Evaluation of Fetal Death

Author: James L Lindsey, MD; Chief Editor: Carl V Smith, MD

Definition of Fetal Death

The loss of a fetus at any stage is a fetal demise. According to the 2003 revision of the Procedures for Coding Cause of Fetal Death Under ICD-10, the National Center for Health Statistics defines fetal death as "death prior to the complete expulsion or extraction from its mother of a product of human conception, irrespective of the duration of pregnancy and which is not an induced termination of pregnancy. The death is indicated by the fact that after such expulsion or extraction, the fetus does not breathe or show any other evidence of life, such as beating of the heart, pulsation of the umbilical cord, or definite movement of voluntary muscles. Heartbeats are to be distinguished from transient cardiac contractions; respirations are to be distinguished from fleeting respiratory efforts or gasps." In the United States, the term stillbirth or fetal demise does not have a standard definition. For statistical purposes, fetal losses are classified according to gestational age. A death that occurs prior to 20 weeks' gestation is usually classified as a spontaneous abortion; those occurring after 20 weeks constitute a fetal demise or stillbirth. Many states use a fetal weight of 350 g or more to define a fetal demise. Although this definition of fetal death is the most frequently used in medical literature, it is by no means the only definition in use. Even within the United States, the differences in the definitions used are substantial. In addition, not all states interpret the weeks of gestation in the same manner. In California, 20 weeks' gestation is worded "twenty utero gestational weeks" and has therefore been interpreted to be 23 weeks from the last menstrual period. (Implantation in the uterus does not occur until 1 wk after fertilization.) Physicians must check the reporting requirements for the state(s) in which they practice.

Frequency of Fetal Death

In 2005, data from the National Vital Statistics Report showed a US national average stillbirth rate of 6.2 per 1000 births.[1] Worldwide, this rate varies considerably depending on the quality of medical care available in the country in question and the definitions used for classifying fetal deaths. Underreporting in developing nations is common, which makes comparisons even more difficult. In 2009, the estimated global number of stillbirths was 2.64 million (uncertainty range, 2.143.82 million).[2] The worldwide stillbirth rate declined by 14.5% from 22.1 stillbirths per 1000 births in 1995 to 18.9 stillbirths per 1000 births in 2009.

Diagnosis of Fetal Death

History and physical examination are of limited value in the diagnosis of fetal death. In most patients, the only symptom is decreased fetal movement. An inability to obtain fetal heart tones upon examination suggests fetal demise; however, this is not diagnostic and death must be confirmed by ultrasonographic examination. Fetal demise is diagnosed by visualization of the fetal heart and the absence of cardiac activity.

Management of Fetal Death

Once the diagnosis of fetal demise has been confirmed, the patient should be informed of her condition. Often, allowing the mother to see the lack of cardiac activity helps her to accept the diagnosis. Labor induction should be offered after diagnosis. Patient responses vary in regard to this recommendation; some wish to begin induction immediately, while others wish to delay induction for a period of hours or days until they are emotionally prepared. When a dead fetus has been in utero for 3-4 weeks, fibrinogen levels may drop, leading to a coagulopathy. This is rarely a problem because of earlier recognition and induction. In some cases of twin pregnancies, induction after the death of a twin may be delayed to allow the viable twin to mature. Induction may be accomplished with preinduction cervical ripening followed by intravenous oxytocin (see Cervical Ripening). Patients with a history of a prior cesarean delivery should be treated cautiously because of the risk of uterine rupture, just as in any birth following cesarean delivery (see Vaginal Birth After Cesarean Delivery). Early fetal demise may be managed with laminaria insertion followed by dilatation and evacuation. In women with fetal death before 28 weeks' gestation, induction may be accomplished using prostaglandin E2 vaginal suppositories (10-20 mg q4-6h), misoprostol (ie, prostaglandin E1) vaginally or orally (400 mcg q4-6h), and/or oxytocin (preferred in women with prior uterine surgery). In women with fetal death after 28 weeks' gestation, lower doses should be used. In women with no uterine scar, misoprostol (25 mcg q4-6h) may be administered for ripening after 28 weeks gestation.[3] For women with a prior cesarean delivery, mechanical ripening can be performed with a Foley catheter, and induction can be continued with oxytocin. The American College of Obstetricians and Gynecologists (ACOG) guidelines for induction of labor states that prostaglandin E2 and misoprostol should not be used in women with a history of a prior uterine incision because of the risk of uterine rupture. In 2003, Dickinson and Evans reported on the efficacy of oral, vaginal, and combined administration of misoprostol for second-trimester induction in women without a uterine scar and found that the superior regimen was misoprostol at 400 mcg vaginally every 6 hours.[3] A meta-analysis of the use of misoprostol for induction in the second and third trimester showed efficacy of

