Maternal, fetal and neonatal mortality: lessons learned from historical changes in high income countries and their potential application to low-income countries

Maternal mortality

In most LIC, the major medical causes of maternal mortality, defined as deaths to
the mother during pregnancy or in the first 42 days after birth, are hemorrhage, hypertensive
diseases of pregnancy and various types of maternal infections 6],8]. Hemorrhage is often classified according to timing, i.e., occurring in the antepartum/intrapartum
or during the post-partum period. The most common antenatal/intrapartum cause is placental
abruption, while the most common cause of post-partum hemorrhage is failure of the
uterus to contract after delivery or uterine atony 8],9]. The most dangerous hypertensive disease of pregnancy is preeclampsia, which may
lead to a number of potentially deadly complications including strokes and seizures
(eclampsia) 10]. Maternal infection includes bacterial sepsis, HIV, malaria, syphilis, and various
other infections. Additionally, two other obstetric conditions are related to maternal
mortality from hemorrhage and infection. Obstructed or prolonged labor may lead to
maternal death from hemorrhage and infection – sometimes after uterine rupture. Women
who undergo unsafe abortion may also die from complications of hemorrhage and infection.

Stillbirth

Stillbirth, variably defined as deaths in utero from after 20 to 28 weeks gestation
– depending on local standards, often results from maternal complications 11]-13]. The most common maternal conditions leading to stillbirth include hypertensive diseases
of pregnancy, especially preeclampsia and eclampsia, placental abruption, and various
types of maternal infection, such as syphilis and malaria. Thus, most stillbirths
result from asphyxia prior to or during labor, often associated with hypertensive
diseases, abruption, obstructed or prolonged labor, and obstetric complications such
as breech presentation and umbilical cord accidents. Treatment of maternal conditions,
e.g., early delivery for preeclampsia, may reduce the associated fetal mortality but
increase the risk of prematurity. Placental lesions, especially necrosis and thrombosis,
but also placental signs of hemorrhage, are often discovered on placental histological
examination in cases of stillbirth and some authors attribute the majority of fetal
deaths to a placental abnormality 14],15].

Neonatal mortality

Neonatal mortality, defined as death to a live-born baby within 28 days of life, in
LIC is typically ascribed to three major causes: infection, asphyxia and prematurity
16]. The most common type of infections causing mortality are bacterial such as group
B streptococcus (GBS), often acquired during labor, but infections causing mortality
also may include malaria, syphilis, and tetanus 17],18]. Neonatal asphyxia is predominantly caused by maternal complications such as abruption,
or preeclampsia 19]. Among preterm infants, conditions that contribute to mortality include 1) respiratory
distress syndrome (RDS), 2) intraventricular hemorrhage (IVH), 3) necrotizing enterocolitis,
and 4) infections 7],20],21]. In summary, a majority of all neonatal deaths are associated with one of the maternal
or fetal conditions described above.

History of pregnancy outcome improvements in high income countries and evidence-based
interventions for low-income countries

Maternal mortality: history

Significant reductions in maternal, fetal and neonatal mortality in HIC and many MIC’s
have occurred during the last century. In these countries, until about 1935, maternal
mortality ratios ranged from 500 to 1000 deaths per 100,000 births, i.e., nearly 1%
of pregnant women died (Figure 1) 6],22]-24]. Until about 1935, this situation in many countries had remained essentially unchanged
for hundreds of years, although slow reductions in maternal mortality in Sweden have
been attributed to the introduction of trained midwives 22]. In recent years, many HIC have reported maternal mortality ratios of about 10/100,000
births or less 1].

Figure 1. Maternal mortality, 1900–2000, in select high-income countries. Adapted from Goldenberg 6].

Several papers have explored this reduction from 1935 through 1970–1980 6],22]-24]. Interventions responsible for the reductions included the introduction of prenatal
care and hospitalization for delivery (1920’s and 1930’s), antibiotics to treat infection
(late 1930’s and 1940’s), and uterotonics and blood transfusion (1940’s) (Figure 2). The management of preeclampsia/eclampsia steadily improved during the 1940’s to
1950’s with prenatal care to diagnose the condition (blood pressure measurements and
urine protein determination), hospitalization to monitor the condition, and a transition
from watchful waiting to immediate delivery for severe or progressing disease. With
antibiotics, blood availability, and improvements in anesthesia, cesarean sections
became safer and were more commonly used to terminate life-threatening pregnancies,
such as those with prolonged labor or eclampsia. Thus, beginning around 1935, introduction
of new, effective interventions were associated with significant decreases in maternal
mortality. As these interventions were implemented, first in high-income and then
in some middle-income countries, nearly a 99% reduction in maternal mortality was
observed in these settings.

