Pregnancy Loss – Causes, Symptoms, Diagnosis, Treatment

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Pregnancy Loss/Miscarriage is two or more consecutive pregnancy losses. In contrast, infertility is the inability to conceive. In many cases the cause of RPL is unknown. After three or more losses, a thorough evaluation is recommended by the American Society of Reproductive Medicine.[rx] About 1% of couples trying to have children are affected by recurrent miscarriage.[rx][rx]

Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester and affects 1% to 2% of women, half of whom have no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with an increasing number of miscarriages.

Causes of Pregnancy Loss

Relative incidences of causative findings in cases with recurrent miscarriage.[rx]

There are various causes for recurrent miscarriage, and some can be treated. Some couples never have a cause identified, often after extensive investigations.[rx] About 50–75% of cases of recurrent miscarriage are unexplained.[rx]

  • Chromosomal disorders – A balanced translocation or Robertsonian translocation in one of the partners leads to unviable fetuses that are miscarried. This explains why a karyogram is often performed in both partners if a woman has experienced repeated miscarriages.[rx] Aneuploidy may be a cause of a random spontaneous as well as recurrent pregnancy loss.[rx] Aneuploidy is more common with advanced reproductive age reflecting decreased germ cell quality.[rx][rx]
  • Lifestyle factors – While lifestyle factors have been associated with increased risk for miscarriage in general, and are usually not listed as specific causes for RPL, every effort should be made to address these issues in patients with RPL. Of specific concern are chronic exposures to toxins including smoking, alcohol, and drugs.[rx]
  • Anatomical conditions – Fifteen percent of women who have experienced three or more recurring miscarriages have some anatomical reason for the inability to complete the pregnancy.[rx] The structure of the uterus has an effect on the ability to carry a child to term. Anatomical differences are common and can be congenital.
  • Cervical conditions – In the second trimester, a weak cervix can become a recurrent problem. Such cervical incompetence leads to premature pregnancy loss resulting in miscarriages or preterm deliveries. It has been estimated that cervical insufficiency is a cause in about 8% of women with second-trimester recurrent miscarriages.[rx]
  • Endocrine disorders – Women with hypothyroidism are at increased risk for pregnancy losses. Unrecognized or poorly treated diabetes mellitus leads to increased miscarriages. Women with polycystic ovary syndrome also have higher loss rates possibly related to hyperinsulinemia or excess androgens. Inadequate production of progesterone in the luteal phase may set the stage for RPL.
  • Thrombophilia – An important example is the possible increased risk of miscarriage in women with thrombophilia (propensity for blood clots). The most common problem is the factor V Leiden and prothrombin G20210A mutation.[rx] Some preliminary studies suggest that anticoagulant medication may improve the chances of carrying a pregnancy to term but these studies need to be confirmed before they are adopted in clinical practice.[rx] Note that many women with thrombophilia go through one or more pregnancies with no difficulties, while others may have pregnancy complications. Thrombophilia may explain up to 49–65% of recurrent miscarriages.[rx]
  • Immune factors – A common feature of immune factors in causing recurrent pregnancy loss appears to be a decreased maternal immune tolerance towards the fetus.[rx]
  • Antiphospholipid syndrome – Antiphospholipid syndrome is an autoimmune disease that is a common cause of recurrent pregnancy loss.[rx][rx] Around 15% of the women who have recurrent miscarriages have high levels of antiphospholipid antibodies.[rx] Women who have had more than one miscarriage in the first trimester, or a miscarriage in the second trimester, may have their blood tested for antibodies, to determine if they have antiphospholipid syndrome.[rx] Women diagnosed with antiphospholipid syndrome generally take aspirin or heparin in subsequent pregnancies, but questions remain due to the lack of high-quality trials.[rx][rx]
