BACKGROUND:

Severe maternal morbidity (SMM) comprises an array of conditions and procedures denoting an acutely life-threatening pregnancy-related condition. SMM may further compromise fetal well-being. Empirical data are lacking about the relation between SMM and infant mortality.

METHODS:

This population-based cohort study included 1 892 857 singleton births between 2002 and 2017 in Ontario, Canada, within a universal health care system. The exposure was SMM as an overall construct arising from 23 weeks’ gestation up to 42 days after the index delivery. The primary outcome was infant mortality from birth to 365 days. Multivariable modified Poisson regression generated relative risks and 95% confidence intervals (CIs), adjusted for maternal age, income, rurality, world region of origin, diabetes mellitus, and chronic hypertension.

RESULTS:

Infant mortality occurred among 174 of 19 587 live births with SMM (8.9 per 1000) vs 5289 of 1 865 791 live births without SMM (2.8 per 1000) (an adjusted relative risk of 2.93 [95% CI 2.51–3.41]). Of 19 587 pregnancies with SMM, 4523 (23.1%) had sepsis. Relative to births without SMM, the adjusted odds ratio for infant death from sepsis was 1.95 (95% CI 1.10–3.45) if SMM occurred without maternal sepsis and 6.36 (95% CI 3.50–11.55) if SMM included sepsis.

CONCLUSIONS:

SMM confers a higher risk of infant death. There is also coupling tendency (concurrent event of interest) between SMM with sepsis and infant death from sepsis. Identification of preventable SMM indicators, as well as the development of strategies to limit their onset or progression, may reduce infant mortality.

What’s Known on This Subject:

Severe maternal morbidity (SMM) comprises life-threatening pregnancy conditions and has risen over time in North America and Europe. As a consequence of SMM, the unborn fetus can be exposed to an adverse intrauterine environment, whether antepartum or intrapartum.

What This Study Adds:

In this population-based cohort study of 1.9 million maternal-infant pairs in Ontario, Canada, SMM was associated with a nearly 3 times higher risk of infant death. A coupling tendency was also seen between sepsis-related SMM and sepsis-related infant death.

Severe maternal morbidity (SMM) comprises an array of diagnoses and procedures denoting an acutely life-threatening pregnancy-related condition like sepsis, postpartum hemorrhage, and severe preeclampsia. SMM indicators are derived by using administrative hospital discharge data and International Classification of Diseases diagnosis and procedure codes, with a greater number of indicators conferring a higher risk of maternal death.13  SMM affects up to 2% of births, depending on the definition authors of a study employ,46  and has risen over time in North America and Europe.5,79  SMM has multiple implications for the fetus and infant. First, as a consequence of maternal critical illness, the unborn fetus can be exposed to an adverse intrauterine environment, whether antepartum or intrapartum. The fetus of a mother with SMM may experience the same underlying critical illness as the mother, such as Gram-negative bacteremic sepsis10  or group B streptococcal disease,11  as well as adverse effects from maternal hypoxia, hypotension, and uterine vasoconstriction.12  Second, because of factors predisposing to SMM, or in the setting of SMM, the newborn may have experienced poor fetal growth in utero and/or severe prematurity born out of the necessity to urgently deliver a mother who is ill.13  Third, a neonate may be separated from a mother affected by SMM if she requires interfacility transfer or admission to an adult ICU or if she dies postpartum from her acute illness.13 

Empirical data are lacking about the association between SMM and infant mortality. The current study was undertaken to characterize the risk of infant, neonatal, and fetal mortality, each in association with SMM as an overall construct, while considering maternal demographics, preexisting conditions like diabetes mellitus, timing and mode of delivery, and newborn characteristics, such as newborn sex and growth restriction. Given the recent call to reduce maternal and neonatal deaths related to sepsis,14  especially from coinfection,15  this study additionally evaluated whether there exists a coupling tendency between sepsis-related SMM and sepsis-related infant mortality. Coupling tendency herein means a concurrent event of interest (ie, sepsis) occurring in both the mother and her infant.

