Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade. Until recently, there has been no effective therapy for MPS II, and care has been palliative. Enzyme replacement therapy (ERT) with recombinant human iduronate-2-sulphatase (idursulfase), however, has now been introduced. Weekly intravenous infusions of idursulfase have been shown to improve many of the signs and symptoms and overall wellbeing in patients with MPS II. This paper provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides recommendations for the use of ERT. The issue of treating very young patients and those with CNS involvement is also discussed. ERT with idursulfase has the potential to benefit many patients with MPS II, especially if started early in the course of the disease.
Introduction
First described by Major Charles Hunter in 1917 [15], mucopolysaccharidosis type II (MPS II or Hunter syndrome; OMIM +309900) is an X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase (I2S). This enzyme cleaves O-linked sulphate moieties from the glycosaminoglycans (GAGs) dermatan sulphate and heparan sulphate as the first step in their degradative pathway. The clinical phenotype of MPS II (Fig. 1) is characterised by progressive pathological lysosomal storage of GAGs in nearly all cell types, tissues and organs.
Fig. 1Appearance of a child with mucopolysaccharidosis type II (Hunter syndrome) at (a) 6 years of age and (b) 12 years of age, illustrating the ‘typical’ clinical phenotype at the more severe end of the disease spectrum. The manifestations of the syndrome and the rate of progression, however, may vary widely among individual patients
Oropharyngeal and tracheo-bronchial deposition of GAGs leads to severe airway obstruction due to macroglossia, supraglottic narrowing, and tracheomalacia. This obstructive anatomy and physiology leads to sleep apnoea and airway obstruction. As the disease progresses, the respiratory system is further compromised by pulmonary restriction secondary to the effects of the disease on the thoracic skeleton. Deposition of GAGs in the heart, liver and spleen leads to cardiomyopathy, cardiac valve dysplasia and hepatosplenomegaly. Bone and joint involvement results in severe skeletal deformities and limitations of joint mobility. In patients with CNS involvement, severe learning difficulties and progressive neurological decline occur. The clinical manifestations of MPS II generally lead to death in the first or second decade of life, although in the more attenuated form of MPS II, death may occur in early adulthood, and some patients have survived into their fifth and sixth decades of life.
Until recently, there has been no effective therapy for MPS II. Care has been palliative, focusing on management of the multiple clinical symptoms. Haematopoietic stem cell therapy (HSCT) has been attempted in some patients [36], but the long-term results have been unsatisfactory. The recent introduction of enzyme replacement therapy (ERT) with recombinant human I2S (idursulfase), however, has raised the possibility that the burden of GAG storage can be reduced and that the progressive tissue and organ damage associated with MPS II can be slowed or even prevented. The availability of ERT thus requires a greater awareness and understanding of the disease amongst a range of medical specialists and primary care physicians, so that early diagnosis can be made and treatment started before organ damage becomes irreversible.
This article gives an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides, for the first time, recommendations for the use of ERT.
Incidence and inheritance
Data from The Netherlands and Germany indicate that the incidence of MPS II is 1.3 per 100,000 male live births [1, 23]. Two-thirds of patients present with CNS involvement, representing the more severe end of the disease phenotype. There have been very few reports of recurrent or common mutations within the gene encoding I2S. As a consequence, genotype–phenotype correlations have been difficult to establish, with the exception of those patients who present with large deletions, which are most often associated with more severe disease [38].
As MPS II is an X-linked recessive condition, it would not be expected to affect females. Despite this, a few girls have been reported with MPS II [35]. Affected females generally have low levels of I2S activity and an attenuated clinical phenotype, although the somatic abnormalities can be severe in some individuals. In affected heterozygous females, skewed inactivation of the X-chromosome prevents expression of the normal allele [35].
Molecular basis of MPS II
MPS II is the only known X-linked MPS disorder. The human gene encoding I2S has been mapped to Xq28. It contains nine exons spread over 24 kb. Individuals with major deletions or rearrangements in the gene usually have severe MPS II. An I2S-like pseudogene, comprising copies of exons 2 and 3 and intron 7, is located about 20 kb from the active gene [34]. A recurring rearrangement is due to recombination between the intron region of the gene and a homologous region near exon 3 of the pseudogene, with inversion of the intervening DNA [3]. Very large deletions of the I2S locus may extend to adjoining genes, as the neighbouring DNA is gene rich. A contiguous gene syndrome involving fragile X mental retardation (FMR1 and FMR2) genes could possibly explain the unusual phenotypes seen in some severely affected patients [33]. Over 150 different mutations, resulting in a spectrum of disease phenotypes, have been described.
General disease manifestations and diagnosis
Treatment of possible disease complications can greatly improve quality of life. Early diagnosis is therefore essential, particularly with the recent introduction of ERT. Table 1 shows the common presenting features of patients with MPS II, together with the range of specialists who are likely to be involved in diagnosis and care.
Table 1Presenting features of patients with mucopolysaccharidosis type II (Hunter syndrome) and the specialists likely to be involved in diagnosis and treatmentPresenting featureSpecialistRecurrent upper respiratory tract infections, recurrent otitis media, developmental delay, hepatosplenomegaly, joint restriction, coarse faciesPaediatricianPaediatric neurologistOtolaryngologistRecurrent ear infections, abdominal distension, stiff jointsPrimary care physicianUmbilical and inguinal hernias with recurrenceSurgeonHip dysplasia, arthropathyOrthopaedic specialistUpper airway obstruction, sleep apnoea, recurrent ear infections requiring tube placementOtolaryngologistPapilloedema in the absence of raised intracranial pressureOphthalmologistValvular thickening on echocardiographyCardiologistJoint pain and restrictionRheumatologistPapular pearly rash across the scapulaeDermatologistRestrictive joint range of motionPhysiotherapistCarpal tunnel syndromeHand surgeonCervical myelopathyNeurosurgeon
Clinical spectrum of MPS II
MPS II is a variable, progressive, multisystem disorder. In most patients, symptoms are severe and death occurs at an early age. In other patients the disease has a more chronic and protracted course. The age of presentation of MPS II is also variable, as are the presenting signs and disease complications. Figure 2 shows the age at onset of the main signs and symptoms of the disease in a cohort of 82 patients enrolled in HOS, the Hunter Outcome Survey. This is a multinational long-term outcomes survey to investigate the natural history of MPS II and the safety and efficacy of ERT with idursulfase [8].
Fig. 2Reported age at onset and prevalence of clinical features in 82 patients with mucopolysaccharidosis type II (Hunter syndrome) enrolled in HOS, the Hunter Outcome Survey
The traditional classification of patients into ‘mild’ or ‘severe’ subtypes, on the basis of length of survival and the presence or absence of CNS disease, is a gross simplification. The disorder should rather be regarded as a continuum between two extremes (severe and attenuated). It is important to note that individuals who are diagnosed with an attenuated form of the disease may still have symptoms and complications that lead to significant morbidity and disability, and may present with mild to moderate learning difficulties. Although the clinical course for the more severely affected patients is relatively predictable, there is considerable variability in the clinical phenotype and progression of the more attenuated form of the disease.
Individuals with attenuated MPS II are most often diagnosed between the ages of 4 and 8 years. For the majority of these affected patients, the clinical course is very similar to the intermediate form of MPS I (MPS IH/S, Hurler–Scheie disease). Survival to adulthood is common, but death often occurs between the ages of 20 and 30 years from cardiac or respiratory disease (Fig. 3). A few patients are less severely affected. In these, life expectancy can be near normal, and such affected males may have children [9].
Fig. 3Mortality by age of patients with mucopolysaccharidosis type II (Hunter syndrome) in the UK. Data are from the Society for Mucopolysaccharide Diseases (MPS Society) and are based on patients registered with the MPS Society between 1950 and October 2006
Patients with the more severe form of MPS II exhibit a chronic and progressive disease involving multiple organs and tissues. They appear normal at birth, although they tend to be heavy, some have inguinal or umbilical hernias and there is an increased incidence of Mongolian blue spots [25]. The age at diagnosis is usually between 18 and 36 months, compared with 9 months for severe MPS I [6]. Death from a combination of neurological deterioration and cardiorespiratory failure usually occurs in the mid-teenage years.
Physical appearance
The typical patient with attenuated MPS II is short with some change of facial features. Significant arthropathy and connective tissue involvement lead to joint contractures. A combination of hepatomegaly and lax abdominal muscles leads to abdominal prominence.
In the more severely affected patients, the typical facial features become apparent in the first 3 years. They are most likely caused by a combination of storage in the soft tissues of the orofacial region and underlying facial bone dysostosis. Thickening of the alae nasi, lips, ear lobules and tongue becomes progressively more obvious. The patients often develop a plethoric, rosy-cheeked appearance. Thickening of the calvaria results in macrocephaly. Facial and body hypertrichosis is often seen and the scalp hair becomes coarse, straight and thatch-like. Patients also develop specific, pearly, papular skin eruptions, which are usually first seen around the scapulae, but then spread to involve the trunk and upper thighs. These skin eruptions, first noted in Hunter’s original presentation, are said to be pathognomic for MPS II [32].
Development
Infants with MPS II appear normal at birth, and early developmental milestones may also be normal, even in the presence of significant somatic disease. Developmental outcomes, however, are highly variable. Significant psychosocial problems occur in affected teenagers and young adults [40]. Even in patients with attenuated disease, cranial magnetic resonance imaging (MRI) scans are often grossly abnormal, with extensive white matter changes as well as dilated perivascular spaces, despite apparently normal intellectual skills [27].
