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Magnesium Sulfate for the Management of Eclampsia and Pre-eclampsia: Some Economic and Cost Reflections

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Title: Magnesium Sulfate for the Management of Eclampsia and Pre-eclampsia: Some Economic and Cost Reflections


1
Magnesium Sulfate for the Management ofEclampsia
and Pre-eclampsia Some Economic and Cost
Reflections
Andrew FarlowResearch Fellow in Economics, Oriel
CollegeUniversity of Oxford Maternal Mortality
day-conference, Oxford, June 2007
2
A note
  • This presentation is a requested response to the
    EngenderHealth/MacArthur Foundation background
    document The Utilization of Magnesium Sulfate
    for the Management of Pre-eclampsia and
    Eclampsia, June 2007.
  • Prepared, as requested, with an eye to research
    issues from an economics/social science
    perspective. Hence, a series of economics/social
    science lenses and not a rounded approach to the
    issue of maternal mortality.
  • Many of the themes have resonance in many other
    areas An opportunity to address cross-cutting
    issues?

3
Key themes identified in MacArthur background
paper
  • Risk
  • Coordination
  • Health systems health service providers
  • The need for context-sensitive solutions
  • Cost and supply
  • Provision and use of cost effectiveness evidence
  • Diagnostics/information/monitoring
  • Political processes (especially when they
    overlook some solutions in preference for other
    solutions)
  • Some of these may overlap in interesting ways
  • risk/coordination with health system issues
  • diagnostics with cost effectiveness and risk
  • risk with cost and supply issues, etc.

4
Maternal Mortality per 100,000 live births in
2000 (2005 source)
Source WHO The World Health Report 2005 make
every mother and child count (2005) http//www.wh
o.int/whr/2005/chap1-en.pdf
5
Causes of maternal mortalitya
6
Some background
  • Approximately 63,000 pregnant women die every
    year because of eclampsia and severe
    pre-eclampsia, which are also associated with a
    higher risk of newborn deaths.
  • That is nearly 200 women every day.
  • Pre-eclampsia/eclampsia ranks second only to
    hemorrhage as a specific, direct cause of
    maternal death.
  • The risk that a woman in a developing country
    will die of pre-eclampsia or eclampsia is about
    300 times that for a woman in a developed
    country.
  • Magnesium sulfate is the mainstay of treatment of
    pre-eclampsia and eclampsia in most developed
    countries. In other parts of the world diazepam
    and phenytoin (used for other types of seizures,
    including epilepsy) are more widely used.
  • Balancing the Scales Expanding Treatment for
    Pregnant Women With Life-Threatening Hypertensive
    Conditions in Developing Countries, a Report on
    Barriers and Solutions to Treat Pre-eclampsia
    Eclampsia EngenderHealth 2007 http//www.engender
    health.org/files/pubs/maternal-health/EngenderHeal
    th-Eclampsia-Report.pdf

7
Risk 1
  • There is no proof that evidence, no matter how
    clearly it is formulated and spoon-fed to
    clinicians, will change practice. Society would
    clearly benefit from better understanding of what
    drives physicians behavior and decision
    making.(P4)
  • Clinicians perceptions of the dangers of
    magnesium sulphate may have contributed to the
    drugs non-use. Respondents acknowledged that
    the international trials in which Zimbabwe
    collaborated showed clearly that the drug saves
    lives. They also noted, however, that the belief
    of many Zimbabwean clinicians in the drugs
    effectiveness is tempered by their perception of
    its dangers to women.(p7)

Referring to Thorp J. O, Evidence-based
medicine where is your effectiveness? BJOG
2007 1141-2) Sevene E, et al. System and
market failures the unavailability of magnesium
sulphate for the treatment of eclampsia and
pre-eclampsia in Mozambique and Zimbabwe. BMJ
2005 331765-769.)
8
Risk 2
  • Physicians in Zimbabwe who participated in the
    Magpie Study expressed reservations about safety
    of use of magnesium sulfate in low-resource
    settings. (p14)
  • If the utilization of magnesium sulfate were
    expanded, in isolation fromother aspects of
    clinical practice, the safety of magnesium
    sulfate and the overall implications for lowering
    mortality are not known. (p13)
  • These are clearly risk/risk perception issues.
  • Some senior nurses feared that the intervention
    would increase the demand for out-patient and
    inpatient care. (p12)
  • So risk can also refer to risk of impact on
    local health budgets too?
  • This properly needs a risk (and incentive) lens.