A population-based cohort study was completed by using provincial health administrative data collected within a universal health care system. These data sets were linked by using unique encoded identifiers and analyzed at ICES (the Institute for Clinical Evaluative Sciences), Ontario, Canada. Linked maternal-infant pairs were identified in the Institute for Clinical Evaluative Sciences MOMBABY database, and their characteristics and outcomes were captured in the following data sources: the Canadian Institute for Health Information’s (CIHI) Discharge Abstract Database for all hospital live birth and stillbirth details, with up to 25 diagnostic and procedural codes arising within a hospitalization. Diagnostic codes are based on the International Classification of Diseases, 10th Revision, Canada (ICD-10-CA), and procedural codes are based on the Canadian Classification of Health Interventions (CCI). The Ontario Health Insurance Plan (OHIP) database identifies preexisting maternal health conditions by using an International Classification of Diseases, Ninth Revision, Canada diagnostic code for every outpatient visit. The Ministry of Health’s Registered Persons Database (RPDB) contains vital status and sociodemographic information for all individuals ever eligible for OHIP. The Better Outcomes Registry and Network (BORN) database contains additional information and maternal characteristics. The Immigration, Refugees and Citizenship Canada’s permanent resident database includes the country of origin for immigrants who landed in Ontario. Importantly, these data sets have been well validated and studied in a number of previous studies to capture and describe the study participants.2,13,16,17 

We identified all singleton hospital live births and stillbirths born at ≥ 23 weeks’ gestation within the province of Ontario between April 1, 2002, and March 31, 2017. We excluded multifetal births, non–Ontario resident mothers, mothers aged <10 or >55 years, and, for live births, missing gestational age at birth, birth weight, or sex (Fig 1). All inclusion and exclusion criteria and variable definitions are described in Supplemental Table 5. The study was limited to singleton births because they constitute >96% of all births and enable a more straightforward 1-to-1 comparison with each mother. Additionally, multifetal newborns are more likely to experience death from factors not necessarily related to maternal health, such as twin-twin transfusion syndrome or a major congenital anomaly.18 

FIGURE 1

Flow diagram of cohort creation.

FIGURE 1

Flow diagram of cohort creation.

Close modal

SMM was defined by using a modified version of that developed by the Canadian Perinatal Surveillance System,6  as described elsewhere,2  and similar to that developed by the US Centers for Disease Control and Prevention.2,19  SMM includes >40 unique indicators that are based on ICD-10-CA diagnostic codes and CCI procedural codes, such as ICU admission, eclampsia, and use of assisted ventilation, for example. The composite of SMM has been validated against maternal mortality and hospital length of stay and in different countries.2022  The quality of the variables collected within the Canadian hospital data sets is generally high.23 

SMM was captured anytime between the index delivery hospitalization admission date and up to 42 days after the delivery even if there was a readmission to hospital within that time frame. The primary study exposure was the presence versus absence of SMM as an overall construct, further broken down by the number of SMM indicators, as outlined below.

The primary study outcome was infant death from birth to 365 days thereafter. Secondary outcomes included stillbirth at ≥23 weeks’ gestation, neonatal death from birth to 27 days, and postneonatal death from 28 to 365 days. Infant deaths related to sepsis were also analyzed, as described below. Infant deaths were identified on the basis of a discharge disposition from the birth or subsequent inpatient hospital admission or from the RPDB in the case of out-of-hospital deaths. Stillbirths are recorded on the maternal record.

Means and SDs were used to describe normally distributed continuous variables, whereas categorical variables were expressed as counts and proportions. Standardized differences compared women with and without SMM, with a value <0.10 indicating no important difference.24 

In the main model, the relative risk (RR) and 95% confidence interval (CI) of the association between SMM and infant death was estimated by using modified Poisson regression with a robust error variance.25  Generalized estimating equations with an exchangeable correlation structure accounted for correlated errors in the case of multiple pregnancies within the same woman.26  RRs were adjusted for maternal age (continuous); residential income quintile (quintile 1 or unknown, quintiles 2–5); rural residence; world region (Canada or long-term resident, Caribbean or sub-Saharan Africa, South Asia, East Asia or Pacific, other or unknown), each at the time of the index birth; as well as diabetes mellitus and chronic hypertension within 2 years before the index birth (Supplemental Table 5).

The main model of SMM and infant death was further stratified by maternal factors (age [≥40 or <40 years], parity [nulliparous or parous], world region of origin [Afro-Caribbean origin or other], BMI [≥25 or <25], preexisting type 1 or 2 diabetes mellitus, preexisting chronic hypertension, spontaneous or provider-initiated preterm birth <37 weeks’ gestation, and vaginal or cesarean delivery) and by infant factors (sex, timing of birth, birth weight percentile, 5-minute Apgar score, and any congenital or chromosomal anomaly diagnosed in the first year of life). When applicable, a covariate was removed from its respective regression model when it formed a stratification variable. The temporal relation between SMM and infant death was also explored by assessing the timing of onset of SMM: from 23 weeks’ gestation up to, but not including, the hospitalization for the index birth or any time thereafter; from 23 weeks’ gestation up to, and including, the index birth hospitalization; as well as from 23 weeks’ gestation up to 42 days after the index birth date.

