Age and Maternal Mortality in Japan: Increased Maternal Mortality in Advanced Maternal Age

doi:10.21203/rs.3.rs-2726093/v1

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Age and Maternal Mortality in Japan: Increased Maternal Mortality in Advanced Maternal Age

https://doi.org/10.21203/rs.3.rs-2726093/v1

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published 09 Aug, 2023

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Objectives: 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.

Methods: 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 of death, and the number of deaths by cause was calculated. The causes of onset of the most common causes of death were also investigated.

Results: The maternal mortality rates were 0.8 (95% confidence interval [CI], 0.3-4.7) for <20 years of age, 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. Patients who were ≥40 years of age had a significantly higher mortality rate compared to 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.

Conclusion: Maternal mortality is significantly higher in older pregnant women 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 gestational hypertensive nephropathy. These facts should be considered by women who become pregnant at an advanced age and by healthcare providers involved in their perinatal care.

Health sciences/Diseases

Health sciences/Health care

Maternal death

Maternal age

Advanced maternal age

Hemorrhagic stroke

Pregnancy

This study aimed to determine the relationship between advanced maternal age and maternal mortality. All maternal deaths in Japan were investigated from 2010 to 2021 and categorized according to age and cause of death. We found that women aged ≥40 years had a significantly higher mortality rate than younger women and the most common cause of death was hemorrhagic stroke. We have found that increased maternal age significantly increases the risk of maternal mortality, thus, clinicians should be mindful when treating older pregnant women.

There has been an increase in the number of older women who are pregnant, and advanced maternal age (AMA) has been increasing yearly worldwide (1–5). Increasing the age of pregnancy increases various maternal complications (5–7). A study done in Japan reported that AMA increases the need for cesarean section and the risk for gestational hypertensive nephropathy, placenta previa, and preterm delivery (6). It has also been reported that AMA increases the risk of cervical incompetence, gestational diabetes, preterm water breaking, and preterm delivery (5, 7).

AMA has been reported to increase various maternal complications as well as maternal mortality (3). It is predicted that the number of pregnancies at older ages will increase in the future owing to advances in assisted reproductive technologies and lifestyle changes. The relationship between age and maternal mortality in Japan has never been studied. This study aimed to clarify the relationship between maternal mortality and AMA in Japan and to provide useful information that will contribute to future perinatal management.

Maternal mortality data

All maternal deaths in Japan during the 11-year period of 2010–2021 were included. Information on maternal deaths was obtained from data registered in the Maternal Death Registration Project of the Japan Society of Obstetricians and Gynecologists, which was launched in 2010 and covers all maternal deaths in Japan.

Age groups

Registered maternal deaths were categorized by age: <20, 20–24, 25–29, 30–34, 35–39, and ≥ 40 years, and the maternal mortality rate was calculated for each age group.

Maternal mortality rates were calculated for each age group by the major cause of death in Japan. Maternal mortality rates is maternal the number of maternal death per 100,000 birth. No statistical adjustment was made because the population was almost exclusively Japanese, there were no racial differences, and there was no disparity in access to medical care due to the national medical insurance and free maternal health checkup systems.

Maternal deaths among pregnant women aged 40 years and older

Maternal deaths among women aged ≥ 40 years were examined in detail to determine the causes of death, and the number of deaths by cause was calculated. The causes of onset were also investigated for diseases leading to the highest number of deaths.

Statistical analysis

Statistical analyses were performed to determine perinatal mortality using JMP 13.2.0 (SAS Institute Inc., Cary, NC, USA). Unless otherwise specified, univariate statistics and 95% confidence intervals (CI) were calculated for the primary endpoint, perinatal mortality. Comparisons of perinatal mortality were performed using the Mann-Whitney U test. Statistical significance was set at p < 0.05.

Number of deaths and maternal mortality rates by age group

Between 2010 and 2021, 512 maternal deaths were registered in the Maternal Death Registration Project. The number of maternal deaths by age group was as follows: <20 years, 1 case; 20-24 years, 26 cases; 25-29 years, 89 cases; 30-34 years, 161 cases; 35-39 years, 176 cases; and 40 years, 65 cases (Figure 1A).