Figure 2. Interventions associated with historical reduction in maternal mortality, United States,
1900–2000. Adapted from Johnson 2001 23].

Maternal mortality: evidence-based recommendations

Prevention of hemorrhage, the leading cause of maternal mortality, can be accomplished
through cesarean section for prolonged labor and the reduction of unsafe abortions
25],26]. For abortion-related complications, uterine suction or curettage, antibiotics, blood
and sometimes hysterectomy prevent maternal mortality 26]. Use of uterotonics, such as misoprostol or oxytocin at delivery, can reduce post-partum
hemorrhage associated with an atonic uterus 27]. The case fatality rate associated with hemorrhage may also be reduced through a
reduction in anemia, usually accomplished prenatally with iron and vitamin supplementation
28]. However, major reductions in mortality from hemorrhage usually occur with appropriate
treatment of hemorrhage once it occurs. Treatment varies with the cause of the hemorrhage
and may include surgery for lacerations or a ruptured uterus, manual removal, suction
or curettage for a retained placenta or placental fragments, uterotonics to treat
hemorrhage from an atonic uterus, and for antepartum hemorrhage due to a placental
abruption or previa, a cesarean section 9]. Hysterectomy (and sometimes other abdominal procedures) is the surgery of last resort
for many types of obstetric hemorrhage. Also for hemorrhage of any type, blood products
are often life-saving. An important message is that even within a single condition
such as hemorrhage, there are many causes requiring substantial provider skills to
assess the appropriate prevention and treatment. No single intervention is likely
to have a large impact on hemorrhage-related maternal mortality.

After hemorrhage, the most frequent cause of maternal mortality is hypertensive disease,
and particularly preeclampsia and eclampsia 10]. Prevention may be possible through maternal treatment with calcium and aspirin,
but effectiveness of these interventions remains uncertain. Women die from many complications
of preeclampsia/eclampsia including asphyxia during seizures, aspiration pneumonia,
strokes and cardiac, liver and kidney failure, as well as hemorrhage secondary to
clotting disorders and placental abruption 29]. Since preeclampsia is often asymptomatic until late in its course, diagnosing this
condition early is the key to saving maternal lives. Since the condition is generally
defined by hypertension and proteinuria, tests for both, repeated in prenatal care
throughout the second half of pregnancy are required to effectively diagnose this
condition. Once preeclampsia is diagnosed, close observation with delivery by induction
of labor or cesarean section for worsening disease is often life-saving. Magnesium
sulfate reduces initial and repeat seizures and may provide time to affect delivery
prior to new or recurrent seizures 30]. Thus, a combination of prenatal care to diagnose the condition and facility care
for delivery with labor induction and cesarean section capabilities are necessary
to reduce maternal mortality from this condition.

Infection is the third major killer of mothers 31]-33]. Malaria is an important cause of maternal death in endemic areas, and can be responsible
for maternal deaths both during acute malarial episodes and after the acute episode
due to its effect on maternal anemia 31]. Most important, however, are the bacterial infections of the uterus 32]. During and immediately after the delivery, the uterus provides an excellent culture
medium for bacteria, and uterine infections are very common. The use of non-sterile
delivery techniques, prolonged labor, and instrumentation including cesarean section
all increase the risk of infection 34]. Prevention of infection includes use of clean delivery sites, provider hand washing,
and avoiding prolonged labors and instrumentation whenever possible. Treatment generally
consists of the timely administration of appropriate antibiotics.

In summary, most maternal deaths can be prevented by decreasing the prevalence of
the conditions that cause the deaths or providing appropriate treatment for those
conditions. Since, with a few important exceptions, most complications leading to
maternal death cannot be predicted or prevented, care for these conditions must be
readily available to all women. Most maternal deaths occur during labor, delivery
and in the immediate post-partum period 6],24]. When the conditions causing maternal death are considered, it becomes clear that
the treatments for these conditions need to be readily available during labor and
after delivery. Few of these interventions are available in the home and unfortunately,
in most LICs, many of these interventions are not available in the clinics and even
in some hospitals. For these reasons, many have advocated for hospital deliveries,
with these interventions available 35],36].