The same modeling approach used in the main model was applied in the analysis of the number of SMM indicators (0, 1, 2, 3, 4, ≥5) and infant death from birth to 365 days, as well as for SMM and stillbirth, SMM and neonatal death from birth to 27 days, and SMM and postneonatal death from 28 to 365 days after birth.

The association between sepsis-related SMM (ICD-10-CA code O75.3) and infant death with a diagnosis of bacterial sepsis (ICD-10-CA code P36) at the time of or preceding death was analyzed by using multinomial logistic regression to generate odds ratios (ORs) and corresponding 95% CIs.27  ORs can be interpreted as risk ratios when the event rate is rare.28  The odds of an infant death with and without sepsis was evaluated in relation to SMM with sepsis and SMM without sepsis, each relative to no SMM, and adjusted for the same covariates as in the main model.

All analyses were performed by using SAS statistical software, version 9.4 (SAS Institute, Inc, Cary, NC). The use of data in this project was authorized under section 45 of Ontario’s Personal Health Information Protection Act, which does not require review by a research ethics board.

There were 2 007 880 maternal-infant live-born or stillborn pairs during the study period, of which 115 023 (5.7%) were excluded predominantly because of multifetal birth (Fig 1). Of the eligible 1 892 857 singleton pregnancies ending in a live birth or stillbirth from 23 weeks’ gestation onward, 20 107 were affected by SMM, corresponding to a rate of 10.6 per 1000 births (Table 1). There were 20 164 pregnancies affected by SMM or maternal death (10.7 per 1000 births). Women with SMM were more likely than those without SMM to be of Caribbean or sub-Saharan African origin, have chronic hypertension (27.3% vs 14.7%), a cesarean delivery (44.6% vs 19.8%), a provider-initiated preterm birth (12.0% vs 3.1%), and a low Apgar score (2.2% vs 0.7%) (Table 1).

TABLE 1

Baseline Characteristics of the Cohort According to Whether a Woman Experienced SMM Arising From 23 Weeks’ Gestation Up to 42 Days After Birth