Maternal mortality rates by age group are shown in Figure 1B. The maternal mortality rates were 0.8 (95% CI, 0.3-4.7) for those <20 years, 2.6 (95% CI, 1.7-3.8) for those 20-24 years, 2.9 (95% CI, 2.3-3.6) for those 25-29 years, 3.9 (95% CI, 3.3-4.5) for those 30-34 years, 6.8 (95% CI, 5.9-7.9) for those 35-39 years, and 11.2 (95% CI, 8.8-14.3) for those ≥40 years of age. Pregnant women ≥40 years of age had significantly higher mortality rates compared to other age groups. The maternal mortality rates by cause are shown in Table 1.

Maternal mortality in the 40 years and older group

Table 2 and Figure 2 shows the background 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. Figure 3shows a breakdown of the causes of hemorrhagic stroke, the most common cause of death. The most common causes of hemorrhagic stroke were preeclampsia (8/15 [54%]), cerebral aneurysm (2/15 [13%]), cerebral arteriovenous malformation (2/15 [13%]), moyamoya disease (1/15 [7%]), and unknown (2/15 [13%]).

In this study, AMA in Japan was found to be associated with a significantly higher maternal mortality rate than pregnancies at a younger age. Previous studies have also reported that an increase in maternal age is associated with an increase in various obstetric complications and maternal mortality (9-11). The results of the present study are similar to those previously reported.

Although the comorbidity of chronic diseases such as malignant, cardiovascular, and renal diseases is increased in AMA (12), 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 (13, 14), and more than half of the deaths due to hemorrhagic stroke were associated with gestational hypertensive nephropathy. In general, the incidence of gestational hypertensive nephropathy is reported to be 3-4% but increases to 5-10% in those 40-49 years of age and to 35% in those >50 years of age (15). 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 (16). It is clear that the incidence of gestational hypertensive nephropathy is increased in AMA, especially in pregnant older Japanese and Asian women, and adequate attention should be paid to the development of hemorrhagic stroke due to gestational hypertensive nephropathy during pregnancy. When restricted to 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 (17, 18). In the present study, the proportion of women who had undergone assisted reproductive medical treatment and those with mortality at age ≥ 40 years was low. In addition, there were no cases of maternal mortality due to hemorrhagic stroke caused by gestational hypertensive nephropathy among those who had undergone assisted reproductive therapy-induced pregnancy. 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 gestational hypertensive nephropathy 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. This also suggests that we should not focus solely on hemorrhagic stroke.

In Japan, the maternal mortality rate in women <20 years of age 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 increase compared to those among pregnant women in their 20s (3). This is the major difference between Japan and other countries. Japan has a lower rate of pregnancies in women under the age of 20 years compared to other countries. 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. In addition to the Japanese health care system, the racial groups enrolled in this study were almost exclusively Japanese, which provides a background that is less prone to biases other than age.

The limitations of this study include, first, that it is a mono-ethnic study and does not adjust for maternal mortality owing to several confounding factors, although the Japanese insurance system provides a background for the uniform provision of medical care. Second, although we have detailed data on deaths, we do not have detailed data on survivors. Third, we did not have information on hospital sources, 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, increasing age is proportional to maternal mortality in Japan. In particular, the mortality rate is 2.3 times higher for those aged ≥40 years than for those aged 35-39 years. In addition, hemorrhagic stroke is the most common cause of maternal mortality among those aged ≥ 40 years, and more than half of hemorrhagic strokes are associated with gestational hypertensive nephropathy. These facts should be considered by women who become pregnant at an advanced age and by healthcare providers involved in their perinatal care.

Maternal mortality is significantly higher in older pregnant women 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 gestational hypertensive nephropathy. These facts should be considered by women who become pregnant at an advanced age and by healthcare providers involved in their perinatal care.