multiple routes (vaginal, oral, sublingual), frequencies (every 3-12 h), and dosages (100-400 mcg).[4] Pain management in patients undergoing induction of labor for fetal demise is usually easier to manage than in patients with live fetuses. Higher doses of narcotics are available to the patient and often a morphine or Dilaudid PCA is sufficient for successful pain control. Should a patient desire superior pain control to intravenous narcotics, epidural anesthesia should be offered. See the image below for an example of a checklist that can be used in the management of fetal demise.

This is an example of a checklist to be used following fetal death. Courtesy of Santa Clara Valley Medical Center.

Causes of Fetal Death

The etiology of fetal demise is unknown in 25-60% of all cases. In cases where a cause is clearly identified, the cause of fetal death can be attributable to fetal, maternal, or placental pathology. One prospective study attributed 64.9% of fetal death to placental pathology overall. The same study noted higher rates of fetal demise secondary to placental pathology at late gestational age.[5] A meta-analysis of 96 population-based studies found that maternal overweight and obesity was the highest-ranking modifiable risk factor for stillbirth.[6] Advanced maternal age (>35 y) and maternal smoking were also significant. Small size for gestational age and abruption were the highest-ranking pregnancy disorder risk factors for stillbirth. Preexisting diabetes and hypertension are also important contributors to stillbirth.

Maternal

Prolonged pregnancy (>42 wk) Diabetes (poorly controlled) Systemic lupus erythematosus Antiphospholipid syndrome Infection Hypertension

Preeclampsia Eclampsia Hemoglobinopathy Advanced maternal age Rh disease Uterine rupture Maternal trauma or death Inherited thrombophilias

Fetal

Multiple gestations Intrauterine growth restriction Congenital abnormality Genetic abnormality Infection (ie, parvovirus B19, CMV, Listeria) Hydrops

Placental

Cord accident Abruption Premature rupture of membranes Vasa previa Fetomaternal hemorrhage Placental insufficiency

Risk factors (weak predictive value)

African American race Advanced maternal age History of fetal demise Maternal infertility History of small for gestational age infant Small for gestational age infant Obesity Paternal age

Evaluation of Fetal Demise

The time following a fetal death is extremely difficult for both the family and the health care providers. In this stressful time, use of a checklist is helpful to prevent oversights in the evaluation of the mother, fetus, and placenta as well as to ensure that the emotional needs of the family are met. The following image is an example of such a checklist, which is used at Santa Clara Valley Medical Center.

