This article is part of the 2017 Women's Health Special Issue. Read the full issue or download it here.
Abstract
Recurrent pregnancy loss (RPL) is the spontaneous loss of at least 2 consecutive pregnancies in a nulliparous woman, or 3 consecutive pregnancies in a woman who has experienced a live birth. Although genetic abnormalities are responsible for the majority of early pregnancy losses, multiple, consecutive losses suggest other factors may be at play. Potential nonchromosomal causes include immune-mediated loss, thrombophilias, hormonal and metabolic issues, and stress. Women who meet criteria for evaluation of RPL should receive a medical workup that includes a thorough medical history and relevant testing, guided by stage of loss and suspected causes. Given that over half of cases of RPLs remain unexplained, a holistic approach to evaluation and treatment that includes addressing overall health and optimizing immune function may help lift barriers to successful live birth.
Introduction
Miscarriage and pregnancy loss can be a dark topic. Whether they treat infertility or not, most clinicians have seen women who have experienced a pregnancy loss, either elective or spontaneous, even if it was not the patient’s chief reason for the visit. Whether a practitioner is focused on primary care or on fertility and pregnancy, it is essential that every clinician understand the foundations behind miscarriage and pregnancy loss and know when and how to help a woman who has lost a pregnancy.
Spontaneous abortion (SAB) describes the sudden loss of a pregnancy and occurs in 15% to 25% of all clinically recognized pregnancies. Typically, this occurs early in the pregnancy, before 6 weeks gestation.1 Spontaneous abortion is not necessarily problematic from a medical perspective, but it is often disappointing and can result in significant mental and emotional trauma. Spontaneous abortions most often occur in instances in which genetic abnormalities prevent viability, which is why they often occur early. After a single miscarriage, the likelihood of achieving a healthy subsequent pregnancy is 76%, which is equivalent to the likelihood of healthy pregnancy in a woman who has never experienced a pregnancy loss.1 After 2 or more subsequent losses, the concern of an underlying factor other than genetic abnormalities contributing to a woman’s inability to carry to term increases, and a thorough naturopathic workup is warranted. Some patients will meet the criteria for recurrent pregnancy loss (RPL).1
Studies have shown significant improvement in pregnancy outcomes in patients with RPL with provision of close monitoring and support by their provider. Naturopathic physicians are well-positioned to provide this additional care.
Recurrent pregnancy loss used to be defined as 3 or more consecutive spontaneous pregnancy losses. According to this definition, between 1% and 2% of women experience RPL.2 The definition has been refined and now applies to women with only 2 consecutive pregnancy losses if they have not previously had a live birth. The current definition allows for earlier workup in these patients.
Patients experiencing RPL or late gestation losses require a deeper evaluation and level of management than those experiencing isolated miscarriage. This paper focuses on women experiencing RPL.
Find the Root Cause: Evaluation
Although many factors contribute to RPL, the greatest risk factor is maternal age. Two known chromosomal causes include parental chromosomal structural abnormalities and antiphospholipid antibody syndrome (APS). Anatomic abnormalities can also play a role. While these causes are undisputed, other factors that may come into play include hormonal irregularity, untreated hypothyroidism, hyperprolactinemia, polycystic ovary syndrome, thrombotic disorders, and immunologic causes. There has been little research on the effects of these conditions on RPL, although theoretically they could impact the uterine environment in early pregnancy and therefore contribute to pregnancy loss. A cause is determined in only 50% to 60% of cases of RPL.1
When assessing the possible cause(s) of RPL, the timing of the loss is a key piece of information to guide the clinical evaluation algorithm. Pregnancy can be divided into 3 stages—the preembryonic stage (conception through week 4), the embryonic stage (5-9 weeks’ gestation), and the fetal stage (weeks 10 through delivery):
- During the preembryonic stage, implantation occurs and the preembryo develops into a trilaminar disc of cells with a central neural axis, all before the first missed menstrual period.
