Maternal Mortality in The United States - Trends and Opportunities For Prevention

Annual Review of Medicine
Maternal Mortality in the

United States: Trends and
Opportunities for Prevention
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Annu. Rev. Med. 2023.74:199-216. Downloaded from www.annualreviews.org
Siwen Wang,1 Kathryn M. Rexrode,2 Andrea A. Florio,1

Janet W. Rich-Edwards,3,4 and Jorge E. Chavarro1,3,4
1
Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University,
Boston, Massachusetts, USA; email: jchavarr@hsph.harvard.edu
2
Division of Women’s Health, Department of Medicine, Brigham and Women’s Hospital and
Harvard Medical School, Boston, Massachusetts, USA
3
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard
University, Boston, Massachusetts, USA
4
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s
Hospital and Harvard Medical School, Boston, Massachusetts, USA
Annu. Rev. Med. 2023. 74:199–216 Keywords

The Annual Review of Medicine is online at
maternal mortality, disparity, preconception health, preconception
med.annualreviews.org
counseling, adverse pregnancy outcomes
https://doi.org/10.1146/annurev-med-042921-
123851 Abstract
Copyright © 2023 by the author(s). This work is
Maternal mortality is unusually high in the United States compared to other
licensed under a Creative Commons Attribution 4.0
International License, which permits unrestricted wealthy nations and is characterized by major disparities in race/ethnicity,
use, distribution, and reproduction in any medium, geography, and socioeconomic factors. Similar to other developed nations,
provided the original author and source are credited.
the United States has seen a shift in the underlying causes of pregnancy-
See credit lines of images or other third-party
material in this article for license information. related death, with a relative increase in mortality resulting from diseases
of the cardiovascular system and preexisting medical conditions. Improved
continuity of care aimed at identifying reproductive-age women with
preexisting conditions that may heighten the risk of maternal death, precon-
ception management of risk factors for major adverse pregnancy outcomes,
and primary care visits within the first year after delivery may offer opportu-
nities to address gaps in medical care contributing to the unacceptable rates
of maternal mortality in the United States.
199
INTRODUCTION
The World Health Organization (WHO) defines reproductive health as “a state of complete
physical, mental and social well-being and not merely the absence of disease or infirmity, in all
matters relating to the reproductive system and to its functions and processes” (1). Reproduc-
tive health requires multidisciplinary care across the life course, beyond the narrow window of
pregnancy and traditional field of obstetrics. Internal medicine has an important role to play in
maternal morbidity and mortality. Recent research has highlighted the role of chronic disease sta-
tus before pregnancy in determining maternal mortality risk (2–20), as well as the implications
of adverse pregnancy outcomes (APOs) for long-term maternal health (21–25). As women play
increasingly diverse roles in society, women’s health is more important than it has ever been in
history, demanding improved understanding of sex-specific risk factors contributing to morbidity
and mortality.
Maternal mortality has been widely used as a measure to assess quality of care and advances in
medical care of women. It is traditionally considered mainly a challenge for developing countries,
but the United States is one of only two countries worldwide to report a significant increase in
maternal mortality since 2000 (26). In the United States, more than 60,000 women experience life-
threatening maternal morbidity each year, resulting in more than 700 pregnancy-related deaths
annually (Figure 1a), with significant racial, geographical, and socioeconomic disparities that have
persisted over decades (27–29).
Emerging initiatives are under way to reduce the unacceptably high maternal mortality and
morbidity rates in the United States. Strategic plans focus on improving surveillance, screening,
and healthcare delivery to address adverse events that have a seemingly immediate effect on ma-
ternal mortality during pregnancy and the perinatal period (27). Less attention has been paid to
the preconception period, which is a critical time window for appropriate interventions targeting
biological, medical, and behavioral risk factors to reduce risks of future pregnancy complications
(30). Similarly, the time period beyond the initial 6 weeks after delivery is often overlooked, though
it has been increasingly documented as an important period of increased mortality in the United
States and other developed nations (31). The importance of health during and immediately after
pregnancy notwithstanding, it is crucial to remember that women’s health is not limited to preg-
nancy health. Reproductive traits and events throughout the reproductive years, including the
timing and pattern of menses and medical complications of pregnancy, have a long-term impact
on the health of women (21–25, 32, 33).
This review describes the leading causes of disparities in maternal mortality in the United
States and challenges in addressing them. It also highlights opportunities for prevention and early
identification of high-risk women, focusing on the periods before and after pregnancy as important
assessment and intervention points to improve women’s overall health across the lifespan.
MATERNAL MORTALITY
Maternal mortality rates nearly tripled in the United States between 1990 (8.0 deaths per 100,000
live births) and 2019 (20.1 deaths per 100,000 live births) (29, 34). The COVID-19 pandemic
further exacerbated this trend. During the first year of the pandemic, maternal mortality con-
tinued to increase across all segments of the population, reaching 23.8 deaths per 100,000, but
it increased more steeply among women of color (29), mirroring a similar pattern of maternal
mortality observed in the 2009 H1N1 pandemic (35). As US maternal mortality has increased,
the distribution of causes of pregnancy-related deaths has shifted. Compared to the 1990s, tra-
ditional causes of maternal mortality [such as hemorrhage, hypertensive disorders of pregnancy
200 Wang et al.

a Delivery b
Maternal mortality per 100k live births

30
Pregnancy 6 weeks 1 year
25
Maternal deaths (mortality): deaths from health problems related to pregnancy
20
Pregnancy-related death: deaths from health problems related to pregnancy 15
Pregnancy-associated death: deaths from conditions unaffected by pregnancy 10
0
1990 1995 2000 2005 2010 2015
Year
High socio-demographic index Western Europe