  • Thyroid antibodies – Anti-thyroid autoantibodies are associated with an increased risk of recurrent miscarriage with an odds ratio of 2.3 with a 95% confidence interval of 1.5–3.5.[rx]
  • Increased uterine NK cells – Natural killer cells, a type of white blood cell, are present in uterine tissue. High levels of these cells may be linked to RPL but high numbers or the presence of these cells is not a predictor of pregnancy loss in women who have not have had a miscarriage.[rx]
  • Parental HLA sharing – Earlier studies that perhaps paternal sharing of HLA genes would be associated with increased pregnancy loss have not been confirmed.
  • Male-specific minor histocompatibility – Immunization of mothers against male-specific minor histocompatibility (H-Y) antigens have a pathogenic role in many cases of secondary recurrent miscarriage, that is, recurrent miscarriage in pregnancies succeeding a previous live birth. An example of this effect is that the male-female ratio of children born prior and subsequent to secondary recurrent miscarriage is 1.49 and 0.76 respectively.[rx]
  • Luteal phase defect – The issue of a luteal phase defect is complex. The theory behind the concept suggests that an inadequate amount of progesterone is produced by the corpus luteum to maintain the early pregnancy. Assessment of this situation was traditionally carried out by an endometrial biopsy, however recent studies have not confirmed that such assessment is valid.[rx] Studies about the value of progesterone supplementation remain deficient, however, such supplementation is commonly carried out on an empirical basis.
  • Infection – Infections are estimated to be responsible for between 0.5 and 5% of cases with recurrent miscarriage. The main suspected pathogens are mycoplasma, ureaplasma, Chlamydia trachomatisListeria monocytogenes, and herpes simplex virus. An infectious evaluation may be warranted in people with immunodeficiency, or with signs of chronic endometritis/cervicitis on examination,.[rx] Otherwise, there is no evidence that routine infectious evaluation is appropriate or productive.[24]
  • Chronic endometritis (CE) – due to common bacteria has been found to be prevalent in some women with a history of recurrent miscarriage. One study found that 71 percent of women who tested positive for this condition were successfully treated by an antibiogram-based antibiotic treatment. 78.4 percent of these women subsequently became pregnant in the year following treatment. The study concludes that CE is frequent in women with recurrent miscarriages, and that antibiotic treatment seems to be associated with an improved reproductive outcome.” The authors also conclude that hysteroscopy should be a part of the diagnostic workup of infertile women complaining of unexplained recurrent miscarriage.[rx]
  • Anatomic – Congenital Mullerian tract anomalies can cause RPL. Some of the uterine abnormalities which can predispose to RPL are septate, unicornuate, bicornuate, didelphic, and arcuate uteri. Septate uterus is considered to be the most common congenital uterine anomaly. A meta-analysis of several studies concluded that congenital uterine defects were present in about 12.6 percent of the patients with recurrent pregnancy loss. Acquired uterine anomalies like fibroids, polyps, and Asherman syndrome can also increase the women’s risk for RPL.
  • Environmental factors – Cigarette smoking is suggested to affect the trophoblastic function and is linked to an increased risk of RPL. Obesity is independently associated with an increased risk of recurrent pregnancy loss in women who conceive naturally. Other lifestyle habits such as alcohol consumption (3 to 5 drinks per week), cocaine use, and increased caffeine consumption (more than 3 cups of coffee per day), are also associated with increased risk of spontaneous miscarriages.
  • Immunological – Routine testing of women with RPL for inherited thrombophilias is not currently recommended. Screening for inherited thrombophilias may be indicated when a patient has a personal history of venous thromboembolism in the setting of a nonrecurrent risk factor (such as surgery) or a  relative with a known or suspected high-risk thrombophilia. Prospective cohort studies have failed to confirm the association between hereditary thrombophilia and fetal loss.
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Therapeutic Interventions for Recurrent Pregnancy Loss Based on Etiology

