Why do you get preeclampsia?

Preeclampsia is a hypertensive disorder of pregnancy, characterized by the presence of protein in the urine (proteinuria) in addition to hypertension. It can also cause symptoms such as blurry vision, headache, and abdominal pain.

Most seriously, preeclampsia increases the risk of adverse pregnancy outcomes for mom and baby and can become life-threatening if not treated.

There are several science-backed strategies to help prevent preeclampsia and reduce symptom severity, even in high-risk women, and I’ll be sharing those with you in my next blog.

But first, I want to delve into the critical question, “Why do you get preeclampsia?”

It’s estimated that 2-10% of the general population will develop preeclampsia, but certain people have a much greater risk.

This blog explores preconception risk factors for preeclampsia—for women and men. As well as action steps that both parents can take to reduce risk before conception even occurs.

Why do you get preeclampsia? An answer we never expected

The factors that affect preeclampsia risk are complex and may surprise you. There is much more at play than maternal health alone; the most fascinating finding we made while researching this blog relates to the paternal contribution to preeclampsia.

According to Cnattinguis et al. (2004), genetics significantly influence preeclampsia risk—and not just the mother’s genetics.

A cohort study found that 35% of the genetic risk is due to the mother, 20% is due to the fetus (10% mother and 10% father), and 13% is due to the “couple effect,” how the maternal and paternal genes interact (1). The remaining bulk of the risk (32%) is attributed to unmeasured factors, which likely include external influences that will be addressed later in the blog.

Additionally, the placenta, which is well known to be a vital part of the etiology of preeclampsia, is genetically equal parts mother and father.

“The placenta is the cornerstone of preeclampsia and poses important paternal genetic determinants; in fact, the existence of a “paternal antigen” has been proposed” (2).

Studies examining multiple partners and preeclampsia risk also demonstrate paternal influence on preeclampsia. Several studies have documented that a woman may have a healthy first pregnancy, but her second pregnancy, if with a different partner, may result in preeclampsia (2).

Esplin et al. (2001) discovered that men born to a mother with preeclampsia were more likely to have a pregnant partner with preeclampsia themselves (OR: 2.1, 95% CI, 1.0 – 4.3; P=0.04). This incredible finding supports the couple effect and the impact of fetal genetics on the mother (3).

In comparison, women born to a mother with preeclampsia were three times more likely to have preeclampsia during their pregnancy (OR: 3.3, 95% CI, 1.5 – 7.5; P=0.004) (3).

In a study of 1011 pregnancies, Robillard et al. (1994) discovered that the incidence of gestational hypertension was 11.9% in the first delivery and 4.7% for subsequent pregnancies. However, in women whose second pregnancy was with a different father, the incidence increased to 24% (4).

And more fascinatingly, this was all influenced by sexual cohabitation with the father before conception (4).

There is an inverse relationship between the length of sexual cohabitation and the risk of preeclampsia. In other words, the longer a woman is having intercourse with her partner, the less likely she is to develop hypertension during her first pregnancy or subsequent pregnancies (4).

For women living with their sexual partner longer than 12 months, the incidence of gestational hypertension dropped from 10.6% to 5.1%. This protective effect was more pronounced for women pregnant with their first child, decreasing from 11.9% to 3.3% (4).

The hypothesis behind this phenomenon is that sperm affect the female immune system, which can either increase risk or have a protective effect depending on the length of exposure. More recent studies support earlier findings regarding gestational hypertension, preeclampsia, and sexual cohabitation (5).

A 2020 review of 7125 pregnancies found a significantly lower rate of preeclampsia in partners with sexual cohabitation >12 months (13.6% vs. 17.8%, OR: 0.73, 95% CI, 0.59 – 0.90) (5).

Because exposure to sperm seems to trigger an inflammatory response in women, repeated exposure may prime the immune system, allowing tolerance to occur and thus reducing the inflammatory immune response.

