High maternal mortality rate associated with advanced maternal age in Japan

This study aimed to clarify the relationship between maternal mortality and advanced maternal age in Japan and to provide useful information for future perinatal management. Maternal death rates by age group were investigated for all maternal deaths in Japan for an 11-year period, from 2010 to 2021. Maternal deaths among those aged ≥ 40 years were examined in detail to determine the cause, and the number of deaths by cause was calculated. The causes of onset of the most common causes of death were also investigated. The maternal mortality rates were 0.8 (95% confidence interval [CI] 0.3–4.7) for < 20 years, 2.6 (95% CI 1.7–3.8) for 20–24 years, 2.9 (95% CI 2.3–3.6) for 25–29 years, 3.9 (95% CI 3.3–4.5) for 30–34 years, 6.8 (95% CI 5.9–7.9) for 35–39 years, and 11.2 (95% CI 8.8–14.3) for ≥ 40 years of age. Patients who were ≥ 40 years of age had a significantly higher mortality rate compared to that in other age groups. Hemorrhagic stroke was the most common cause of death in patients aged ≥ 40 years (15/65 [23%]), and preeclampsia (8/15 [54%]) was the most common cause of hemorrhagic stroke. Maternal mortality is significantly higher in older than in younger pregnant women in Japan, with hemorrhagic stroke being the most common cause of maternal death among women > 40 years of age. More than half of hemorrhagic strokes are associated with hypertension disorder of pregnancy. These facts should be considered by women who become pregnant at an advanced age and by healthcare providers involved in their perinatal care.


Results
Overall maternal deaths and international classification of diseases maternal mortality (ICD-MM) classification system.Between 2010 and 2021, 512 maternal deaths were registered in the Maternal Death Registration Project.The number of births in Japan during the same period was 11,557,975 cases.Of the 512 maternal deaths, 335 (65.4%) were direct deaths and 150 (29.3%) were indirect deaths.Twentyseven (5.3%) were unclassifiable.
Maternal mortality in the 40 years and older group.Table 2 and Fig. 2 shows the background data and the number of cases of maternal mortality among those aged ≥ 40 years.The most common cause of death was hemorrhagic stroke (15/65 [23%]), followed by obstetric hemorrhage (8/65 [12%]) and suicide (8/65 [12%]).The maternal mortality rates of hemorrhagic stroke, pulmonary thromboembolism, and suicide were significantly higher among those aged ≥ 40 years than among the other age groups (P < 0.01 for hemorrhagic stroke, pulmonary thromboembolism, and suicide).Figure 3 shows a breakdown of the causes of hemorrhagic stroke, the most common cause of death.The most common causes of hemorrhagic stroke were preeclampsia (