9
Risk 3
  • If magnesium sulfate is given to women already
    with preeclampsiathe clinician is already facing
    a high-risk situation.
  • If not being recommended for usage for mild to
    moderate preeclampsia, this means it is being
    recommended for sever cases only (p3).
  • What is the personal cost-benefit of those
    administering in terms of the risk they bear?
    What are their perceptions of that risk?
  • What is the global risk versus individual risk
    situation?
  • Is the globally efficient solution bearable by
    those at the local level?
  • How are they insured? Can their risk be better
    handled?
  • Clinicians long use of other drugs to manage
    eclampsia (p6). Is this part of a risk averse
    strategy, or the sign of some other failure?

10
Risk 4
  • What is distribution of risk across the players
    of a strategy that emphasizes the use of
    magnesium sulfate particularly for eclampsia, and
    that places less emphasis on its use for
    preeclampsia? (p14)
  • What about distribution of risk across the
    players using a strategy of shorter (targeted?)
    courses of magnesium sulfate? (p14)
  • The appropriate risk-based strategy is For each
    possible impact, minimize risks then find
    optimal solution in impact space (this may be
    context sensitive see below)
  • It may be a very second best-looking solution.
  • References to very limited drug budgets (p6), and
    hence priority given to first-line drugs
  • Hints also at perceptions of personal
    (clinician/hospital manager) risk and trade-off
    of personal benefit v social benefit (latter
    could be high, even if clinician/manager benefit
    not high).

Weeks, AD, et al. Correspondence. The Lancet.
Vol 360 October 26, 2002, p1329-1331.
11
Coordination issues
  • Magnesium sulfate absent in Nigeria.
  • Present in only 5, 12, and 25 of facilities in
    Burkina Faso, Tanzania, and Rwanda respectively
    (p4).
  • Even after formal approval of the drug,
    difficulties with distribution and management
    gave the impression to clinicians that the drug
    was still unavailable. As a result, they
    continued to use alternative treatments and did
    not request magnesium sulphate from the Central
    Medical Stores or the pharmacy in their own
    health unit. (p5)
  • Referring to case of Mozambique Central Medical
    Stores composed a list of purchases that included
    both the medicines listed in the formulary and
    other drugs that clinicians regarded as
    necessary. Magnesium sulphate had not been
    requested by clinicians, however, and was
    therefore not included. (p5)
  • A coordination problem/prisoners dilemma?
  • A does not do since has to rely on B, who
    does not do since has to rely on C who does not
    do because does not think A is going to do,
    etc. Magnesium sulphate not used because
    magnesium sulphate not used!
  • Also practical differences since an emergency
    drug, and distribution across a health system has
    (maybe?) all or nothing/coordination features?

12
Health system issues 1
  • There are several reasons to be circumspect when
    estimating degree to which mortality might be
    decreased by increasing availability of magnesium
    sulfateA very significant portion of the
    maternal deaths from eclampsia reported from many
    developing countries are among women who had
    multiple seizures outside the hospital and those
    without prenatal care Improvements in
    facility-based care are not likely to affect
    these women nor prevent their deaths.It is the
    standard practice in many countries to discharge
    women soon after childbirth. (p13)

Sibai BM. Diagnosis, Prevention, and Management
of Eclampsia. Am J Obstet Gynecol
2005105(2)402-410 and Katz VL, et al.
Preeclampsia into eclampsia toward a new
paradigm. Am J Obstet Gynecol 2000 1821389-96).
13
Health system issues 2
  • One of the most significant barriers to
    improving care of women with PEE is the fact
    that fewer than 60 of women in some countries
    have access to services where preeclampsia could
    likely be diagnosed and fewer than 40 have
    access to professionals who could administer
    magnesium sulfate.(p8)