This theory has also been supported in studies on sperm donor pregnancies. For people who conceive via donor sperm, the odds of preeclampsia significantly increase compared to a pregnancy from a partner’s sperm (OR: 1.63, 95% CI, 1.36 – 1.95) (6).

What are the mechanisms behind this?

During pregnancy, the maternal immune system downregulates the T-helper cell 1 (Th1) response and favors a T-helper cell 2 (Th2) response.

Th-2 dominance differs from a healthy immune response in a non-pregnant person, whose immune system can switch between Th1 and Th2 depending on pathogen exposure (Th1 helps fight off bacteria and viruses, and Th2 protects against allergies and parasites).

But for the expecting mother, the immune shift towards temporary Th2 dominance is a safeguard to protect the developing fetus from the maternal immune system.

Some researchers have hypothesized that immune maladaptation is a factor in preeclampsia etiology, and sperm exposure may contribute to maternal immune dysfunction.

“The immune maladaptation theory involves a maternal alloimmune reaction triggered by a rejection of the fetal allograft that could be prevented through paternal sperm exposure before pregnancy by initiating a type-2 immune response towards paternal antigens that may inhibit the induction of type-1 responses against the semi-allogenic fetal unit” (5).

This theory would explain why long-term sperm exposure protects against preeclampsia—the mother’s immune system has had enough time to develop immunological tolerance to her partner or a Th3 response.

Tan et al. (2008) investigated a fascinating connection between paternal/fetal human leukocyte antigen (HLA-G) and preeclampsia risk.

Multigravida women exposed to a variant of HLA-G called HLA-G*0106 in the fetus had a 9.6-fold increased risk of preeclampsia only if they did not carry the HLA-G*0106 allele themselves (OR: 9.6, 95% CI, 2.4 – 38.7, p<0.001) (7). The fetus inherits this genetic variant from the father, resulting in a genetic mismatch affecting the mother’s immune response.

Additionally, it has been suggested that this risk can be mediated if the mother has gradually repeated exposure to paternal HLA-G*0106 before conception (8).

Common risk factors for preeclampsia

Beyond the genetic and paternal contribution, several more well-known factors increase a woman’s risk of developing preeclampsia.

According to the National Institute of Health, preeclampsia risk factors include:

History of previous preeclampsia or gestational hypertension
Chronic high blood pressure or kidney disease before conception
Overweight and obesity, which may increase preeclampsia risk in the first and subsequent pregnancies
Being pregnant with twins or multiples
Being age 40 or older
Having a family history of preeclampsia
Race – African American women are more likely to develop preeclampsia during their first and subsequent pregnancies (9)

Lesser known preeclampsia risk factors

A literature review reveals a handful of lesser-known factors that greatly increase the chance a woman will develop preeclampsia.

Connective tissue disease

Fischer-Betz & Specker (2017) noted that women with systemic lupus erythematosus (SLE) are at increased risk compared to the general population (10).

“In the general population, pre-eclampsia complicates approximately 5%-8% of pregnancies, while in SLE patients, the occurrence is between 12% and 35%” (10).

A large meta-analysis of 25,356,688 pregnancies found that women with a history of antiphospholipid syndrome, an autoimmune connective tissue disorder that leads to misplaced immune attacks on proteins in the blood and an elevated risk of clotting, had an increased rate of preeclampsia (11).

Women with positive antiphospholipid antibodies may have a nearly 10-fold increased risk of developing preeclampsia (OR: 9.72, CI: 4.34 – 21.75) (12).

Nulliparity

Women who have never given birth may have a 3-fold risk of preeclampsia, perhaps due to the immunological effects discussed above (OR: 2.91, 95% CI, 1.28 – 6.61) (12):

“Many hypotheses attribute this [connection between parity and preeclampsia] to immunological reasons. A feasible explanation is that a suboptimal maternal adaptation to fetal or paternal alloantigens may indirectly result in impaired uteroplacental perfusion, which accounts for the pathogenesis of preeclampsia. Nulliparous women were also proposed to endure an “angiogenic imbalance,” manifested as a higher circulating sFlt1 level and sFlt1/PIGF ratio, which may also contribute to their tendency of developing preeclampsia” (13).

