Landscape Analysis of Maternal and Perinatal Infections
The following Executive Summary is excerpted from a report prepared by PATH, June 2012.
Executive Summary
Introduction
Maternal, perinatal, and newborn infections are important yet under-researched and poorly controlled
contributors to developing-country mortality. The lifetime risk of maternal death for a woman in a
developing country may be more than 300 times greater than for a woman living in an industrialized
country. Africa and Asia account for the vast majority of maternal deaths globally, with sub-Saharan
Africa contributing 56 percent and South Asia 29 percent of the global total burden. In absolute numbers,
approximately, 287,000 women die each year from complications during pregnancy and childbirth.1
Additionally, up to 20 million women survive their pregnancy but suffer injury, infection, disease, and
disability outcomes that are largely preventable.2 Although maternal morbidity is generally poorly
understood and little-researched, Fortney and Smith (1996) estimated that the ratio of women with
morbidities to maternal mortality was 186:1 in Bangladesh and 251:1 in India.3 Similar to maternal
deaths, 98 percent of neonatal deaths occur in low- and middle-income countries (LMICs); however, the
figures are even more striking. Within the first 28 days of life, an estimated 3.3 million babies die
annually.4 Other estimates indicate that the total number of perinatal deaths, which groups stillbirths with
early neonatal deaths, is as high as 5.9 million deaths annually.5
The major causes of maternal mortality and morbidity are fairly well understood, with the largest
proportion of deaths accounted for by five obstetric causes, including hemorrhage, hypertensive disorders
often linked to eclampsia, septic abortion, obstructed labor, and puerperal sepsis. Maternal infections
(which include puerperal sepsis as well as infections incidental to and/or aggravated by pregnancy and
puerperium) are one of the most understudied yet important contributors to morbidity and mortality of
both the mother and neonate during the pregnancy, intrapartum, and early postpartum periods in
developing countries. Infections are implicated in 15 percent or more of maternal deaths, and 36 percent
or more of neonatal deaths.6 Estimates of perinatal and newborn deaths attributed to infection are underreported, as deaths associated with infection among premature and/or low-birthweight babies are often
recorded as deaths due to prematurity. Intrauterine infection is strongly associated with preterm birth7 and
is recognized as being one of the most important and potentially preventable causes of early preterm birth.
Infections are thought to be responsible for up to 50 percent of extreme preterm births of less than 28
weeks of gestation, while preterm birth associated with infection is rare beyond 34 weeks of gestation.
Low birth weight, closely associated with intrauterine infection, is the underlying factor in 60 to 80
percent of neonatal deaths.8 Furthermore, maternal infection has been identified as an underlying risk
factor of intrapartum hypoxia and related sequelae.9
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A broad array of pathogens contributes to maternal infections that have heterogeneous modes of
transmission, treatment requirements, and sequelae for mother and baby. The major categories of
pathogens that impact mother and baby are sexually transmitted infections (STIs), vaginally acquired nonsexually transmitted infections, urinary tract infections (UTIs), and environmentally acquired Gramnegative bacteria acquired during labor and delivery. Risk and outcomes associated with these groups of
pathogens are often modulated by co-infection with other diseases such as HIV, tuberculosis, malaria, and
viral hepatitis in these women. Although in many cases the reporting systems are weak and subject to
inaccuracies in areas with high perinatal and neonatal mortality, it is clear that infections, including
sepsis, pneumonia, tetanus, and diarrhea, account for the largest proportion of neonatal deaths globally.