Characteristics and MeasuresSMM (n = 20 107)No SMM (n = 1 872 750)Standardized Difference
Of the mother    
 Age, y    
  Mean (SD) 30.8 (5.9) 30.1 (5.5) 0.13 
  10–19 707 (3.5) 61 262 (3.3) 0.01 
  20–34 13 823 (68.7) 1 414 759 (75.5) 0.15 
  35–39 4304 (21.4) 328 003 (17.5) 0.10 
  40–44 1165 (5.8) 65 440 (3.5) 0.11 
  45–55 108 (0.5) 3286 (0.2) 0.06 
 World region of origin    
  Canada or long-term resident 14 474 (72.0) 1 368 950 (73.1) 0.02 
  Caribbean or sub-Saharan Africa 1107 (5.5) 64 324 (3.4) 0.10 
  South Asia 1480 (7.4) 152 516 (8.1) 0.03 
  East Asia and/or Pacific 1339 (6.7) 118 416 (6.3) 0.01 
  Other or unknown 1707 (8.5) 168 544 (9.0) 0.02 
 Residential income quintile    
  Quintile 1 or unknown 5152 (25.6) 423 041 (22.6) 0.07 
  Quintile 2 3975 (19.8) 373 848 (20.0) 0.00 
  Quintile 3 3995 (19.9) 378 364 (20.2) 0.01 
  Quintile 4 3941 (19.6) 390 305 (20.8) 0.03 
  Quintile 5 3044 (15.1) 307 192 (16.4) 0.03 
 Urban residence 17 757 (88.3) 1 680 348 (89.7) 0.05 
 Parity    
  Median (IQR) 1 (0–1) 1 (0–1) 0.03 
  0 9630 (47.9) 842 448 (45.0) 0.06 
  1 6417 (31.9) 669 578 (35.8) 0.08 
  2+ 4059 (20.2) 360 713 (19.3) 0.02 
 Prepregnancy BMIa    
  Mean (SD) 26.5 (6.8) 25.8 (6.5) 0.11 
  Unknown 16 637 (82.7) 1 567 324 (83.7) 0.03 
  <25 1781 (8.9) 168 519 (9.0) 0.00 
  25–29.9 843 (4.2) 75 933 (4.1) 0.01 
  ≥30 846 (4.2) 60 974 (3.3) 0.05 
 Pregestational diabetes mellitus ≤ 2 y preceding the index birth 3380 (16.8) 252 093 (13.5) 0.09 
 Chronic hypertension ≤ 2 y preceding the index birth 5498 (27.3) 275 589 (14.7) 0.31 
 Cesarean delivery at the index birth 8968 (44.6) 371 397 (19.8) 0.55 
 In vitro fertilizationa 193 (1.0) 8283 (0.4) 0.06 
 Maternal death ≤42 d after the index birth 64 (0.3) 57 (0.0) 0.08 
Of the fetus or newborn    
 Birth type    
  Stillbirth 524 (2.6) 6955 (0.4) 0.18 
  Term live birth 16 711 (82.9) 1 753 219 (93.6) 0.34 
  Spontaneous preterm birth <37 wk’ gestation 509 (2.5) 55 366 (3.0) 0.03 
  Provider-initiated preterm birth <37 wk’ gestation 2420 (12.0) 57 153 (3.1) 0.34 
 Female sex 9632 (47.9) 908 078 (48.5) 0.01 
 Gestational age at live birth, wk    
  Mean (SD) 38.0 (2.9) 38.9 (1.8) 0.36 
  <32 618 (3.1) 13 959 (0.7) 0.17 
  32–36 2300 (11.4) 98 571 (5.3) 0.22 
  ≥37 16 669 (82.9) 1 753 261 (93.6) 0.34 
 Birth wt percentile at live birth    
  Below the fifth 1201 (6.0) 93 472 (5.0) 0.04 
  Fifth to <10th 1048 (5.2) 95 228 (5.1) 0.01 
  ≥10th 17 338 (86.2) 1 677 091 (89.6) 0.10 
 5-min Apgar score at live birtha    
  Low (0–6) 443 (2.2) 12 771 (0.7) 0.13 
  Normal (7–10) 9408 (46.8) 959 355 (51.2) 0.09 
  Unknown 10 256 (51.0) 900 624 (48.1) 0.06 
Characteristics and MeasuresSMM (n = 20 107)No SMM (n = 1 872 750)Standardized Difference
Of the mother    
 Age, y    
  Mean (SD) 30.8 (5.9) 30.1 (5.5) 0.13 
  10–19 707 (3.5) 61 262 (3.3) 0.01 
  20–34 13 823 (68.7) 1 414 759 (75.5) 0.15 
  35–39 4304 (21.4) 328 003 (17.5) 0.10 
  40–44 1165 (5.8) 65 440 (3.5) 0.11 
  45–55 108 (0.5) 3286 (0.2) 0.06 
 World region of origin    
  Canada or long-term resident 14 474 (72.0) 1 368 950 (73.1) 0.02 
  Caribbean or sub-Saharan Africa 1107 (5.5) 64 324 (3.4) 0.10 
  South Asia 1480 (7.4) 152 516 (8.1) 0.03 
  East Asia and/or Pacific 1339 (6.7) 118 416 (6.3) 0.01 
  Other or unknown 1707 (8.5) 168 544 (9.0) 0.02 
 Residential income quintile    
  Quintile 1 or unknown 5152 (25.6) 423 041 (22.6) 0.07 
  Quintile 2 3975 (19.8) 373 848 (20.0) 0.00 
  Quintile 3 3995 (19.9) 378 364 (20.2) 0.01 
  Quintile 4 3941 (19.6) 390 305 (20.8) 0.03 
  Quintile 5 3044 (15.1) 307 192 (16.4) 0.03 
 Urban residence 17 757 (88.3) 1 680 348 (89.7) 0.05 
 Parity    
  Median (IQR) 1 (0–1) 1 (0–1) 0.03 
  0 9630 (47.9) 842 448 (45.0) 0.06 
  1 6417 (31.9) 669 578 (35.8) 0.08 
  2+ 4059 (20.2) 360 713 (19.3) 0.02 
 Prepregnancy BMIa    
  Mean (SD) 26.5 (6.8) 25.8 (6.5) 0.11 
  Unknown 16 637 (82.7) 1 567 324 (83.7) 0.03 
  <25 1781 (8.9) 168 519 (9.0) 0.00 
  25–29.9 843 (4.2) 75 933 (4.1) 0.01 
  ≥30 846 (4.2) 60 974 (3.3) 0.05 
 Pregestational diabetes mellitus ≤ 2 y preceding the index birth 3380 (16.8) 252 093 (13.5) 0.09 
 Chronic hypertension ≤ 2 y preceding the index birth 5498 (27.3) 275 589 (14.7) 0.31 
 Cesarean delivery at the index birth 8968 (44.6) 371 397 (19.8) 0.55 
 In vitro fertilizationa 193 (1.0) 8283 (0.4) 0.06 
 Maternal death ≤42 d after the index birth 64 (0.3) 57 (0.0) 0.08 
Of the fetus or newborn    
 Birth type    
  Stillbirth 524 (2.6) 6955 (0.4) 0.18 
  Term live birth 16 711 (82.9) 1 753 219 (93.6) 0.34 
  Spontaneous preterm birth <37 wk’ gestation 509 (2.5) 55 366 (3.0) 0.03 
  Provider-initiated preterm birth <37 wk’ gestation 2420 (12.0) 57 153 (3.1) 0.34 
 Female sex 9632 (47.9) 908 078 (48.5) 0.01 
 Gestational age at live birth, wk    
  Mean (SD) 38.0 (2.9) 38.9 (1.8) 0.36 
  <32 618 (3.1) 13 959 (0.7) 0.17 
  32–36 2300 (11.4) 98 571 (5.3) 0.22 
  ≥37 16 669 (82.9) 1 753 261 (93.6) 0.34 
 Birth wt percentile at live birth    
  Below the fifth 1201 (6.0) 93 472 (5.0) 0.04 
  Fifth to <10th 1048 (5.2) 95 228 (5.1) 0.01 
  ≥10th 17 338 (86.2) 1 677 091 (89.6) 0.10 
 5-min Apgar score at live birtha    
  Low (0–6) 443 (2.2) 12 771 (0.7) 0.13 
  Normal (7–10) 9408 (46.8) 959 355 (51.2) 0.09 
  Unknown 10 256 (51.0) 900 624 (48.1) 0.06 

