Have you experienced a pregnancy loss? If so, our hearts go out to you and we are so very sorry for your loss. Unfortunately, as many as 26 percent of pregnancies result in miscarriage due to a number of factors, often related to abnormal chromosomes. (1) Recurrent miscarriage is defined as three or more consecutive losses before the 20th week of pregnancy. Some doctors and statistics include pregnancies that are lost before they are confirmed by ultrasound, while others do not include biochemical pregnancies or losses before five or six weeks. Regardless, recurrent pregnancy loss affects between one and two percent of women. (2)
While many doctors will begin investigating causes of recurrent loss after two consecutive miscarriages, sometimes it can take three or more losses before a physician will intervene.
Understanding the causative factors of recurrent pregnancy loss can empower you to ask for the medical support you need so you can do everything in your power to have a healthy, viable pregnancy.
While 75 percent of women with recurrent loss will go on to have a successful pregnancy, those rates are lower in women who are older and who have had increasingly more miscarriages. (3)
3 Causes of Recurrent Miscarriage
Recurrent miscarriages have numerous causes, which are often multifaceted, making them difficult to isolate. However, a major point, often overlooked, needs to be addressed:Causes of recurrent miscarriage go beyond the condition of the mother and her genetics.
While a woman’s genetics and overall health status must be considered, the other factors that are also always in play are:
- Genetics of the father
- Methylation status of the fetus
1. Genetics and Health of the Mother
The World Health Organization points out that 50 percent of all miscarriages are caused by non-preventable chromosome abnormalities, while the other 50 percent tend to present as euploid, or normal, losses. The traditional medical view when this occurs is to then assume that the mother who loses euploid pregnancies has a “maternal and potentially curable disease.” (4)
In some cases, this is true, as 15 percent of women with recurrent pregnancy loss test positive for antiphospholipid syndrome. This is diagnosed when anti-cardiolipin or lupus anticoagulant antibodies are present. (5) When a woman is diagnosed with antiphospholipid syndrome, she is often prescribed baby aspirin or blood thinners, sometimes along with steroids and progesterone. Regardless, this protocol does not guarantee a positive pregnancy outcome and research shows mixed results.
Two genetic mutations in the mother are strongly associated with miscarriage:
- MTHFR
- Factor V Leiden
According to the CDC, there are now 93 publications and six meta-analyses associating MTHFR with miscarriage. (6)
Yet most doctors will only address Factor V Leiden or multiple copies of MTHFR, and even then, they will typically prescribe high dose folic acid—the inactive form that can actually block folate receptors in the body, leading to folate deficiency.
It may not be possible to understand why every miscarriage happens, but starting with the health of the mother, you can rule some things out or minimize their risks. Methylation is a major point that is often ignored during fertility treatments or miscarriage testing.
Still, even if you thoroughly address every aspect of the mother’s methylation, diet, and lifestyle, she could continue having losses. This is because she is only one-third of the picture.
What to do?- Ask for MTHFR, Factor V Leiden, and antiphospholipid testing if it has not been done
- Take methylfolate or folinic acid, not folic acid
- Speak with your doctor about using blood thinning medications such as baby aspirin, heparin, lovenox, or nattokinase during pregnancy
2. Genetics and Health of the Father
While it’s often assumed that only the woman’s health or genetics could influence the health of a pregnancy, half of the fetal chromosomes come from the father, which means he has at least 50 percent of the role in whether or not the initial genetic material is healthy.
A Turkish study found that recurrent miscarriage causes were related to combined parental clotting genetic mutations, not just in the mother. These included even being heterozygous (having only one copy of the gene) for Factor V Leiden, FVR2, ACE, and ApoE2 genes. These in both the father and the mother should be considered as risk factors for recurrent pregnancy loss. (7)
This means that genes passed on to the fetus from the father have a direct connection to increased risk of blood clotting development that could cause pregnancy loss.
What to do?- Have your doctor evaluate the mother for uterine clots or clots in the placenta, if applicable
- Ask for the same genetic and blood clotting tests to be done on the father as well as the mother
- Speak with your doctor about baby aspirin, heparin, lovenox, or nattokinase for the father as well as the mother, although the father’s treatment would need to be started 90 days before conception to improve odds
3. Methylation Status of the Fetus
While the genetics of the mother and father are certainly crucial for the foundation of a healthy, viable pregnancy, from the moment of conception, the embryo and then the fetus has its own combined genetic traits and characteristics.
