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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

The consequences of preterm birth (PTB), to the individual and society at large, remain a major financial and personal burden. Babies born at the limits of viability, who survive, often have major neurological impairments, such as cerebral palsy, developmental delay and blindness. The cost of initial hospitalisation is more than $200 000 for each birth but takes no account of future costs once they leave the hospital. The major morbidities associated with extreme prematurity are respiratory distress syndrome (RDS), intraventricular haemorrhage (IVH) and necrotising enterocolitis (NEC). With advancing gestational age at birth, the financial costs and morbidity associated with these conditions decrease. The major morbidities (RDS, IVH and NEC) are rare by 34 weeks of gestation, with the exception of RDS, which complicates 7% of deliveries at this gestational age. While the vast majority of infants survive the first year of life, the infant mortality rate is markedly increased by three- to five-fold even for the mildly preterm infants, as compared with that of the term infants. Neonates born after 34 completed weeks of gestation rarely have mortality or major morbidity, but the financial costs remain significant ($7000 per case), and efforts to prevent delivery at this gestational age are probably indicated. Economic costs associated with PTB include the cost of initial hospitalisation, the cost of any chronic diseases resulting from the prematurity and social costs including loss of gainful employment by a family member taking care of the infant or child and loss of potential future earnings of the affected child. Antenatal steroids, if given to the mother at least 48 hours prior to a PTB, have shown significant reductions in RDS, IVH and NEC. Efforts to prevent, or avoid, PTB include the use of tocolytic agents which have been shown to prolong gestation for a minimum of 48 hours, or longer in some cases. The range of tocolytic agents used to delay or prevent PTB work through many different pathways, with varying degrees of success. Which tocolytic agent to use depends on many factors including underlying maternal status, gestational age of the fetus and documented efficacy of agent used.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Preterm birth (PTB) continues to be a major financial, emotional and social burden in the developed and developing world. In the USA in 2003, the March of Dimes reported that total hospital costs related to PTB were in excess of $18 billion. Research into the causes of PTB and various treatment regimes to prevent premature birth has been pursued for decades. There has been no decrease in the PTB rate. Indeed, with the increase in assisted reproduction techniques, the rate of multiple pregnancy has increased more than 60%, which has resulted in an increase in the rate of PTB. While the PTB rate has not improved, the birthweight-specific neonatal mortality rate has improved due to the development of, and wider use of, the neonatal intensive care unit (NICU), which has resulted in more elective PTBs. Specialised care in the NICU has improved survival and decreased morbidity for low birthweight (LBW) neonates. With infants who are born at the limits of viability, long-term neurological impairment, including cerebral palsy (CP), has increased.1,2

Efforts to delay or prevent PTB have included a multifactorial approach. Antenatal glucocorticoids have been shown to decrease the major morbidities of respiratory distress syndrome (RDS), intraventricular haemorrhage (IVH) and necrotising enterocolitis (NEC) if PTB can be delayed for a minimum of 48 hours.3,4 Tocolytic therapy has been used for decades in an attempt to delay or prevent preterm delivery, despite conflicting evidence of effectiveness. In the present study, the financial and social costs of dealing with a PTB will be examined.

The cost of PTB

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

The financial burdens of PTB can be separated into several groups. The cost associated with initial hospitalisation is the largest and most clearly described financial burden. In Figure 1, the cost of hospitalisation for preterm neonates who have survived until hospital discharge is shown. In this population-based study of PTBs in California, the more preterm the newborn, the higher the individual cost of hospitalisation. While each case is very expensive ($203 000 at 25 weeks of gestation), the number of cases is rare. If one examines the total financial cost for all surviving preterm neonates at each week of gestation, the costs are similar (Figure 2). The number of PTBs increases with each advancing week of gestation, but the cost per case decreases so that the total expense is similar until near term when the number of cases outpaces the decreasing costs (Figure 2). Governmental organisations and health policy specialists who seek to develop initiatives to combat PTB and decrease costs can choose any gestational age because all have similar levels of total expenditure. Simply focusing efforts on preventing very PTBs may not save as much money as efforts at later gestations. In the California study, the authors estimated that almost $50 million would have been saved in 1996 if the nonindicated deliveries between 34 and 37 weeks of gestation could have been delayed until 38 weeks of gestation.5

image

Figure 1. Hospital costs (in 1000 dollars) in 1996 of individual, surviving, premature newborns separated into weeks of gestation from 25 to 37 weeks. Reproduced with permission from Gilbert, et al. Obstet Gynecol 2003;102:488–92.5