All data are shown as n (%) unless otherwise indicated. IQR, interquartile range.

a

Limited to births from April 2006 to March 2014.

There were 5463 infant deaths within 365 days after a birth. Infant death occurred more often in mothers with SMM (8.9 per 1000 live births) than in those without SMM (2.8 per 1000 live births) (an unadjusted RR of 3.12 [95% CI 2.68–3.64] and an adjusted relative risk [aRR] of 2.93 [95% CI 2.51–3.41]; Table 2).

TABLE 2

Risk of Infant Mortality Within 365 Days of Birth in Association With SMM Arising From 23 Weeks’ Gestation Up to 42 Days After Birth

ExposureNo. Infant Deaths (Rate per 1000)RR of Infant Death (95% CI)
UnadjustedAdjusteda
No SMM (n = 1 865 791) 5289 (2.8) 1.00 (referent) 1.00 (referent) 
SMM (n = 19 587) 174 (8.9) 3.12 (2.68–3.64) 2.93 (2.51–3.41) 
ExposureNo. Infant Deaths (Rate per 1000)RR of Infant Death (95% CI)
UnadjustedAdjusteda
No SMM (n = 1 865 791) 5289 (2.8) 1.00 (referent) 1.00 (referent) 
SMM (n = 19 587) 174 (8.9) 3.12 (2.68–3.64) 2.93 (2.51–3.41) 
a

Adjusted for maternal age (continuous); residential income quintile (quintile 1 or missing, quintiles 2–5); rural residence; world region (Canada or long-term resident, Caribbean or sub-Saharan Africa, South Asia, East Asia or Pacific, other or unknown), each at the time of the index birth; as well as diabetes mellitus and chronic hypertension within 2 years before the index birth.

The greater risk of infant mortality with SMM was robustly seen across various maternal characteristics (Fig 2A). The exception was among women with SMM and a prepregnancy BMI ≥25. A greater risk of infant death in the presence of SMM remained after stratification by infant factors, except for extreme preterm births <32 weeks’ gestation and infants affected by an anomaly (Fig 2B). The risk of infant mortality was higher regardless of when SMM occurred (Supplemental Table 6). The rate of infant mortality generally increased with the number of SMM indicators: 0 (2.8 per 1000 births), 1 (7.6 per 1000 births), 2 (11.4 per 1000 births), 3 (9.2 per 1000 births), 4 (13.9 per 1000 births), and ≥5 (34.9 per 1000 births), the latter corresponding to an aRR of 12.13 (95% CI 6.85–21.48; Table 3).