High income average Australasia
USA Canada
c High-income Asia Pacific
100.00
90.00
Proportion of deaths within period
80.00 Unknown
Other noncardiovascular medical conditions
70.00
Other cardiovascular conditions
60.00 Cardiomyopathy
Cerebrovascular accidents
50.00 Anesthesia complications
40.00 Thrombotic pulmonary or other embolism
Hypertensive disorders of pregnancy
30.00 Amniotic fluid embolism
20.00 Infection
Hemorrhage
10.00
0.00
During Day of 1–6 days 7–42 days 43–365 days Total
pregnancy delivery postpartum postpartum postpartum
50 South
d AR
45
Maternal mortality per 100k live births
KY
40
AL
35
Northeast OK Midwest West
30
GA
NJ TN LA
25 SC IN
AZ
NY
20 TX
Overall MA
VA FL MO MI
WA
15 PA MD OH
NC CA
10 IL
0
(Caption appears on following page)
www.annualreviews.org • Maternal Mortality in the United States 201
Figure 1 (Figure appears on preceding page)
(a) Definitions of maternal deaths, pregnancy-related deaths, and pregnancy-associated deaths (data from 35). (b) Maternal mortality in
high-income countries, 1990–2015 (data from 31). (c) Maternal mortality in the United States in relation to the end of pregnancy and
overall, 2011–2015. Cause of death categories are mutually exclusive (data from 39). (d) Maternal mortality within 42 days of
termination of pregnancy, by state, 2018 (data from 49).
(HDPs), thromboembolism, and anesthesia complications] have steadily declined, whereas deaths
due to diseases of the cardiovascular system (peripartum cardiomyopathy, myocardial infarction,
and cerebrovascular conditions) and other medical conditions (e.g., endocrine, hematologic, im-
munologic, and renal) have increased (36). In the past decade, almost one in three maternal deaths
in the United States was due to cardiovascular events (37). The majority of pregnancy-related
deaths now take place in the postpartum period; deaths taking place after 42 days (6 weeks) post-
partum now account for approximately one in five maternal deaths (38–40). In this last group,
most deaths are a result of peripartum cardiomyopathy (∼40%), other diseases of the cardiovas-
cular system (∼15%), and other medical conditions (∼15%) generally considered to be partially
preventable (38–40) (Figure 1c). Although the high rate of maternal mortality in the United States
is an anomaly among developed nations (31) (Figure 1b), the shift in the underlying causes of death
away from obstetric complications and toward a greater contribution from diseases of the cardio-
vascular system and other chronic conditions is also observed in other developed economies (31).
Several factors may contribute to the changing epidemiology of maternal mortality. Improvements
in obstetric and prenatal care have reduced perinatal mortality (41). Population-wide increases
in delayed childbearing and obesity (35, 42) not only contribute to a higher rate of pregnancy-
specific pathology (43–46) but also increase the rate of chronic medical conditions among women
of childbearing age.
Lack of standardized, consistent, and integrated obstetric practice (47), lack of community-
based care (28), and pervasive racial and socioeconomic health disparities (27, 48) are additional
factors that may contribute to the high maternal mortality rates in the United States relative to
other developed nations. Notably, there is substantial state-level variation in maternal mortality
(49) (Figure 1d). Besides differences in the distribution of demographic and medical risk factors,
disparities across states may also reflect differences in social and political factors, including state-
level policies influencing access to reproductive health services and medical insurance, as well as
differences in healthcare infrastructure between states (48).
The most pronounced and long-standing disparity in US maternal mortality is by race/
ethnicity, which has persisted over time, regardless of age and socioeconomic status (37). Black
and American Indian/Alaska Native women consistently experience 2–3 times higher pregnancy-
related mortality ratios than do White, Hispanic, and Asian/Pacific Islander women (37). This
difference to some extent reflects growing differences in behavioral and medical risk factors for
poor pregnancy outcomes by race/ethnicity (37, 50). Other contributing factors include but are not
limited to community (housing, access to transportation), healthcare (treatment decisions, qual-
ity of care, continuity of care, management of chronic diseases, racial bias in healthcare delivery),
patient/family (genetic susceptibility, medical knowledge, adherence to medical regimens, family
support, family structure, stress levels), and system-wide factors (healthcare coverage, access to
care, case coordination, racial discrimination) (39, 51). Studies have also revealed an age-related
racial gap in which the maternal mortality disparity widens drastically starting in the mid to late
twenties. This indicates a more rapid deterioration of reproductive and overall health during the
prime childbearing years among US Black women, the “weathering effect” (37, 51). Race/ethnicity
disparities are also tied to different causes of pregnancy-related death. For instance, maternal
deaths among Black and American Indian/Alaska Native women are disproportionately due to
202 Wang et al.