Discussion
This study is the first to report on the relationship between age and maternal mortality in Japan.Two important new findings were extracted from the present study.First, AMA in Japan was found to be associated with a significantly higher maternal mortality rate than that noted among pregnancies at a younger age in this study.Previous studies have also reported that an increase in maternal age is associated with an increase in various obstetric complications and maternal mortality [19][20][21] .The results of the present study are similar to those previously reported.However, Maternal mortality was notably lower among women younger than 20 years of age, a point of difference.Second, this is a clarification of the causes of maternal mortality among women over 40 years of age.
Although the rate of chronic diseases, such as malignant, cardiovascular, and renal diseases, as comorbidities is increased among AMA cases 22 , the rate of their involvement as a cause of death was low.The most common cause of death in the AMA group in this study was hemorrhagic stroke.The association of hemorrhagic stroke, rather than stroke, with maternal mortality is a problem unique to Asian populations 23,24 , and more than half of the deaths due to hemorrhagic stroke were associated with preeclampsia.In general, the overall incidence of preeclampsia is reported to be 3-4% but increases to 5-10% in those aged 40-49 years and to 35% in those aged > 50 years 25 .In addition, at ≥ 40 years, the relative risk of mortality was reported to be 1.68 (95% CI 1.23-1.39)for first-time mothers 26 .It is clear that the incidence of preeclampsia increases in AMA cases 27 .Older Japanese and Asian pregnant women are more likely to develop hemorrhagic stroke 28,29 , and adequate attention should be paid to the development of hemorrhagic stroke due to preeclampsia.Further, in Asian populations, uterine artery Doppler, angiogenesis factors, and aspirin therapy should be used to monitor and prevent the occurrence of hypertensive nephropathy in pregnant women > 40 years old.Among assisted reproductive therapies, frozen-thawed embryo transfer and egg donation in particular have been reported to be risk factors for preeclampsia 30,31 .In the present study, the proportion of maternal mortality cases at age ≥ 40 years among those who had undergone assisted reproductive therapy was low.In addition, there were no cases of maternal mortality due to hemorrhagic stroke caused by preeclampsia among assisted reproductive therapy-induced pregnancy cases.The proportion of assisted reproductive technology-induced pregnancies in Japan is expected to increase in the future, as increasing age increases the dependence on assisted reproductive technology.Therefore, it is important to be aware of the possibility of developing preeclampsia after the use of assisted reproductive technology.
In addition to hemorrhagic stroke, pulmonary thromboembolism, infectious diseases, cardiovascular diseases, and suicide significantly increased maternal mortality in older pregnant women, suggesting that we should not focus solely on hemorrhagic stroke as a cause of maternal mortality.
This study showed that the maternal mortality rate increased with AMA in Japan.This is consistent with reports from other developed countries 3,32 .However, other developed countries have higher rates of maternal mortality among young women as well as among AMA cases, indicating a bimodal nature of this association, while the maternal mortality rate among women aged < 20 years in Japan was low.In the United Kingdom, the maternal mortality rate among pregnant women aged 20-29 years is the lowest, and the maternal mortality rates for pregnancies among those < 20 years of age and ≥ 30 years increased compared to those among pregnant women in their 20 s 3 .In addition, Japan provides generous medical insurance coverage to all citizens regardless of the financial status.During pregnancy, women are given a medical checkup slip almost free of charge and can visit a hospital every four weeks in the first trimester, every two weeks in the second trimester, and every week in the last trimester of pregnancy.Further, the groups enrolled in this study were almost exclusively Japanese, which provided a sample cohort that is less prone to biases other than age.
The limitations of this study include, first, that it was a mono-ethnic study and did not adjust the maternal mortality rates for several confounding factors, although the Japanese insurance system provides a background for the uniform provision of medical care.Second, although we had detailed data on deaths, we did not have detailed data on survivors.Third, we did not have information on hospital resources, infrastructure, and staff that contribute to maternal mortality and risk.It is not possible to determine whether high-risk women benefit from being in a particular healthcare setting.Fourth, because of the relatively low maternal mortality rates, the denominators for some of the groups were relatively small, making it impossible to make meaningful comparisons between the groups in terms of mortality rates.
In conclusion, maternal mortality increased proportionally with age in Japan.In particular, the mortality rate was 2.3 times higher for those aged ≥ 40 years than for those aged 35-39 years.In addition, hemorrhagic stroke was the most common cause of maternal mortality among those aged ≥ 40 years, and more than half of the hemorrhagic strokes were associated with preeclampsia.These facts should be considered by women who become pregnant at an advanced age and by healthcare providers involved in their perinatal care.

Conclusion
Maternal mortality rates were significantly higher among older pregnant women than among younger pregnant women in Japan, with hemorrhagic stroke being the most common cause of maternal death among women > 40 years of age.More than half of the hemorrhagic strokes were associated with preeclampsia.These

Figure 1 .
Figure 1.(A) Maternal deaths by age group.(B) Maternal mortality rates by age group.

Figure 3 .
Figure 3. Causes of hemorrhagic stroke in maternal deaths among those over 40 years of age.

Table 1 .
Maternal death rate for each causative disease according to age group.