FIGURE 2

RR of infant death ≤365 days after birth, according to the presence or absence of SMM, further stratified by (A) maternal factors and (B) infant factors. All models were adjusted for maternal age, residential income quintile, rural residence, and world region of origin, each at the time of the index delivery, as well as maternal diabetes mellitus and chronic hypertension within 2 years before the index birth. When applicable, a maternal covariate was removed from its respective regression model when it formed a stratification variable. cHTN, chronic hypertension; DM, diabetes mellitus; PI-PTB, provider-initiated preterm birth at <37 weeks; sPTB, spontaneous preterm birth at <37 weeks.

FIGURE 2

RR of infant death ≤365 days after birth, according to the presence or absence of SMM, further stratified by (A) maternal factors and (B) infant factors. All models were adjusted for maternal age, residential income quintile, rural residence, and world region of origin, each at the time of the index delivery, as well as maternal diabetes mellitus and chronic hypertension within 2 years before the index birth. When applicable, a maternal covariate was removed from its respective regression model when it formed a stratification variable. cHTN, chronic hypertension; DM, diabetes mellitus; PI-PTB, provider-initiated preterm birth at <37 weeks; sPTB, spontaneous preterm birth at <37 weeks.

Close modal
TABLE 3

Risk of Infant Mortality Within 365 Days of Birth in Association With the Number of Indicators of SMM Arising From 23 Weeks’ Gestation Up to 42 Days After Birth

No. SMM IndicatorsNo. Infant Deaths (Rate per 1000)RR of Infant Death (95% CI)
UnadjustedAdjusteda
0 (n = 1 865 791) 5289 (2.8) 1.00 (referent) 1.00 (referent) 
1 (n = 14 929) 114 (7.6) 2.69 (2.23–3.24) 2.52 (2.09–3.04) 
2 (n = 2905) 33 (11.4) 4.01 (2.84–5.66) 3.67 (2.61–5.17) 
3 (n = 977) 9 (9.2) 3.18 (1.62–6.24) 3.00 (1.54–5.86) 
4 (n = 432) 6 (13.9) 4.90 (2.21–10.88) 4.81 (2.17–10.67) 
≥ 5 (n = 344) 12 (34.9) 12.12 (6.83–21.50) 12.13 (6.85–21.48) 
No. SMM IndicatorsNo. Infant Deaths (Rate per 1000)RR of Infant Death (95% CI)
UnadjustedAdjusteda
0 (n = 1 865 791) 5289 (2.8) 1.00 (referent) 1.00 (referent) 
1 (n = 14 929) 114 (7.6) 2.69 (2.23–3.24) 2.52 (2.09–3.04) 
2 (n = 2905) 33 (11.4) 4.01 (2.84–5.66) 3.67 (2.61–5.17) 
3 (n = 977) 9 (9.2) 3.18 (1.62–6.24) 3.00 (1.54–5.86) 
4 (n = 432) 6 (13.9) 4.90 (2.21–10.88) 4.81 (2.17–10.67) 
≥ 5 (n = 344) 12 (34.9) 12.12 (6.83–21.50) 12.13 (6.85–21.48) 
a

Adjusted for maternal age (continuous); residential income quintile (quintile 1 or missing, quintiles 2–5); rural residence; world region (Canada or long-term resident, Caribbean or sub-Saharan Africa, South Asia, East Asia or Pacific, other or unknown), each at the time of the index birth; as well as diabetes mellitus and chronic hypertension within 2 years before the index birth.

Out of 19 587 pregnancies with SMM, 4523 (23.1%) had maternal sepsis. Relative to births without SMM, the adjusted OR for infant death from sepsis was 1.95 (95% CI 1.10–3.45) associated with non–sepsis-related SMM and 6.36 (95% CI 3.50–11.55) with sepsis-related SMM (Table 4).

TABLE 4

Multinomial Logistic Regression Analysis: OR of Sepsis-Related Infant Mortality Within 365 Days of Birth in Association With SMM, With or Without Sepsis, Arising From 23 Weeks’ Gestation Up to 42 Days After Birth