Patients with more severe MPS II also appear normal at birth, and early developmental milestones may be normal. Some patients fail hearing screening tests in the first year, and speech delay is not unusual in more severely affected patients. By 18–24 months, developmental delay is usually apparent. Most patients make very slow progress after this stage, with a developmental plateau beginning between 3 and 5 years of age. Unlike children with severe MPS I, who are usually placid, more severely affected children with MPS II can be hyperactive and aggressive. By the time of death in their second decade, most patients with CNS involvement are severely mentally handicapped and dependant on care providers for all their needs.
Biochemical diagnosis
Assessing urinary GAGs (heparan and dermatan sulphates) is the usual first screening test for MPS II, and can be quantitative (measurement of total urinary uronic acid) or qualitative (GAG electrophoresis). Although neither test can offer a definitive diagnosis, abnormal measurements indicate the likely presence of an MPS disorder. The sensitivity of these tests, however, is not perfect, particularly when measurements are made on samples of dilute urine. Definitive diagnosis is established by enzyme assay in leukocytes, fibroblasts or plasma, using substrates specific for I2S. Another sulphatase should be measured in conjunction, in order to exclude multiple sulphatase deficiency. This is a much rarer disorder than MPS II and is generally associated with a very poor prognosis. It should be noted that the amount of enzyme activity measured in vitro from cellular extracts does not indicate where an individual falls within the MPS II spectrum of disease severity.
Prenatal diagnosis
Prenatal testing is available for foetuses at risk of MPS II. This is generally carried out by enzyme assay of I2S in uncultured chorionic villi, allowing early testing and rapid diagnosis of affected foetuses. Very low activities have been measured in some pregnancies with a (heterozygous) female foetus, emphasising the need to combine an enzyme assay with foetal sex determination [7]. Molecular-genetic prenatal testing can be performed if the mutation is known in the family.
Carrier testing
Previous methods of carrier detection based on an I2S assay in either plasma or hair roots are now known to be unreliable, as there is considerable overlap between the normal and heterozygous ranges. The only definitive test for determining carrier status is based on DNA analysis. In a small number of families, however, the mutation remains elusive, despite full sequencing of the I2S locus.
Symptomatic treatment
Even with the introduction of ERT, patients with MPS II still require supportive symptomatic treatment from a wide range of specialists. A comprehensive initial assessment of each patient at diagnosis should therefore be undertaken, and should be followed by regular reviews. Supportive management and the anticipation of possible complications can greatly improve the quality of life of affected individuals and their families. Family members should be offered genetic counselling, and contact with other affected families, patients and support groups can be helpful.
Skeletal abnormalities
Orthopaedic complications, caused by a combination of direct bone involvement and severe arthropathy, can lead to significant disability. The destructive arthropathy, which especially affects the hip joints, is a feature of the skeletal disease in some patients and may be due to secondary events occurring within chondrocytes and/or osteoblasts as a result of storage.
Progressive arthropathy may affect all joints and leads to severe restriction of motion. The hip joints appear to be particularly vulnerable and severe erosive hip dysplasia can be especially disabling. Poor hand function, due to the characteristic claw-hand deformity, carpal tunnel syndrome and interphalangeal joint stiffness, is also common.
Abnormal joint function is largely a result of both metaphyseal deformities and thickened joint capsules. Secondary erosive joint disease is particularly disabling and is extremely difficult to manage medically and/or surgically. The deformed acetabulum and pelvis makes prosthetic surgery a challenge, and many patients become wheelchair-bound because of hip pain. The role of physical therapy in MPS II is not well studied, but range-of-motion exercises appear to offer some benefit in preserving joint function and should be started at an early age. If significant restriction of joint movement has already occurred, range-of-motion exercises may slow further progression.
Cardiovascular system
Cardiac abnormalities detected by echocardiography are common in patients with MPS II. Valvular involvement, with thickening and stiffening of the valve leaflets, commonly leads to mitral and aortic regurgitation and/or stenosis [24]. Cardiomyopathy is much less common but may be associated with an increased risk of cardiac arrhythmia [14]. Valve replacement surgery may be necessary, and annual cardiac evaluation with echocardiography is essential. Bacterial endocarditis prophylaxis should be used where appropriate. The prevalence and age at onset of the main cardiovascular signs and symptoms as reported in HOS are shown in Table 2.
Table 2Prevalence and reported age at onset (median and 10th–90th percentiles) of the main cardiovascular manifestations of mucopolysaccharidosis type II (Hunter syndrome) in a cohort of 82 patients in HOS, the Hunter Outcome SurveyCardiac manifestationnPrevalence (%)Age at onset (years)Valvular disease34536.2 (2.9–13.8)Murmur32526.4 (3.7–12.3)Cardiomyopathy497.6 (5.2–27.3)Any cardiovascular sign/symptom49726.0 (2.9–13.7)
Respiratory disease and upper airway manifestations
Chronic recurrent rhinitis and persistent copious nasal discharge without obvious infection are common. Enlargement of the tonsils and adenoids, a narrowed trachea, tracheomalacia, thickened vocal cords, redundant tissue in the upper airway, and an enlarged tongue can contribute to upper airway complications [4, 26, 39]. The upper airway involvement leads to noisy breathing, particularly at night, and is probably a major component of obstructive sleep apnoea, which is a common complication in the later stages of the disease [16]. Because of the airway disease, there is a high risk associated with anaesthesia in these patients [17].
In patients with attenuated MPS II, rhinorrhoea tends to improve with age, but upper airway obstruction and sleep apnoea become more troublesome with increasing age. A progressive restrictive respiratory defect also becomes apparent with increasing age, mainly due to progressive changes in the thoracic skeleton.
Sleep studies should form part of the regular assessment schedule, and significant episodes of hypoxia should be managed by continuous or bilevel positive airway pressure devices. Severely affected patients often find such treatment difficult to tolerate. In these patients, supplemental oxygen alone may be an acceptable alternative, but should be used with caution in patients with documented hypercapnia.
Tonsillectomy and adenoidectomy are frequently performed to correct Eustachian tube dysfunction and to decrease airway obstruction. Severely affected patients also tend to have frequent ear infections and constant rhinorrhoea. Early placement of ventilating tubes is recommended in severely affected individuals.
Gastrointestinal system
Protuberance of the abdomen and hernias caused by progressive hepatosplenomegaly are common. Although organ size can become massive, storage of GAGs in the liver and spleen does not lead to either liver or splenic dysfunction. Patients are prone to periodic bouts of watery diarrhoea, which occur without apparent cause and are not associated with malabsorption. Rectal biopsies in affected patients have demonstrated storage within gut neural cells, and an autonomic cause for episodes of diarrhoea has been postulated [10]. With age, loss of muscle strength and physical inactivity lead to constipation.
Abdominal hernias should be repaired surgically, though recurrence can occur. Diarrhoea can be controlled by diet and the use of antimotility drugs.
Central nervous system
Communicating high pressure hydrocephalus, which is common in MPS I, is rare in MPS II. Other CNS complications, such as seizures, are more common. They are usually tonic–clonic in nature and respond to standard anticonvulsant treatment.
Progressive compression of the spinal cord with resulting cervical myelopathy due to thickening of the dura (hypertrophic pachymeningitis cervicalis) and hyperplasia of the transverse ligament is common [21]. In addition, MRI scans of the craniocervical junction will often show deposition of GAG around the tip of the odontoid process. Most patients have a well-formed odontoid process and atlanto-axial subluxation is usually not a feature of MPS II. Cervical myelopathy may initially present as reduced activity, exercise intolerance or difficulty in rising from a sitting position. If it remains untreated, irreversible cord damage can occur.
Hypertrophic pachymeningitis cervicalis and cervical compression secondary to hyperplasia of the transverse ligaments should be quickly and aggressively treated in patients with attenuated disease. Early and careful cervical decompression performed by an experienced team may prevent severe and devastating consequences.
Peripheral nervous system
Carpal tunnel syndrome is common in patients with attenuated forms of MPS II and should be promptly investigated and treated. Nerve conduction studies should be conducted to monitor patients, as the typical symptoms of compression (pain, tingling or numbness) do not occur [13]. Surgical decompression of the median nerve at an early stage of involvement results in either partial or complete improvement in most patients.
Visual problems
Although corneal opacity has been reported [31], it is not generally a feature of MPS II and helps to distinguish the disorder clinically from severe MPS I and MPS VI. In addition glaucoma is rarely present, even in severely affected patients. Retinal degeneration resulting in decreased peripheral vision and poor dark adaptation is common, but often difficult to investigate fully in a severely affected patient. Disc oedema, uveal effusions and epiretinal membranes have all been reported as part of the variable ocular pathology [2, 20, 37].
Electroretinography confirms retinal degeneration in many patients, but a disturbance of vision apart from nyctalopia (‘night blindness’) is rare. Chronic papilloedema without evidence of raised intracranial pressure is common and may be due to deposition of GAGs within the sclera causing pressure on the optic nerve at the interscleral level [2].
Regular, annual, ophthalmological assessment is required and should include a measure of intraocular pressure. Spectacles should be prescribed as appropriate.