Maternal age

Women younger than 25 and older than 35 have a higher risk of developing preeclampsia (14).

Sheen et al. (2020) observed a U-shaped relationship between maternal age and preeclampsia severity, with those aged 18-24 and 40-54 at greatest risk. Interestingly, those aged 15-17 had the highest risk of eclampsia (a more severe manifestation that can include seizures and coma) compared to other age groups (15).

The 15-17 and 18-24 year old age groups were more likely to be from the lowest two ZIP code income quartiles.

Preexisting diabetes and insulin resistance

It is estimated that 15-20% of type 1 pregnant women will develop preeclampsia, and 10-14% of type 2 pregnant women will develop preeclampsia (16).

In comparison, the same source estimated the rate of preeclampsia in the general population to be between 2-7% (16),

“… insulin resistance at 22-26 weeks gestation was a significant independent predictor of preeclampsia after adjustment for these common risk factors [obesity, advanced maternal age, non-white race, chronic hypertension, diabetes and gestational diabetes], suggesting an independent effect” (16).

Poor glycemic control increases the risk of preeclampsia, and researchers have demonstrated this by observing the relationship between A1C and preeclampsia. The Diabetes and Preeclampsia Intervention Trial found that in early pregnancy (median nine weeks gestation), women with an A1C >8% had a 3.68-fold increased risk of developing preeclampsia (17). Additionally, elevated A1C before conception significantly increased preeclampsia risk.

Preexisting renal disease

Chronic kidney disease is a well-known risk factor for preeclampsia, and it has been observed that even mild forms of kidney dysfunction can increase risk. In a 2020 review, Kattah noted that unilateral renal agenesis (being born with one kidney), a history of kidney donation, and previously resolved acute kidney injury are risk factors for preeclampsia (18).

The exact reason renal dysfunction is linked to preeclampsia isn’t fully understood, though mild or transient reduction in glomerular filtration rate is likely. Still, there seems to be a complex relationship involving endothelial dysfunction, the complement pathway, and the renin-angiotensin-aldosterone system (RAAS) (18).

Preconception solutions for preeclampsia: reduce your risk before pregnancy

While certain preeclampsia risk factors are not modifiable, such as family history or nulliparity, others are.

Let’s examine what can be done to reduce risk and practical action steps.

Harness the power of epigenetics

Epigenetics is a term that describes changes in gene expression as a result of environmental and lifestyle factors without any change in the DNA sequence itself. Epigenetics means “above the gene” or “beyond the gene.”

The study of epigenetics has shown us that factors such as nutrition, metabolic health, exercise, and mindfulness affect gene expression and may reduce disease.

Several epigenetic changes occur in preeclampsia, with DNA methylation critical in developing the disease (19).

“Among the different epigenetic changes, DNA methylation in relation to PE [preeclampsia] is the most important factor. In addition to this, one of the causes of PE disease is abnormal DNA methylation during placentation. In PE placentas, changed global DNA methylation models are related to maternal blood pressure” (19).

Both over-methylation and under-methylation can increase preeclampsia risk. There are several ways that methylation can be supported, helping reduce the risk of preeclampsia before conception.

Use functional foods to support balanced methylation

Micronutrients and polyphenols can be therapeutic for the optimization of methylation pathways.

For example, certain foods help regulate matrix metalloproteinase-9 (MMP-9), an enzyme that is affected by abnormal DNA methylation. MMP-9 imbalance has been observed in preeclampsia (19, 20).