Research from China published in BMC Medicine found that defects in DNA methylation within the embryo, not the mother, were associated with implantation and development problems. (8) The study goes on to show that disturbance of the maintenance methylation with a DNMT1 inhibitor could be associated with impaired embryonic development and inhibit proper attachment to endometrial cells.
In other words, methylation in the developing baby is directly related to the ability to have a healthy pregnancy outcome, independent of the methylation status of the mother or the father.
What to do?- Support healthy methylation in the mother and father before, during, and after pregnancy.
- Identify genetic defects in the methylation pathway, especially MTHFR, in both parents and supplement accordingly. This could help bypass the methylation defect and increase the odds of normal methylation in the developing embryo.
- Identify DNMT inhibitors and reduce or remove in both parents for 3+ months prior to conception, and in the mother throughout the rest of the pregnancy.
DNMT stands for DNA methyltransferase. DNMT is necessary to balance methylation processes in the body. There are several DNMT genes, but DNMT1, in particular, seems to be significant when it comes to recurrent pregnancy loss. (9)
DNMT inhibitors, which can be problematic for cases of recurrent loss, are compounds which directly or indirectly have a negative impact on the function of DNMT in the body. If recurrent miscarriage is a problem, then both parents should avoid them leading up to pregnancy and, for the mother, for the duration of the pregnancy.
DNMT inhibitors include:
- 5-azacytidine
- 5-aza-2-deoxycitidine
- Zebularine
- Hydralazine
- Epigallocatechin gallate (EGCG)
- Psammaplin A
While most of these might look or sound like gibberish, EGCG is a primary one to focus on. You may not even realize that it could be prominent in your diet.
EGCG is found in green tea. While some consider green tea in small amounts to be beneficial for fertilization, too much is certainly not.
Research from Italy shows that in animal studies, a small amount of ECGC (10 mcg/mL) during IVF treatment was able to significantly increase fertilization rates, while higher amounts (greater than 25 mcg/mL) decreased the percentage of fertilized eggs. It could be concluded that the risk is the same or at least increased for human fertilization, both relating to spontaneous conception or IVF. (10)
Even if DNMT inhibitors are not excessively present in the diet, cells or enzymes can have antibodies against them, which would partially or completely prevent them from working.
Given the prevalence of autoimmune disease, the potential for DNMT antibodies is important to consider. While there is no direct research identifying DNMT antibodies or their effect on DNMT function, it’s easy to assume that they exist in humans since they’ve been proven to exist in the laboratory. (11)
The good news is that even if we can’t prove they exist, the clinical way to lessen their potential effects would be to ingest foods high in folate or to supplement with methylfolate and folinic acid.
What to do?- Eliminate gluten from the diet, especially wheat
- Identify and remove food intolerances, sensitivities, and allergies
- Supplement with effective probiotics
- Get vitamin D levels assessed and work to achieve a range of 45 to 50 ng/mL
Bottom Line
There are numerous factors to consider when it comes to recurrent pregnancy loss. Some of them are obvious considerations in clinical settings, like Factor V Leiden or chromosome abnormalities. Others, however, are less proven and not part of the standard of care.
The most important points to take away as you consider the implications for your own health journey are:
- Recurrent miscarriage causes expand beyond the mother to the father and the fetus, too.
- Paternal genetics need to be evaluated in the same way that the mother’s do.
- DNMT inhibitors, especially EGCG and green tea, should be avoided.
- Optimize methylation of both mother and father with foods high in natural folate as well as supplementation with folinic acid or methylfolate. This is important to consider before achieving pregnancy, at least 90 days before.
Pregnancy loss can be devastating, but with the right nutritional support and a doctor who will thoroughly address your own unique factors, achieving a successful pregnancy even after recurrent loss is possible.
Reference:
(1) https://www.ncbi.nlm.nih.gov/books/NBK532992/
(2) https://www.aafp.org/afp/2008/1015/p977.html
(3) https://www.aafp.org/afp/2008/1015/p977.html (4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829626/ (5) https://www.aafp.org/afp/2008/1015/p977.html (6) https://phgkb.cdc.gov/PHGKB/phenoPedia.action?firstQuery=Abortion,%20Habitual&cuiID=C0000809&typeSubmit=GO&check=y&which=2&pubOrderType=pubD (7) https://www.ncbi.nlm.nih.gov/pubmed/22047507 (8) https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-10-26 (9) https://www.ncbi.nlm.nih.gov/gene/1786 (10) https://www.ncbi.nlm.nih.gov/pubmed/18343490 (11) https://www.antibodyresource.com/search/Antibodies/1cbe8772-5e3a-5219-a45a-fc4614c91838/DNMT