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image

Figure 2. Total hospital cost of all surviving newborns in California (in million dollars) by week of gestation from 26 to 38 weeks in 1996. Reproduced with permission from Gilbert, et al. Obstet Gynecol 2003;102:488–92.5

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Wang et al.6 found that babies born at 35–36 weeks + 6 days of gestation had hospital care costs that were significantly greater than that for term infants. They reported that the care of each infant costs a mean of $2630, which was three-fold greater than that for term infants. The increased costs could be explained by an increase in other diagnoses including temperature instability, hypoglycaemia, RDS and jaundice. They concluded that near-term infants had significantly more medical problems and costs than term infants and that they may represent an unrecognised high-risk group.6

A second cost associated with PTB is the effect on family finances. While the neonate is in the NICU, often one or more family members will spend large amounts of time visiting and caring for the neonate, preventing them from performing their daily job. If the infant has developmental delay or CP, as the child comes home, family members must often stay at home with the child or hire skilled day care providers to care for the affected child. These types of financial burdens are not well described in the medical literature but could be significant with a severely affected child with a long life expectancy. In a prospective case–control study, which compared measures of healthcare use (contacts with medical services, child health services and social welfare system registration) in families who suffered a PTB at <32 weeks with families who delivered an infant at term, Leijon et al.7 found that the former group used more services, including parental temporary leave from work and child healthcare visits. The families of preterm infants were well socialised by 4 years of age, similar to the group that delivered at term gestation. In countries with good social systems, like Sweden, family social networks may be better able to deal with the complications associated with PTB compared with other less socially aware societies like the USA.

Costs of PTB: neonatal mortality

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Neonatal survival has improved in the developed world primarily due to two factors: antenatal steroids and improved NICU. In 1972, Liggins and Howie4 reported a decrease in neonatal mortality with antenatal steroid use, and this has been confirmed by many other studies since then.3,8 Despite this overwhelming evidence of improved survival and decreased neonatal morbidity, in 1994, the frequency of antenatal steroid use in the USA for eligible women was only 16%.8 Currently, more than 90% of eligible women receive antenatal steroids in the USA. The other cause of the decrease in neonatal mortality has been the development of NICU. Historically, many preterm neonates died of complications related to RDS and other complications of PTB. Neonatal survival remains tenuous at the limits of viability, although survival improves dramatically with each advancing week of gestation beyond 23 weeks.1 At 23 weeks of gestation, survival was only 24%, increasing to 57% at 24 weeks of gestation and 74% at 25 weeks.

Neonatal mortality is caused by extreme prematurity. If lethal congenital malformations and birth trauma are excluded, neonatal mortality is a rare phenomenon after 30 weeks of gestation, such that most clinicians may not try to stop spontaneous preterm labour beyond 34 weeks of gestation.9 After this gestational age, antenatal steroids are not administered, and many physicians will withhold tocolytic therapy because of the excellent survival rates. Kramer et al.10 examined a group of preterm neonates from the USA and Canada and their risk of death in the first year of life. They separated the infants into two groups: a mildly preterm group (babies born at 34–36 weeks of gestation) and a moderately preterm group (babies at 32–33 weeks + 6 days of gestation). Compared with a control group of neonates born at term, the risk of death in the first year or life in the moderately preterm group was 6.6-fold higher (relative risk [RR] 6.6, 95% CI [6.1–7.0]) in a population in the USA and 15.2-fold higher (RR 15.2, 95% CI [13.2–17.5]) for a similar group in Canada. The mortality rate was less for the mildly preterm group as compared with that of the moderately preterm group, but it was still statistically significantly higher (RR 2.9, 95% CI [2.8–3.0]) in the USA and (RR 4.5, 95% CI [4.0–5.0]) Canada compared with that for those born at term. The authors concluded that this group of preterm neonates were high risk and that they accounted for a significant proportion of infant deaths.10 Babies born preterm may still suffer morbidity and mortality even if they survive until discharge from hospital.