Hearing
Hearing loss is common in patients with severe MPS II and is correlated with the severity of somatic disease. Manifestations leading to hearing loss include frequent middle ear disease secondary to Eustachian tube dysfunction, dysostosis of the ossicles of the middle ear, scarring of the tympanic membrane, and damage to the eighth nerve. Audiological abnormalities usually consist of conductive deafness early in the course of the disease but as the child ages a sensorineural element appears and most patients have combined deafness once the disease is fully established [29]. Moderate to severe hearing loss develops in most adults with attenuated MPS II. In most patients there is a mixture of both conductive and sensorineural deafness [22]. Appropriate regular audiology assessment and provision of the correct auditory aids are required.
Education and behaviour
Given the intellectual involvement in the more severely affected patients, it is important that infants with MPS II are provided with a stimulating environment to encourage as much learning as possible during the early stages, as some skills may be retained during the later period of general deterioration. For patients with more attenuated forms of the disease, deafness and physical limitations may impact on education. Educational assessments of special needs should be undertaken to ensure that an appropriate educational environment is provided. This may be in a mainstream school with additional help or within a special school system.
Many patients with severe MPS II exhibit hyperactivity and aggression. Psychological assessment, behaviour management and the use of medication should be considered in these patients. The hyperactivity generally responds poorly to methylphenidate, and over-sedation is a risk with other forms of medication.
Anaesthetic complications
All patients with MPS II present major anaesthetic risks, and death can result if appropriate precautions are not taken [12]. Patients should only undergo general anaesthesia in centres staffed with anaesthesiologists experienced in these disorders. The most important complications relate to the following.
Dysostosis multiplex leading to rigidity of the neck and spine. Although instability of the spine is rare, significant cervical compression may be present in patients with attenuated disease. This can result in sudden neurological deterioration if excessive neck manipulation is performed during attempts to intubate the patient.Induction may be difficult because of an inability to maintain an adequate airway.Intubation may require smaller-than-anticipated endotracheal tubes and a narrow trachea and thickened vocal cords will impede view. It is recommended that a paediatric pulmonologist or ear, nose and throat specialist should be present during intubation. Fibre-optic laryngotracheoscopy is usually essential.Extubation can also be hazardous for these patients, and there is an increased incidence of post-obstructive pulmonary oedema.Recovery from anaesthesia may be slow, and post-operative airway obstruction is always a risk.
Enzyme replacement therapy
Recombinant I2S (idursulfase; Elaprase, Shire Human Genetic Therapies, Cambridge, MA, USA) has recently been licensed for treatment of patients with MPS II in the United States, European Union and Switzerland. Idursulfase is produced in a continuous human cell line and is a purified form of the natural lysosomal enzyme I2S. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains of the glycoprotein enzyme allow specific binding of idursulfatase to M6P receptors on the cell surface, leading to cellular internalisation and targeting of the enzyme to lysosomes, and subsequent catabolism of accumulated GAGs.
Phase I/II trial
Twelve patients were enrolled in a randomized, double-blind, placebo-controlled trial of idursulfase for 24 weeks, followed by an open-label extension study.
Urinary GAGs were reduced within 2 weeks of initiating idursulfase treatment and remained low for the 48 weeks of the study (P < 0.0001). Both liver and spleen volumes were decreased at 24 weeks (P < 0.01) and 48 weeks (P < 0.001). The distance that patients could walk in 6 min (6-min walk test) increased by an average of 48 m after 48 weeks (P = 0.013). Six patients developed IgG antibodies that did not appear to influence the clinical response to idursulfase [18].
Phase II/III trial
A multinational, randomized, double-blind, placebo-controlled trial was performed to evaluate the safety and efficacy of idursulfase, 0.5 mg/kg administered weekly, compared with placebo. Additionally, the trial evaluated idursulfase, 0.5 mg/kg every other week, compared with placebo. Ninety-six patients were randomized to one of three groups with each patient receiving a total of 52 infusions of either idursulfase, idursulfase alternating weekly with placebo, or placebo. The primary efficacy endpoint of the trial was a composite of two clinical measures – forced vital capacity and the 6-min walk test.
Patients receiving the weekly dosing regimen of idursulfase showed a statistically significant improvement in the primary efficacy endpoint (P < 0.005) compared with placebo. Patients receiving the alternate-week dosing regimen of idursulfase also showed a statistically significant improvement (P < 0.05) compared with placebo [19].
Treatment with idursulfase was generally well tolerated. The most common adverse events observed were associated with the clinical manifestations of MPS II. Of the adverse events considered possibly related to idursulfase, infusion-related reactions were the most common and were generally mild. There were two patient deaths during the study, both of which were considered unrelated to treatment with idursulfase. IgG and IgM antibodies were observed in the idursulfase-treated patients at some point during the course of the study. When antibodies occurred, there was a transient increase in urinary GAGs, presumably due to a neutralising effect. This did not correlate with any of the clinical variables measured (Shire HGT, data on file). No IgE antibodies were observed and no patient withdrew from the trial due to an adverse event considered related to idursulfase [19].
Current treatment with idursulfase
Idursulfase is given by weekly intravenous infusion over 3 h at a dose of 0.5 mg/kg diluted in an appropriate volume of saline (according to weight). Patients may receive premedication with antipyretics and/or antihistamines at the discretion of the prescribing physician. Patients who have experienced infusion-related reactions should be premedicated for subsequent infusions. Consideration should be given to the possibility of sodium overload in small infants, and, if necessary, the total volume of the infusion can be decreased to 50 ml. Although the treatment is generally safe and infusion-related reactions are no more frequent than with other protein-based therapies, anaphylactoid reactions have been reported.
Early response to ERT
The response to ERT appears to depend on the severity of the individual’s condition and the age at which the treatment begins. In our experience, the first sign of efficacy in most young (prepubertal) patients is usually an enhanced feeling of wellbeing and greater energy, manifesting as an increased ability to take part in normal daily activities. By 2 months, most patients have urinary GAG levels approaching the normal range and there is usually evidence of a reduction in size of the liver and spleen. After a further month of therapy there is often an improvement in soft-tissues joint contractures and the beginning of a growth spurt. By 6 months of treatment, most patients have improved the distance that they can achieve in the 6-min walk test and most show stabilisation (if not improvement) in pulmonary function tests. Most of the improvement occurs in the first 12–18 months of treatment. After this period of time, gains are very slow and the condition of most patients will generally have stabilised, although physicians still need to be vigilant and look actively for possible disease-related complications.
ERT for particular patient groups
Treating very young patients
Experience of treating children under the age of 5 years with idursulfase is limited, as the clinical trials enrolled patients above this age so that the patients would be able to comply with and be able to cooperate with repeated pulmonary function and endurance testing. The following is therefore based on our personal clinical experience. Treating patients at a very young age leads to practical problems with the infusions. These may be resolved with indwelling vascular access devices. Outcomes are likely to be better in patients treated from a very young age, but there are currently no recommendations on how to monitor the response to treatment, especially in patients either too young to cooperate with the tests used in the clinical trials (pulmonary function tests and 6-min walk test) or in patients who are not yet showing symptoms of the disease. This situation would be improved by identifying a suitable biomarker that would reflect the disease burden and that would respond promptly to therapy.
We believe that these challenges should not prevent the introduction of treatment in patients under the age of 5 years after discussion with parents. Careful clinical follow-up, however, will be necessary in these patients, accompanied by regular (annual) developmental assessments. As of October 2006, there were 12 patients below 5 years of age in HOS.
Treating patients with severe CNS involvement
Idursulfase is not expected to cross the blood–brain barrier and therefore would not be expected to lead to any improvement in CNS dysfunction in patients with severe MPS II. In most patients there is likely to be some initial benefit in terms of enhanced respiratory function due to airway improvement and reduction in size of the liver and spleen. In addition, joint mobility may improve as a result of ERT on peri-articular soft tissue. The burden of weekly intravenous therapy may be significant in some patients with very severe CNS disease. The authors believe that patients with severe CNS involvement may be offered the possibility of treatment for a ‘trial’ period of 12–18 months, after which time a decision should be made as to whether to continue. Decisions on whether to start and continue treatment should be made only after detailed discussion with the parents.
Home therapy
More than 90% of patients treated with idursulfase have had no infusion-related reactions and, in those who do, the reactions are mostly minor and respond promptly to reducing the rate of infusion and using antipyretics and antihistamines for future treatments. Under these circumstances, it would appear that idursulfase is a therapy that could be administered safely in the patient’s home after a minimum of 12 infusions in hospital.
Depending on the labelling and clinical practices in particular countries, a logical approach would appear to be to consider home therapy for those patients with minimal or no obstructive airway disease (as judged by sleep study and pulmonary function tests). It should be stressed, however, that ERT during respiratory infections or other intercurrent illnesses are contraindicated. Treatment should be postponed under such circumstances, regardless of whether treatment is given in the hospital or home setting.
Management of infusion reactions
Infusion-related reactions appear to be of two types: those occurring during the infusion and ‘late’ reactions occurring 12 h or more after the infusion.
The classic reactions occurring during the infusion, with fever, chills and urticaria, respond to temporarily stopping the infusion, administering paracetamol (acetominophen) and antihistamines, and restarting the infusion after at least 30 min but at a slower rate. Before subsequent infusions, patients should be premedicated with acetominophen and antihistamines 1 h before the infusion. If the reactions continue despite this premedication, consideration should be given to pretreatment with corticosteroids; for example, prednisolone, 1 mg/kg, 12 h and 1 h before infusion.