- In the embryonic stage, the trilaminar disc folds to become cylindrical and the head and tail regions of the embryo are established; during this critical time, organogenesis begins with development of a beating heart and delivery of oxygen and nutrients through the umbilical cord and placenta.
- The fetal stage begins when maternal blood contacts villous trophoblast cells and progresses through gestation.
The majority of all pregnancy losses, including SAB and RPL cases, occur in the preembryonic and embryonic stages. In a study of 200 women with suspected normal pregnancies, a 13% pregnancy loss rate was reported; 87% of those losses occurred during the preembryonic and embryonic states, while only 13% occurred after 10 weeks’ gestation.1 Some of the key contributing factors to pregnancy loss by stage of pregnancy are listed in Table 1.
Preembryonic and embryonic losses are most commonly associated with genetic factors. As this is the time for early organogenesis, many genetic abnormalities that impact protein synthesis, and thus organ synthesis, can hinder development to a point of nonviability of the embryo. Other factors that contribute to loss at this phase include defects in endometrial thickening, low progesterone, and thrombotic events. Maternal age also plays a role, as age contributes to other genetic factors; increased reactive oxygen species, oxidative stress, and poor nutrient status can affect the health of the DNA in egg and sperm, contributing to an increased incidence of genetic abnormality.
In fetal losses (gestational age 10 weeks or greater), the likelihood of genetic factors contributing to pregnancy loss decrease, and the likelihood of other underlying concerns increases. It is recommended that any woman who loses a pregnancy after 10 weeks be evaluated for their pregnancy loss through workup of the patient, as well as genetic evaluation of the fetus. After 10 weeks, the most common contributing factors to loss are thrombotic disorders, anatomical problems with the uterus, and autoimmune factors.1
Patient Evaluation for Recurrent Pregnancy Loss
If a patient meets the criteria for evaluation of RPL (see Figure 1), evaluation should begin with a complete medical history, including personal and/or family history of autoimmunity, metabolic disorders, pelvic infection, surgeries, and thrombotic disorders. It is also essential to document prior pregnancies and their outcomes as well as prior testing or procedures. This intake and history can be helpful to determine possible labs to consider to further evaluate the patient (see Table 2).
Genetic (Cytogenic) Testing
Today, relevant genetic testing is made available to patients experiencing pregnancy loss where the embryonic or fetal tissue can be recovered. About 60% of products of conception that are analyzed after sporadic early pregnancy loss are associated with chromosomal abnormalities, primarily trisomies. In women under age 35, the risk of miscarriage due to genetic abnormality is 9% to 12%. Once women are over 40, that risk increases to 50%. In cases of RPL, genetic origins only account for 2% to 5% of cases, indicating that while it is a common cause of spontaneous miscarriage, another factor may be at play if a couple suffers subsequent losses.1
Genetic testing, while more readily available, is still rudimentary and rarely helpful for developing a longer-term treatment plan. Still, it can help guide patients to genetic counseling for a deeper workup. Once both partners are evaluated independently, genetic counselors can predict the likelihood of having a healthy pregnancy given the couple's specific genetic factors. Couples may be encouraged to consider in vitro fertilization (IVF) with preimplantation genetic testing (PGT) of the embryo, amniocentesis, or chorionic villus sampling to detect abnormality in offspring. Also, genetic counseling can help identify a cytogenetic cause with either partner suggestive that gamete donation (egg or sperm) could be helpful.3
A systematic review revealed that IVF with preimplantation genetic diagnosis had a live birth rate of 31% to 35% per cycle, compared to 55% to 74% live birth rate per cycle with natural conception, so it may be the case that mother nature is still a better discerner of good quality gametes and embryos that will continue through pregnancy to live birth.4