This is an example of a checklist to be used following fetal death. Courtesy of Santa Clara Valley Medical Center. Another useful resource is a grief packet that can be given to the parents following the demise. This usually includes referrals for counseling, support groups, and other resources. A container or folder can be included so that the family can preserve keepsakes such as photos, footprints, or a lock of hair. Spiritual support is an important resource during such difficult times and should always be offered to patients and their families. Currently, which tests are most effective in evaluating a fetal demise have not been agreed upon. Therefore, authorities vary in their recommendations. Most of the testing recommendations in the past have been based on expert opinion rather than scientific studies. The Stillbirth Collaborative Research Network currently has ongoing studies, which will hopefully define the optimal diagnostic evaluation for this difficult clinical problem. In an effort to better understand the underlying pathophysiology that leads to fetal demise and thereby create appropriate interventions, experts proposed a uniform international classification system and recommended a complete stillbirth workup for every case of fetal demise.[7] Up to 60% of stillbirths have no identifiable etiology. Attempting to determine the cause of fetal death remains important because it may influence estimates of recurrence and future preconceptional counseling, pregnancy management, prenatal diagnostic procedures, and neonatal management. Many institutions use a selective workup based on clinical findings. For example, when clinical findings strongly suggest a cause for the fetal demise at Santa Clara Valley Medical Center, either no further testing or limited testing is performed. Causes deemed fairly obvious include cord accident (ie, prolapse, entanglement, true knot, tight nuchal cord), anencephaly, or previously known lethal karyotype. In such cases, no further workup is necessary. If severe clinical abruption is present, testing can be limited to toxicology screening and possibly a thrombophilia workup. The most important part of the workup of a fetal demise is the autopsy of the fetus. The decision to proceed with an autopsy must be made by the parents and informed consent is necessary. With parents who are resistant to the idea of a complete autopsy, a limited fetal evaluation should be discussed with the family. Although uncommon, postmortem MRIs can

provide valuable information in the evaluation of a fetus when an autopsy cannot be performed. The placenta and the membranes should be carefully examined, including cultures. Again, an algorithm or checklist is helpful to avoid omissions (see image below). This inspection is even more important if the family declines an autopsy.

This is an example of a checklist to be used following fetal death. Courtesy of Santa Clara Valley Medical Center. Fetal karyotype can be obtained from a sample of amniotic fluid (preferred), fetal blood, or fetal tissue (skin or fascia lata). Fetal karyotype should be considered in all cases. It is especially important if the fetus is dysmorphic, has growth retardation, is hydropic, or has anomalies or other signs of chromosomal abnormality. Chromosomal analysis should also be considered in patients with multiple pregnancy losses, especially with a history of secondand third-trimester losses or when a parent has a balanced translocation or mosaic chromosomal pattern. Many authorities (including the ACOG committee on evaluation of stillbirth) recommend obtaining this test in every fetal demise. A summary of the protocol for the fetus and placenta is as follows:

Careful inspection Placental cultures for suspected listeria infection (To obtain placental cultures, separate the amnion and the chorion and submit a culture specimen using Stuart media.) Radiographs, if indicated Autopsy MRI, if no autopsy Fetal karyotype

Maternal Studies
Maternal studies that should also be considered during the workup of a fetal demise include the following:

Diabetes testing using hemoglobin A1C and a fasting blood glucose Syphilis screening using the VDRL or rapid plasma reagent test Thyroid function testing (ie, TSH, FT4) Urine toxicology screening

The above tests have traditionally been a part of an evaluation for the etiology of fetal demise. If diabetes screening has been performed during the prenatal period, repeat testing for diabetes is probably not necessary. Similarly, if the patient has no signs or symptoms of thyroid disease, thyroid dysfunction is unlikely to be the cause of the demise. However, these tests are inexpensive and normal results may be reassuring to the patient. Additional tests that should be considered are as follows:

Antibody screening CBC count with platelet count Kleihauer-Betke test Laboratory tests for antiphospholipid syndrome: See Antiphospholipid Antibody Syndrome and Pregnancy. Inherited thrombophilia panel o The enthusiasm for laboratory testing for inherited thrombophilias for adverse pregnancy outcome is waning. Inherited thrombophilias are common in the general population but are probably rare causes of fetal demise. A multicenter, prospective, observational cohort study concluded that there was no association between prothrombin G20210A mutation and pregnancy loss, preeclampsia, abruption, or SGA neonates in a low-risk population.[8] The current ACOG Practice Bulletin, Management of Stillbirth, is now recommending inherited thrombophilia testing only in selected cases.[9] In a more recent ACOG Practice Bulletin, Inherited Thrombophilias in Pregnancy, there is no recommendation to screen for inherited thrombophilias with pregnancy loss.[10] o While some authorities recommend maternal testing in all cases of fetal demise, a more selective approach is to limit testing to patients who have a history of venous thrombosis, positive family history, severe placental pathology, severe preeclampsia in the second or early third trimester, abruption, or significant intrauterine growth retardation. The value of thrombophilia testing in any circumstance in obstetrics has recently been questioned.[11] Infection: See Bacterial Infections and Pregnancy. Infection is a cause of fetal demise. The frequency is higher in developing countries. Autopsy and histologic evaluation of the placenta is probably the best way to document an infectious etiology for a fetal demise.