Late reactions typically consist of a sunburn-type rash and mild wheezing. The rash can be managed as above, but the wheezing requires bronchodilator treatment and, possibly, oxygen supplementation. All patients who have significant infusion-associated reactions should have specific immune testing. Reducing the rate of infusion is mandatory in these patients.
To assess the efficacy of ERT in individual patients and to ensure the appropriate management of possible infusion-related reactions, it is recommended that the treatment of patients receiving ERT is overseen by experienced physicians in centres with expertise in treating lysosomal storage diseases.
Haematopoietic stem cell therapy
The potentially beneficial effect of HSCT on lysosomal storage diseases is thought to be due to the replacement of deficient macrophages with marrow-derived donor macrophages (Kupffer cells – pulmonary, splenic, nodal, tonsillar and peritoneal macrophages – and microglial cells) which constitute an ongoing source of enzyme capable of gaining access to various storage sites. HSCT has been successful in modifying the course of the disease in patients with severe MPS I and MPS VI. In a single small study of HSCT in MPS II, however, the results of treatment were not positive, with nine of ten patients continuing to exhibit progressive neurodegeneration [36].
The future
Whilst ERT is likely to benefit many patients with MPS II, the problems associated with severe CNS involvement are unlikely to be solved by intravenous ERT. Other methods of treatment, including alternative routes of enzyme administration, will therefore need to be studied. Direct administration of enzyme into the cerebrospinal fluid, either into the ventricle or lumbar space, has not prevented progressive neurological deterioration in another lysosomal storage disorder, type II Gaucher disease [28]. This approach has not been attempted in MPS II, and formal studies are required, perhaps with the addition of immunosuppression to prevent antibody formation. Currently, there are no suitable methods for infusion directly into the brain, and repeated intracerebral injections would not be practical. It may be that to treat CNS disease more effectively, peripheral ERT may have to be combined with other approaches, such as cell-based therapies, perhaps involving gene enhancement or replacement.
Gene therapy is the logical approach for treating disorders of the CNS, and animal work on other MPS disorders is beginning to show promise [5, 30]. Choice of vector, the use of immunosuppression and the route of administration are all issues that need addressing before the first human clinical trials of gene therapy involving MPS disorders are performed.
Use of nanoparticles containing engineered myoblasts expressing I2S has been reported. Scaling-up studies, however, are required to evaluate the feasibility of such devices [11].
Conclusion
MPS II (Hunter syndrome) is a severe progressive multisystemic disorder that has the potential to cause disease in most body systems and is usually fatal in the second or third decade of life. Ideally, management should be centralised in major medical centres with access to all medical specialties. Management is multidisciplinary and a holistic approach to the patient is required, especially for those who have severe neurological involvement. ERT is an important new therapy that has the potential to help many patients, providing that it is started early in the course of the disease. CNS disease remains a major challenge and an innovative approach to treatment will be needed if this is to be addressed fully.

mucopolysaccharidosis type ii
hunter syndrome
enzyme replacement therapy
idursulfase
treatment recommendations


Letrozole in advanced breast cancer: the PO25 trial

Tamoxifen has been a standard first-line endocrine therapy for post-menopausal women with hormone-responsive advanced breast cancer, but more than half of patients fail to respond and time to progression is less than 12 months in responders. The third-generation aromatase inhibitors were developed to provide more effective alternatives to tamoxifen. In the Femara Study PO25, post-menopausal women with advanced breast cancer were randomized to receive letrozole 2.5 mg (n = 453) or tamoxifen 20 mg (n = 454) given orally daily until progressive disease occurred. Patients were permitted to cross over to the other treatment at progression. In the primary efficacy analysis, median time to progression (TTP) was significantly longer with letrozole than with tamoxifen (9.4 months vs. 6.0 months, respectively; P < 0.0001). The objective response rate (ORR) was significantly higher for letrozole than for tamoxifen (32% vs. 21%; P = 0.0002). Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival (OS) compared with tamoxifen over the first 24 months of the trial. An exploratory analysis of patients, who did not cross over, indicated a median OS benefit of 14 months for letrozole compared with tamoxifen. Letrozole is the only third-generation aromatase inhibitor that has demonstrated significant improvements in ORR, TTP, and early OS.
Introduction and rationale
The treatment goals for advanced or metastatic breast cancer (MBC) are to delay disease progression and to prolong survival [1, 2] and to optimize patient care in terms of ameliorating symptoms, thereby improving or maintaining quality of life [3–5]. Although treatment may include surgery and radiation therapy for the treatment of locally advanced tumors or isolated metastases, systemic therapies (endocrine, cytotoxic, biologic, and palliative) are the foundation of disease management [6, 7]. Systemic therapy for patients with advanced breast cancer should be tailored according to specific tumor biology, particularly with respect to hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, the growth rate of disease, presence of visceral metastases, history of prior therapy and response, susceptibility to treatment-related toxicity, and individual patient preference [7–14]. Systemic therapy can prolong survival and enhance patient quality of life but is not curative [1]. Consequently, minimally toxic endocrine therapies are generally preferred to cytotoxic therapy as initial therapy for patients with hormone-responsive tumors [6, 15].
Since the 1980s, endocrine therapy with tamoxifen was well established as a standard first-line treatment for post-menopausal women with advanced breast cancer, even though estrogen receptor (ER) expression was not always used routinely to select patients for endocrine therapy [16–18]. The first-generation aromatase inhibitor aminoglutethimide or a progestin such as megestrol acetate has provided a reasonable second-line alternative [19–22]. The objective response rate (ORR) to tamoxifen was shown to be in the range of 25%–45% [16, 17, 19, 21, 23–32], indicating that more than half of the patients with advanced breast cancer are intrinsically resistant to tamoxifen. Furthermore, the short median time to treatment failure (TTF), in the range 6–8 months, demonstrates a relatively rapid emergence of resistance in patients initially sensitive to tamoxifen [19, 27]. Loss of ER expression appears to be the dominant mechanism of de novo resistance, and most ER/progesterone receptor negative (PgR−) tumors do not respond to tamoxifen [18, 33–36]. However, the majority of patients who develop acquired tamoxifen resistance still express ER at the time of progression [37, 38] and may respond to alternative endocrine therapies [39].
The third-generation aromatase inhibitors letrozole, anastrozole, and exemestane were developed in the search for more effective therapeutic alternatives to tamoxifen. Aromatase inhibitors prevent estrogen synthesis by potently inhibiting the aromatase enzyme, which converts androgens to estrogen [40]. Unlike tamoxifen, the aromatase inhibitors do not have any partial estrogen-agonist activity [41] and are less susceptible to the emergence of resistance associated with long-term estrogen deprivation [42]. The development and mechanism of action of aromatase inhibitors is described in detail in the article by Dr. Bhatnagar in this supplement.
Studies of aromatase inhibitors in the second-line setting
The initial randomized controlled trials of third-generation aromatase inhibitors were conducted in patients with advanced breast cancer in whom tamoxifen had failed (i.e., second-line setting). Letrozole, anastrozole, and exemestane all demonstrated evidence of clinical superiority to megestrol acetate in the second-line setting [43–47]. Thus, the individual trials demonstrate a trend or even a significant difference in favor of the third-generation aromatase inhibitors in one or more efficacy end points; in addition, the aromatase inhibitors were shown to be associated with improved tolerability versus comparator endocrine therapy in these randomized trials.
One trial demonstrated a significantly higher ORR for letrozole (2.5 mg dose) compared with megestrol acetate (24% vs. 16%, respectively; P = 0.04) and a trend toward longer time to progression (5.6 vs. 5.1 months, P = 0.07) [45]. In this trial, low-dose letrozole (0.5 mg) was associated with similar efficacy outcomes compared with megestrol acetate. However, in another similarly designed trial with letrozole versus megestrol acetate, overall response rates with the two doses of letrozole (0.5 and 2.5 mg) and with the comparator were similar (21%, 16%, and 15%, respectively). In this trial, low-dose letrozole was superior to megestrol acetate in terms of time to progression (TTP) (P = 0.044) and survival (P = 0.053). Differences in the distribution of baseline variables may explain the different outcomes in the two trials in terms of the superiority of letrozole over megestrol acetate according to dose [48]. Letrozole was significantly better tolerated than megestrol acetate, specifically in terms of serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain [45].
Third-generation aromatase inhibitors have demonstrated greater potency and selectivity than the first-generation compound aminoglutethimide [49]. Two doses of the most potent aromatase inhibitor letrozole (2.5 mg and 0.5 mg) [49] were compared with aminoglutethimide in a randomized controlled trial in the second-line setting and demonstrated superior efficacy and improved safety [50]. The higher dose of letrozole showed a trend (P = 0.06) toward superior ORR (19.5%) compared with aminoglutethimide (12.4%). Letrozole 2.5 mg was also significantly superior in TTP, TTF, and overall survival (OS). Fewer patients taking letrozole experienced adverse events than those taking aminoglutethimide (33% vs. 46%) [50]. Letrozole has also been compared with anastrozole in a randomized, unblinded trial in the second-line setting in patients with MBC. The trial showed that letrozole was associated with a statistically higher ORR than anastrozole (19.1% vs. 12.3%, respectively; P = 0.013), whereas TTP (the major end point), TTF, and clinical benefit and duration of response were similar between the two agents [51]. Both letrozole and anastrozole were well tolerated, and a similar incidence of adverse events was observed in the two groups.