14
Countries with a critical shortage of health
service providers (doctors, nurses and midwives)
Source WHO World Health Report (2006)
15
Distribution of health workers by level of health
expenditure and burden of disease
Source WHO World Health Report (2006)
16
Maternal mortality and skilled birth attendants
Source WHO The World Health Report 2005 make
every mother and child count (2005) http//www.wh
o.int/whr/2005/chap1-en.pdf
17
Health systems issues 3
  • Global shortage of about four million health-care
    workers.
  • The richer world sucking in these workers
  • UK and Europe Failures in domestic provision?
  • US Lack of long-term human resource planning
    with an aging population?
  • Not to deny workers right to relocate to better
    themselves Also have to make more attractive to
    stay in home country.
  • In addition, some recent studies have shown that
    efficiency of health workers in some
    resource-poor settings is heavily impaired by
    their need/incentive to work outside health
    sector to supplement income, absenteeism, and own
    ill-health (figures of efficiency as low as 25
    in some settings).

18
Estimated deathsprevented by vaccination(deaths
prevented in blue, lives not saved in grey)The
point of inserting this in this presentation The
diseases at the top have cheap effective
solutions, in an area we have spent billions on,
where all the issues are completely downstream.
Yet coverage is highly imperfect, and many lives
are still not saved.In case of TB though,
current BCG vaccine is not good enough even if
cheap.
19
DTP3 coverage 1980-2004 Shows improvement in
1980s, but average global delivery not much
changed in 1990s and 2000s in spite of heavy
funding in the latter period, and highly variable
at even more disaggregated level
Source WHO/UNICEF estimates, 2005, 192 WHO
Member States. Data as of September 2005
20
Health systems issues 4
  • Two-thirds of all African children who die under
    the age of five could be saved by low-cost
    treatments such as
  • Vitamin A supplements
  • Oral rehydration salts
  • Existing combination therapy drugs against
    malaria
  • Insecticide-treated bed-nets to combat malaria
  • A tenth of all the diseases suffered by African
    children are caused by intestinal worms
  • These can be treated for 25 US cents per child
  • Again, the point is that there are many other
    areas with low-cost solutions where delivery is
    very imperfect.
  • There must therefore be common research themes.

21
Context sensitive solutions
  • Magnesium sulfate might be the drug of choice
    (p2) and the use of magnesium sulfate is now
    recommended worldwide (p15) But what about the
    local context?
  • before undertaking any intervention to improve
    the management of PEE, a thorough understanding
    of the local situation is needed. (p10)
  • We must avoid applying a solution that is
    unnecessarily complex, expensive, fragile, or
    inconvenient. (p9)
  • However, Aasserud et al. conclude that The
    difficulties in obtaining information, combined
    with the wide and differing range of barriers
    between settings, makes it difficult to envisage
    any single intervention strategy(p13)
  • Trying to get our heads around the argument that
    there is a lack of commercial incentive. How
    true is this?
  • Where is really at the heart of the problem?

22
Cost and supply issues 1
  • One hypothesis for under-use is that magnesium
    sulfate may be too inexpensive to motivate mass
    manufacturing, licensing, production and
    distribution. (p4)
  • At the same time While magnesium sulfate is an
    inexpensive drug, the cost of this drug is
    ultimately a small factor in the overall cost of
    management of PEE. (p11)
  • What are the exact scale effects in manufacturing
    magnesium sulfate (say, if large bulk purchases
    were possible)?
  • Many cross-cutting examples where, to the
    contrary, lower COGS (Cost of Goods Sold) is
    requisite for success. What key differences?
  • Case of Hep B where importance of scale and
    appropriate technology (and appropriate holders
    of the technology) and good regulatory systems
    were key. Hypothesis (p6), complex mechanisms
    of drug approval act as barrier There are
    lessons from Hep B.
  • TB vaccine investment case. Driving down COGS is
    key to uptake of booster and prime-boost vaccine
    combinations.
  • Ditto, new generation malaria combination
    therapies.
  • Ditto pneumococcal vaccine (where poor cost
    pressure and technology decisions are harming
    potential impact).