cardiomyopathy and other chronic medical conditions (37). Although causal attribution for these
disparities is not entirely clear, they are likely to reflect, at least in part, disparities in socioeconomic
and physical environment and healthcare access across the life course.
Despite structural issues, racial disparities can be improved with medical interventions specif-
ically aimed at decreasing maternal mortality. In 2021, the US Preventive Services Task Force
(USPSTF) and the American College of Obstetricians and Gynecologists (ACOG) updated rec-
ommendations regarding the use of low-dose aspirin (LDA) (81 mg/day) for the prevention of
preeclampsia (52, 53) after 12 weeks gestation among women at high risk of developing preeclamp-
sia. Both organizations recommended LDA for Black women, while noting that Black race, as a
risk factor for preeclampsia, is a proxy for racism instead of representing biological effects of
race (52, 53). This recommendation is notable as a preventive pharmacological intervention with
the goal of addressing a societal risk factor, but also as a concrete treatment for optimizing pre-
natal care with the goal of decreasing maternal mortality. Although the ACOG and USPSTF
recommendations are limited to pregnancy, secondary analyses of randomized trials suggest that
(a) preconception initiation of LDA may result in better pregnancy outcomes, particularly among
women of low socioeconomic status and women with metabolic syndrome (54, 55), and that
(b) starting LDA preconception may reduce risk of pregnancy loss (56). Although replication of
these findings is needed, they are consistent with the more general idea that interventions aimed
at preventing APOs and their long-term consequences may offer additional benefits when started
before conception.
Regardless of the complex causal structure underpinning the high rates of maternal mortality
in the United States, its shifting epidemiology demonstrates that maternal mortality is no longer
a discipline-specific issue confined to obstetrics. Instead, reducing maternal mortality requires
integrated and continued care that spans the preconception period, pregnancy, and the period
after delivery. At the two ends of this continuum, expertise of primary care providers and internists
may be particularly useful in identifying and addressing issues that could result in a mother’s
premature death.
PREPREGNANCY HEALTH, ADVERSE PREGNANCY OUTCOMES,

AND MATERNAL MORTALITY
The shift in underlying causes of maternal mortality suggests that some of these deaths could be
prevented by screening for and management of preexisting medical conditions. It is critical for
primary care providers to identify modifiable contributors of maternal mortality, ideally before
pregnancy. The preconception period may represent a particularly effective period for preven-
tive interventions, as motivation to optimize health in anticipation of pregnancy is particularly
high (57). A key limitation in operationalizing this opportunity is the difficulty of identifying the
preconception period and the specific interventions that are likely to have a positive impact on
health during pregnancy and beyond. Uniformly screening individuals of reproductive potential
with the ACOG recommended question “Would you like to become pregnant in the next year?”
provides an opening for preconception care (30). Pregnancy intention assessed by this question
correlates with the desire to avoid pregnancy (58), but its ability to identify women who may be-
come pregnant is unclear. A similar question appears to distinguish women according to their
1-year probability of pregnancy. Pregnancy rates over 1 year of follow-up among participants in a
nationwide study who reported whether they were “actively trying to get pregnant,” “not actively
trying but I may become pregnant within the next year,” or “not trying and don’t think I will be
pregnant within a year” were 45%, 28%, and 1%, respectively (59).
In terms of preconception care, both ACOG (30) and WHO (60) recommendations include
bringing patients up to date in vaccination schedules; optimizing management of chronic diseases

present before pregnancy, including review of medications that may be teratogenic or pose other
risks during pregnancy; providing adequate micronutrient supplementation; discouraging smok-
ing and recreational drug use; and encouraging the adoption of lifestyle habits including healthy
diet, exercise, and weight management (Table 1).
Chronic Diseases
The frequency of chronic disease–related pregnancy complications in the United States has paral-
leled trends in delayed childbearing and increased prevalence of obesity and metabolic syndrome
(35, 42). Chronic diseases prior to pregnancy—including hypertension, type 2 diabetes, heart
disease, chronic kidney disease, systemic lupus erythematosus, asthma, and thyroid disease—are
associated with higher risk of most APOs (2–20, 61–64) (Table 2). Furthermore, women who have
more than one chronic condition have a nearly threefold higher risk of severe maternal morbidity
and mortality compared to those without prepregnancy morbidity (65).
The identification and management of preexisting heart disease are of particular importance,
given the increased cardiovascular demands of pregnancy itself and the increasing contribution
of diseases of the cardiovascular system to pregnancy-related death. In-depth practice guidelines
for the management of heart disease in pregnancy are discussed elsewhere (66). Briefly, practice
guidelines emphasize the importance of identifying cardiac pathology and relevant family history
most likely to result in hemodynamic destabilization and significant morbidity during pregnancy,
including structural defects (e.g., congenital heart defects, valve disease), arrhythmias, and func-
tional impairment. Screening for mutations in MYH7, which is linked to cardiomyopathy, may be
considered. Identification of any of these issues should result in a cardiology consultation and the
establishment of a pregnancy heart team comprising the obstetrician, the primary care provider,
and a consulting cardiologist, with increasing involvement of cardiology, maternal–fetal medicine,
and other medical and obstetric subspecialists as necessary (66).
Despite high consistency across guidelines recommending preconception management for
women with preexisting diseases, data on the effectiveness of preconception interventions are
scarce. Evidence from observational studies suggests, however, that preconception education of
women with established diabetes results in meaningful reductions in pregnancy complications
(67). Preconception control of hyperglycemia could result in a significant reduction in HbA1c
in the first trimester and lower the risk of preterm birth and congenital abnormalities (68).
Whether similar benefits could be achieved by active preconception management of other chronic
conditions is uncertain.
Lifestyle Factors
In addition to management of chronic conditions, addressing behavioral and lifestyle risk factors
during the preconception period is key to pregnancy health. There is universal agreement that
use of alcohol, tobacco products, and illicit drugs during the preconception period and pregnancy
must be discouraged on the basis of evidence linking these to APOs (30). There is less consensus
about the role of other lifestyle factors in preventing APOs.
Prepregnancy weight management. In 2018, ∼40% of US women of reproductive age had obe-
sity (69), defined as a body mass index (BMI) over 30 kg/m2 . More than half of women who entered
pregnancy did so with overweight or obesity (70). Prepregnancy overweight and obesity are well-
documented risk factors for a wide range of adverse pregnancy and neonatal events including
pregnancy loss, gestational diabetes mellitus (GDM), preeclampsia, cesarean delivery, and post-
partum hemorrhage (44, 45). A 10% increase in prepregnancy BMI was associated with at least a
10% higher risk of preeclampsia, GDM, preterm delivery, and stillbirth (46).
204 Wang et al.