Questions remain concerning the impact of methyltetrahydrofolate reductase (MTHFR) mutation and its impact on pregnancy and miscarriage. At this time, the current literature demonstrates that MTHFR does not occur with any greater frequency in patients with RPL than in the general population.5 Elevated homocysteine and B12 deficiency have been linked with increased risk of RPL,6,10 so there may be a relevant downstream link not due to the genetic mutation, but to downstream effects of that mutation.10
Treating Patients with RPL Due to Genetic Malformation
There is little published data on whether or how to treat patients who are trying to conceive who have genetic abnormalities in their gametes. For any individual, there is a possibility of genetic abnormality, which makes identification of those who require intervention difficult. Studies have shown that markers such as glutathione levels have been linked to egg and sperm health, so supporting antioxidant status generally, and glutathione levels specifically, may be of benefit.7 It also makes sense to assess and remove any known exposures to teratogenic substances and to work with the patient through lifestyle adaptation to increase antioxidant intake. Starting with basics such as organic fruits and vegetables, prenatal vitamin support, and use of known antioxidants such as green tea, turmeric, and rosemary through the diet could be of benefit. Some studies have shown that prescriptive use of antioxidants such as N-acetylcysteine (a known glutathione precursor) at a dose of 600 mg daily, taken with folate, significantly increased live birth rate over administration of folate alone.8
Immune-associated Pregnancy Loss
Much of pregnancy, especially early pregnancy, is a “black box” of biology, where we don’t have much information to work from. Research during this time is difficult, because most women are evaluated during or after a loss, and it’s very difficult to discern whether the observed uterine environment at that time is representative of what led to the pregnancy loss or is a result of the body’s innate “cleanup” process.
Incredible immunological changes that allow the embryo to go undetected by the mother’s immune system occur in early pregnancy, a necessary protection to keep the body from attacking that foreign tissue. While we don’t know the details of every immune interaction, the process is multifactorial and the well-regulated immune response is vital for the health of the pregnancy.
Both autoimmune and alloimmune reactions have been postulated and evaluated in association with recurrent pregnancy losses, but are hotly debated in scientific literature. Research in this area presents many difficulties. First, the literature is full of small, uncontrolled studies. Second, it is difficult to recruit patients with multiple pregnancy loss into randomized controlled trials. Third, peripheral measurements (serum, for example) may not adequately reflect the immunological state at the maternal-fetal interface. Lastly, it is difficult to distinguish between immune alterations that cause miscarriage and those that result from loss. Factoring in these variances, studies show a range of attribution ranging from 8% to 42% of RPL being tied to immunologic factors (mean 15% of cases).1
Alloimmune responses refer to the mother’s immune reactions to the foreign embryonic/fetal tissue, and autoimmune responses refer to the mother’s immune system reacting with her own tissues (ie, endometrium). For alloimmunity, which is plausible, there are many tests available, but commercially available tests have not been proven to be clinically useful. Some of these include mucosal CD16-natural killer (NK) cell testing, cytokine profiles (measuring T helper cell [TH]1/TH2 balance), human leukocyte antigen (HLA) typing, anti-paternal leukocyte antibodies, and others. Ultimately, no tests are currently supported by scientific evidence.
Established science around autoimmunity does exist, and we know that it plays a role in many cases of RPL. Antibodies to phospholipids, nuclear antigens, thyroid proteins, histones, and single-stranded and double-stranded DNA have all been evaluated.1 Some antibodies are very worthwhile to test for, but panels are expensive, many are unproven, and they can be misleading, so caution is recommended when choosing labs for evaluating a patient with RPL.1
Antiphospholipid antibody syndrome
One well-documented example of immune-mediated pregnancy loss is antiphospholipid antibody syndrome (APS). This condition is widely accepted, readily diagnosed, and effectively treated. In APS, autoimmune reactions trigger thrombotic events that impair blood flow to the embryo and fetus. It can harm placental development. Antiphospholipid antibody syndrome is worthwhile to test for both in early and in later pregnancy loss.