Functional foods to help regulate MMP-9:

pomegranate peel powder
fish/fish oil
chia
flax seed
walnut
olive oil
red cabbage
strawberry
onion
radish leaves
dill
berries
green tea
blueberry
cranberry
cacao
celery
peppers
thyme
peppermint
oregano
citrus
bitter orange peel
radicchio

Reduce BPA exposure

BPA is an endocrine-disrupting chemical present in many types of plastic products. Maternal exposure to BPA has been observed to increase preeclampsia (21, 22).

Women with high serum and urine levels of BPA have a significantly increased risk of developing preeclampsia. One study reported a 16-fold increase (adjusted OR = 16.46, 95% CI = 5.42 – 49.85) in women with high serum BPA vs low BPA (22).

Studies have shown that BPA alters DNA methylation, downregulating genes involved in trophoblast invasion and placental spinal artery remodeling (19, 23).

BPA is found in many products, but there are effective ways to reduce your BPA exposure before conception and during pregnancy:

Choose fresh foods over canned foods (canned foods have BPA or harmful toxicants in their epoxy lining)
Avoid foods packaged in plastics whenever possible.
Thermal paper from shopping and ATM receipts have high levels of BPA. Minimize handling your receipts by asking the clerk to dispose of them for you or putting them in a dedicated receipt bag rather than carrying them by hand. At the ATM, opt out of the printed receipt.
Store food in glass containers. Even if you purchase food in plastic, you can always transfer the contents into glass jars at home.
Avoid placing hot foods in plastic containers, and avoid heating food in plastic. For example, a plastic bag holding frozen peas in the freezer will transfer much less plastics than a plastic jar holding oil left on the countertop, especially if the oil is hot when placed in the container.
Be extra careful with storage and heating with plastic if the food or product has a high fat content. A high fat content can increase the leeching of plastic chemicals into the food since many of these chemicals are fat-soluble.
Use a high-quality water filter that uses minimal plastic in its parts, or better yet, purchase spring water in glass containers.
Brew coffee or tea, if you drink them, in glass or stainless steel rather than plastic.
Get cotton tablecloths—they are versatile, and you can use them at home and on camping trips. They wash well and last a long time.
Wear clothing made out of natural fibers when possible, especially underwear, bras, camisoles, and socks. Synthetic clothing is made of plastic fibers.
Purchase non-plastic cups and dinnerware.

Optimize metabolic health and whole-body wellness

It is ideal for both partners to optimize their metabolic health, nutrition, exercise, and mindfulness practices before conception occurs.

By addressing these modifiable risk factors, both parents are increasing their chances of having healthier pregnancy outcomes, including lowering preeclampsia risk.

Metabolic health is vital to preeclampsia prevention and is affected by nutrition, physical activity, and stress levels.

Because obesity in either parent is associated with increased preeclampsia risk, when one or both prospective parents are obese during preconception, it is ideal, whenever possible, to devise and implement a plan to reduce weight.

With that said, I must insert a word of caution here: GLP-1 agonists like Ozmepic are highly popular and are widely seen by medical professionals and the general public alike as a quick fix for obesity. However, they come with a growing list of known risk factors, including severe gastrointestinal dysfunction (24) and potentially serious psychiatric side effects, including increased risk of suicide (25).

It is unknown what impact these medications may have when used during preconception on the successive pregnancy and health of the offspring.

Also, for males, metformin use during preconception is likely associated with an increased risk of certain birth defects (26).

Thus, a healthy weight loss plan should include nutrition, movement, and emotional/behavioral dynamics that affect nutrition and exercise habits. Pharmaceutical interventions should be used only when every effort at food and lifestyle change has been made, and the doctor and patient have carefully discussed risks and benefits.

In addition to diet and physical activity, stress should also be addressed during the preconception period. Developing authentic self-care practices to reduce stress may help reduce preeclampsia risk (27).

Stay tuned for the next part of this series, where I’ll cover strategies to reduce preeclampsia severity and improve outcomes for preeclampsia patients.

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