Table 1 Recommendations during the preconception period by the American College of Obstetricians and
Gynecologists (ACOG) and World Health Organization (WHO)
Topic ACOG recommendations WHO recommendations Comments
Immunization Annual assessment for tetanus Routine immunization against None
toxoid, reduced diphtheria vaccine-preventable infectious
toxoid, and acellular pertussis diseases, including rubella,
(Tdap); tetanus, and hepatitis B
measles–mumps–rubella; Complete COVID-19 vaccine
hepatitis B; and varicella series, including booster doses, as
Annual influenza vaccination recommended by local health
Complete COVID-19 vaccine authorities
series
Chronic conditions Optimal management before Screening and management of Identification and optimal
pregnancy chronic conditions management of preexisting
Review of medication that may Counseling about medications that chronic conditions
affect reproduction and may have teratogenic risks Review of medications and
pregnancy identification of potential
teratogens
Sexually transmitted Screening and counseling Screening and education None
infection
HIV Antiretroviral therapy Antiretroviral prophylaxis (therapy) None
Reduction of risk of perinatal Reduction of risk of perinatal
transmission transmission
Genetic conditions Counseling and screening Counseling and screening None
Other infectious Counseling about potential None None
diseases exposure to infectious
diseases, such as Zika
Lifestyle: body weight Achievement and maintainance BMI in normal range Lifestyle or surgical
of body mass index (BMI) in interventions to maintain
normal range healthy BMI
Prevention of long-term weight
gain by adoption of healthy
lifestyle
Lifestyle: nutrition Folic acid and multivitamin Adequate intake of micronutrients No clear recommendation of
supplement what constitutes a healthy diet
Dietary quality
Lifestyle: physical Regular physical exercise Promotion of exercise Existing data do not suggest
activity (exercise moderately at least harms associated with physical
30 min/day, 5 days/week, for activity
a minimum of 150 min
moderate exercise per week)
Lifestyle: recreational Assessment and cessation advice Interventions on alcohol, tobacco, None
substances on use of alcohol, nicotine and psychoactive substances
products, and drugs
Teratogens and Assessment and education Education and prevention None
environmental
exposures
(Continued)

Table 1 (Continued)
Topic ACOG recommendations WHO recommendations Comments
Violence Screening for exposure to Screening and intervention for None
violence, intimate partner interpersonal violence
violence, and reproductive
and sexual coercion
Mental health None Assessment, education, counseling, None
and management of mental
health disorders
Female genital None Screening and treatment for None
mutilation complications
Given the well-documented increased risk of APOs associated with excess adiposity, efforts
to lose weight prior to pregnancy among women with overweight and obesity should be en-
couraged. For women eligible for bariatric surgery, benefits may outweigh risks. Meta-analyses
of observational studies have found that bariatric surgery is related to a substantially reduced
risk of GDM, hemorrhage, and HDP (with comparable benefits for preeclampsia and gestational
hypertension) (71, 72). Furthermore, the risk of adverse maternal outcomes in pregnancies follow-
ing bariatric surgery may approach that observed in women without obesity (72). Nevertheless,
bariatric surgery is associated with a significant reduction in gestational length and increased risk
of preterm birth, possibly due to continued maternal weight loss or micronutrient deficiency that
affect fetal nutrition (72, 73). Surgery-to-conception interval and type of surgery do not seem to
influence pregnancy outcomes (72, 73). While some studies have suggested that high risk of preg-
nancy loss persists 1–2 years after the surgery, findings remain inconclusive, and there is no robust
evidence reporting benefits from a delayed surgery-to-conception time (44).
Evidence on the benefits of weight loss through lifestyle interventions is more equivocal. A
meta-analysis reported that preconception lifestyle interventions aimed at weight reduction low-
ered risk of HDP by ∼50% (71). Similarly, the PREPARE trial found that a behavioral weight
loss intervention improved glycemia in early gestation (74) and decreased the risk of spontaneous
pregnancy loss (75), although the trial found no differences in gestational weight gain (the trial’s
primary outcome), GDM, pregnancy-induced hypertension, or preterm birth. It is worth noting
that even though the difference in the risk of GDM was not statistically significant, the observed
differences (25% in the intervention arm versus 35% in the control arm) were substantial (75)
and suggest an actual benefit of preconception weight loss on GDM risk despite the trial being
underpowered for this outcome.
Results of preconception weight loss trials in special populations pose challenges to interpret-
ing the net benefit of preconception weight loss among women with overweight and obesity.
For example, weight loss trials among women with infertility not only have found no benefit of
weight loss on fertility but also have found no differences in APOs despite substantial prepreg-
nancy weight loss (76–78). Discrepant findings, and the possibility that weight loss efforts may not
yield immediate benefits related to pregnancy health, do not mean that these are wasted efforts.
Although numerous weight loss trials have documented that many individuals regain weight after
discontinuing weight loss interventions, long-term follow-up of infertile women in one of these
weight loss trials revealed that women randomized to intervention who lost weight during the
trial were able to maintain this weight loss 4–7 years after the conclusion of the trial (79). It is
unclear if this finding is an outlier within the broader literature of weight loss trials or if weight
loss interventions in the preconception period may result in different long-term outcomes than
interventions at other points in the life course.
206 Wang et al.