Cost of PTB: neonatal morbidity

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Beyond 24 weeks of gestation, the majority of preterm neonates survive, and the main concern relates to neonatal morbidity and long-term outcome. The three main causes of neonatal morbidity and mortality in preterm neonates are RDS, IVH and NEC. RDS can lead to many short- and long-term complications, most of which relate to the effects of decreased oxygen delivery to the neonate. Hypoxemia secondary to RDS can cause organ malfunction throughout the body including the brain, kidneys and lungs. If the hypoxemia is significant enough, it can lead to IVH. Grade III and IV IVH is associated with a significant risk of CP and other developmental problems. NEC is rarer than the other two major complications but can result in major neonatal morbidity and mortality. In a population-based study of PTB in California, these three morbidities decreased with advancing gestational age at birth (Figure 3). By 30–32 weeks of gestation, the incidences of both IVH and NEC virtually disappeared (Figure 3). The risk of RDS also decreases with advancing gestational age at birth, although it remains a significant cause of morbidity until at least 34 weeks.5

image

Figure 3. Frequency of RDS, IVH and NEC by week of gestation from 26 to 38 weeks in 1996. Reproduced with permission from Gilbert, et al. Obstet Gynecol 2003;102:488–92.5

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While the above complications of PTB can cause morbidity and mortality, in many cases, the infant develops normal gastrointestinal and pulmonary function. The major concern of most long-term survivors is some form of neurological impairment, such as CP. Weber et al.,1 in addition to reporting neonatal mortality at the limits of viability, also reported the incidence of CP. They found that CP was diagnosed in 50% of neonates born at 23 weeks of gestation and the diagnosis decreased to 33% at 24 weeks and 26% at 25 weeks. While CP is a significant outcome, there are other pulmonary and neurological abnormalities, of less severity than CP, which can affect the preterm neonate. Mikkola et al.2 examined 206 children at 5 years of age who weighed less than 1000 g at birth. They found that in survivors, 20% had major disabilities and 19% had minor disabilities. Approximately 61% of children had no abnormal functional changes but had subtle developmental delays.2 Finally, they found that only 26% were normal at 5 years of age. Almost 75% of children born at this extremely LBW were not completely normal.

Rehospitalisation after NICU discharge

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Escobar et al.11 examined the hospital readmission rate for babies discharged from a NICU. They examined and obtained follow up on 6054 infants discharged from one of six NICU during the time period 1992–95. They found that a neonate discharged from NICU was 20% more likely to be readmitted to the hospital than normal term infants. The most common indications for readmission were jaundice (37.6%), problems with feeding (15.2%) and length of stay less than 4 days if delivered between 33 and 36 weeks of gestation (5.7%). They concluded that while the readmission rate was higher following PTB, most of the complications were not life threatening.11

Tocolysis to prevent PTB

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Investigators and clinicians have been working for decades to find agents that will stop or prevent preterm labour and prevent PTB. Multiple factors have been identified as causes of spontaneous preterm labour, including infection, uterine over-distension, weak cervix and idiopathic condition. Frequently, the specific cause of spontaneous preterm labour cannot be identified and the appropriate therapy cannot be given. Therapeutic agents for one possible cause of the spontaneous preterm labour (uterine over-distension) may be ineffectual if another factor, such as infection, is the primary cause of the spontaneous preterm labour. Many of the following agents have been used for years for the treatment of spontaneous preterm labour, despite overwhelming evidence that they are not effective.

Magnesium sulphate

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Magnesium sulphate is a therapeutic agent with a long history of usage in obstetrics and gynaecology in the USA. For many years, it has been used as a front line medication for seizure prevention in women with pre-eclampsia. It is only within the past few years that randomised controlled trials (RCTs) have shown its efficacy for this purpose.12 Magnesium sulphate has also been used for many years despite an accumulation of evidence that it is ineffective as a tocolytic agent.13 A recent, small, prospective randomised study found that not only was it ineffective for the prevention of PTB but neonates also were more likely to die if they received magnesium sulphate.14 The Cochrane review concluded that magnesium sulphate was not only ineffective but also led to an increase in the stillbirth rate.13

Beta-agonists

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Beta-adrenergic agents have been used for many years as tocolytic agents because of the known effects on beta receptors within the myometrium. Stimulation of beta receptors relaxes smooth muscle cells in many areas including the uterus and bronchioles. Ritodrine, a beta-receptor agonist, was the only agent approved by the US Food and Drug Administration for use as a tocolytic agent for the treatment of spontaneous preterm labour but went out of fashion in the late 1980s due to marked maternal adverse effects and complications. Today, terbutaline is the beta agonist used most frequently in the USA for the treatment of spontaneous preterm labour. The 2004 Cochrane review of 11 RCTs found that terbutaline delayed delivery for 48 hours (RR 0.63, 95% CI [0.53–0.75]) when compared with placebo, allowing time for the administration of antenatal steroids.15 As an oral agent after inhibition of preterm discharge, terbutaline is not superior to placebo. As a generic drug with different routes of administration, terbutaline is a treatment of spontaneous preterm labour with a low cost to high value ratio.

