-effective
way to decrease rates of both PDA and IVH. In a study comparing indomethacin to standard NICU treatment, Moya
found no difference in the expected survival rate of the indomethacin group. However, there was a significant difference
in quality-adjusted life years, resulting in 11 and 10 years for
the indomethacin and control groups, respectively. The inhospital cost of the indomethacin treated cohort was lower
than the control group with rates of $95,157 and $99,955,
S. Rushing and L.R. Ment
448
respectively. The cost per quality added life year was lower in
the indomethacin group than in the control group with costs
of $8443 and $9168, respectively.
Prophylactic indomethacin has been shown to effectively
reduce the rate of intraventricular hemorrhage (Table 1).
However, a meta-analysis by Fowlie suggests that the reduction in IVH does not translate into decreased rates of cerebral
palsy, low IQ, blindness, or sensorineural deafness.74 Indomethacin was not found to increase rates of necrotizing enterocolitis or bronchopulmonary dysplasia (BPD).74
Postnatal Dexamethasone: Low
Cost but Increased Handicap
Treatment with dexamethasone, a powerful long-acting
glucocorticoid, in the postnatal period is controversial.
Dexamethasone is used to help wean infants from the ventilator and thought to reduce primary respiratory morbidity. Despite short-term improvements in bronchopulmonary dysplasia, dexamethasone has not been shown to
improve survival or rates of chronic lung disease (CDL).75
Furthermore, treatment with postnatal dexamethasone
has been associated with a number of deleterious effects
including: increased rates of growth retardation, hyperglycemia, hypertension, infection, hypertrophic cardiomyopathy, gastrointestinal perforation, cerebral palsy, and developmental delay (Table 1).76-79
Although the cost of even a long course of dexamethasone
is relatively inexpensive, a cost-benefit analysis requires one
to factor in the numerous complications now known to be
associated with treatment (Tables 2). The benefits of dexamethasone vary based on the age of the infant at the time of
administration.80 Halliday estimates that the cost-benefit ratio would be negative (ie, the adverse outcomes out weight
the potential reduction in CLD) for early administration
within 96 hours of birth. However, the cost-benefit ratio
would be positive after 7 to 10 days of life.81
Conclusion
Advances in prenatal and perinatal treatment of preterm and
VLBW infants have dramatically increased the survival rate of
these infants. Birth in a center with a NICU improves survival
and decreases the rate of severe disability. Administration of
antenatal steroids increases survival and decreases rates of
periventricular hemorrhage, periventricular leukomalacia,
necrotizing enterocolitis, respiratory distress syndrome, and
severe disability. Administration of antenatal steroids decreases the cost per additional survivor. Addition of surfactant to the treatment of PT infants has also decreased treatment costs. Administration of surfactant is beneficial for
symptomatic RDS but recognizes a greater benefit when
given to infants younger than 30 weeks gestation prophylactically. Treatment with prophylactic indomethacin decreases
the rate of intraventricular hemorrhage and results in cost
savings in survivors. Postnatal administration of dexamethasone can lead to severe disability when administered before 7
to 10 days of life. Postnatal dexamethasone does not increase
survival or decrease rates of chronic lung disease.
Though therapies like antenatal corticosteroids and surfactant can be used to rescue even very young infants, physicians
and parents should recognize the higher risk of severe disability and increased cost associated with saving infants of 24
weeks gestation and younger. If possible, a delay in delivery
by even one week (from 24 to 25 weeks gestation) may lead
to cost savings and increase a neonate’s chance of survival
and life without severe disability.
Acknowledgment
This work was supported by NS 27116 and NS 35476.
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