Nature of SMMNo. Infant Deaths (Rate per 1000 Live Births)Adjusted OR of Infant Death (95% CI)b
Not Sepsis RelatedSepsis RelatedNot Sepsis RelatedSepsis Related
No SMM (n = 1 865 791) 4618 (2.5) 671 (0.4) 1.00 (referent) 1.00 (referent) 
SMM without sepsis (n = 15 064)a 114 (7.6) 12 (0.8) 2.89 (2.39–3.48) 1.95 (1.10–3.45) 
SMM with sepsis (n = 4523)a 37 (8.2) 11 (2.4) 3.15 (2.28–4.36) 6.36 (3.50–11.55) 
Nature of SMMNo. Infant Deaths (Rate per 1000 Live Births)Adjusted OR of Infant Death (95% CI)b
Not Sepsis RelatedSepsis RelatedNot Sepsis RelatedSepsis Related
No SMM (n = 1 865 791) 4618 (2.5) 671 (0.4) 1.00 (referent) 1.00 (referent) 
SMM without sepsis (n = 15 064)a 114 (7.6) 12 (0.8) 2.89 (2.39–3.48) 1.95 (1.10–3.45) 
SMM with sepsis (n = 4523)a 37 (8.2) 11 (2.4) 3.15 (2.28–4.36) 6.36 (3.50–11.55) 
a

Out of 19 587 live births with SMM, 4523 (23.1%) had a sepsis diagnosis therein.

b

Analyzed by using multinomial logistic regression analysis; adjusted for maternal age (continuous); residential income quintile (quintile 1 or missing, quintiles 2–5); rural residence; world region (Canada or long-term resident, Caribbean or sub-Saharan Africa, South Asia, East Asia or Pacific, other or unknown), each at the time of the index birth; as well as diabetes mellitus and chronic hypertension within 2 years before the index birth.

Relative to the absence of SMM, the risks of stillbirth (aRR 6.22; 95% CI 5.69–6.81), neonatal death (aRR 3.33; 95% CI 2.79–3.97), and postneonatal death (aRR 2.12; 95% CI 1.56–2.89) were all higher in those whose mother had SMM (Supplemental Table 7).

In this large population-based study of 1.9 million singleton maternal-infant pairs, SMM was strongly associated with infant mortality as well as with stillbirth. As the number of SMM indicators rose, so did the risk of infant death. A coupling tendency was observed between a woman having SMM marked by sepsis and her infant dying from sepsis.

Recognized risk factors for neonatal mortality at birth include extreme preterm weight, severe growth restriction, and a low 5-minute Apgar score.29,30  Sepsis, lethal congenital or chromosomal anomalies, and sudden infant death syndrome are causes of postneonatal death.31  Recent discussion32  and data33  have emerged about an association between stillbirth and SMM, as well as the relation between stillbirth and maternal death after delivery. For example, among 3.2 million births in Ontario, the maternal mortality rate in the first year delivery was 206 per 100 000 stillbirths compared to 23 per 100 000 live births.33  Among 97 095 women who gave birth in 12 Latin American countries, early neonatal death was associated with SMM, with an OR of 4.77 (95% CI 3.74–6.07).34 

To our knowledge, this is the first study linking SMM with infant mortality, including adjusting for sociodemographic factors like maternal age, income status, and world region of origin, and further stratifying by conventional risk factors for perinatal mortality. As in a previous report of a curvilinear rise in the risk of maternal death with the number of SMM indicators,2  the same pattern for infant mortality was seen in the current study.

This study included almost 2 million singleton maternal-infant pairs within a universal health care system, including 99% of all eligible hospital births over a 15-year period,2,13,16,17  thereby avoiding selection bias. It is unlikely that infrequent outward migration of infants materially altered the current findings, such as the undercapture of infant deaths. The completeness of these population-based data sets enabled precise and generalizable estimates of the rates and risks of infant death. Only singleton births were included herein, so the relation between SMM and infant mortality might differ for multiple births. For example, twins and triplets experience greater neonatal mortality from preterm birth, fetal growth restriction, twin-twin transfusion syndrome, and major congenital abnormalities,18  and their mothers tend to experience greater SMM (eg, preeclampsia).35  Hence, further study is needed about SMM and infant mortality in multifetal pregnancies. Stratifying by gestational age of <32 weeks neutralized any apparent relation (Fig 2B) likely because of collider stratification bias, as described elsewhere.36 