Calcium channel blockers

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Calcium channel blockers have been used for many years for the treatment of hypertension due to their effects on relaxing vascular smooth muscles. Their use for the treatment of spontaneous preterm labour has been more recent because of their low maternal adverse effect profile and equal efficacy to other tocolytic agents like beta-agonists and magnesium sulphate. The Cochrane review examined studies that compared calcium channel blockers with other agents and reported that they were superior by decreasing the numbers of deliveries within 7 days (OR 0.76, 95% CI [0.6–0.97]) and decreasing all the major neonatal morbidities including RDS (RR 0.63, 95% CI [0.46–0.88]), NEC (RR 0.21, 95% CI [0.05–0.96]) and IVH (RR 0.59, 95% CI [0.36–0.98]). The review concluded that calcium channel blockers were the preferred method of tocolysis due to an excellent maternal adverse effect profile and clinical effectiveness.16

Prostaglandin synthetase inhibitors

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Indomethacin is one of the oldest and most widely used prostaglandin synthetase inhibitors due to a long history of use and low cost. There are fewer RCTs in the literature and most are small clinical studies that demonstrate clinical effectiveness at prolonging gestation for at least 48 hours.17,18 While most clinicians know that indomethacin is an effective agent for the treatment of spontaneous preterm labour, especially with polyhydramnios, it can have major adverse effects on the fetus. Indomethacin can cause premature closure of the fetal ductus arteriosus in utero and can decrease renal blood flow, which causes oligohydramnios if the agent is taken for longer than 48–72 hours.17,18 The majority of authors report that indomethacin should not be used beyond 32 weeks due to the fetal adverse effects associated with its use beyond and the high survival rate at this gestation. A recent meta-analysis failed to show adverse outcomes in infants exposed to indomethacin, but the number of RCTs and cases were small.19 Currently in many countries, indomethacin is used as a second-line tocolytic agent in extremely preterm cases at the limits of viability. It is an effective and low-cost agent, but fetal and neonatal adverse effects limit its use.

Oxytocin receptor antagonists

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

The newest agents used for the treatment of spontaneous preterm labour block the surface oxytocin receptor of the myocyte. Atosiban is commercially available for the treatment of spontaneous preterm labour within Europe and other parts of the world, although not the USA. In a meta-analysis, with an indirect comparison of RCTs comparing nifedipine with atosiban, Coomarasamy et al.20 found that the neonates of nifedipine-treated women seemed to have less RDS than those of atosiban-treated women, and delivery was delayed by 48 hours in a nonsignificantly higher proportion of women in the nifedipine group. Importantly, however, unlike nifedipine, atosiban is licensed for use in pregnancy and has been the subject of a comprehensive tocolysis clinical trial programme. A randomised placebo-controlled trial is still required to assess the real tocolytic efficacy differences of nifedipine versus atosiban.

The recent Cochrane review examined six trials comprising almost 1700 women randomised to either atosiban or placebo. They found that atosiban was no better than controls in delaying delivery or improving neonatal outcomes.21 When atosiban was compared with beta-agonists, the rate of very LBW deliveries was increased in the atosiban group (RR 1.96, 95% CI [1.15–3.35]) as compared with the betamimetics group, leading the authors to conclude that atosiban was not effective for the treatment of spontaneous preterm labour.21 This review, however, has been heavily criticised for being flawed and for having failed to meet the high standards normally associated with Cochrane systematic reviews22 as atosiban is supported by a comprehensive programme of RCTs, which have shown superior efficacy compared with placebo and comparable efficacy to beta-agonists but with a significantly superior adverse effect profile.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References