Table 2 Common chronic diseases and risk of adverse maternal pregnancy outcomes and maternal mortalitya
Medical risk factors Adverse pregnancy Estimated relative
(references) outcomes risk (95% CI) Comments
Hypertension (2–5) Pregnancy loss 2.27 (1.27–4.04) Antihypertensive treatment during pregnancy in
Preeclampsia 5.43 (3.85–7.65) women with chronic hypertension may not
Gestational diabetes 1.8 (1.4–2.4) prevent adverse pregnancy outcomes (2)
Preterm delivery 2.23 (1.96–2.53)
Stillbirth 2.24 (1.52–3.32)
Type 2 diabetes (6–9) Pregnancy loss 3.23 (1.64–6.36) Risk increases with severity of disease
Preeclampsia 3.58 (1.76–7.29)
Stillbirth 2.90 (1.81–4.60)
Chronic kidney Pregnancy loss 1.58 (0.92–2.73) It is difficult to disentangle the effect of impaired
diseases (10) Preeclampsia 2.58 (1.33–5.01) renal function per se from consequences of
Preterm delivery 1.73 (1.31–2.27) impaired renal function, such as hypertension
Stillbirth 1.67 (0.96–2.92) and proteinuria
Systemic lupus Pregnancy loss 1.51 (1.26–1.82) Active disease status is associated with worse
erythematosus Preeclampsia 1.91 (1.44–2.53) maternal outcomes
(12, 13) Gestational diabetes 1.08 (0.49–2.41)
Stillbirth 1.70 (1.34–2.16)
Mild congenital heart HDP 11.3 (9.2–14.0) None
diseasesb (14) Preterm delivery 5.8 (4.3–7.9)
Postpartum hemorrhage 10.4 (8.3–13.0)
Moderate congenital Pregnancy loss 16.1 (10.6–23.6) None
heart diseasesc (14) HDP 11.8 (8.9–15.5)
Severe congenital heart Pregnancy loss 33.7 (24.2–44.7) None
diseasesd (14) HDP 10.3 (5.2–19.4)
Asthma (15–17) Pregnancy loss 1.41 (1.33–1.49) Disease severity (e.g., steroid dependency,
Preeclampsia 1.54 (1.32–1.81) exacerbation) is associated with risk of adverse
Gestational diabetes 1.39 (1.17–1.66) outcomes
Antepartum hemorrhage 1.25 (1.10–1.42)
Thyroid diseases Pregnancy loss 2.31 (1.90–2.28) Guidelines recommend controlling TSH level
(18–20) Preeclampsia 1.41 (0.89–2.25) not >2.5 mIU/L for women diagnosed with
Gestational diabetes 1.38 (0.97–1.96) hypothyroidism before pregnancy or with
Preterm delivery 1.30 (1.05–1.60) TPOAb, but not other low-risk women
Stillbirth 2.12 (1.30–3.47) (63, 64). However, preconception TSH >
2.5 mIU/L in women not previously
diagnosed with hypothyroidism is associated
with higher risk of miscarriages, preterm birth,
and operative vaginal delivery (61, 62).
TSH < 0.37 mIU/L is associated with preterm
birth (62)
a
Maternal mortality estimates need to be interpreted with caution because the meta-analysis includes studies with too few events or >50% studies reported
0 events.
b
Mild: atrial septal defect, patent ductus arteriosus, and ventricular septal defect.
c
Moderate: coarctation of the aorta, Ebstein’s, pulmonary stenosis, tetralogy of Fallot.
d
Severe: double-outlet right ventricle, Fontan, pulmonary atresia, transposition of the great arteries, Eisenmenger’s.
Abbreviations: HDP, hypertensive disease of pregnancy; TPOAb, thyroid peroxidase antibodies; TSH, thyroid stimulating hormone.

Preconception weight management should not be synonymous with weight loss among women
who already have overweight or obesity and must also encompass efforts to prevent weight gain.
The rationale for focusing on weight gain prevention is twofold. First, overweight and obesity do
not develop overnight but are instead the result of sustained gain of small amounts of weight over
many years. The average weight gain among nonobese populations is about 0.8 lb/year, arising
from sustained, modest, unintended changes in diet and physical activity that amount to a habit-
ual energy imbalance of approximately 50–100 kcal/day (80). Adoption of modest dietary changes,
including reducing intake of sugary beverages, refined carbohydrates, processed foods, and alco-
hol, while increasing intakes of unprocessed foods (whole grains, fruits, nuts, and vegetables), can
have major impacts on preventing unintended weight gain over extended periods of time, partic-
ularly when coupled with regular exercise, reduced television watching, and adequate sleep habits
(80). Second, weight gain during adulthood is related to a higher rate of APOs, even when weight
gain does not result in overweight or obesity. Meta-analyses of the association of weight gain with
APOs have found that both preconception and interpregnancy weight gain are associated with a
greater risk of GDM, HDP, the fetus being large for gestational age, cesarean delivery, and still-
birth in a dose-dependent fashion, and that these relations are pronounced in women within the
normal BMI range (81, 82).
Nutrition. Although the importance of preconception iron and folic acid supplementation is
well established, benefits of supplementation with additional micronutrients are less definitive.
Based on data from 20 randomized trials comparing the effects of multiple micronutrient (MMN)
supplementation during pregnancy versus iron/folic acid supplementation alone (83), the WHO
recommends that MMN supplements be a core component of routine antenatal care (84). The
MMN formulation recommended by the WHO is consistent with the ACOG recommendation of
preconception supplementation with folic acid (30) and comparable to the formulation of generic
multivitamin supplements available in the United States (Table 3). This and comparable formu-
lations are known to reduce the risk of low birthweight, possibly by reducing the frequency of
preterm births, and in particular very preterm births (before 34 weeks) (83). It is important to
note that 19 of the 20 trials supporting this recommendation were conducted in low- or middle-
income countries where micronutrient deficiencies are more common than in the United States,
and hence the benefits of MMN supplementation in the United States may be more modest than
those identified in the trials supporting the WHO recommendation.
There is currently no consensus on what constitutes a healthy diet during preconception and
pregnancy. Nevertheless, diets consistent with recommendations for the prevention of chronic
diseases in the general population may also have benefits specific to pregnancy. Results from
large prospective cohort studies suggest that greater prepregnancy adherence to healthy dietary
patterns—such as the alternate Mediterranean diet, the Dietary Approaches to Stop Hyperten-
sion (DASH) diet, and the alternate Healthy Eating Index diet—are associated with reduced risk
of GDM (85, 86) and preeclampsia (87).
Physical activity. Extensive evidence from more than 50 randomized trials summarized in multi-
ple meta-analyses shows that physical activity during pregnancy decreases the risk of multiple
pregnancy complications, including GDM (approximately 40–50% lower risk), HDP (∼80%
lower risk, primarily gestational hypertension) and preterm birth (∼35% lower risk among women
with prepregnancy overweight or obesity) (88–90). Notably, these randomized trials have not iden-
tified any major harms associated with physical activity during pregnancy, suggesting that most—if
not all—women would benefit from it, in agreement with current recommendations by ACOG
regarding physical activity during pregnancy and the postpartum period (91).
208 Wang et al.