There is no single international definition of SMM, but the Canadian version employed herein has been validated against maternal mortality and hospital length of stay, is similar to that used by the US Centers for Disease Control and Prevention,2,5,6,19  and aligns with the World Health Organization’s definition of severe acute maternal morbidity (maternal near miss).37  Although SMM may have been based on inaccurate or incorrect use of ICD-10-CA and CCI codes, CIHI periodically completes data quality checks to assess coding accuracy. Although some SMM events may have occurred postpartum, the majority arise antepartum and intrapartum largely because of severe preeclampsia or eclampsia, major obstetric hemorrhage, and sepsis.32  Not all SMM indicators represent a sentinel event, defined as “a patient safety event (not primarily related to the natural course of the patient’s illness or underlying condition) that reaches a patient and results in any of the following: death, permanent harm, or severe temporary harm.”38  Only sepsis from an overall SMM construct was additionally investigated as an exposure. However, other indicators of SMM (eg, placenta previa with hemorrhage) may also affect fetal and neonatal outcomes such as prematurity and low birth weight.39  Hence, it is worth conducting further studies to explore each indicator of SMM and perinatal, neonatal, and infant outcomes. Some common preexisting or chronic conditions (eg, prepregnancy diabetes mellitus and/or chronic hypertension) can adversely influence placental and fetal growth and well-being over time and then evolve into an acute SMM event (eg, severe preeclampsia). Although the current analysis did not distinguish between such chronic and acute factors contributing to SMM, antecedent maternal diabetes mellitus and chronic hypertension were adjusted for.

In North America, the incidence of SMM has increased over the past 2 decades.5,7  Although some SMM indicators (eg, amniotic fluid embolism) are rare, hard to predict, and even tougher to prevent, other SMM indicators are seemingly more preventable and manageable, creating potential opportunities to not only reduce maternal mortality but infant mortality as well. In New Zealand, for example, authors of a multidisciplinary review of SMM suggested that at least one-third of cases are preventable.40  In the United States, a nationwide hospital-level implementation of the Maternal Early Warning Trigger tool significantly reduced the incidence of SMM.19  The effect such a tool has on perinatal mortality remains unknown and requires further investigation. For infant mortality and stillbirth, because the risk of these outcomes may differ by the nature of the SMM, application to each SMM indicator of something like a number needed to prevent might provide insight about which indicator(s) warrants the greatest focus, are most common, or most linked to both maternal and a perinatal death.13  Certainly, one starting point example is the use of low-dose acetylsalicylic acid for the prevention of preeclampsia,41  fetal growth restriction,42  and preterm birth,43  which are all risk factors for stillbirth,44  neonatal death, and prolonged hospital length of stay.45 

It is also of interest that we observed a coupling tendency between sepsis-related SMM and sepsis-related infant death, which is consistent with emerging evidence.15  The Global Maternal and Neonatal Sepsis Initiative aims to “accelerate the reduction of preventable maternal and neonatal deaths related to sepsis.”14  The timing of maternal infection during pregnancy and the postpartum period was not analyzed herein nor was the onset of infant infection. The responsible pathogen(s) for maternal and infant infection was also not documented. Even so, reducing maternal sepsis should, in theory, reduce newborn sepsis as well.

Risk of infant death is greater in the presence of SMM, including a dose-response effect, as is the risk of stillbirth. A coupling tendency exists between sepsis-related SMM and sepsis-related infant death. There now exists a promising opportunity to identify preventable SMM and facilitate care that may limit both the progress of SMM and reduce perinatal mortality.

Dr Aoyama conceived the manuscript, developed the protocol, provided input on the interpretation, and wrote the initial draft of the manuscript; Ms Park conceived the manuscript, developed the protocol, performed analyses, provided input on the interpretation, helped draft the final version, and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis; Mr Davidson developed the protocol, provided input on the interpretation, and helped draft the final version; Dr Ray conceived the manuscript, developed the protocol, performed analyses, provided input on the interpretation, and wrote the initial draft of the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. This study also received funding from the Canadian Institutes of Health Research. Parts of this material are based on data and information compiled and provided by the Ontario Ministry of Health and Long-Term Care and Canadian Institute for Health Information. This study is also based in part on data provided by the Better Outcomes Registry and Network, part of the Children’s Hospital of Eastern Ontario. The interpretation and conclusions contained herein do not necessarily represent those of the Better Outcomes Registry and Network. Dr Aoyama received an Outcomes Research Award from the Department of Anesthesia and Pain Medicine, The Hospital for Sick Children. The funding and data sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.

     
  • aRR

    adjusted relative risk

  •  
  • BORN

    Better Outcomes Registry and Network

  •  
  • CCI

    Canadian Classification of Health Interventions

  •  
  • CI

    confidence interval

  •  
  • CIHI

    Canadian Institute for Health Information

  •  
  • ICD-10-CA

    International Classification of Diseases 10th Revision Canada

  •  
  • OHIP

    Ontario Health Insurance Plan

  •  
  • OR

    odds ratio

  •  
  • RPDB

    Ontario Ministry of Health’s Registered Persons Database

  •  
  • RR

    relative risk

  •  
  • SMM

    severe maternal morbidity

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data