Fetal mortality: history

In HIC, until about 1930, the fetal mortality rates generally ranged from 35 to 50/1000
births. In the recent Lancet Stillbirth Series, nearly all HIC reported current stillbirth rates of 5/1000 births
with several countries reporting rates as low as 2/1000, representing a reduction
of approximately 90% over time 37],38]. As with maternal mortality, the reduction in stillbirth began about 1935, continued
relatively rapidly until about 1980, and then has continued more slowly until the
present (Figure 3). Since the cause of death for a stillbirth is often less clear than for a maternal
death, defining the interventions responsible for the majority of the reduction is
more difficult. However, the interventions responsible for some of the reduction in
fetal death rates are clear 39]-41]. For example, in the 1920’s, syphilis reportedly accounted for up to 20% of US stillbirths.
Today in HICs syphilis is rarely a cause a stillbirth. Eighty years ago, in HIC, preeclampsia
and eclampsia were the major cause of fetal mortality, but today account for only
a small percentage of a much smaller number of stillbirths. Rh disease was until the
1960’s an important cause of stillbirth. With routine Rhogam (anti-D) prophylaxis
for Rh negative mothers, and fetal transfusion for severely affected fetuses, stillbirth
due to Rh disease is rare. Stillbirths associated with abruption also have been much
reduced. Monitoring the fetus for signs of asphyxia prenatally and during delivery,
using various techniques such as fetal heart rate monitoring, with delivery for signs
of distress, has reduced asphyxia-related fetal mortality. The high rates of cesarean
section and labor induction in many HIC occur in part to reduce risk of stillbirth.
Thus it appears that with appropriate care for the mother, stillbirth rates have been
reduced by up to 90%.

Figure 3. Historical stillbirth rates for high-income countries. Reprinted from Goldenberg, 2011 46].

Fetal mortality: evidence based recommendations

As noted, most stillbirths in LIC are caused by intrauterine asphyxia with a smaller
percentage due to infection and an even smaller percentage due to congenital anomalies.
Many of the maternal conditions discussed above lead to fetal asphyxia including prolonged
labor, preeclampsia/eclampsia and placental abruption. Pregnancy complications such
as growth restriction, abnormal presentations, multiple fetuses, and cord complications
also kill fetuses through asphyxia. Appropriate obstetric care including monitoring
for signs of asphyxia – often with cesarean section for fetal distress – can prevent
many stillbirths. Fetal deaths due to infection can in certain cases be prevented.
For example, diagnosing and treating maternal syphilis, preventing maternal malaria
with bednets and intermittent prophylaxis, and eliminating prolonged labor to reduce
asphyxia and bacterial chorioamnionitis, all have a role in reducing stillbirths.
With the possible exception of treatment for maternal GBS infection or membrane rupture,
maternal antibiotic administration has a smaller role, if any, in preventing stillbirths.
Since poor fetal growth is often associated with stillbirth, some studies suggest
that maternal nutritional support that increases fetal growth might result in a reduction
in stillbirths 28].

Neonatal mortality: history

Neonatal mortality in HIC has also fallen substantially in the last 80 years 42]. In 1935, the neonatal mortality rate was about 35/1000 live births and in recent
years the neonatal mortality rate in most HIC has been approximately 3-5/1000 live
births. The decline is related both to a decreasing prevalence of some conditions
and better treatment for others. About one-third of neonatal mortality is associated
with preterm birth. Because in HIC the incidence of prematurity has, if anything,
increased over the last three decades, reduction in the prevalence of preterm birth
is unlikely to be associated with the decreased mortality 20]. Figure 4 depicts the major advances in care for preterm infants, when they were introduced
and the proportion of this decrease likely due to these interventions. Beginning in
about 1960, treatment of RDS with oxygen, and later with various types of ventilation
support including continuous positive airway pressure (CPAP) and mechanical ventilation,
and still later, artificial surfactant, substantially lowered the death rate from
RDS 7]. In HICs beginning in the 1990’s, increasing use of maternal corticosteroids prior
to delivery for women at risk of preterm delivery substantially lowered the incidence
of RDS. The incidence of infection in preterm as well as term newborns was also reduced
with increased clean delivery practices and the use of antibiotics 43], saving many lives. Maternal treatment for syphilis and vaccination for tetanus also
contributed to the reduction of newborn infection-related mortality 44]. The incidence of newborn asphyxia was substantially reduced with better obstetric
care including monitoring for hypoxia prenatally and during labor, and use of cesarean
sections for the indication of fetal distress. Newborn resuscitation techniques improved
and treatment of asphyxia also reduced mortality 45]. Thus, as seen with maternal and fetal mortality, from about 1935 onward, neonatal
mortality rates significantly decreased in HIC.