Table 3 Formulation of multiple micronutrients supplementation recommended by the
World Health Organization (WHO) compared to usual formulation of supplements sold in
the United States
United States formulation
WHO recommended Generic prenatal
Micronutrients formulation Generic multivitamin multivitamin
Vitamin Aa 800 μg 1,050 μg 1,200 μg
Vitamin D 200 IU 1,000 IU 400 IU
Vitamin E 10 mg 13.5 mg 20 mg
Niacin 18 mg 20 mg 20 mg
Folic acid 400 μg 400 μg 800 μg
Vitamin B1 1.4 mg 1.5 mg 1.8 mg
Vitamin B2 1.4 mg 1.7 mg 1.7 mg
Vitamin B6 1.9 mg 2 mg 2.6 mg

Vitamin B12 2.6 μg 6 μg 8 μg
Vitamin C 70 mg 60 mg 120 mg
Zinc 15 mg 11 mg 25 mg
Iron 30 mg 18 mg 28 mg
Selenium 65 μg 55 μg None
Copper 2 mg 0.5 mg None
Iodine 150 μg 150 μg None
Vitamin K None 25 mg None
Calcium None 200 mg 200 mg
Biotin None 30 μg None
Pantothenic acid None 10 mg None
Phosphorus None 20 mg None
Magnesium None 50 mg None
Manganese None 2.3 mg None
Chromium None 35 μg None
Molybdenum None 45 μg None
Chloride None 72 mg None
Potassium None 80 mg None
a
As β-carotene. Preformed vitamin A (retinol) is teratogenic.
Although there is not as much evidence of the potential benefits of physical activity during the
preconception period, data from physical activity trials during pregnancy suggest that earlier ini-
tiation may be favorable. For example, the benefit of physical activity on lowering the risk of HDP
appears to be greater in trials that randomized women early in pregnancy (average 9 weeks gesta-
tional age) (92, 93) than in trials that began the exercise intervention later in pregnancy (average
15 weeks gestational age) (94–96). Data from large prospective cohort studies suggest that pre-
conception physical activity should be part of standard preconception care counseling. Moderate
to vigorous physical activity before pregnancy is related to lower risks of developing gestational
hypertension, preeclampsia (97, 98), and GDM (99, 100). Of note, the potential benefits reported
in these observational studies are restricted to women with the highest activity levels (97, 99).

MATERNAL MORTALITY AFTER THE IMMEDIATE
POSTPARTUM PERIOD
As noted above, about one-fifth of all maternal deaths take place more than 6 weeks after deliv-
ery (38). This suggests that the increasing interest in the so-called fourth trimester and transition
back to primary care (101) may be key for preventing late maternal deaths. Given the increasing
importance of delayed maternal deaths in the United States, and the prominence of cardiomyopa-
thy and other diseases of the cardiovascular system in driving this elevated risk, a fourth-trimester
encounter with a primary care provider would enable identifying and addressing issues that may
result in delayed maternal mortality. Routine and long-term follow-up may be particularly im-
portant for women who experience APOs including GDM, HDP, and preterm delivery, as it is
now well documented that these conditions are associated with elevated risk of future chronic
morbidity.
Hypertensive Disorders of Pregnancy and Long-Term Cardiovascular Risk

HDPs are the pregnancy outcome most consistently associated with long-term cardiovascular
risk. Preeclampsia and preterm preeclampsia are associated with subsequent risk of early-onset
chronic hypertension and subsequent common cardiovascular events as early as 1 year after the
affected pregnancy (25, 102). Even higher risks of cardiovascular disease (CVD) are seen among
women who have preterm preeclampsia or recurrent preeclampsia (103). The association may be
mediated by hypertension and diabetes (25), and risk may be reduced by adherence to a benefi-
cial lifestyle, including keeping a normal weight, high physical activity, high DASH score, and low
sodium/potassium intake (104). Of note, reports that women who experience preeclampsia or ges-
tational hypertension are at an elevated risk of premature death, mostly due to an elevated risk of
CVD-related mortality, provide evidence that elevated risk associated with HDP may persist for
many decades postpregnancy, even in the absence of subsequent development of chronic hyperten-
sion (21). Active surveillance for hypertension and lifestyle interventions focused on cardiovascular
risk reduction are the current recommendations for women with a history of HDP.
Other Adverse Pregnancy Outcomes Associated with Future