These studies generated the hypothesis that letrozole might have superior efficacy to tamoxifen as first-line therapy for advanced breast cancer. A large clinical trial (Femara Study PO25) was therefore conducted to compare the efficacy and tolerability of letrozole with those of tamoxifen as first-line therapy in post-menopausal women with advanced breast cancer [52]. This review will describe the results of the PO25 trial, highlighting the evidence for the superiority of letrozole over tamoxifen as first-line endocrine therapy in this setting.
Trial design and patients
The Femara Study PO25 was the largest phase 3 trial conducted in the advanced breast cancer setting [52, 53]. This randomized, double-blind, double-dummy trial was powered for superiority and needed to enroll approximately 900 patients to demonstrate a 20% reduction in the risk of progression with the more effective treatment. To achieve the recruitment target, the trial was conducted in 201 centers in 29 countries. Local ethics review boards approved the protocol, and all patients gave written informed consent before study enrollment.
Randomized trial design
Patients were randomized to receive letrozole 2.5 mg or tamoxifen 20 mg given orally daily until progressive disease occurred. Patients were permitted to cross over from 1 treatment arm to the other in a double-blind fashion if their first-line treatment was discontinued because of progressive disease or for any other reason (Fig. 1). Patients in whom endocrine therapy was discontinued were subsequently treated as clinically indicated, using chemotherapy, trastuzumab, and bisphosphonates. The crossover design was an integral part of the study, and it probably affected the assessment of OS.
Fig. 1Study design
Patient population
Post-menopausal women with advanced breast cancer, defined as stage IIIB locally advanced disease, locoregionally recurrent disease that was not amenable to surgery or radiotherapy, or metastatic disease, were eligible for inclusion in the trial. All patients presented with measurable or assessable tumors and were candidates for endocrine therapy. Patients had estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PgR+) tumors or unknown HR status. One prior chemotherapy regimen for the treatment of metastatic disease was permitted, but recurrence during or within 12 months of adjuvant antiestrogen therapy and any prior endocrine therapy for advanced breast cancer precluded enrollment.
End points
The primary end point was TTP, defined as the interval between date of randomization and the earliest date of disease progression. Disease progression was determined on the basis of tumor progression (an increase of 25% or more in measurable lesions, an estimated increase of the same magnitude of nonmeasurable lesions, or the appearance of new lesions), treatment discontinuation with evidence of clinical deterioration due to breast cancer, death due to breast cancer, or death of unknown cause (with documented evidence of clinical deterioration due to breast cancer) while receiving treatment or within 6 weeks of discontinuation of treatment.
The secondary end points were ORR, duration of overall response, rate and duration of clinical benefit, TTF, time to response (TTR), time to chemotherapy (TTC), safety, and OS. ORR was defined as the proportion of patients who achieved a complete response (CR) or a partial response (PR), confirmed by a second evaluation 1–3 months later. The duration of overall response was defined for patients with CR or PR, as the interval between date of randomization and the earliest date of disease progression. The rate of clinical benefit was defined as proportion of patients who achieved CR or PR or who stabilized (NC) for at least 24 weeks; the duration of clinical benefit was defined for patients who achieved CR or PR or NC as the interval between date of randomization and the earliest date of disease progression. TTF was defined as the interval between date of randomization and the earliest date of disease progression, withdrawal, lost to follow-up, or death. TTR was defined for CR or PR patients as the interval between randomization and the earliest documentation of response, and TTC was defined as the total duration of endocrine therapy. The duration of OS was defined as the interval between randomization and death for any reason.
Exploratory analyses of OS were performed. The first analysis included all patients with censoring at crossover, whereas the second included only patients with no crossover. The latter group predominantly comprised of patients with “nonresponsive” disease (patients who responded to first-line therapy are more likely to be crossed over later at progression), whereas the former included “nonresponsive” as well as “responsive” patients.
Efficacy
The characteristics of the 907 patients included in the intent-to-treat (ITT) population were well balanced between the letrozole and tamoxifen arms. The median age of the patients was 65 years (range 31–96 years) in the letrozole arm and 64 years (range 31–93 years) in the tamoxifen arm. Patients were predominantly white (86%), and 92% had Karnofsky performance status (KPS) scores of 80–100. The majority (93%) of the study population had metastatic disease. Soft tissue lesions were the dominant metastatic site in one quarter of patients and were present in 63% and 61% of patients in the letrozole and tamoxifen arms, respectively. Bone metastases were the dominant metastatic site in approximately 30% of patients and were present in 54% and 50%, respectively. Visceral metastases were the dominant site in 43% of patients in the letrozole arm and 46% of the patients in the tamoxifen arm. Most patients (71% in the letrozole arm and 66% in the tamoxifen arm) had not received any prior chemotherapy, and few had received chemotherapy for advanced disease (9% and 11%, respectively). The majority of patients (109 of 167) treated with adjuvant tamoxifen received at least 2 years of therapy, and the treatment-free interval between stopping adjuvant therapy and entering the study was more than 2 years in 126 of 167 patients. Of the 907 patients included in the ITT efficacy population, 467 crossed over to the other treatment arm, 75 continued on first-line therapy without progression, and the remainder terminated first-line treatment without crossover (Fig. 2).
Fig. 2Patient disposition
Letrozole was superior to tamoxifen for all primary and secondary efficacy end points, including a prospectively planned survival analysis at 1- and 2-year follow-up [53].
Time to progression
In the primary efficacy analysis, the median TTP was significantly longer with letrozole than with tamoxifen (9.4 months vs. 6.0 months, respectively; P < 0.0001) (Fig. 3) [53]. Of patients in the letrozole arm, 359 (79%) progressed, compared with 387 (85%) in the tamoxifen arm. The hazard ratio of 0.72 represents a 28% reduction in the risk of disease progression with letrozole (P = 0.0001).
Fig. 3Time to progression at median follow-up of 32 months for patients on first-line letrozole versus tamoxifen. Reprinted from ref. [53] with permission from the American Society of Clinical Oncology
The significant improvement in TTP with letrozole was confirmed in supportive multivariate analysis of prospectively defined baseline covariates, including receptor status, prior adjuvant tamoxifen therapy, and dominant site of metastatic disease [52, 54]. The analysis showed that the risk of progression was increased by the presence of either visceral or bone metastases as the dominant site of metastatic disease compared with soft tissue as dominant site. In the multivariate analysis, the significant improvement in TTP with letrozole over tamoxifen (hazard ratio 0.70; 95% confidence intervals [CI] 0.60, 0.81; P = 0.0001) was similar to the benefit observed in unadjusted analysis and was significant for each individual covariate (P = 0.0001) [53]. Median TTP values for letrozole and tamoxifen in the different subgroups are shown in Table 1. In patients with nonvisceral metastases, the risk for progression was 25% lower with letrozole than with tamoxifen, whereas in patients with visceral metastases, excluding the liver, the risk for progression was 34% lower and the median TTP was almost twice as long with letrozole than with tamoxifen [54]. Although TTP was shortest for patients with liver lesions, the risk for progression was still 36% lower with letrozole than with tamoxifen in this subgroup [54].
Table 1Time to progression in different patient subgroups [57]SubgroupLetrozoleTamoxifenDominant disease site: soft tissuen113115Median TTP12.1 months6.4 monthsDominant disease site: bonen145131Median TTP9.5 months6.3 monthsDominant disease site: visceran195208Median TTP8.3 months4.6 monthsPatients who had n9483    received priorMedian TTP8.9 months5.9 months    antiestrogenHazard ratio (95% CI)a0.60 (0.43, 0.84)HR-positiven294305Median TTP9.4 months6.0 monthsHazard ratio (95% CI)a0.69 (0.58, 0.83)HR-unknownn159149Median TTP9.2 months6.0 monthsHazard ratio (95% CI)a0.77 (0.60, 0.99)TTP, time to progression; CI, confidence interval; HR, hormone receptoraHazard ratios < 1.0 indicate superiority for letrozole relative to tamoxifen
Patients with prior adjuvant antiestrogen therapy benefited from letrozole in line with the total group, as did patients irrespective of positive or unknown receptor status of the primary tumor.
A prospectively planned analysis by patient age (<70 years and ≥70 years) also demonstrated that median TTP was significantly longer for letrozole than for tamoxifen in both age groups (8.8 months vs. 6.0 months, respectively, in the younger group and 12.2 months vs. 5.8 months in the older group) [55].
Response to therapy
Letrozole was associated with a significantly better response to therapy compared with tamoxifen [52, 53]. ORR was significantly higher for letrozole than for tamoxifen (32% vs. 21%; P = 0.0002), and the corresponding rate of CRs was also significantly higher for letrozole (9% vs. 3%; P = 0.0004). The rate of treatment failure was lower with letrozole (75%) than with tamoxifen (85%), and median TTF was significantly prolonged (9.0 months vs. 5.7 months, respectively; P < 0.0001).
A supportive multivariate analysis of ORR, adjusted for the same covariates as used for the TTP analysis, showed that prior adjuvant tamoxifen, as well as visceral or bone metastases as the dominant site of metastases, significantly decreased the probability of achieving a response. The analysis also confirmed that letrozole significantly increased the probability of achieving a CR or PR compared with tamoxifen (odds ratio 1.80, 95% CI 1.32–2.47; P = 0.0002) and that the superiority of letrozole remained statistically significant for each of covariates (P = 0.001) [52]. ORRs achieved with letrozole and tamoxifen in the different subgroups are shown in Table 2.