Ethics approval

This study was approved by the ethics boards of the National Cerebral and Cardiovascular Center, Osaka, Japan, and the Japan Association Obstetricians and Gynecologists.

Consent to participate

Not applicable

Availability of data and material

The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Competing interests

The authors have no conflicts of interest to declare.
Funding

None
Authors' contributions

Dr. Hiroaki Tanaka 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.

Concept and design: Hiroaki Tanaka.

Acquisition, analysis, or interpretation of data: Hiroaki Tanaka and Junichi Hasegawa.

Drafting of the manuscript: Hiroaki Tanaka, Kayo Tanaka.

Critical revision of the manuscript for important intellectual content: Tatsuya Arakaki, Masamitsu Nakamura, Eijiro Hayata, Masahiko Nakata, Akihiko Sekizawa, and Isamu Ishiwata

Statistical analysis: Hiroaki Tanaka, Shinji Katsuragi, Kayo Tanaka.

Administrative, technical, or material support: Hiroaki Tanaka, Tatsuya Arakaki, Masamitsu Nakamura, Eijiro Hayata, Masahiko Nakata, Akihiko Sekizawa, and Isamu Ishiwata

Supervision: Shinji Katsuragi, Tatsuya Arakaki, Masamitsu Nakamura, Eijiro Hayata, Masahiko Nakata, Takeshi Murakoshi, Akihiko Sekizawa, Isamu Ishiwata, and Tomoaki Ikeda.

All authors have read and approved the manuscript
Acknowledgements

None

Ministry of Health, Labour and Welfare. Special Report on Demographic Statistics. Update 2021. https://www.mhlw.go.jp/toukei/saikin/hw/jinkou/tokusyu/syussyo07/dl/gaikyou.pdf. [Accessed October 20, 2022].
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Table 1

Maternal death rate for each causative disease according to age group.
Age (years)	19≥	20–24	25–29	30–34	35–39	≥ 40
Obstetric hemorrhage	-	0.15	0.49	1.18	2.14	1.44
Amniotic fluid embolism	-	0.15	0.31	0.54	1.26	1.26
Hemorrhagic stroke	-	0.59	0.72	0.61	1.15	2.69
Pulmonary embolism	-	-	0.54	0.44	0.66	1.08
Infection	-	0.44	0.36	0.57	0.60	0.90
Cardiovascular disease	0.86	0.59	0.36	0.54	0.60	0.72
Suicide	-	0.44	0.31	0.34	0.93	1.44
Malignant disease	-	-	0.09	0.37	0.49	0.36
Other	-	0.88	0.40	0.47	0.71	0.90
Unknown	-	0.59	0.40	0.41	0.99	0.90

Table 2

Background of advanced maternal age (N = 65)
Age at delivery (years)	Case (%)
40	21 (32)
41	18 (28)
42	8 (12)
43	8 (12)
44	3 (5)
45	6 (9)
≥ 46	1 (2)
Parity
0	23 (36)
1	13 (20)
2	15 (23)
3	6 (9)
≥ 4	6 (9)
Unknown	2 (3)
Conception
Spontaneous	43 (67)
Assisted reproduction	7 (10)
Unknown	15 (23)
Multiple pregnancy
Yes	1 (2)
No	64 (98)
Body mass index
18–24	29 (45)
25–29	26 (40)
30–34	5 (7)
35–39	4 (6)
≥ 40	1 (2)
Any pre-existing medical or mental health problem
Yes	16 (25)
No	49 (75)

No competing interests reported.

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Journal Publication

published 09 Aug, 2023

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Editorial decision: Major revision
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Editor invited by journal
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You are reading this latest preprint version

Age and Maternal Mortality in Japan: Increased Maternal Mortality in Advanced Maternal Age

Status:

Journal Publication

Version 1

Abstract

Figures

Synopsis

Introduction

Materials And Methods

Maternal mortality data

Age groups

Maternal deaths among pregnant women aged 40 years and older

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Journal Publication

Version 1