In early pregnancy loss, antiphospholipid antibodies may affect implantation by causing microthrombotic events within the spiral arteries that supply blood flow to the endometrium. It has been suggested that APS could, theoretically, affect even the earliest stages of implantation by interfering with the trophoblast-endometrial interaction, and may be a possible explanation for some cases of unexplained infertility. In later pregnancy losses related to antiphospholipid antibodies, the pathophysiology is often that the antibodies can cause placental damage, hindering the ability of the placenta to deliver nutrients and oxygen effectively to the fetus. It has also been suggested that one mechanism of APS is restriction of endothelial production of nitric oxide.9
Clinical and laboratory criteria for APS evaluation
The clinical criteria for workup for APS includes a known history of vascular thrombosis and pregnancy morbidity factors, including (1) a history of 3 or more spontaneous abortions before 10 weeks’ gestation with exclusion of maternal anatomic and hormonal abnormalities and exclusion of chromosomal abnormalities; (2) the death of a morphologically normal fetus greater than 10 weeks; or (3) 1 or more premature births of morphologically normal neonates (<34 weeks’ gestation) due to severe preeclampsia or placental insufficiency.1
Workup should include testing for lupus anticoagulant, anticardiolipin immunoglobulin (Ig)G or IgM, and anti-B2-glycoprotein 1. Note that antinuclear antibody or antithyroid antibody testing is not recommended as a part of this screening.
Diagnostic criteria include a positive plasma lupus anticoagulant, positive anticardiolipin antibody of the IgG or IgM isotype in serum or plasma present in a medium or high titre (>40 IgG phospholipid units [GPL] or IgM phospholipid units [MPL], or >99th percentile), and positive anti-B2-glycoprotein-1 IgG or IgM antibodies. Testing must be positive on at least 2 occasions tested at least 12 weeks apart (see Table 3).1
Although we have a good understanding of APS as a single model for immune-mediated RPL, further research in this area may begin to uncover several additional autoimmune pathologies that influence both infertility and RPL. A retrospective study on IVF with intracytoplasmic sperm injection (ICSI )showed that patients with elevated antinuclear antibody (ANA) titres exhibited significantly lower rates of mature oocytes, fertilization, pregnancy, and implantation and higher rates of abnormal fertilization and early miscarriage. Effects were seen in patients with both high and low ANA titres, and parameters could be improved through application of prednisone plus low-dose aspirin.10 Studies like this one indicate that the complexities of the immune interactions in the reproductive tract are poorly understood, but likely have an impact.
Treatment of immune-mediated recurrent pregnancy loss
A number of therapies are used conventionally to manage APS in women. These include steroids, immunoglobulins, heparin, and aspirin. Steroids have been tested in several studies, and their use is not well-justified; still, they are prescribed often. Steroids (eg, prednisone) may increase the risk of gestational diabetes.11
Heparin and aspirin are the treatments of choice for women diagnosed with APS. Heparin and aspirin in combination appear to perform better than aspirin alone. It is suspected that the additional benefit is unrelated to the clotting mechanism. One study of 70 women with APS showed that coadministration of both therapies led to a 74.3% live birth rate vs a 42.9% live birth rate in the aspirin-only group, while other studies have shown no advantage to adding heparin to the treatment protocol.12 A Cochrane review published in 2005 found that combined unfractionated heparin and aspirin therapy may be able to reduce pregnancy loss in women with APS by 54%. This same review commented that administration of prednisone and aspirin resulted in a significant increase in prematurity and an increase in gestational diabetes, but no significant benefit to live birth rate. It also noted that intravenous immune globulins did not demonstrate benefits but did increase the risk of pregnancy loss and premature birth when compared to heparin or heparin plus aspirin therapy.13
Newer studies have also demonstrated a link between APS and nitric oxide insufficiency and oxidative stress.14 Both of these factors should be addressed through a plant-based anti-inflammatory diet.
When it comes to naturopathic treatment of APS or other immune-related pregnancy losses, I suggest an integrative treatment plan, using medications like heparin/aspirin in addition to nutritional therapies. One small prospective study in 30 women demonstrated that administration of fish oil produced the same positive pregnancy outcomes as low-dose aspirin administration.15 Considering the severity of APS when it comes to the outcome of the fetus, it is essential that naturopathic and integrative clinicians refer to and offer patients access to treatments with a strong evidence base, including conventional therapies (see Table 3).