Cardiovascular Risk
A preponderance of evidence links a history of GDM with impaired cardiometabolic function
shortly after pregnancy, which increases the risk of type 2 diabetes and CVD later in life (25,
105). Risk of CVD is mostly mediated by progression to chronic diabetes (105, 106). Weight
gain prevention and the adoption of a healthier lifestyle are related to a lower risk of developing
type 2 diabetes among women with GDM (107), reinforcing the need for postpartum care and
encouragement of a healthy lifestyle.
History of preterm birth (including spontaneous and medically indicated) is also a risk factor
for cardiometabolic diseases and premature mortality, and the risk rises with decreasing gestation
length and increasing number of pregnancies ending in preterm birth (24, 108, 109). The relative
risk declines with time but remains pronounced even 40 years after delivery (24, 108); however,
much of the risk mediation continues to be unexplained.
Spontaneous pregnancy loss, but not the elective termination of pregnancy, is associated with
elevated risk of diabetes, hypertension, and hypercholesterolemia (110). Pregnancy loss is also
associated with an elevated risk of CVD and CVD mortality, but this elevated risk appears to be
independent of these metabolic disorders (22, 23). Individuals with recurrent miscarriage present
with even higher risk of CVD and CVD mortality (22).
210 Wang et al.

SUMMARY
Maternal mortality rates in the United States have increased in recent decades and are unusu-
ally high compared to other wealthy nations. Reasons for increasing maternal mortality rates
include increasing frequency of delayed childbearing and higher rates of obesity and chronic
diseases present before pregnancy, but they may also include changes in maternal death docu-
mentation. High US maternal mortality is characterized by major disparities by race/ethnicity as
well as substantial variation across states. As in other developed nations, there has been a shift
in the underlying causes of pregnancy-related death over the last three decades, with a relative
decrease in the frequency of traditional causes of maternal death first detected and treated during
pregnancy and a relative increase in mortality resulting from conditions such as peripartum car-
diomyopathy and CVD. This shifting pattern presents both challenges and opportunities for the
prevention of maternal mortality.
Realizing the opportunities will require more efficient continuity of care across the life course.
Identifying women with preexisting medical conditions that may heighten the risk of death is a
crucial step. Preconception management of risk factors for major APOs through weight manage-
ment, physical activity, and dietary improvements may have a role in preventing maternal deaths
associated with APOs. Primary care visits within the first year after delivery should be seen as an
opportunity to provide preconception counseling for women planning additional pregnancies and
contraceptive care otherwise. Such visits are also opportunities to assess long-term health risks for
women whose APOs may signal increased risk of chronic diseases such as hypertension, diabetes,
and CVD. More generally, recognizing that all primary care encounters with women of repro-
ductive age are opportunities to obtain a reproductive history relevant to long-term health risks,
and to consider preconception care, will begin to address gaps in medical care contributing to the
unacceptable rates of maternal mortality in our country.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
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ME74_FrontMatter ARjats.cls December 6, 2022 14:53
Annual Review of
Medicine
Contents Volume 74, 2023
COVID-19 and Kidney Disease

Maureen Brogan and Michael J. Ross p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
COVID-19 Thrombotic Complications and Therapeutic Strategies
Alexander C. Fanaroff and Renato D. Lopes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p15

COVID-19: Challenges of Viral Variants

Jana L. Jacobs, Ghady Haidar, and John W. Mellors p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p31
Post-COVID-19 Condition
Ani Nalbandian, Amar D. Desai, and Elaine Y. Wan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p55
SARS-CoV-2 Vaccination-Induced Thrombotic Thrombocytopenia:
A Rare but Serious Immunologic Complication
Charles S. Abrams and Geoffrey D. Barnes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p65
Endocrine Disorders and COVID-19
Seda Hanife Oguz and Bulent Okan Yildiz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p75
Cytomegalovirus Therapy: Role of Letermovir in Prophylaxis and
Treatment in Transplant Recipients
Jennifer L. Saullo and Rachel A. Miller p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p89
Gender-Affirming Care of Transgender and Gender-Diverse Youth:
Current Concepts
Janet Y. Lee and Stephen M. Rosenthal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 107
Update in Adult Transgender Medicine
Alyxandra Ramsay and Joshua D. Safer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 117
New Frontiers in Obesity Treatment: GLP-1 and Nascent
Nutrient-Stimulated Hormone-Based Therapeutics
Ania M. Jastreboff and Robert F. Kushner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 125
Advances and Applications of Polygenic Scores for Coronary
Artery Disease
Aniruddh P. Patel and Amit V. Khera p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 141
Valvular Heart Disease: New Concepts in Pathophysiology and
Therapeutic Approaches
Mackram F. Eleid, Vuyisile T. Nkomo, Sorin V. Pislaru, and Bernard J. Gersh p p p p p p p p p 155
v
Myocardial Infarction with Nonobstructive Coronary Arteries

H.R. Reynolds and N.R. Smilowitz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171
Lessons Learned from the ISCHEMIA Trial for the Management of
Patients with Stable Ischemic Heart Disease
William E. Boden and Peter H. Stone p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189
Maternal Mortality in the United States: Trends and Opportunities
for Prevention
Siwen Wang, Kathryn M. Rexrode, Andrea A. Florio, Janet W. Rich-Edwards,
and Jorge E. Chavarro p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 199
Primary Aldosteronism and the Role of Mineralocorticoid Receptor
Antagonists for the Heart and Kidneys
Jordana B. Cohen, Irina Bancos, Jenifer M. Brown, Harini Sarathy,

Adina F. Turcu, and Debbie L. Cohen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 217