Table 2Objective response rate in different patient subgroups [57]SubgroupLetrozoleTamoxifenDominant disease site: soft tissuen113115ORR50%34%Dominant disease site: bonen145131ORR23%15%Dominant disease site: visceran195208ORR28%17%Patients who hadn8483    received priorORR26%8%    antiestrogenOdds ratio (95% CI)a3.85 (1.50, 9.60)HR-positiven294305ORR33%22%Odds ratio (95% CI)a1.78 (1.20, 2.60)HR-unknownn159149ORR30%20%Odds ratio (95% CI)a1.79 (1.10, 3.00)ORR, objective response rate; CI, confidence interval; HR, hormone receptoraOdds ratios >1.0 indicate superiority for letrozole relative to tamoxifen
Overall survival
The median OS was 34 months for the letrozole group and 30 months for the tamoxifen group (P = 0.53). Prospectively planned analyses of the ITT population showed that letrozole significantly improved OS compared with tamoxifen over the first 24 months of the trial [53]. A Kolmogorov-Smirnov analysis to compare the survival distributions in the 2 arms [56] demonstrated a significant difference in favor of letrozole between 6 and 20 months (P = 0.003) and showed that the maximum difference in survival occurred at 14 months; at this time point, there were 85 deaths (19%) in the letrozole arm compared with 132 deaths (29%) in the tamoxifen arm. In addition, repeated log-rank tests performed at 6-month intervals indicated that survival was significantly greater with letrozole between 6 and 24 months (6 months: P = 0.0167; 12 months: P = 0.0038; 18 months: P = 0.0010; 24 months: P = 0.0246) (Fig. 4). The OS curves for the letrozole and tamoxifen groups crossed at around 36 months, at which time point most patients had either crossed over to the other study drug or had switched to different second-line treatments [53].
Fig. 4Letrozole versus tamoxifen: patients alive at 6-month intervals. Reprinted from ref. [48] with permission from Elsevier
Additional exploratory analyses were therefore performed to determine the influence of crossover on OS. The crossover design was an integral part of the trial and, as with all crossover designs, had a confounding influence on the assessment of OS. Second-line endocrine therapy is generally less effective than first-line treatment in patients responsive to first-line therapy [16]; therefore, evaluation of OS may be impaired if the second-line treatment is actually more effective than the original first-line treatment. Furthermore, patients who are responsive to first-line therapy are more likely to cross over than are patients with nonresponsive disease who do not obtain benefit from first-line therapy.
Approximately 50% of patients crossed over to the other treatment arm (Fig. 2), and almost all of the crossovers had occurred by 36 months. The median time to crossover was longer for patients initially randomized to the letrozole arm (17 months for letrozole to tamoxifen vs. 13 months for tamoxifen to letrozole). The median OS from initial randomization, censoring time to death at crossover, was 42 months (95% CI 36 months to not estimable) for letrozole and 30 months (95% CI 27 to <36 months) for tamoxifen [53]. The superior efficacy of letrozole compared with tamoxifen was also indicated by an analysis of mortality rates and OS following crossover to the alternate treatment. The analysis showed that the mortality rate was substantially reduced (47% vs. 63%, respectively), and OS improved in patients who crossed over to second-line letrozole compared with those who crossed over to second-line tamoxifen (31 months; 95% CI 22–40 months vs. 19 months; 95% CI 17–24 months, respectively) [53].
This OS analysis included all patients censored at the time of crossover (i.e., both “nonresponsive” and “responsive” patients). A second exploratory efficacy analysis of OS included only patients who did not cross over to the other arm and thus predominantly comprised patients with nonresponsive disease. This second analysis, limited to the patients who did not cross over to the alternate drug at progression, indicated a median OS benefit of 14 months for letrozole (35 months; 95% CI 29–43 months) compared with tamoxifen (20 months; 95% CI 16–26 months) [57].
Time to chemotherapy
Hormone therapy is the preferred treatment strategy for patients with hormone-responsive advanced breast cancer, except for those individuals with rapidly progressive disease for whom initial chemotherapy is indicated [15]. Extending the TTC is thus an important goal with hormone therapy and can maintain quality of life without having a detrimental effect on outcome. In the PO25 trial, TTC was significantly longer for patients whose initial treatment was letrozole compared with those initially randomized to receive tamoxifen (16.3 vs. 9.3 months; P = 0.005).
Safety
Both letrozole and tamoxifen were well tolerated [52, 53]. The incidence of adverse effects related to study drug during first-line treatment was similar for letrozole (38%) and tamoxifen (37%). Hot flushes (16% and 13%, respectively), nausea (6% and 6%, respectively), and hair thinning (5% and 3%, respectively) were the most common treatment-related adverse events reported. Bone fractures of any etiology occurred in 5.3% of patients in the letrozole group, compared with 4.2% in the tamoxifen arm, resulting in fracture rates per patient-year of treatment of 0.0427 and 0.0451, respectively [52].
A quality-adjusted time without symptoms or toxicity (Q-TWiST) follow-up study assessed the trade-offs between progression-free survival and toxicity in the ITT population from the PO25 trial [58]. The Q-TWiST approach quantitatively adjusts periods in which treatment toxicities or symptoms of disease progression are present to reflect the potentially reduced value for the patient; this methodology divides the survival time of the patient into various health states, assigns utility states to each, and compares treatments based on OS experience [59]. The Q-TWiST analysis of the clinical trial data from the PO25 trial showed that the longer TTP with letrozole compared with tamoxifen is achieved without increased time with adverse events (2.2 vs. 2 months, respectively), resulting in a significantly greater quality-adjusted survival for patients on letrozole (2.5-month advantage; P < 0.0001) [58].
Time to worsening of KPS (decrease of ≥20 points) was significantly delayed for first-line letrozole compared with first-line tamoxifen (hazard ratio 0.62; P = 0.001) [54]. A subset analysis according to sites of metastases demonstrated that in patients with visceral metastases without liver involvement (mostly lung metastases), significantly fewer letrozole patients (14%) than tamoxifen patients (30%) experienced deteriorations in their KPS scores by ≥20 points [54]. However, KPS was relatively insensitive to change in these first-line patients.
Cost-effectiveness
In addition to its clinical superiority over tamoxifen, economic analyses have also shown that letrozole is highly cost-effective as first-line endocrine therapy in post-menopausal women with advanced breast cancer [60–62]. A follow-up analysis of patient data from the PO25 trial calculated the cost-effectiveness of first-line letrozole and tamoxifen by determining the ratio: difference in costs of breast cancer care to the difference in life years (LYs) between the two treatments [60]. The mean costs of care were $7323 and $5468 for letrozole and tamoxifen, respectively, representing $1855 in incremental costs with first-line letrozole. Mean LYs to death or to the end of first- or second-line hormonal therapy were 1.54 and 1.29 for patients randomized to first-line letrozole or tamoxifen, respectively. Thus, the incremental cost per LY saved with first-line letrozole vs. tamoxifen was $7420 (1855/0.25 = 7420) (2.5–97.5 percentiles $6470–$14,865).
In another economic analysis conducted in the United Kingdom, data from the PO25 trial were used to estimate the effectiveness of treatment [61]. The analysis showed that the mean cost of providing first- and second-line hormonal therapy was GBP4765 for first-line letrozole and GBP3418 for first-line tamoxifen (a difference of GBP1347). Since patients receiving first-line letrozole gain an additional 0.228 LYs, or 0.158 quality-adjusted life years (QALYs), the cost-effectiveness analysis showed that first-line hormonal therapy with letrozole gains additional LYs at a cost of GBP5917, whereas the cost per additional QALY gained is GBP8514, which is well within the accepted cost range.
The PO25 trial data were also used in a Canadian analysis that compared the cost-effectiveness of letrozole, anastrozole, and tamoxifen [62]. The analysis showed an incremental cost per quality-adjusted progression-free year of CAN$12,500 and CAN$19,600 for letrozole and anastrozole, respectively, relative to tamoxifen. The authors concluded that both letrozole and anastrozole are economically acceptable alternatives to tamoxifen.
Conclusions
The Femara Study PO25 has provided evidence from a well-powered, randomized, controlled trial to show that letrozole provides a significant advantage in OS compared with tamoxifen as first-line treatment of patients with advanced breast cancer [53]. Letrozole is the only aromatase inhibitor to demonstrate consistent superiority over tamoxifen in this setting [53, 54].
Randomized first-line therapy trials of anastrozole, as part of the TARGET study [63–66], and exemestane in the EORTC study [67, 68] have provided evidence of clinical equivalence or superiority to tamoxifen in post-menopausal women with advanced breast cancer. However, none of these trials demonstrated statistically significant improvements in all three end points (ORR, TTP, and OS) for the aromatase inhibitor compared with tamoxifen. The PO25 study was the largest of these randomized trials in the first-line setting and demonstrated extremely strong clinical benefits, evidenced by significant superiority in TTP and ORR, with letrozole compared with tamoxifen as first-line hormone therapy. The benefits of letrozole were observed in all patient subgroups, defined by prior antiestrogen therapy, dominant site of metastatic disease, HR status (positive or unknown), and age [52–55]. Furthermore, letrozole is the only aromatase inhibitor associated with an OS advantage for the first-line setting indication at 1-year and 2-year follow-up [53]. As demonstrated in the exploratory analysis of patients who did not cross over to the alternative treatment arm, letrozole prolonged OS by 14 months compared with tamoxifen. Thus, for every 100 patients treated with hormone therapy, eight more will be alive at 1 year if they receive letrozole instead of tamoxifen.