Naturopathic Therapies for Immune-Related Pregnancy Loss
Once a diagnosis of RPL is established, it is recommended that naturopathic therapies be used to augment conventional therapies and support the couple to a live birth.
In cases of autoimmune-mediated pregnancy loss, there is no published data regarding naturopathic therapies either as standalone or adjunctive to conventional treatments. A few considerations should include recommending an anti-inflammatory diet, addressing stress, which can affect the immune response, and assisting with nutritional status of essential fatty acids like those from fish oil.
Immune-modulating botanical therapies such as turmeric, ginger, boswellia, and others could hold promise by decreasing overall autoimmune antibody production, but data is lacking to support a recommendation at this time.
Other Causes of Pregnancy Loss
Thrombophilias
Another category of cause of pregnancy loss includes other (non-APS) thrombophilias, primarily factor V Leiden mutation (a procoagulant); prothrombin gene mutations; and protein C, protein S, and antithrombin deficiencies. Thrombophilias are first discovered during miscarriage and infertility workups. Screening for thrombophilias is warranted if the patient has a history of venous embolism in a setting of a nonrecurring risk factor (eg, surgery) or has a first-degree relative with a known or suspected thrombophilia.1 Routine screening for thrombophilias in women with RPL is not currently recommended, but could be helpful in cases where no other diagnosis can be established.
Women with thrombophilias have an increased pregnancy risk including deep vein thrombosis and pulmonary embolism, preeclampsia and eclampsia, preterm labor, and placental abruption. For this reason, many women who are diagnosed with a thrombophilia choose not to carry children; if they do, they should be comanaged with an experienced hematologist.
Anatomic abnormalities
While not common, congenital uterine abnormalities are associated with second trimester loss, when the growing fetus begins to experience restriction. Relevant uterine abnormalities include unicornuate, bicornuate, didelphic, septate, and arcuate uteri. Assessment of uterine anatomy with ultrasound is recommended in recurrent early pregnancy loss as well as later pregnancy loss. The role of noncongenital uterine anatomic abnormalities such as fibroids, uterine polyps, and Asherman’s syndrome (intrauterine adhesions) in RPL has not been established.
Hormonal and metabolic factors
Maternal endocrine disorders should be ruled out in every woman with pregnancy loss. These include diabetes, thyroid dysfunction, and prolactin abnormalities.1 Prolactin abnormalities are a commonly recognized cause of ovulatory dysfunction but can also affect the ability to retain a pregnancy.16 Elevated prolactin can alter the hypothalamic-pituitary-ovarian (HPO) axis, resulting in a shortened luteal phase and impaired folliculogenesis. In women with RPL and elevated prolactin, treatment with bromocriptine increased birth rate from 52.4% to 85.7%.17 Vitex, which binds directly to dopamine receptors in the brain, has also been shown to have a prolactin-lowering effect. One study demonstrated that 40 mg per day of dried vitex berry lowered prolactin equivalent to 5 mg per day of bromocriptine. Studies of vitex have not been conducted in patients with RPL, but it is a promising therapy.18
Luteal phase defect, or a shortened luteal phase associated with lower progesterone levels, could also contribute to early pregnancy loss. If women have a menstrual cycle shorter than 26 days, and ovulation is suspected around day 14, the shortened luteal phase may not allow sufficient time for implantation. In those with luteal phase defect, the cytokine and vascular processes that trigger menstruation begin 3 to 4 days before the onset of menstruation. A fertilized embryo takes approximately 7 days to get to the endometrium, where it can implant. A shorter cycle can cause the timeframes to overlap so that the menstruation process begins prior to implantation.