Adeno-Associated Virus Gene Therapy for Hemophilia
Benjamin J. Samelson-Jones and Lindsey A. George p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 231
Clonal Hematopoiesis and Its Impact on Human Health
Herra Ahmad, Nikolaus Jahn, and Siddhartha Jaiswal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 249
Hepcidin and Iron in Health and Disease
Elizabeta Nemeth and Tomas Ganz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 261
Multispecific CAR T Cells Deprive Lymphomas of Escape
via Antigen Loss
Fateeha Furqan and Nirav N. Shah p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279
FGFR2 Inhibition in Cholangiocarcinoma
Arndt Vogel, Oreste Segatto, Albrecht Stenzinger, and Anna Saborowski p p p p p p p p p p p p p p p p 293
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Pathway: Effects of Genetic and Pharmacological Perturbations
Gregg L. Semenza p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307
Cytokine Storm Syndrome
Randy Q. Cron, Gaurav Goyal, and W. Winn Chatham p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 321
Systemic Lupus Erythematosus: New Diagnostic and Therapeutic
Approaches
Stephanie Lazar and J. Michelle Kahlenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339
Genetics of Kidney Disease: The Unexpected Role of Rare Disorders
Mark D. Elliott, Hila Milo Rasouly, and Ali G. Gharavi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 353
SGLT2 Inhibitors: The Sweet Success for Kidneys
Atit Dharia, Abid Khan, Vikas S. Sridhar, and David Z.I. Cherney p p p p p p p p p p p p p p p p p p p p p 369
vi Contents
Use of Race in Kidney Function Estimation: Lessons Learned and the

Path Toward Health Justice
Dinushika Mohottige, Opeyemi Olabisi, and L. Ebony Boulware p p p p p p p p p p p p p p p p p p p p p p p p p 385
Origins of Racial and Ethnic Bias in Pulmonary Technologies
Michael W. Sjoding, Sardar Ansari, and Thomas S. Valley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 401
Cystic Fibrosis Modulator Therapies
Shijing Jia and Jennifer L. Taylor-Cousar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Club Cell Secretory Protein in Lung Disease: Emerging Concepts
and Potential Therapeutics
Tereza Martinu, Jamie L. Todd, Andrew E. Gelman, Stefano Guerra,
and Scott M. Palmer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 427
Chronic Neuromuscular Respiratory Failure and Home Assisted

Ventilation
Hugo Carmona, Andrew D. Graustein, and Joshua O. Benditt p p p p p p p p p p p p p p p p p p p p p p p p p p p 443
Biological Phenotyping in Sepsis and Acute Respiratory
Distress Syndrome
Pratik Sinha, Nuala J. Meyer, and Carolyn S. Calfee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 457
Diverse Approaches to Gene Therapy of Sickle Cell Disease
Shanna L. White, Kevyn Hart, and Donald B. Kohn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 473
Exome/Genome Sequencing in Undiagnosed Syndromes
Jennifer A. Sullivan, Kelly Schoch, Rebecca C. Spillmann, and Vandana Shashi p p p p p p p p 489
All the Tau We Cannot See
Bradley Hyman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 503
Indexes
Cumulative Index of Contributing Authors, Volumes 70–74 p p p p p p p p p p p p p p p p p p p p p p p p p p p 515

Cumulative Index of Article Titles, Volumes 70–74 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519
Errata
An online log of corrections to Annual Review of Medicine articles may be found at

http://www.annualreviews.org/errata/med
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Annual Review of Medicine

Maternal Mortality in the

Siwen Wang,1 Kathryn M. Rexrode,2 Andrea A. Florio,1

Annu. Rev. Med. 2023. 74:199–216 Keywords

200 Wang et al.

Maternal mortality per 100k live births

Pregnancy-related death: deaths from health problems related to pregnancy 15

Pregnancy-associated death: deaths from conditions unaffected by pregnancy 10

High socio-demographic index Western Europe

202 Wang et al.

PREPREGNANCY HEALTH, ADVERSE PREGNANCY OUTCOMES,

www.annualreviews.org • Maternal Mortality in the United States 203

204 Wang et al.

www.annualreviews.org • Maternal Mortality in the United States 205

206 Wang et al.

www.annualreviews.org • Maternal Mortality in the United States 207

208 Wang et al.

Vitamin B6 1.9 mg 2 mg 2.6 mg

www.annualreviews.org • Maternal Mortality in the United States 209

Hypertensive Disorders of Pregnancy and Long-Term Cardiovascular Risk

Other Adverse Pregnancy Outcomes Associated with Future

210 Wang et al.

www.annualreviews.org • Maternal Mortality in the United States 211

pregnancy: a systematic review and meta-analysis. BMC Pregnancy Childbirth 19:179

212 Wang et al.

www.annualreviews.org • Maternal Mortality in the United States 213

214 Wang et al.

www.annualreviews.org • Maternal Mortality in the United States 215

216 Wang et al.

Contents Volume 74, 2023

COVID-19 and Kidney Disease

Alexander C. Fanaroff and Renato D. Lopes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p15

COVID-19: Challenges of Viral Variants

Myocardial Infarction with Nonobstructive Coronary Arteries

Jordana B. Cohen, Irina Bancos, Jenifer M. Brown, Harini Sarathy,

Adina F. Turcu, and Debbie L. Cohen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 217

Use of Race in Kidney Function Estimation: Lessons Learned and the

Chronic Neuromuscular Respiratory Failure and Home Assisted

Cumulative Index of Contributing Authors, Volumes 70–74 p p p p p p p p p p p p p p p p p p p p p p p p p p p 515

An online log of corrections to Annual Review of Medicine articles may be found at

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