In high-income countries, early onset neonatal infection (during the first week of life) is often attributed
to maternal infections of the genital or urinary tract, while those that occur after the first week of life are
often attributed to environmentally acquired infections either from the home or nosocomially.10
Furthermore, vaginally acquired nonsexually transmitted infections, such as bacterial vaginosis, are
implicated in the pathogenesis of premature birth. In LMICs a review of the available evidence presents a
different clinical picture for early-onset infections during the first week of life—an overwhelming
majority of Gram-negative organisms and a high frequency of Staphylococcus aureus.11,12 This pattern of
pathogens suggests that early infections in the first week of life in LMICs may be acquired predominantly
from the hospital or community environment due to poor hygienic practices during delivery and postnatal
care, rather than from maternal exposure as conventionally understood in high-income countries. Beyond
the first week, the most common isolates from community-acquired infections are E. coli; group B
Streptococcus; and S. aureus, as well as Streptococcus pneumoniae, S. pyogenes, and Salmonella
species.12
Although data from LMICs are limited in both quality and quantity, the available information speaks to
the need for state-of-the-art microbiologic or molecular diagnostics to reliably define the etiology of
serious infections and to devise community-based tools that lead to better control of these infections in
high-mortality low- and middle-income settings. In the developed world, diagnostic tools are laboratorybased, allow for rapid return of results in some cases, and can have impact on control of pathogens
associated with poor maternal and neonatal health outcomes. Unfortunately, the currently available
diagnostic tools and the systems that deliver them are not configured to provide actionable information
for effective care of mothers and babies in low-resource settings. Additionally, physical proximity to
health services; the lack of qualified staff; cultural beliefs among families, especially in low-income
areas; and financial barriers to accessing health care may inhibit efficient uptake of services which could
prevent maternal and neonatal death.
The Integrated Management of Pregnancy and Childbirth (IMPAC) calls for an integrated policy,
technical, and managerial approach to maternal and neonatal survival and health improvement.13 Central
to the IMPAC strategy is the rational provision of effective disease prevention and health outcome,
detection and management, and treatment tools during a continuum of care that begins prior to conception
and continues through childbirth for mother and baby. This strategy requires a movement toward earlier,
more frequent, and more impactful interactions between trained clinicians and mothers, and subsequently
their babies, and investment in the health system, healthcare workers, and in encouraging pregnant
women to access services. However, severe human resource constraints in many LMICs, especially in
rural areas and among impoverished or ethnic or religious minority populations, prevent poorer mothers
and newborns from accessing care by trained clinicians, contributing to remarkable inequities in health
outcomes within individual countries. Improved diagnostics that target biomarkers for pathogens and/or
the specific and relevant host immune responses in developing countries may improve the ability of
health workers to manage infections at or near the point of care with resultant improvement in equity. It is
unclear at present what combination of new diagnostic and therapeutic tools, human resources, timing,
and setting of patient and health worker interaction will provide the most impact in terms of mortality and
morbidity reduction.
The identification and management of maternal infections has important implications for pregnancy
outcomes for both mothers and neonates. In addition to the puerperal sepsis and serious infections, with
resultant maternal death and morbidity, maternal infections during pregnancy are implicated in the
pathway to preterm births, stillbirths, and early infection of preterm and term neonates. Maternal
mortality from infection remains high in developing countries due to inadequate quality case management
and infection control. In both developing and developed countries, there is limited understanding of the
role of early infection during pregnancy in eventual pregnancy outcomes for mothers and babies.
Diagnostics that detect infection early through direct pathogen detection, specific host response, or
markers of immune system regulation; guide treatment; and expand care opportunities are lacking in most
clinical settings in developing countries.
This landscape exercise sought to achieve the following three primary objectives:
1. To consolidate and evaluate global evidence on the burden of pathogens associated with serious
maternal and perinatal infections and identify promising diagnostic tests and platforms for
detection of these infections.
2. To analyze country-level factors that support or inhibit the uptake of maternal and neonatal
infection diagnostic control measures.
3. To integrate results from global evidence and country-level research and identify opportunities,
barriers, and gaps in knowledge around promising diagnostics that support control of maternal
and perinatal infections.
To this end, we evaluated and reconciled three bodies of evidence: (1) epidemiological evidence on
priority pathogens and their association with other important infectious causes of morbidity and mortality
(e.g., HIV, TB, malaria, hepatitis); (2) academic, commercial, and clinical evidence on potentially
impactful diagnostic, management, and treatment modalities; and (3) country-based contextual evidence
on the needs, feasibility, and acceptability of existing and novel maternal, perinatal, and neonatal
infection management approaches.
Project activities began in 2010 and spanned a two-year period. They included a desk-based literature
review around the pathogen and diagnostic landscape and primary research in two high-burden countries
(Bangladesh and Uganda), one low-HIV-prevalence setting, and one high-HIV-prevalence setting.
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Collaborating partners included the Seattle-based Global Alliance for the Prevention of Prematurity and
Stillbirth (GAPPS), International Center for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), and
the Makarere University School of Public Health, Uganda.