DisorderTherapy
GeneticGenetic counseling
Balanced translocationsIVF with a preimplantation genetic diagnosis
Donor gametes
Anatomic
Müllerian anomaliesHysteroscopic resection of septa, adhesions, and submucosal fibroids
Asherman syndromeMyomectomy for those intramural and subserosal fibroids >5 cm
Leiomyomas
Endocrine
PCOSMetformin
HypothyroidismThyroid hormone replacement
Luteal phase defect/unexplainedProgesterone supplementation
Diabetes mellitusAppropriate management of diabetes, insulin if indicated
InfectiousAntibiotics for endometritis or underlying infection
AutoimmuneLow-dose aspirin plus prophylactic LMWH in women without a history of a systemic autoimmune disease such as SLE, or a history of thrombosis
APS
OtherCombined thrombophilic defects—therapeutic anticoagulation
Non-APS thrombophiliasIsolated defect and no personal or strong family history of thrombotic complications—prophylactic anticoagulation
Environmental exposuresHyperhomocysteinemia—supplemental folic acid (0.4–1.0 mg/d), vitamin B6 (6 mg/d), and possibly vitamin B12 (0.025 mg/d)
Consider prophylactic anticoagulation if hyperhomocysteinemia refractory to dietary intervention
Limit exposures that could be factors (eg, tobacco, alcohol, caffeine)

Symptoms of Pregnancy Loss

Some women experience signs and symptoms before a miscarriage actually occurs; others do not. Some of the signs that a miscarriage may be about to start are vaginal spotting, which is usually dark brown and changing to pink or red; a decrease in breast tenderness or fullness; and absence of fetal movement or heart sounds. Cramping and vaginal bleeding are signs that the miscarriage is occurring. Be proactive and call your doctor immediately.

Even if ends up to be nothing wrong, peace of mind will go a long way. If you do find that you are bleeding, try to keep track of the amount of bleeding that occurs. If you notice any tissue has passed, try to save it. This may sound strange to some, but many doctors will want it for laboratory evaluation to help determine the cause of the miscarriage.

Diagnosis of Pregnancy Loss

History and Physical

A thorough and detailed history should be taken and must include all the details of previous pregnancy losses. The gestational age of prior pregnancy loss is critical to know, as RPL typically occurs at a similar gestational age in successive pregnancies. The method of treatment of previous pregnancy loss is also important to know, as dilation and curettage can increase the risk of Asherman syndrome, cervical incompetence, which can predispose to RPL.

It is also essential to document full medical (thyroid problems, diabetes), surgical, and menstrual history. Family and personal history of venous and arterial thrombosis, history of smoking, alcohol, drugs, and exposure to environmental toxins must be documented. Physical examination should include a detailed general exam and pelvic exam.

Evaluation

Evaluation of couples with RPL should be thorough and should include the following:

  • Assessment of Medical Problems – Studies should be performed to rule out diabetes, thyroid problems , and hyperprolactinemia.
  • Genetic Evaluation – Karyotype assessment of the couples has to be offered to recognize underlying balanced, reciprocal, or Robertsonian translocations or mosaicism that might be transmitted to the fetus, causing RPL. Though these tests are of low yield and expensive, one should consider evaluating the karyotypes of the couples with RPL.
  • Assessment of the Uterine Anomalies – There are several modalities that can be used to identify congenital and acquired uterine anomalies, some of the valuable tools are the following Pelvic ultrasound, Saline infusion sonohysterography, Hysterosalpingogram, Hysteroscopy, MRI is very valuable in identifying congenital uterine anomalies.
  • Immunologic Work Up – Investigations for antiphospholipid antibody syndrome must be undertaken. Measurement of Anticardiolipin antibody, lupus anticoagulant, and anti-beta 2 glycoprotein should be done for patients with RPL. Studies have reported that anticardiolipin antibody and lupus anticoagulant has been associated with pregnancy loss, and testing for APAS  for patients with RPL is recommended.
  • Hormonal Tests – Ask to have a prolactin, thyroid, and progesterone level taken if you haven’t had these already. If they are abnormal and treatment is given, make sure that you are re-tested to check your levels.
  • Structural Tests – A hysterosalpingogram is done to evaluate the shape and size of your uterus and to rule out possible scarring in the uterus, polyps, fibroids, or a septal wall, which could affect implantation. If there is concern about the uterine cavity, a hysteroscopy (examination done in combination with laparoscopy or as an office procedure) can be done. In some women, the cervical muscle is too loose causing pregnancy loss after the first trimester. A special exam is done when a woman is not pregnant to check for an incompetent cervix.
  • Uterine Lining Tests – An endometrial biopsy is done on cycle day 21 or later and will document if your lining is getting thick enough for the fertilized egg to implant. If you have a lag of two or more days in the development of the lining, you will be treated with various hormones (Clomiphene, hCG, Progesterone). It is important to have the biopsy repeated after several cycles to make sure the treatment is helping. If you are on Progesterone, discuss the various advantages of the oral, vaginal gel creams or tablets or injection routes with your doctor
  • Progesterone Level – Routine assessment of serum progesterone levels is not recommended, as it is not predictive of future pregnancy outcomes.
  • Endometrial Biopsy – A large number of studies show that this test is not reflective of fertility status in a woman.
  • Testing for Infections – In a healthy woman without symptoms, routine vaginal and cervical cultures for chlamydia, gonorrhea, bacterial vaginosis, and testing for TORCH serology are not useful in the evaluation of RPL.
  • Evaluation of products of Conception (POC) – Using a 24-chromosome microarray analysis adds significantly to the ASRM (American Society of Reproductive Medicine) recommended RPL assessment. Genetic evaluation of miscarriage tissue obtained at the time of the second and subsequent pregnancy losses should be offered to all couples with two or more consecutive pregnancy losses. The combination of a genetic evaluation on miscarriage tissue with an evidence-based assessment for RPL will identify a probable or definitive cause in over 90 percent of miscarriages.
  • Ultrasound – is the gold standard for examining intrauterine contents and viability. This paired with a quantitative human chorionic gonadotropin (hCG) hormone level can help determine viability. hCG levels should double in 48 hours on serial exams.
  • Karyotype– – a mapping of your chromosomes, used to diagnose genetic defects.
  • Hysterosalpingogram– – a radiology procedure that uses fluoroscopy and a special dye to evaluate the shape of the inside of your uterus and the patency of the fallopian tubes.
  • Saline Sonohysterogram– –a procedure where sterile water is placed into the cavity of the uterus while performing a transvaginal
    ultrasound.  This procedure is useful to look for endometrial cavity abnormalities such as polyps, fibroids, and scar tissue that may increase
    the risk of a miscarriage.
  • Hysteroscopy– – a procedure in which your doctor uses a narrow fiberoptic scope inserted into the uterus to look inside the uterine cavity.
  • Vaginal ultrasound– – a scan that uses high-frequency sound waves to detect abnormalities in and around the uterus, ovaries, and fallopian tubes.
  • Blood hormone levels– – blood tests that reveal the levels of certain hormones in your blood, such as prolactin, thyroid-stimulating hormone, and progesterone.
  • Endometrial biopsy– – a procedure in which a sample of the endometrial tissue is examined under a microscope to determine if there is an infection present preventing the pregnancy from progressing.
  • Glucose screening– – a blood test used to diagnose diabetes mellitus which, if left uncontrolled increases the likelihood of miscarriage.
  • Antiphospholipid antibody testing– – blood tests used to detect an immune system abnormality.
  • Ovarian reserve testing— Testing of egg quantity and quality may help determine if the age-related decline in ovarian function is contributing to pregnancy loss.
  • Sperm DNA fragmentation testing– a test to determine if sperm quality and DNA fragmentation may be contributing to pregnancy loss.
  • At hCG levels between 1000 to 2000, it has been determined that transvaginal ultrasound (TVUS)-  is the most sensitive study for identifying intrauterine contents such as a gestational sac with or without a fetus or embryo. There have been multiple studies that reveal a correlation between hCG levels and the stage of embryonic development seen on ultrasound. For instance, at a range of serum hCG between 800 to 1500 UI/I, a 1 to 3 mm gestational sac should be visible on TV. Furthermore, a yolk sac should be detectable within the range hCG level of 4500 to 7500 UI/I; with fetal heart motion visible at a range 8650 to 12,200 U/I.
  • Prenatal genetic testing – such as preimplantation genetic diagnosis, chorionic villus sampling, or amniocentesis to identify genetic anomalies in the fetus and decide about further treatment options. Although embryos with unbalanced chromosomal arrangements can theoretically be screened out, PGT (preimplantation genetic testing) is not routinely advised since the likelihood of a pregnancy with an unbalanced karyotype surviving into the second trimester is low.
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Etiologies of recurrent pregnancy loss recommended tests for diagnosis and treatment options