Spontaneous preterm labour and PTB remain major burdens on society, and the rate appears to be increasing. With the increase in assisted reproduction techniques, the rate of higher order births has increased by 60%. While the number of triplet pregnancies is much smaller than twins, their rate of increase is much higher. The triplet pregnancy rate is being brought under control with regulations in most of Europe and with reproductive endocrinologists acting more responsibly in the USA. NICUs are continuing to save neonates at the limits of viability, despite high rates of developmental abnormalities. The older tocolytic agents are modestly effective in delaying PTB to allow the administration of antenatal glucocorticosteroids, which decrease perinatal morbidity and mortality. Finally, the costs of PTB, whether financial or social, will continue to increase partly due to the cost of improving technology for managing neonates in the NICU and also due to the increase in number of PTBs secondary to assisted reproduction techniques.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. The cost of PTB
  5. Costs of PTB: neonatal mortality
  6. Cost of PTB: neonatal morbidity
  7. Rehospitalisation after NICU discharge
  8. Tocolysis to prevent PTB
  9. Magnesium sulphate
  10. Beta-agonists
  11. Calcium channel blockers
  12. Prostaglandin synthetase inhibitors
  13. Oxytocin receptor antagonists
  14. Conclusion
  15. References
  • 1
    Weber C, Weninger M, Klebermass K, Reiter G, Wiesinger-Eidenberger G, Brandauer M, et al. Mortality and morbidity in extremely preterm infants (22-26 weeks of gestation): Austria 1999-2000. Wien Klin Wochenschr 2005;117:7406.
  • 2
    Mikkola K, Ritari N, Tommiska V, Salokorpi T, Lehtonen L, Tammela O, et al. Neurodevelopmental outcome at 5 years of age of a national cohort of extremely low birth weight infants who were born in 1996–1997. Pediatrics 2005;116:1391400.
  • 3
    NIH Consensus Development Panel on the Effect of Corticosteriods on Perinatal Outcomes. Effect of corticosteroids for fetal maturation on perinatal outcomes. JAMA 1995;273:41318.
  • 4
    Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:51525.
  • 5
    Gilbert WM, Nesbitt NS, Danielsen B. The cost of prematurity: quantification by gestational age and birthweight. Obstet Gynecol 2003;102:48892.
  • 6
    Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near term infants. Pediatrics 2004;114:3726.
  • 7
    Leijon I, Finnstrom O, Sydsjo G, Wadsby M. Use of healthcare resources, family function, and socioeconomic support during the first four years after preterm birth. Arch Dis Child Fetal Neonatal Ed 2003;88:F41520.
  • 8
    Crowley P, Chalmers I, Keirse MJN. The effects of corticosteriod administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97:1116.
  • 9
    How HY, Zafaranchi L, Stella CL, Recht K, Maxwell RA, Sibai BM, et al. Tocolysis in women with preterm labour between 32 0/7 and 34 6/7 weeks of gestation: a randomized controlled pilot study. Am J Obstet Gynecol 2006;194:97681.
  • 10
    Kramer MS, Demissie K, Yang H, Platt RW, Sauve R, Liston R. The contribution of mild and moderate preterm birth to infant mortality. JAMA 2000;284:8439.
  • 11
    Escobar GJ, Joffe S, Gardner MN, Armstrong MA, Folck BF, Carpenter DM. Rehospitalization in the first two weeks after discharge from the neonatal intensive care unit. Pediatrics 1999;104:19.
  • 12
    Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J, et al. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002;359:187790.
  • 13
    Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev 2002;CD001060 [DOI: 10.1002/14651858.CD001060].
  • 14
    Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocolytic magnesium sulphate associated with increased total paediatric mortality? Lancet 1997;350:151718.
  • 15
    Anotayanonth S, Subhedar NV, Garner P, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2004;CD004352 [DOI: 10.1002/14651858.CD004352].
  • 16
    King JF, Flenady VJ, Papatsonis DNM, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev 2003;CD002255 [DOI: 10.1002/14651858.CD002255].
  • 17
    Niebyl JR, Blake DA, White RD, Kumor KM, Dubin NH, Robinson JC, et al. The inhibition of premature labour with indomethacin. Am J Obstet Gynecol 1980;136:101420.
  • 18
    Zuckerman H, Shalev E, Rubinstein I. Inhibition of human premature labour by indomethacin. Obstet Gynecol 1984;44:78791.
  • 19
    Loe SM, Sanchez-Ramos L, Kaunitz AM. Assessing the neonatal safety of indomethacin tocolysis: a systemic review with meta-analysis. Obstet Gynecol 2005;106:1739.
  • 20
    Coomarasamy A, Knox EM, Gee H, Song F, Khan KS. Effectiveness of nifedipine versus atosiban for tocolysis in preterm labour: a meta-analysis with an indirect comparison of randomised trials. BJOG 2003;110:10459.
  • 21
    Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2005;CD004452 [DOI: 10.1002/14651858.CD004452].
  • 22
    Goodwin TM. Comments posted on the Cochrane Collaboration website. [www.cochranefeedback.com/cf/cda/citation.do?id=9541#9541;9535#9535;9476#9476;and9448#9448]. Accessed 13 October 2006.