Figure 4. Estimated reductions in RDS-associated mortality with various interventions, by approximate
year of introduction. Adapted from Kamath B 7].

Neonatal mortality: evidence based implications

As noted, neonates in LIC die from three major causes; asphyxia, infection, and preterm
birth. Asphyxia is best prevented; the same maternal interventions that reduce stillbirth
also reduce the prevalence of neonatal asphyxia 46]. Thus, appropriate care for women with obstructed or prolonged labor, abruption,
preeclampsia/eclampsia, or for fetal growth restriction will not only reduce stillbirths,
but also neonatal asphyxia and neonatal mortality. Neonatal resuscitation is also
important in reducing deaths of those infants born with mild asphyxia 46]. Care for newborns with significant asphyxia, including respiratory, temperature
and nutritional support, can save some additional lives. Thus, appropriate treatment
of maternal conditions as well as newborn resuscitation and neonatal care can have
a profound impact on neonatal deaths from asphyxia.

Preventing deaths from neonatal infection also involves multiple approaches, some
directed at the mother and some at the neonate. For example, preventing prolonged
labor, treating the mother’s syphilis, immunizing her against tetanus and giving antibiotics
in the face of maternal colonization with GBS or ruptured membranes will all likely
reduce neonatal infection and mortality. The use of sterile/clean techniques including
hand-washing at the time of delivery and in the newborn period, prophylactic antibiotics
– especially in preterm infants and appropriate cord care – now often with chlorhexidine,
especially for home births – also reduce neonatal infections and mortality 47]. For neonatal infections, antibiotic treatment often proves lifesaving. Thus, to
achieve substantial reductions in neonatal infection-related mortality, a variety
of maternal and newborn interventions are needed.

The predominant cause of preterm neonatal mortality is RDS, but preterm infants also
die from other causes including necrotizing enterocolitis, IVH and bacterial infection
20]. While there are few if any interventions that effectively prevent preterm births,
prevention of some of the above conditions associated with preterm birth is possible.
Depending on the setting, corticosteroids given to the mother in the days prior to
delivery may prevent 30% of RDS as well as necrotizing enterocolitis, IVH and neonatal
mortality 48]. For those neonates with RDS, oxygen, ventilatory support and surfactant can substantially
reduce mortality. Thus, a program for reducing mortality from preterm birth also has
maternal and neonatal components, and when they are applied appropriately, much of
the preterm neonatal mortality currently occurring in LIC can be eliminated.

Summary of evidence-based interventions to reduce mortality

The interventions needed to reduce maternal, fetal and neonatal mortality are thus
well known and there is every reason to believe that if these were made available
within a system of care to pregnant women and their newborns, pregnancy related mortality
rates in LIC should approach those in HIC 36]. These types of reductions have been demonstrated in several countries in transition
including China, Malaysia and Sri Lanka 1],2],5]. The most important question that arises is not which interventions should be introduced,
but how to make these interventions widely available with high quality of care in
low and middle income countries. All too often, studies suggest that while an intervention
may be available, it is performed on the wrong patients, performed poorly or too late.
Thus, not only the coverage of an intervention, but also the quality performance of
that intervention is crucial. Finally, it has become clear that introducing one intervention
at a time rarely reduces mortality significantly. Instead, developing an understanding
of the population that needs to be served and the capabilities within the system to
provide care to that population is an appropriate starting point in any geographic
area. Often termed “the systems approach” there is substantial evidence that defining
the population, the goals of that care, the resources and personnel available in the
clinics, hospitals, and in the home, and then creating a system of care – provides
the most success in reducing maternal, fetal and neonatal mortality 49]. In summary, to save the life of a mother, fetus or neonate with any particular condition,
the condition must either be prevented or be diagnosed and treated in an appropriate
and timely manner. Knowing the conditions that kill mothers, fetuses and newborns
and when and where they die is therefore crucial.