23
Cost and supply issues 2
  • The cost of magnesium sulfate and the hospital
    care involved with providing it were seen as
    barriers in some countries. This problem of cost
    is reflected in the discrepancies between private
    and public facilities in the availability of
    treatment with magnesium sulfate. (p8)
  • What comparative work has been done on public v
    private facilities, to draw out the key drivers
    of provision/delivery?
  • Role of product price mark-ups Recent studies
    (GFHR) show that mark-ups on drugs are seen as a
    source of revenue for cash-strapped health
    systems.
  • In comparison, is magnesium sulfate sold in ways
    making this difficult? If so, what are the
    implications for revenue and incentives to use?
  • What pricing power is there? Does it depend on
    the sector (public or private) accounting for
    provision of magnesium sulfate or way it is sold,
    etc.?
  • Comparisons and contrasts with, say, way malaria
    drugs are sold?
  • Nature of it as only an emergency drug?

24
Cost effectiveness issues 1
  • Targeting to maximize cost effectiveness (p11)
  • 4 randomized trials comparing the use of
    magnesium sulfate versus no treatment (placebo)
    to prevent eclamptic seizures 71 women with
    severe preeclampsia needed to be treated to
    prevent one case of eclampsia.
  • In a subset of these patients those women with
    signs of imminent eclampsia (severe headaches,
    blurred vision, or upper abdominal pain) 36
    women required treatment to prevent one case of
    eclampsia.

Sibai BM. Diagnosis, Prevention, and Management
of Eclampsia. Am J Obstet Gynecol
2005105(2)402-410).
25
Cost effectiveness issues 2
  • Referring to Simon et al., ...it was calculated
    that the additional hospital care costs per woman
    receiving magnesium sulfate in high, middle, and
    low GNI countries were 65, 13, and 11,
    respectively. Many women with preeclampsia need
    to be treated to prevent one case of eclampsia.
  • If treatments were reserved for only women with
    severe preeclampsia, the incremental cost of
    preventing one case of eclampsia in high, middle,
    and low GNI countries were 12,942, 1179, and
    263, respectively.
  • While the authors did not calculate the cost of
    preventing deaths, those costs would be
    considerably higher given that it is known that
    only up to about 14 of women who experience
    eclamptic seizures actually die. (p11)
  • So, cost effectiveness evidence seems to need
    some more analysis?
  • Although magnesium sulfate is cheap, there are
    significant other cost hurdles. How/when do these
    bite?

26
Cost effectiveness issues 3
  • In low-resource settings, to what extent does
    magnesium sulfate compete with other drugs,
    such as diazepam (which is also on the WHOs
    Essential Drugs List)? Diazepam has many other
    clinical applications, including use as a
    pre-operative medication and for the treatment
    for epileptic convulsions. If staff at some
    hospitals believe that stocking Diazepam is
    easier to justify, how might this attitude be
    changed? (p14)
  • Diazepam and phenytoin have multiple uses, so
    while magnesium sulfate might dominate on simple
    cost effectiveness comparison basis, what happens
    if there is a more complex cost effectiveness
    /organisational comparison?
  • Similar issues in, e.g., malaria vaccine cost
    effectiveness measures, since tackling malaria
    involves a package of measures
  • Wrong only to do cost effectiveness narrowly
    related to vaccine use
  • Ditto for TB interventions.

27
Cost effectiveness issues 4
  • It should be noted, however, that if only
    eclampsia were treated with magnesium sulfate
    (and not preeclampsia) the use of magnesium
    sulfate would be an extraordinarily
    cost-effective intervention. Only two eclamptic
    women would need to be treated to save one life
    because maternal deaths are almost halved with
    the use of magnesium sulfate.
  • There are potentially additional factors in
    cost-effectiveness equations that are not
    factored into the above calculations. The
    Jamaican experience, cited below, suggests
    overall cost savings because of a reduction in
    bed-days. (p11)
  • C.f. malaria/TB/HIV calculations where the
    economic costs to society are orders of magnitude
    higher when these sort of costs are measured.
  • Worth getting a better grasp on ALL avenues of
    cost effectiveness?

28
Cost effectiveness issues 5
  • Second-best thinking on cost effectiveness.
  • Unrealistic to imagine in all cases that we do
    not have to accept compromise and trade-off (even
    deaths versus other things).
  • In the vaccine world, it has recently become an
    almost rule of law that advocacy needs better
    cost effectiveness evidence and huge effort has
    gone into gathering it.
  • Lessons from other initiatives to develop and
    deliver health products?

