Anembryonic Pregnancy

Etiology

The exact etiology of anembryonic pregnancies is difficult to ascertain. The etiological factors for anembryonic pregnancies are generally understood and studied in the broader context of early pregnancy loss (EPL), which includes both embryonic and anembryonic pregnancies. Etiologies of anembryonic pregnancies include the following:

• Morphological abnormalities: Morphological abnormalities of an embryo prevent implantation or prevent long-term survival of the embryo after implantation. These morphological abnormalities are thought to be related to chromosomal abnormalities.[5] 
• Chromosomal abnormalities
  • Autosomal trisomy, polyploidy, sex chromosomal polysomy, and monosomy X are likely the most common etiologies of EPL. However, half of all anembryonic pregnancies have been found to have normal chromosomes.[8]
  • Trisomies are the primary fetal chromosomal abnormality in sporadic cases of miscarriage (30% of all miscarriages) and represent 60% of chromosomally abnormal miscarriages (recurrent miscarriages). Trisomies with monosomy X (15% to 25%) and triploidy (12% to 20%) account for over 90% of all chromosomal abnormalities found in sporadic cases of miscarriage. According to a study by Edmonds in 1992, trisomy 16, the most common chromosomal abnormality found in 15% of anembryonic pregnancies, gave rise to rudimentary embryonic growth with an empty sac, while other trisomies often resulted in early embryonic demise.[9] 
  • The incidence of other trisomies in anembryonic pregnancies is as follows: trisomy 22 (9.6%), trisomy 15 (3.8%), and trisomy 19 (3.8%).[8]
• Other genetic and chromosomal abnormalities: Translocations, inversions, single-gene perturbations, and placental mosaicism are some of the other genetic abnormalities that can cause anembryonic pregnancies.[10] Consanguineous marriages resulting in anembryonic pregnancies have also been noted, suggesting the role of single-gene determinants.[11] A probable link between DNA damage in sperm and miscarriage has been noted.[12]
• Obesity and advanced maternal age: These factors are well-established contributors to EPL.[13] Aneuploidies are more commonly seen in anembryonic pregnancies in women of advanced maternal age than in younger women.[8]
• Infection: Infectious etiologies are thought to play a role in anembryonic pregnancies. Tuberculosis in the developing world, as well as reproductive tract infections worldwide, can predispose to EPL.[14] The complications of genital tract infections, including intrauterine adhesions, can impede implantation and embryo growth.
• Uterine abnormalities: Malformations of the uterus, including didelphic, bicornuate, and septate uteri, can impede or prevent the long-term implantation of an embryo.
• Immunologic disorders: Maternal immunologic conditions, eg, NK cell dysfunction, autoantibodies, hereditary, and acquired thrombophilia, among others, can lead to the maternal immunological rejection of the implanting embryo in the uterus, resulting in miscarriage.
• Hormonal factors:  Low levels of progesterone and endocrinological disorders, including thyroid autoimmunity and thyroid dysfunction, are a few of the hormonal factors that may play a complex role in miscarriage. Polycystic ovarian syndrome is also associated with infertility and pregnancy loss.
• Alcohol consumption: Maternal alcohol use has been established to have an associated increased risk of miscarriage.[15]

Epidemiology

Although difficult to definitively establish, anembryonic pregnancy possibly represents half of all miscarriages in the first trimester of pregnancy.[16][17] The incidence of early pregnancy loss (before 12 weeks) is estimated to be about 15% of clinically evident conceptions, with significant variations in incidence based on patient age. The incidence ranges from 10% in women aged 20 to 24 years to 51% in women aged 40 to 44 years.[18] A prior history of early pregnancy loss also predisposes a patient to miscarriage.[19] 

History and Physical

The signs and symptoms of an anembryonic pregnancy can potentially mirror those of an ectopic pregnancy. Anembryonic pregnancy is often incidentally noted on an initial first-trimester obstetric sonogram. If an anembryonic pregnancy progresses to an early pregnancy loss, the patient can present with abdominal cramping and vaginal bleeding. Conversely, early pregnancy loss in the setting of an anembryonic pregnancy can be clinically asymptomatic. A previous anembryonic pregnancy is a risk for another similarly abnormal pregnancy.