EtiologyTests for diagnosisTreatment options
Uterine factor3D ultrasonography, sonohysterography, hysterosalpingography, hysteroscopy
Magnetic resonance imaging
Hysteroscopic resection of the septum
Myomectomy, hysteroscopic removal of polyps Adhesiolysis
Antiphospholipid syndromeACL, Anti-β2GP1, lupus anticoagulantHeparin + aspirin
Endocrine abnormalityThyroid-stimulating hormone
Prolactin
Fasting glucose or HbA1c
Levothyroxine
Bromocriptine
Diabetes control (weight loss, nutrition, metformin)
GeneticKaryotype of a product of conception
Parental karyotype
Genetic counseling
Preimplantation genetic diagnosis for a balanced translocation
Environmental factorsScreen for smoking, drug use, excessive alcohol, and caffeine intakeEliminate environmental toxins
PsychologicalPsychological support in a specialized setting
UnexplainedProgesterone supplementation (no consensus)
Immunomodulating treatments (no consensus)
Preimplantation genetic screening (no consensus)
Other (no consensus)
 Luteal phase deficiencyMid-luteal progesterone, endometrial biopsyProgesterone supplementation
 Chronic endometritisEndometrial biopsyAntibiotic treatment
 Other infectionsCulturesAppropriate treatment
 Male factorDNA fragmentation test on spermLifestyle modifications, multivitamins, donor sperm

Treatment of Pregnancy Loss

Unfortunately, despite a comprehensive medical evaluation, some patients will be left with a diagnosis of unexplained recurrent pregnancy loss. Although this diagnosis can be frustrating, treatment options to lower the risk of miscarriage are available. These options include:

  • Ovulation induction.
  • Progesterone therapy.
  • Low dose aspirin.
  • Injectable blood thinners.
  • Antibiotics for presumed chronic inflammation of the uterus.
  • In vitro fertilization.
  • Preimplantation Genetic Testing for Aneuploidy (PGT-A).
  • Intracytoplasmic sperm injection (ICSI) with the assistance of the
    ZyMotTM device.

Medical management can be used in the absence of contraindications including severe anemia, bleeding disorders or infection. Misoprostol, a prostaglandin analog, is given in 1 or 2 doses to achieve induced passage of intrauterine contents. Misoprostol can be taken in the oral form, sublingual, or as a vaginal suppository. Most women will achieve complete expulsion within 3 days, and very few need subsequent uterine curettage.

Blood-thinning medicines – Women with autoimmune or clotting (thrombophilia) problems may be treated with low-dose aspirin and heparin. These medicines can be taken during pregnancy to lower the risk of miscarriage. You should talk to a healthcare provider before using these medicines because they increase the chances of serious bleeding problems (such as stomach ulcers).

Medical Conditions

Women with thyroid conditions, diabetes, obesity, and other medical problems should be treated as medically appropriate. Consultation with an endocrinologist is also a suitable option for the management of uncontrolled thyroid conditions and diabetes. Patients with elevated thyroid peroxidase antibodies are at high risk for RPL and should be managed appropriately.

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The conventionally accepted regimen for medical management consists of misoprostol 800 mcg vaginally, with a repeated dose if needed any time from three hours to seven days after the first dose. Premedication with mifepristone 200 mg orally 24 hours before the first dose of misoprostol may result in a higher success rate than misoprostol alone. Surgical management consists of dilation and suction curettage with sharp curettage, as needed, in either the operating room or office setting. There is evidence that suction curettage alone, without sharp curettage, is sufficient and decreases the risk of intrauterine adhesions, as long as there is reasonable certainty that the uterus is empty. Due to a lack of evidence on the safety of expectant management of second-trimester miscarriage, medical or surgical management is preferred beyond 12-13 weeks gestational age.

Chromosomal Anomalies  

In couples with chromosomal abnormalities, the first step is a referral to genetic counseling. Couples should be educated on the potential likelihood of having fetal chromosomal abnormalities in future pregnancies. They may choose to proceed with

Uterine Anomalies

Congenital and acquired uterine abnormalities causing RPL could be managed surgically. Some of the surgical procedures are hysteroscopic septum resection, lysis of adhesions, myomectomy, and repair of a bicornuate uterus. Referral to a reproductive endocrinologist is appropriate for these surgical interventions whenever possible.

