Introduction of advanced maternal age based on mortality-specific severe morbidity

Abstract

Advanced maternal age was introduced into obstetric medicine in the 1980s when Dr. Hook found the risk of genetic abnormalities, pregnancy loss, and infertility were increased in pregnant women over age 35.¹ This observation has been reaffirmed in subsequent larger scale studies.² Despite these risks, birth rates continue to increase for individuals over age 35, with recent data showing a 5% and 12% increase for females aged 40–44 and over age 45, respectively.³

Increasing maternal age is also associated with an elevated risk of maternal delivery complications.⁴ While the concept of advanced maternal age originated primarily on genetic risks and pregnancy outcomes, given the rise in maternal age and the parallel increase in severe maternal morbidity, it is worthwhile to broaden the definition of “advanced maternal age” to include severe maternal morbidity at delivery. The objective of the current study was to examine the association between maternal age at delivery and concomitant severe maternal morbidity and mortality.

The University of Southern California Institutional Review Board deemed this study exempt due to the use of publicly available, deidentified data (HS-16-00481). This cross-sectional study utilized the Healthcare Cost and Utilization Project's National Inpatient Sample.⁵ The study population was comprised of 21 512 807 hospital deliveries from 2016 to 2021.

For the first-step analysis, a Poisson log-linear regression model was created to identify the Centers for Disease Control and Prevention-defined severe maternal morbidity indicators independently associated with maternal death at delivery. A total of 20 indicators were included in the initial modeling per their definitions,⁶ and conditional backward selection method was used to retain only the significant indicators at the level of P < 0.05 in the final stopping rule.

In the second-step analysis, a linear segmented regression model with log-transformation utilizing 1-year age increments was fitted to identify the inflection point of maternal age for the occurrence of core-morbidity indicators defined in the prior step. The inflection points were identified in the automated fashion. In this exploratory analysis (i) advanced maternal age was defined as the first inflection point of maternal morbidity; and (ii) very advanced maternal age in this study was defined as the maternal age that the core-morbidity incidence rate first reached to 10 per 1000 deliveries in a view of prior investigations.⁷

The last-step analysis was to assess the association between very advanced maternal age and core-morbidity risk, adjusting for priori clinical obstetric characteristics (year, hypertensive disorder, diabetes mellitus, obesity, asthma, prior uterine scar, gestational age at delivery, and delivery route). In a sensitivity analysis, this exposure-outcome association was examined according to race and ethnicity (five most frequent groups: White, Black, Hispanic, Asian, and American Indian). Race and ethnicity were examined as these factors were associated with severe maternal morbidity and mortality.

Among 20 severe maternal morbidity indicators per the Centers for Disease Control and Prevention definition, 12 were independently associated with maternal death (in descending order of odds ratio): Acute respiratory distress syndrome, cardiac arrest/ventricular fibrillation ventilation, sickle cell disease crisis, sepsis, cardiac rhythm conversion, disseminated intravascular coagulation, heart failure/arrest, amniotic fluid embolism, acute myocardial infarction, puerperal cerebrovascular disorders, and shock (all, adjusted-P < 0.001; Table S1).

The incidence of these core-morbidity indicators started increasing past patients aged 32 years and reached a maximum of 10 per 1000 deliveries at patients aged 44 years (Figure 1). Accordingly, the cohort was categorized into three groups: non-advanced maternal age (≤32 years), advanced maternal age (33–44 years), and very advanced maternal age (≥45 years).

After controlling for clinical obstetric characteristics, the risk of developing core-morbidity compared to patients aged ≤32 years was increased by 21% for patients aged 33–44 years (adjusted-odds ratio [aOR] 1.21, 95% CI: 1.19–1.22) and by 49% for patients aged ≥45 years (aOR 1.49, 95% CI: 1.37–1.61), respectively (Table S2). When assessing for race and ethnicity (Table S2), the increased risks of core-morbidity for patients aged ≥45 years versus ≤32 years was particularly high in American Indian (aOR 6.06, 95% CI: 3.21–11.41) and Asian patients (aOR 2.11, 95% CI: 1.76–2.53).

The results of this contemporary, logic-based investigation suggest that maternal age thresholds of 33 and 45 years may represent inflection points where an increased risk of mortality-specific severe maternal morbidity is present. The concept that increasing maternal age is associated with worse obstetric outcomes partly aligns with prior studies⁸; however, the current study provides a unique perspective on risk stratification by age. This data can assist in triaging and counseling patients with potentially increased risks of serious and possibly fatal complications at delivery.

Key limitations of this study included the lack of information on cause of death, unknown definition and severity of measured morbidity as solely relying on administrative codes, and the inability to assess the accuracy of data due to the lack of actual medical record review. Despite these limitations, the results of the present study are novel and are clinically compelling considering the increasing severe maternal morbidity and mortality at delivery.

Aaron D. Masjedi and Koji Matsuo: Conceptualization. Rachel S. Mandelbaum: Data curation. Koji Matsuo: Formal analysis. Koji Matsuo: Funding acquisition. All authors: Investigation. Koji Matsuo: Methodology. Koji Matsuo: Project administration. Joseph G. Ouzounian: Resources. Rachel S. Mandelbaum and Koji Matsuo: Software. Joseph G. Ouzounian and Koji Matsuo: Supervision. Koji Matsuo: Validation. Koji Matsuo: Visualization. Aaron D. Masjedi and Koji Matsuo: Writing—original draft. All authors: Writing—review and editing. Koji Matsuo affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. The National Inpatient Sample is developed for the Healthcare Cost and Utilization Project that is sponsored by the Agency for Healthcare Research and Quality, and the program is the source of the de-identified data used; race/ethnicity was grouped by the program; and the program has not verified and is not responsible for the statistical validity of the data analysis or the conclusions derived by the study team.

Ensign Endowment for Gynecologic Cancer Research (Koji Matsuo). The funder 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 manuscript and decision to submit the manuscript for publication.

The authors confirm there are no conflicts of interest.