Evaluation

Clinical signs and symptoms, along with pregnancy testing and ultrasound evaluation, confirm the diagnosis of an anembryonic pregnancy. Pregnancy testing may be performed using urine or serum hCG levels to support clinical suspicion and guide further assessment.

Transabdominal or transvaginal ultrasound classically demonstrates an empty gestational sac without visualization of an embryo (see Image. Anembryonic Pregnancy). Diagnostic confirmation occurs when ultrasound imaging shows no discernible embryo within a gestational sac measuring 25 mm or more in mean sac diameter. Diagnosis may also be established on follow-up endovaginal imaging when no embryo is visualized by 11 days or more after a prior scan that demonstrated a gestational sac with a yolk sac but no embryo, or 14 days or longer after a scan that demonstrated a gestational sac without an embryo or a yolk sac.

Treatment / Management

The 3 treatment options for early pregnancy loss include expectant management, medical management, and surgical treatment. Medical therapy with mifepristone and/or misoprostol, as well as surgical intervention, represents effective treatment for anembryonic gestations. Selection of a management strategy depends on an informed discussion between the patient and clinician, unless a clear indication for surgical intervention exists. If the success rate for medical management were higher than 65%, then most patients would prefer to manage their anembryonic pregnancy in this manner.

Expectant Management

Expectant management is a watchful-waiting approach in which the patient undergoes close follow-up without immediate intervention to allow for spontaneous and complete passage of tissue. Repeat sonograms and serial hCG measurements help confirm complete tissue expulsion. Confirmation of a negative hCG level after vaginal passage of tissue is recommended.

Medical Management 

Medical management involves administration of mifepristone and/or misoprostol through vaginal, oral, or buccal routes, using varying doses and timing regimens. Ongoing research continues to evaluate optimal dosing strategies. This option offers a more predictable clinical course.

Surgical Treatment 

Surgical treatment involves uterine evacuation using manual vacuum aspiration or dilation and curettage. Clinicians frequently select this approach for patients with hemodynamic instability or for those unable to tolerate the cramping and bleeding associated with medical therapy. Uterine aspiration or evacuation provides a faster completion time, particularly in the outpatient setting.[7]

Differential Diagnosis

The differential diagnosis for an anembryonic pregnancy includes the following:

• Pseudogestational sac, which reveals a small amount of intrauterine fluid but no pregnancy tissue
• Early intrauterine pregnancy
• An ectopic pregnancy
• Implantation bleeding from an otherwise viable pregnancy
• Gestational trophoblastic disease (Please see StatPearls' companion resource, "Gestational Trophoblastic Disease," for further information)
• Complications relating to a viable pregnancy 

Pertinent Studies and Ongoing Trials

Maternal amino acids are crucial for early embryonic growth because the developing embryo relies entirely on the mother’s supply, delivered through uterine secretions and later the placenta. Proper placental development and a healthy maternal–fetal interface depend on adequate amino acid levels and transport. In a normal early pregnancy, maternal amino acid concentrations typically decline as the embryo begins to use them.

However, despite evidence that abnormal placentation contributes to anembryonic pregnancy, changes in maternal serum amino acid patterns in these pregnancies have not previously been studied. The viability of many early pregnancies is difficult to determine by ultrasound alone. Maternal serum amino acids are higher in individuals with anembryonic pregnancy. Using 17 amino acid levels, especially as a combined profile, has been shown to improve the diagnostic accuracy. This approach may offer a useful tool for early risk screening of anembryonic pregnancy in the future.[20]

Prognosis

Prognosis and successful management of an anembryonic pregnancy depend on multiple factors, including gestational age. Outcomes are generally favorable with all 3 management approaches.

Expectant management has demonstrated acceptable outcomes. A meta-analysis of 20 studies concluded that both expectant and medical management represent appropriate treatment options for incomplete abortion.[21] Medical management shows improved success with multiple-dose misoprostol regimens. Patients with incomplete abortion experience higher success rates with medical therapy compared with expectant management.

Surgical treatment demonstrates high efficacy. At least 1 large randomized controlled trial reported a higher success rate with surgical intervention than with medical management, while also concluding that both approaches maintain an overall favorable safety profile.[22]

Complications

Serious complications of anembryonic pregnancy treatment are uncommon, but can include:

• Heavy bleeding and hemorrhage
• Uterine perforation from surgical management
• Infection or septic abortion, which can be fatal
• Complications from a missed diagnosis of ectopic pregnancy [7]