29
Cost effectiveness issues 6
  • What opportunities exist to collaborate or
    piggy-back with related efforts such as overall
    maternal mortality reduction initiatives or
    projects aimed at reducing maternal-to-fetal
    transmission of HIV? (p14)
  • Again recent GFHR work
  • Plenty of practical examples in other areas. Any
    transferable lessons?
  • What is cost effectiveness evidence of this
    piggy-backing?
  • What past examples of piggy-backing worked? And
    why?

30
Monitoring/diagnosis issues 1
  • RCOG recommends monitoring patients receiving
    magnesium sulfate by regular assessment of the
    urine output, maternal reflexes, respiratory rate
    and oxygen saturation. (p3)
  • Careful monitoring of blood pressure and
    measurement of urine protein are required.
    Laboratory studies of blood count, liver
    function, and kidney function should be
    obtainedFurthermore, monitoring and treatment
    should continue postpartum as appropriate. (p3)
  • How costly is all this monitoring? How does it
    impact cost effectiveness and practicability of
    this intervention?

Re to RCOG, Royal College of Obstetricians and
Gynaecologists, The Management of Severe
Pre-Eclampsia. Guideline 2006 recommendations.
31
Monitoring/diagnosis issues 2
  • Monitoring of condition that is relatively
    infrequent, and this causes resistance to doing
    so (p4).
  • How easy is it to get compliance with monitoring
    when patient and practitioner are less informed
    about risk/costs/benefits?
  • Patient and practitioner perceptions of what is
    of value to them
  • MMV rice story
  • Patients asked why they did not turn up for
    malaria-related appointments. They explained they
    sat around for hours (at cost to them), only to
    be sent away almost immediately when seen by
    nurse/doctor. This generated a rumor of wasted
    time.
  • Better compliance when attendees were told a
    story they understood that is was like
    searching rice grains for bad ones. All the good
    grains need nothing. Only the bad need attention.
  • Lesson Manage expectations and educate even if
    it seems obvious to the experts what is
    happening.

32
Monitoring/diagnosis issues 3
  • How is cost effectiveness evidence impacted by
    diagnostics?
  • Besides, there is An insufficient number of
    qualified clinicians to monitor the use of
    magnesium sulfate or even to prescribe the drug
    in peripheral hospitals.
  • Again, lessons from other product fields. Those
    working on TB, malaria, and dengue (examples
    known to the author) realized at some point that
    cost and speed of product development and cost
    effectiveness of intervention and uptake were
    heavily impacted by state of diagnostics
  • Gates funded Foundation for Innovative New
    Diagnostics, FIND, to tackle some of these issues
    (for TB and malaria and others)
  • Are there diagnostic issues in the case of
    pre-eclampsia and eclampsia that affect cost
    effectiveness, that need addressing and may also
    have been overlooked?
  • Mindful that this may not be comparable with the
    above cases.
  • Re to RCOG, Royal College of Obstetricians and
    Gynaecologists,
  • The Management of Severe Pre-Eclampsia.
    Guideline 2006 recommendations.

33
Political/international organization processes?
  • What really drives flows of resources and
    priority-setting globally?
  • Pneumococcal vaccine (GAVI/G8), combined 1.8bn
    to solve about 1-2 of the total problem between
    now and 2030?
  • Evidence from distribution of resources across
    areas of RD?
  • Intellectual Property debates (e.g. recent WHO
    initiatives like CIPIH) Maybe IP-based debates
    are easier for advocacy groups to push for, than
    delivery debates pushed for by delivery groups?
  • Sustainability of funding flows/initiatives after
    the first big-hit. Many recent initiatives have,
    or shortly will come up against, financial
    sustainability issues. Does the need to sustain
    funding have impact on advocacy and delivery
    issues?
  • Crowding out of lower profile initiatives?
  • How does advocacy and the politics of provision
    really work?

34
THANK YOUComments and feedbackalways
welcomeandrew.farlow_at_oriel.ox.ac.uk
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