In conclusion, third-generation aromatase inhibitors are effective and well tolerated. Letrozole should be considered as the first-line endocrine treatment in post-menopausal women with hormone-sensitive advanced or MBC. Of the available agents, only letrozole has demonstrated significant improvements in ORR, TTP, and early OS.

letrozole
advanced breast cancer
tamoxifen
aromatase inhibitors
postmenopausal


Prevalence of Risk Factors for Adverse Pregnancy Outcomes During Pregnancy and the Preconception Period—United States, 2002–2004

Objectives: To assess the prevalence of risk factors for adverse pregnancy outcome during the preconception stage and during pregnancy, and to assess differences between women in preconception and pregnancy. Methods: Data from the 2002 and 2004 Behavioral Risk Factor Surveillance System, United States, were used to estimate the prevalence of selected risk factors among women 18–44 in the preconception period (women who wanted a baby in the next 12 months, and were not using contraception, not sterile and not already pregnant) with women who reported that they were pregnant at the time of interview. Results: Major health risks were reported by substantial proportions of women in the preconceptional period and were also reported by many pregnant women, although pregnant women tended to report lower levels of risk than preconception women. For example, 54.5% of preconception women reported one or more of 3 risk factors (frequent drinking, current smoking, and absence of an HIV test), compared with 32.0% of pregnant women (p < .05). The difference in the prevalence of these three risk factors between preconception and pregnancy was significant for women with health insurance (52.5% in preconception vs. 29.4% in pregnancy, p < .05), but not for women without insurance (63.4% vs. 52.7%, p > .05). Conclusions: Women appear to be responding to messages regarding behaviors that directly affect pregnancy such as smoking, alcohol consumption and taking folic acid, but many remain unaware of the benefits of available interventions to prevent HIV transmission and birth defects. Although it appears that some women reduce their risk for adverse pregnancy outcomes after learning of their pregnancy, the data suggest that a substantial proportion of women do not. Furthermore, if such change occurs it is often too late to affect outcomes, such as birth defects resulting from alcohol consumption during the periconception period. Preconception interventions are recommended to achieve a more significant reduction in risk and further improvement in perinatal outcomes.
Introduction
Although the US has achieved substantial gains in improving the health of women and children, and infant mortality has reached record low levels, the US presently ranks 27th among established market economies in infant mortality [1]. Four recurring causes account for more than half of all infant deaths: birth defects, disorders related to short gestation and preterm birth, maternal complications of pregnancy (including complications of the placenta, cord and membranes), and sudden infant death syndrome [2]. In recent years some causes of infant mortality have increased, particularly in the percentage of births that were preterm and of low birth weight [3]. In 2002, congenital anomalies, low birth weight, preterm delivery, and maternal complications of pregnancy accounted for 14,263 (50.9%) of the 28,034 infant deaths [2].
Relatively little is known about the risk factors underlying the continued increase in these adverse outcomes. Adequate prenatal care has long been considered as an opportunity to reduce such risks. However, despite increases in access to and utilization of early prenatal care, interventions and efforts directed at addressing such risk factors fall short of their goal. Indeed, the effects of such efforts may have reached their peak, and new approaches may be necessary. Reviews on selected risk factors indicate that a large proportion of women enter pregnancy with pre-existing risks for adverse pregnancy outcomes. Although some women tend to take action to reduce their risk as soon as they learn that they are pregnant, the extent of pregnancy related change in risk factors varies considerably and often does not occur early in pregnancy when teratogenic effects are more pronounced. Moreover, post-pregnancy relapse is high [4]. For example in the period 1996–1998 the reported reduction in the use of alcohol, tobacco and illicit drugs in the first trimester was 46, 28, and 28% respectively [4]. Such information is important to the emerging emphasis on preconception care as a complementary approach to reduce risks to pregnancy. This paper provides nationally-representative estimates on risks during the preconception period and describes the apparent reductions in risk achieved during pregnancy for all known risk factors for which data are available.
Data
The estimates presented herein are based on data from the 2004 Behavioral Risk Factor Surveillance System (BRFSS) [5]. However, because not all risk indicators that were considered were included in the 2004 BRFSS, 2002 data were used for a small number of risk indicators for which the 2002 BRFSS provided the most recently available data. The BRFSS is an ongoing annual telephone survey of the non-institutionalized adult civilian population aged 18 years and older conducted in each state. The survey obtains information on a wide range of modifiable risk behaviors. In 2004 the median response rate for the BRFSS state surveys was 52.7 percent. This rate represents an estimate of the percentage of eligible respondents that completed telephone interviews, and is computed based on procedures recommended by the Council of American Survey Research Organizations (http://www.casro.org/resprates.cfm.) In comparison with other national surveys, BRFSS data appear to be of good quality [5]. Additional technical information is available online at http://www.cdc.gov/brfss/.
The survey includes core modules asked in all states, rotating modules asked every second year in all states, and optional modules that are included only in some states. Being a general survey, the BRFSS lacks information on some factors of interest to the present topic, for example month of pregnancy for pregnant women, or information on prenatal care. Further, the BRFSS is not designed specifically to study all known risk behaviors at preconception or pregnancy. In addition, as an interview survey, the survey relies on self-reported data which contain an unknown level of reporting error.
Identification of women in the preconception group in the BRFSS is made possible by questions introduced in the “family planning section” of the questionnaire. The availability of these questions makes it possible to compare risk behaviors among women about to become pregnant with those who are already pregnant on a large and nationally-representative sample of women. Women in the preconception period were identified as those who reported that they wanted a baby in the next 12 months, were not using contraception, were not sterile and were not already pregnant. Women who were pregnant were identified based on the response to the question “To your knowledge are you now pregnant?” Age of gestation was not assessed in this survey. Data were aggregated across states to make national estimates. For 2004 this resulted in a total national U.S. sample of 70,917 women aged 18 to 44 years, of whom 2308 (3.4%) were classified into the preconception period, and 2998 (4.7%) reported that they were pregnant at the time of their interview. The corresponding number of women in the 2002 are 61,284 women 18–44, with 2204 (3.7%) in the preconception period, and 2556 (4.6%) pregnant women. The analysis on folic acid and vitamins are based on surveys in 12 states in 2004. The results for these items are generalizable to the populations of these 12 states (shown in Table 2) but not to the entire United States population.
Table 1Comparison of age and race/ethnicity, 2004 Women in preconception and pregnant (BRFSS) and Births (Vital Statistics data)BRFSSPreconception womenPregnant womenVital statisticsPercentCIPercentCIbirths PercentAge group 18–192.00.97.52.27.1 20–2416.33.326.53.026.1 25–2923.43.126.52.727.9 30–3428.43.126.22.824.4 35–3918.52.510.21.512.0 40–4411.42.23.10.92.6100.0100.0Race/ethnicity NH White64.93.960.13.456.8 NH Black11.92.511.51.913.6 Hispanic16.03.523.03.422.5 Others7.22.15.51.67.2100.0100.0100.0Note. For BRFSS estimates, 95% confidence interval = Percent +/− CI. Vital statistics data: Hamilton BE, Martin JA, Ventura SJ, Sutton PD, Menacker F. Births: Preliminary data for 2004. National vital statistics reports; vol 54 no 8. Hyattsville, Maryland: National Center for Health Statistics. 2005.Table 2Health risk indicators by pregnancy status Women 18–44, 2004 and 2002 BRFSSPreconception womenPregnant womenPercentCIPercentCI2004 data–nationwidea General Health  Poor/fair general health status8.32.16.41.7  14+ days in past month mental health not good*12.82.49.61.9  No health plan*18.83.511.92.3  No dental visit past year28.33.230.23.1  Told had diabetes*2.00.90.70.4 HIV  Don’t know about prevention of MTC HIV transmission38.23.534.13.0  Never tested for HIV*34.93.424.43.0  1 or more HIV risk category*4.31.46.91.8 Alcohol/smoking  Any alcohol in past month*53.93.710.71.8  Average 1 or more drink per day, past month*6.02.00.80.5  Binging: Any occasions of 5+ drinks in past month*10.72.11.90.9  Frequent drinking: binging or 1 or more drinks per day*12.92.52.20.9  Current smoker*19.42.78.41.5 Obesity  Overweight, body mass index (BMI) >2546.03.6NA  Obese, BMI >3022.43.1NA2004 data, 12 states onlyb,c Folic acid  Don’t know about folic acid for birth defects prevention46.16.938.45.6  Don’t take vitamins of any kind*36.97.110.23.6  Don’t take folic acid or multivitamin*38.47.017.54.5  Don’t take folic acid or multivitamin daily*44.86.919.94.7Nutrition (2002 BRFSS)d Fewer than 5 servings/fruit and vegetables*74.93.164.73.5 Fewer than 1 servings/fruit and vegetables3.31.12.91.3Note. 95% confidence interval = Percent +/− CI.aUnweighted number of observations: Preconception women (2308), Pregnant Women (2998).bUnweighted number of observations: Preconception women (607), Pregnant Women (756).cStates: AZ, CO, FL, KY, MN, MT, NC, ND, NE, TX, VA, WI.dUnweighted number of observations: Preconception women (2204), Pregnant Women (2556).*p < .05, preconception vs. pregnant women.**HIV risk: Any statement is true: in past year illegal drug injection, treated for STD, exchange for money/drugs, uprotected anal intercourse.
