By Dawn Fallik
August 16, 2018
ARTICLE IN BRIEF
PRECAUTIONS should be taken to monitor mothers with grand multiparity beyond their pregnancies for heightened risk for Alzheimer's disease, study authors suggest.
Researchers reported that women who had five or more complete pregnancies had about a 1.7-fold higher risk of AD than those who experienced one to four completed pregnancies. Those who had incomplete pregnancies had about half of the level of AD risk than those who were never pregnant.
Women who have given birth to more than five children run a higher risk of developing Alzheimer's disease (AD) than those with fewer or no children, according to a study in the July 18 online edition of Neurology.
The researchers said they were unsure of the causation but said that patients and doctors should be made aware of the risks, and that precautions should be taken to monitor mothers with grand multiparity beyond their pregnancies.
The study followed 3,549 women to assess the associations of completed and incomplete pregnancy with the risks of mild cognitive impairment and AD. They found that women who had five or more complete pregnancies showed about a 1.7-fold higher risk of AD than those who experienced one to four completed pregnancies. Those who had incomplete pregnancies had about half of the level of AD risk than those who were never pregnant.
The lead author, Ki Woong Kim, MD, PhD, a psychiatrist in the department of neuropsychiatry at Seoul National University College of Medicine in Korea, said that based on previous research, the team expected that pregnancy may be associated with the risk of AD, but they were “quite surprised” that incomplete pregnancy was associated with the lower risk of AD.
The researchers drew data from two member studies of the Cohort Studies of Memory in an International Consortium, one group from Korea and the other from Greece. Participants who took hormone replacement therapy or had a history of oophorectomy or hysterectomy were excluded.
The investigators speculated that sex hormones such as estradiol may play key roles in the effect of multiple childbirths on the risk of AD.
Estradiol, the most potent form of estrogens, gradually increases during pregnancy, and its levels in the third trimester are more than 10 times higher than the highest level of estradiol in the menstrual period. After childbirth, levels of estradiol abruptly decrease and return to physiological levels in the menstrual period within 48 hours, said Dr. Kim.
“Extremely high levels of estrogen during pregnancy and the abrupt withdrawal of estrogen after childbirth may be harmful to neurons and decrease brain or cognitive reserve,” Dr. Kim wrote in an email from Korea.
“Furthermore, levels of free estrogen in menopausal women are lower in women with multiple childbirths than in primiparous women even after childbirth. Lower levels of estrogen, which have a neuroprotective effect against neurotoxic amyloid-beta, may increase the risk of AD.”
Dr. Kim said the study did not investigate the impact of higher-risk pregnancies on AD, but that it may be useful for medical doctors to identify reproductive histories to identify high risk groups of AD in women.
“In grand multiparous women, cognitive function should be evaluated regularly in late life and preventive strategies against AD such as cognitive enhancement training, regular diet and exercise should be emphasized to reduce the risk of AD,” said Dr. Kim.
Dr. Kim said that the researchers will focus next on incomplete pregnancies.
“Based on this result, we are going to develop a pulse hormone replacement therapy that can induce similar hormonal changes to those induced in the first trimester of pregnancy, and to evaluate its efficacy in reducing the risk of AD in women,” he said. “In addition, we want to investigate the cost-effectiveness of random dementia screening in grand multiparous women.”
Liisa AM Galea, PhD, a professor in the department of psychology, and a member of the Centre for Brain Health and Neuroscience Program at the University of British Columbia, said it's known that pregnancy affects the level of the body's estrogens dramatically. It crashes after pregnancy and the placenta is released for about 180 days, but the effects have not been well studied in connection to AD.
She said that while pregnancy certainly impacts the body, additional stresses caused by multiple children may impact cognitive function as well. In an analysis of short and long-term consequences of motherhood on women's health (in press in Current Opinion in Physiology) studies have shown that reduced grey matter is detected in multiple regions after motherhood, and that changes to neuroplasticity and cognition may have lasting consequences.
DR. KI WOONG KIM: “Extremely high levels of estrogen during pregnancy and the abrupt withdrawal of estrogen after childbirth may be harmful to neurons and decrease brain or cognitive reserve.”
“It's not just limited to the pregnancy,” Dr. Galea said. “There are a lot of psychosocial factors [that can have an impact] such as the stress of caring for an infant and the demands of multiple children. There is plenty of evidence that stressful events can negatively affect the brain,” Dr. Galea said.
Kejal Kantarci, MD, a professor of radiology at Mayo Clinic in Rochester, MN, said she was not surprised that women with multiple pregnancies had a risk for developing late dementia. She was particularly interested in whether pregnancy-related hypertensive disorder and other pregnancy-related complications were linked to dementia later in life.
“Unfortunately, this study falls short in addressing the mechanisms that could be linked to dementia and looking at the underlying increased risks of multiple pregnancies,” she said.
As a radiologist, she said, she has observed that pregnancy-related hypertension and pregnancy-related diabetes, as well as other complications of pregnancy all result in cardiovascular risks, which can lead to neurodegenerative changes on brain MRIs and cognitive decline later in life. Multiple pregnancies with complications could lead to repeated insults on the brain.
“We don't know from the study if all of these women had normal pregnancies, or if they had complications,” said Dr. Kantarci, “but I think the study points out the fact that women who have had multiple pregnancies should be closely monitored for complications, because they're at increased risk with each subsequent pregnancy.”
DR. LIISA AM GALEA: “It's not just limited to the pregnancy. There are a lot of psychosocial factors [that can have an impact] such as the stress of caring for an infant and the demands of multiple children. There is plenty of evidence that stressful events can negatively affect the brain.”
DR. KEJAL KANTARCI: “We don't know from the study if all of these women had normal pregnancies, or if they had complications, but I think the study points out the fact that women who have had multiple pregnancies should be closely monitored for complications, because they're at increased risk with each subsequent pregnancy.”
None of the doctors interviewed thought women would not have children, or have fewer children because of the study, but believed that studying pregnancy's impact on the brain could result in better mechanisms for monitoring and treatments in the future.
The study provides “an awareness that reproductive history matters, even later in life,” said Dr. Galea. “It's important that we understand the risks. For example, one of the best things to offset dementia is exercise, so a doctor might be particularly careful to prescribe exercise for women with multiple pregnancies, and that might be more beneficial compared to men.”