Authority opinions vary as to which panel of tests is appropriate. Traditionally, most authorities have recommended obtaining TORCH (toxoplasmosis, rubella, cytomegalovirus,

and herpes simplex virus) antibody titers. In reality, this is rarely helpful in the diagnosis. In addition, it is questionable whether cytomegalovirus virus causes fetal demise. If no obvious cause for the demise is established or if clinical signs or symptoms suggest infection, consider testing for (1) cytomegalovirus (acute and chronic titers), (2) rubella virus (acute and chronic titers, if not immune), (3) parvovirus (acute and chronic titers), and (4) Toxoplasmosis gondii (acute and chronic titers) and (5) syphilis. A more cost-effective approach is to limit testing for cytomegalovirus, rubella virus, and T gondii to those patients in whom clinical findings suggest the possibility of intrauterine infection (ie, those with intrauterine growth restriction, microcephaly).

Testing for Fetal Demise

The following provides a summary of the current status of testing for fetal demise. This is adopted with permission from the work of Dr. Robert M. Silver and the Stillbirth Collaborative Research Network. This summary has been modified as more recent studies have become available.

Commonly accepted tests

Thorough maternal history Fetal autopsy Placental evaluation Karyotype Indirect Coombs test Serologic test for syphilis Testing for fetal-maternal hemorrhage (Kleihauer-Betke or other) Urine toxicology screen Parvovirus serology Lupus anticoagulant, for antiphospholipid testing Anticardiolipin anticoagulant, for antiphospholipid testing Anti-B 2 -glycoprotein 1 IgG or IgM antibodies

Useful in some circumstances

Factor V Leiden Prothrombin mutation Protein C, protein S, and antithrombin III deficiency TSH Hemoglobin A1C TORCH titers Placental cultures Testing for other thrombophilias

Developing technology

Comparative genomic hybridization Testing for single gene mutations Testing for confined placental mosaicism Nucleic acid-based testing for infection

Management of Future Pregnancy

If a particular medical problem is identified in the mother, it should be addressed prior to conception. For example, tight control of blood glucose prior to conception can substantially reduce the risk of congenital anomalies in the fetus. Preconceptional counseling is helpful if congenital anomalies or genetic abnormalities are found. Genetic screening and detailed ultrasound can evaluate future pregnancies. In some cases, such as cord occlusion, the patient can be assured that recurrence is very unlikely. Fetal death of unknown cause is a special problem. Because a large number of etiologies of fetal demise exist, a provider has difficulty determining risk of stillbirth for any particular pregnancy. Evidence-based models such as Active Management of Risk In Pregnancy At Term (AMOR-IPAT) are being created in an effort to better estimate this risk.[12] Although recurrent fetal loss is uncommon, patients are naturally anxious. Most patients find increased fetal surveillance with the next pregnancy reassuring, even though such testing is not clearly beneficial. The ACOG recommends antepartum testing starting at 32-34 weeks' gestation in an otherwise healthy mother with history of stillbirth.[9] Weekly biophysical profile or fetal heart rate testing can be combined with maternal kick counts in the third trimester. For patients who have experienced earlier loss, frequent ultrasound is reassuring. Optimal management of chronic medical conditions is important prior to the next pregnancy.