Statistical methods
The percentage of women exposed to 21 risk indicators was identified for women in 2 groups: women in the preconception period, and pregnant women (Table 1). The categories of risk indicators for which data are available include perceived general and mental health, lack of medical insurance, knowledge of HIV prevention and practices, alcohol and tobacco use, obesity, nutrition including folic acid uptake for the prevention of birth defects, and presence of chronic medical conditions.
Because these are not longitudinal data it was not possible to observe behavior change in individual women. Rather the prevalence of risk factors was compared between preconception and pregnant women as a proxy measure of pregnancy-related risk reduction [6], although is is possible that other factors could influence the differences between preconception and pregnant women. The statistical significance between preconception and pregnant women of the percentage reporting each risk factor, was assessed using a t-test. All statistical analysis was based on weighting factors designed to produce unbiased estimates, and statistical tests were adjusted for complex sample design using the software for survey data analysis (SUDAAN, Research Triangle Institute, Research Triangle Park, NC).
Results
Comparisons with vital statistics data on births in 2004 indicate that the 2004 BRFSS respondents in the preconception stage and pregnant when interviewed were distributed very similarly by age and race-ethnicity to women giving birth in 2004 (Table 1). Overall, for many risk factors, pregnant women reported lower prevalence of risk than preconception women (Table 2). Percentages reporting alcohol consumption and smoking were much lower for pregnant women than preconception women. For example, 53.9% of preconception women reported any use of alcohol in the past month, compared with 10.7% of pregnant women, 19.4% of preconception women reported current smoking in contrast to 8.4% of pregnant women, and, in the 12 states that included the question, 44.8% of preconception women reported not taking vitamins with folic acid versus 19.9% of pregnant women.
For some risk indicators, no statistically significant difference was observed between women in the preconception period and pregnant women. The lack of awareness about methods to prevent mother-to-child HIV transmission (PMTCT) was not significantly different between preconception women and pregnant women (38.2% vs. 34.1%). However, a small but significantly higher percentage of pregnant women reported HIV risk (6.9%) compared to preconception women (4.3%), which is perhaps related to sexual risk behaviors being causally linked to both HIV and to unplanned pregnancies.
Of concern, is that although a lower percentage of pregnant women compared with preconception women had never been tested for HIV, about one-fourth of pregnant women remained untested, despite national recommendations that call for all pregnant women to be tested for HIV [7].
In the case of chronic diseases such as diabetes, the lower level of disease among pregnant women may indicate self-selection of diabetic women to avoid pregnancy. Of note, nearly one fifth of the women in preconception period were obese (defined as having a body mass index or BMI of greater than 30) and twice that number were overweight (BMI of greater than 25) (Table 2). Most preconception and pregnant women did not report consuming the recommended 5 servings of fruits and vegetables per day [8], although the percentage was lower for pregnant women (64.7%) compared with women in the preconception period (74.9%). Indicators of general well being and recent dental care were not different between women in preconception period and pregnancy.
A composite measure of 3 basic pregnancy risks was formed, frequent alcohol consumption, current smoking and lack of an HIV test, in order to use the BRFSS data to illustrate the size of the target populations for preconception care. These are risk factors for which we have data that are generalizable to the US population, and for which interventions or information are widely available or promoted. The results indicate that 54.5% of preconception women reported one or more of these 3 risk factors, which represents approximately 1 million preconception women (Table 3); 32.0 percent of pregnant women had one or more of these risks, which is equivalent to 835,000 pregnant women. Table 3 also shows this composite risk factor by 2 measures of access to health care, whether the woman had a health plan or insurance and whether she had a personal physician. Pregnant women had a lower percent at risk in all categories except for those without health insurance. Among women without insurance, the percentage reporting risk was not significantly lower for pregnant women, compared with preconception women. This suggests that women with poorer access to health care, as indicated by no health insurance, are not as likely as others to adopt healthier behaviors when they become pregnant.
Table 3Percentage and estimated number reporting any of 3 risks for pregnancy outcomea for preconception and pregnant women aged 18–44 Women 18–44, 2004 BRFSSPreconception women (Estimated number)Currently pregnant women (Estimated number)PercentCI1000sCINPercentCI1000sCINTotal54.5*3.71,02494228632.03.18351012949No health plan/insurance63.411.72225232852.710.315650303Others52.5*3.780279195729.43.2679882646No personal doctor64.1*9.02785944846.39.223473467Others51.6*3.974573183728.62.9601712482Note. 95% confidence interval = Percent +/− CI and Estimated number +/− CI. Estimated number is the estimated number of women in the category with one of the risk factors.aAny of 3 risk factors: frequent drinking, current smoker, no HIV test.*difference between preconception and pregnant women significant, p < .05.
Discussion
The 2004 BRFSS provides an opportunity to measure the extent of risk behaviors on a relatively large sample of women who are planning to become pregnant. These nationally-representative survey data indicate that major health risks were reported by substantial proportions of US women in the preconception period. The data suggest that among those at risk during preconception, the majority continued the risk into pregnancy. Women appear to respond to messages regarding behaviors that can improve pregnancy outcomes such as consuming of folic acid, and the reduction in smoking, alcohol consumption, but many remain unaware of the benefits of available interventions to prevent HIV transmission and birth defects. The fact that more than one-third of preconception and pregnant women were not aware of methods to prevent mother-to-child HIV transmission and did not know about the benefits of taking folic acid during pregnancy suggests that education and public information programs could have some effect in reducing risk behaviors.
Risk reduction appears to be lower among women who have no health insurance. Other data are not available for comparison of the overall burden of risk for adverse pregnancy outcomes among women in the preconception period or pregnancy. However, data on selected indicators presented here for pregnant women are comparable to the reported range from other studies [4, 6, 8–11].
The finding that the percentage who report some risk behaviors is significantly lower among pregnant women compared with women in the preconception period may indicate the desire of many pregnant women to adopt healthier behaviors to achieve the best possible outcome for their pregnancy. Examination of three well known risk factors for which interventions are available (frequent alcohol consumption, current smoking, or never having been tested for HIV) illustrates that risks for adverse pregnancy outcomes exist among more than half of women in the preconception period and among one-third of pregnant women. Nationwide, this represents approximately one million women in the preconception period and 835,000 pregnant women.
The data from the BRFSS are subject to potential errors associated with survey research such as exclusion from the sampling frame, non-response and reporting errors. BRFSS is a telephone-based survey and might not be representative of the small percentage of the population without telephones. The BRFSS methodology contains steps to ensure accurate estimation, including the use of weighting factors to compensate for non-response rates. In addition, estimates from BRFSS data have been found to be consistent with data from other surveys [5]. The preconception and pregnant women identified were distributed very similarly to women giving birth in 2004 by age group and race/ethnicity, providing support for the representativeness of the data. In this report, the reported risk behavior of women in the preconception stage and pregnant women have been compared as a proxy for the type of behavior change occurring between preconception and pregnancy, but other factors could affect the actual change in behavior among individual women.
For known risk factors, progress in efforts to reduce such risks among pregnant women has been slow. For example, as indicated in data collected on earlier rounds of the BRFSS, alcohol consumption among pregnant women has remained relatively steady over the past decade [10]. Even among those who reduce consumption of alcohol, tobacco, or drugs, post pregnancy relapse of such behaviors have been found to be very high [4]. Of the 17 maternal and infant health objectives included in the Healthy people 2010 objectives, progress has been made toward the target in 8 objectives [12]. Little positive progress has occurred in the areas of maternal death, fetal alcohol syndrome, and low birth weight.
To close the gap in reduction of poor maternal and child health outcomes, current maternal and child health initiatives should be complemented with alternate approaches, including more emphasis on preconception health promotion strategies among women of childbearing age. Recent experience in the prevention of alcohol-exposed pregnancy and prevention of neural tube defects through folic acid supplementation has shown that such efforts are useful. In 2003, the Project CHOICES Research Group reported the findings of a feasibility study designed to provide prevention counseling to women at high risk for an alcohol–exposed pregnancy [13]. Brief interventions were found to be effective in reducing hazardous alcohol use in adults in a number of well-controlled studies. Interventions generally consist of advice, feedback, goal setting, and follow-up for further assistance and support [14]. The use of a counseling style referred to as “motivational interviewing” has also proven to be effective in reducing problem drinking [15]. Results of the initial follow-up assessment, suggest that this approach can be effective among women of childbearing age [13], and a larger efficacy trial is now underway.
To summarize, our results were consistent with a high prevalence of risk factors in the preconception period, and a high degree continuation of risk into pregnancy. This underscores the need for new approaches to complement current prevention efforts. Given that women of childbearing age in the United States have on an average 6.4 visits to physicians each year [16], it may be feasible to inform them and engage them for interventions. Such contacts may provide an opportunity to assess and advise on many elements of health mentioned here. Our finding of high risk levels among women who had no insurance or no personal doctor strongly suggests that ensuring access to such services will remain the key determinant of maximum uptake of known intervention services. Medicaid and other funding programs can play an important role to address the access gap—whether during, before, or after pregnancy. Attempts to improve the health of would-be mothers not only improve pregnancy and infant health, but also help reduce the long-term impact of many risk factors on the women themselves.