This report includes the results of three separate studies designed to address the specific objectives listed
above. Chapter 1 provides an overview of the etiology and incidence of maternal infections to identify
opportunities and challenges for screening, treatment, and prevention. Chapter 2 presents findings from a
literature review of current and potential diagnostic technologies for the syndromes and pathogens
delineated in Chapter 1. Chapter 3 details the results of primary research undertaken in Bangladesh and
Uganda around community and provider receptivity and perceived barriers to potential diagnostic testing
during the continuum of care. Additionally, at the request of the Bill & Melinda Gates Foundation, some
exploratory work was undertaken around the commercial feasibility and health impact of “bundling”
diagnostics. Chapter 4 presents findings of a landscape study of manufacturers producing rapid
diagnostic tests for use during antenatal and peripartum care. Chapter 5 provides the results of a
preliminary modeling exercise to assess the scope and potential of improved antenatal diagnostic testing
for HIV and malaria in two sub-Saharan African settings.
Summary of Findings and Conclusions
Landscape Review of Serious and Life-Threatening Maternal Infections
Serious infections during pregnancy are an important preventable cause of maternal and neonatal
mortality and morbidity. Our literature review revealed significant gaps in the understanding of the
microbiology of life-threatening maternal infections in low-resource settings, and the need for rapid
recognition and treatment call for clinical, syndromic management of infections. Five life-threatening
clinical syndromes account for the majority of maternal deaths and adverse maternal and neonatal
outcomes. These include chorioamnionitis and postpartum endometritus (together referred to as puerperal
sepsis), pyelonephritis, septic abortion, and rapidly progressive soft tissue infections. These syndromes
occur at distinct time points during pregnancy, offering specific opportunities for “bundled interventions”
for screening, prevention, and treatment. To facilitate these needs we recommend:

Improved diagnostics that target biomarkers for pathogens and/or specific and relevant host
immune response to improve the ability of health workers to recognize and to manage infections
at or near the point of care.

Point-of-care screening for selected pathogens across the continuum of pregnancy care.

Development and validation of context-specific diagnostic and treatment algorithms suitable for
both community and facility health care workers.

Ongoing microbiologic surveillance surveys to identify shifts in microbial flora or emergence of
microbial resistance.
Nonobstetric infections, including malaria, HIV, tuberculosis, and curable STIs are also recognized as
significant contributors to maternal morbidity and mortality.
Literature Review of Diagnostics Technologies for Common Pathogens Associated With
Maternal Infection During Pregnancy
Our landscape review of the different diagnostic technologies, their performance, and the types of
specimens required to identify the common pathogens associated with maternal infections during
pregnancy focused on the diagnostic methods used to detect the primary pathogens associated with UTIs,
septic abortion, chorioamnionitis, endometritis, soft tissue infection, and the risk of vertical transmission
of group B Streptococcus. While rapid diagnostic tests are available for the diagnosis of maternal
infections and syndromes, they generally require confirmatory testing. The available literature is heavily
weighted in favor of primary pathogens of concern to developed world health care, where infrastructure,
trained staff, and good logistics permit technology of much greater complexity or procedures that would
be high-risk in low-resource settings (e.g., amniocentesis). Fully integrated technologies are emerging for
nucleic-acid based diagnosis, but these are currently prohibitively expensive and infrastructure-dependent,
missing the majority of the intended population in this project. As with many other diseases, biomarkers
have potential, but the identification of optimal ones to strongly indicate infection is difficult for a variety
of reasons. Some potential technologies were identified as having potential, but these are still in
development and none are expected to be on or close to market in the next three years. Given the fact that
diagnostics, including rapid diagnostic tests, for STIs were covered by other work in our project, they
were not a focus of this review.
Landscape Assessment of Community and Providers
Findings from our landscape assessment of providers and communities indicate that women seek
antenatal care (ANC) with a formal provider at least once in their pregnancy. Return visits are rare unless
dictated by an emergency. Where there is a strong perception of risks and benefits of diagnostic testing, as
in the case of HIV in Uganda, it often becomes a major driver for formal ANC. Traditional birth
attendants continue to be the provider of choice for labor and delivery care. The postpartum period
constitutes an important cultural milestone and is generally viewed as being outside the continuum of
care, with little perceived need for biomedical care. Husbands and mothers-in-law significantly shape
women’s behaviors around care seeking. Cost as well as physical and cultural access to facilities act as
significant barriers to care seeking. Diagnostic testing during ANC was generally viewed positively;
however, women and their families would prefer that any proposed diagnostic tests be administered by
skilled and trained providers. Communities expressed reservations in providing biological specimens
during labor and the immediate postpartum period. Families expressed almost universal preference for
immediate turnaround of results, though some concerns were expressed about “quality” with too rapid a
return of results.