General recommendations

Based on the information detailed above, proposed lists of interventions appropriate
for low and middle-income countries to reduce maternal, fetal, and neonatal mortality,
with estimates of potential lives saved, have been proposed 36]. Figure 5, from the Lancet, estimates the number of maternal, fetal and neonatal lives saved in low-income countries
with various interventions, and emphasizes the importance of basic and emergency care
during labor and delivery. Since most maternal and fetal as well as many neonatal
deaths occur around the time of delivery as shown in Figure 650], the United Nations has promoted two strategies to reduce mortality: ensuring a skilled
birth attendant at delivery and ensuring prompt access to emergency obstetric care.
Ideally, all women would have access to essential obstetric care which includes intrapartum
monitoring with early detection and management or referral for complications [Table 1]. In this description, basic essential emergency obstetric care is comprised of 6
non-surgical functions including parenteral antibiotics, parenteral oxytocic drugs,
parenteral anticonvulsants, manual removal of the placenta, removal of retained products
of conception, and assisted vaginal delivery by forceps or vacuum extraction 51]. Neonatal resuscitation is often included in this proposed package. Comprehensive
emergency obstetric care would add blood transfusion and cesarean section to the list.
Staffing for basic emergency obstetric care would include at least two skilled birth
attendants available 24 hours a day, seven days a week assisted by trained staff.
Comprehensive emergency obstetric care would require staff trained to provide blood
and perform a cesarean section. Since saving many maternal, fetal and newborn lives
requires a cesarean section, timely access to this intervention is crucial to achieve
mortality rates comparable to those seen in high-income countries.

Figure 5. Potential maternal, fetal and neonatal lives saved by obstetric and newborn interventions. Adapted from Pattinson R, 2011 38].

Figure 6. Intrapartum-related maternal, fetal and neonatal mortality. Reprinted from Lawn et al. 53].

Table 1. Components of basic and comprehensive emergency obstetric care

Birth attendant capacity

Within any system of care, the capability of the birth attendant is crucial to reducing
maternal, fetal and neonatal mortality. In low-income countries, historically, most
often the birth attendant has been an unskilled or traditional birth attendant (TBA)
52]. For the most part, studies have shown that even with additional TBA training, the
maternal mortality rates do not decline substantially, although with training in resuscitation,
there may be some reduction in stillbirth and neonatal mortality 50],53]. For this reason, the World Health Organization (WHO) and other organizations have
recommended the use of skilled birth attendants for delivery. However, the training
and skills of these “skilled attendants” vary widely, and many cannot perform a cesarean
section, give blood or administer antibiotics, interventions often necessary to save
a life 52]. Even the ability of the most skilled attendant to save a life is limited if there
is no blood or antibiotics, or if the facilities necessary to do a cesarean section
are not available. While a full review is beyond the scope of this manuscript, it
should be obvious that in creating an effective system of care, great attention must
be paid to the skill level of the birth attendant and the circumstances in which that
attendant will attempt to provide life-saving care to the mother, fetus and newborn.

Data

In low-income countries, one of the major obstacles to program development aimed at
improving pregnancy related outcomes is lack of reliable data on these outcomes, the
causes of these outcomes and the coverage existing for the interventions that might
improve these outcomes. Without these types of data, and the ability for a hospital,
a geographic area, or a political district to compare their outcomes with other similar
entities, the likelihood that improvement will occur is much reduced 54]. Without the ability for these entities to compare current outcomes to those achieved
historically, the impact of newly introduced programs or interventions will not be
understood. Only with reliable data used to focus attention on continuous quality
of care improvement, is it likely that sustained improvement will occur. In virtually
every geographic area where reductions in maternal, fetal and neonatal mortality have
occurred, improvements in care and outcomes have gone hand in hand with the development
of data systems that capture outcomes, causes of poor outcomes and intervention coverage.