Immunological                                                                                                                         

Patients with antiphospholipid antibody syndrome and RPL are generally treated with aspirin and heparin, and it appears to improve pregnancy outcomes. However, in women with thrombophilias, this treatment may improve maternal outcomes but does not prevent RPL. Treatment strategies like aspirin and low molecular weight heparin (LMWH) are standard medications in RPL, although only a few placebo-controlled trials have proven their benefit with respect to living birth rate. There is emerging evidence that new treatment options, including drugs like TNF (tumor necrosis factor-alpha) inhibitors and granulocyte colony-stimulating factor (G-CSF), might be beneficial in some cases of RPL. However, more extensive clinical trials must be completed to further prove or disprove the benefits of these drugs in the treatment of patients with RPL. Lipid emulsion infusions have been evaluated in only one RCT that tested whether a 250 mL infusion on the day of oocyte retrieval (with further infusions if there was a positive pregnancy test) could increase chemical pregnancy rates in patients with RPL with elevated peripheral blood NK cells (more than 12 percent) undergoing IVF. The study concluded that Intralipid supplementation did not increase the frequency of chemical pregnancy. However, findings related to ongoing pregnancy and live birth should be investigated further.

Unexplained RPL

A recent meta-analysis using strict criteria for defining unexplained RM found no RCTs involving prednisolone. Two recent meta-analyses of intravenous immunoglobulin (IVIG) use in patients with RPL found no evidence of improved live birth rates.


Surgery

Surgery can fix some problems in the uterus (womb), like extra tissue that divides the uterus (septum), some fibroids (benign tumors), or scar tissue. Correcting the shape of the inside of the uterus can often lower the chance for miscarriage. The surgeon uses a tool with a camera (hysteroscope) passed through the vagina to repair the inside of the uterus. This is usually a 1-day procedure and recovery time is a few days to a week.

Main Points

  • Spontaneous pregnancy loss is common, with approximately 15% of all clinically recognized pregnancies resulting in miscarriage.
  • When recurrent pregnancy loss (RPL) is defined as 3 consecutive pregnancy losses prior to 20 weeks from the last menstrual period, 1% to 2% of women will be affected.
  • Because the risk of subsequent miscarriages is similar among women that have had 2 versus 3 miscarriages, and the probability of finding a treatable etiology is similar among the 2 groups, most experts agree that there is a role for evaluation after 2 losses.
  • Accepted etiologies for RPL include parental chromosomal abnormalities, untreated hypothyroidism, uncontrolled diabetes mellitus, certain uterine anatomic abnormalities, and the antiphospholipid antibody syndrome (APS). Other probable or possible etiologies include additional endocrine disorders, heritable and/or acquired thrombophilias, immunologic abnormalities, and environmental causes. After evaluation for these causes, more than 33% of all cases will remain unexplained.
  • Diagnostic evaluation should include maternal and paternal karyotypes, assessment of the uterine anatomy, and evaluation for thyroid dysfunction, APS, and selected thrombophilias. In some women, evaluation for insulin resistance, ovarian reserve, antithyroid antibodies, and prolactin disorders may be indicated.
  • Therapy should be directed toward any treatable etiology, and may include in vitro fertilization with preimplantation genetic diagnosis, use of donor gametes, surgical correction of anatomic abnormalities, correction of endocrine disorders, and anticoagulation or folic acid supplementation.
  • In cases of unexplained RPL, progesterone has been shown to be beneficial in decreasing the miscarriage rate in women who had experienced at least 3 losses. Low-dose aspirin benefits those with a history of losses at more than 13 weeks of gestation.
  • Antenatal counseling and psychological support should be offered to all couples experiencing RPL, as these measures have been shown to increase pregnancy success rates.
  • Prognosis will depend on the underlying cause for pregnancy loss and the number of prior losses. Patients and physicians can be encouraged by the overall good prognosis, as even after 4 consecutive losses a patient has a greater than 60% to 65% chance of carrying her next pregnancy to term.

References

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