Regarding care provision, providers currently rely on physical examination and signs and symptoms for
diagnoses. While providers are familiar with the concept of diagnostic testing, there is limited use of
diagnostics in maternal health care, with HIV testing in Uganda being a notable exception. Providers had
strong recognition of logistic limitations, and while they saw a definite advantage of diagnostic testing in
terms of patient management, they also expressed reservations about the additional workload this would
necessitate.
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Findings suggest diagnostic testing may provide an opportunity to optimize ANC by utilizing bundled or
multiplexed tests that can be administered together to optimize what may often be a single antenatal
contact. This would have the added advantage of providing better perceptions of the quality of care
received and potentially additional uptake of follow-on ANC.
Landscape Analysis of Maternal and Perinatal Infection Diagnostic Manufacturers
At the request of the Foundation, PATH also conducted a landscape study of potential manufacturing
partners to identify and engage diagnostics companies capable of producing improved infectious disease
rapid diagnostic tests for use during antenatal care in low-resource settings. Secondary research and
contact with more than 50 potential partner companies indicate that the most impactful way forward is in
developing serology test bundles for HIV, malaria, syphilis, and/or hepatitis B. Not only is there a wide
array of capable companies and technologies in this space, but there appear to be clear paths forward to
introduce impactful products in the near term. The landscape is less promising for UTIs, where few
products are available in the short term to meet all needs of women in low-resource settings. A small but
well defined group of tests exists for anemia, with known issues related to performance and logistics.
Several available tests are available for premature rupture of membranes diagnosis, but it is unclear how
to gauge their value against the high costs involved. More work around analyzing current needs is
required to gauge the impact of a new product. It seems clear that a single manufacturer or product will
not necessarily best serve every low-resource market or region. A strategy that incorporates multiple
products suited to specific markets, aggressively implementing short-term solutions while developing
longer-term solutions, would be appropriate. Finally, there is a clear need for an overall commercial plan
to define the markets in the context of the product concepts. As a next step, knowledge gaps around the
specific clinical needs in the regions of interest, specific product criteria, and market information need to
be filled in order to construct a clear and attractive business case that would be the foundation for
negotiations with manufacturing partners.
Modeling the Potential Impact of Improved Diagnostic Testing During Pregnancy
Preliminary modeling was undertaken in two geographical settings—Mali in West Africa, in which
malaria prevalence is high but HIV prevalence is low, and Malawi in Southern Africa, where both malaria
and HIV prevalence are high. For HIV, results demonstrate that there remain large numbers of women
attending ANC who are HIV-positive but have not received an HIV test, and hence there is scope to
improve universal HIV testing with improved diagnostics. The potential impact of improved diagnosis on
maternal life-years saved and in preventing onward transmission to infants is greatest in rural areas due to
the large number of women residing in such areas. For malaria, the current rates of uptake of malaria
testing depend on access to ANC, which we found varied in the two countries. In Malawi, where
attendance at ANC is high, there was substantial opportunity to increase diagnostic testing and treatment
or prophylaxis. In Mali, while the medical benefits of improving diagnosis and treatment remain high,
access to ANC first needs to be improved, particularly in rural areas, where the malaria burden is the
highest but attendance at ANC remains low. In countries with high HIV prevalence, the risk of malaria
co-infection during pregnancy can be substantial. In Malawi, we found women who did not receive the
recommended malaria intervention during their previous pregnancy to be more likely to be HIV-positive,
with a large proportion of these women being unaware of their HIV status. Thus, improved combined
diagnosis of HIV and malaria in this setting has significant potential to improve health outcomes.
1
UNFPA, UNICEF, WHO, World Bank (2012) Trends in Maternal Mortality: 1990 to 2010. Available at:
http://www.unfpa.org/webdav/site/global/shared/documents/publications/2012/Trends_in_maternal_mortality_A41.pdf. Last accessed June 11, 2012.
2
UK All Party Parliamentary Group on Population, Development and Reproductive Health. Better Off Dead? A
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3
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8
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13
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