In animal models of luteal phase defect, it has been observed that oxidative stress can be an underlying factor that impairs development of the corpus luteum, leading to low progesterone.19 In humans, melatonin (3 mg/d at 10pm) given through the luteal phase as an antioxidant increased serum progesterone concentrations compared to the unmedicated group.20
Stress
Pregnancy loss can induce significant stress, which is compounded when there are multiple losses and especially when workup discerns no clear explanation. Furthermore, significant stress itself can contribute to pregnancy loss. A 2002 prospective study of 61 patients with unexplained pregnancy losses found that the degree of baseline depressive symptoms, as assessed by questionnaire, predicted the likelihood of miscarriage.21
A provider’s care and support can have a significant impact on future pregnancy outcomes. In one study of 158 couples with more than 3 pregnancy losses without a known cause, women were entered into 2 treatment arms, to receive either standard obstetric (OB) care (n=42) or “TLC” care (n=116), which consisted of psychological support with weekly medical and ultrasound exams and instructions to take it easy. The live birth rate was 36% in the OB-only control group and 85% in the TLC group.22 At least 2 additional nonrandomized studies have shown significant improvement in pregnancy outcomes in patients with RPL with provision of close monitoring and support by their provider.23 Naturopathic physicians are well-positioned to provide this additional care.
Conclusion
There is still so much we have yet to understand about pregnancy loss, including the whys and hows. For about half of all cases of RPL, no clear etiology is uncovered.4 Early data suggests that gamete quality (egg and sperm), environmental exposures, inflammatory state of the mother, and other factors may be involved.24 While concrete published data on integrative therapies are lacking, holistic-minded practitioners possess the tools to provide a deeper evaluation of couples with RPL and help couples improve their overall health and nutrition status, which can optimize immune and metabolic functions, lifting barriers to a successful live birth.
| Fetal stage | Timing | Key milestones | Contributing factors to loss |
| Pre-embryonic | LMP to week 4 | Implantation | Genetic, implantation-related (thrombotic, thin uterine lining, low progesterone) |
| Embryonic | Week 5-9 | Organogenesis, O2 and nutrients through placenta | Genetic, hormonal (eg, low progesterone) |
| Fetal | Week 10-delivery | Autoimmune, thrombotic, anatomic |
Abbreviations: LMP, last menstrual period
| Genetic | Parental karyotype Balanced reciprocal translocations, Robertsonian translocations |
| Anatomic | HSG Saline-infused hysteroscopy Hysteroscopy 2D or 3D ultrasound |
| Endocrine | TSH w/antibodies Insulin resistance (fasting glucose, insulin, A1C) Prolactin Ovarian reserve testing (FSH, AMH, antral follicle count) |
| Infectious | Not recommended unless evidence of chronic endometritis/cervicitis or patient is immunocompromised |
| Autoimmune | Anticardiolipin antibody levels (IgG and IgM) Lupus anticoagulant |
| Non-APS thrombophilias | Homocysteine Factor V Leiden Prothrombin promotor mutation Activated protein C resistance |
Abbreviations: AMH, antimullerian hormone; APS, antiphospholipid syndrome; FSH, follicle stimulating hormone; HSG, hysterosalpingogram; Ig, immunoglobulin; TSH, thyroid stimulating hormone.
| Description | Test | Treatment |
| Proven/Validated | Lupus Anticoagulant | Anticoagulant therapies |
| Anticardiolipin antibody (ACA) | Anticoagulant therapies | |
| Anti B2-glycoprotein-1 antibodies | Progesterone supplementation | |
| Promising | Antiphosphatidylserine Antibodies | Intravenous Immune globulin |
| NK cell testing | Prednisone/steroid/anti-inflammatory treatments | |
| Potentially misleading | Extensive antibody panels | |
Parental HLA typing | ||
| Th1/Th2 profiling | ||
| ANA Panels |
Abbreviations: ANA, antinuclear antibody; HLA, human leukocyte antigen; NK, natural killer cell; Th, T helper cell
Figure 1.
Criteria for Evaluation of Pregnancy Loss (RPL)
- 3 spontaneous consecutive pregnancy losses in a patient with a previous history of live birth
- 2 spontaneous consecutive pregnancy losses in a patient with no live birth history
- Any loss of a fetus after 10 weeks’ gestation
