Sunday, September 26, 2021

Stillbirth Case File

Posted By: Medical Group - 9/26/2021 Post Author : Medical Group Post Date : Sunday, September 26, 2021 Post Time : 9/26/2021
Stillbirth Case File
Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 27
A 37-year-old G3P2002 African American female at 38 weeks’ gestation presents to labor and delivery complaining of absent fetal movement for 1 day. The nurse is unable to obtain fetal heart tones. The patient has a history of chronic hypertension diagnosed 2 years prior to pregnancy and was previously treated with a diuretic. She discontinued her medication when she found out that she was pregnant and has not required medication during this pregnancy. She had two previous term uncomplicated vaginal deliveries both weighing approximately 7 lb. 

Aneuploidy screening, maternal serum alpha-fetoprotein (MSAFP), and anatomy ultrasound at 20 weeks’ gestation were within normal limits. She declined amniocentesis for fetal karyotype. Her initial prenatal laboratories are as follows: O Rh-positive, indirect Coombs test negative (ICT), rubella immune, rapid plasma reagin nonreactive (RPR), hepatitis B surface antigen negative (HBsAg), and HIV negative. In addition, urine culture was negative, baseline 24-hour urine protein collection was less than 300 mg, and serum creatinine was 0.6 mg/dL. Her 1 hour 50 g oral glucose challenge was 109 mg/dL, RPR was nonreactive at 28 weeks, and group B streptococcus performed at 35 weeks was also negative. Fetal growth has been followed by ultrasound since 28 weeks with the last ultrasound at 36 weeks showing appropriate fetal growth and amniotic fluid. Fetal surveillance with weekly biophysical profiles (BPP) was initiated at 32 weeks and has been reassuring. 

Today she denies contractions, vaginal bleeding, loss of fluid, headache, visual changes, or epigastric pain. Her BP is 138/88 mm Hg, HR 98 beats per minute, weight 225 lb, BMI 36 kg/m2, and negative protein on urine dip. Her physical examination is within normal limits including a benign abdominal examination. Fundal height is at 37 cm. Her cervical examination is 1 to 2 cm long, −3 station, and posterior. She has 2+ deep tendon reflexes bilaterally. There are no contractions by external tocodynamometer. Bedside this, ultrasound examination confirms absent fetal cardiac activity. Fetal biometry is consistent with 37 weeks’ gestation and amniotic fluid index is appropriate. The only additional finding is that of overlapping cranial bones.

➤ What is your next step?
➤ What are potential maternal complications of stillbirth?


Summary: This is a 37-year-old African American female G3P2002 at 38 weeks’ gestation with chronic hypertension and stillbirth.

Next Step: counsel the patient about the diagnosis of stillbirth and discuss recommendations for evaluation emphasizing the importance of fetal karyotype, fetal autopsy, and placental evaluation.

Potential maternal complications of fetal demise: Maternal complications with expectant management include infection and maternal coagulopathy. In addition, patients with adverse pregnancy outcome are at higher risk for postpartum blues and depression.

  1. Identify risk factors and causes of stillbirth.
  2. Become familiar with the evaluation of stillbirth.
  3. Understand management options and recurrence risk of stillbirth.


The first priority for the clinician in a patient who complains of decreased or absent fetal movement is to ascertain fetal heart tones. If this is unsuccessful, real-time ultrasonography should be performed to definitively diagnose the presence of a fetus and the absence of fetal cardiac activity. If the physician is inexperienced with ultrasound, the diagnosis should be confirmed by a different examiner with appropriate expertise. 

There are numerous risk factors for stillbirth and this patient has four: advanced maternal age, obesity, race, and chronic hypertension. Women greater than 35 years of age at delivery have a twofold risk of stillbirth compared to those that are younger. This patient is also obese based on her body mass index (BMI) of 36 kg/m2. Obese women have a twofold risk of stillbirth compared to nonobese women. Moreover, stillbirth rates are highest in African Americans compared to other races. Finally, abruptio placentae, superimposed preeclampsia, intrauterine growth restriction, and perinatal death are complications more common in women with chronic hypertension. Even uncomplicated chronic hypertension is associated with increased perinatal death.

When discussing the diagnosis of stillbirth with this patient it is important to convey sensitivity and offer support. In many instances such as this, the cause of stillbirth may not be apparent at the time of diagnosis and, in approximately half of the cases, an identifiable cause of stillbirth may not be known even after appropriate evaluation. It is important to convey this to the patient so that reasonable expectations are set. Once the diagnosis of stillbirth has been made and if the patient is clinically stable, it is appropriate to offer her time alone with her family or friends before further discussion of the evaluation and management. Involvement of religious leaders at any time is an option and should be offered to any patient. It is also important for all health care providers to refer to the baby by name if the patient desires. 

A thorough medical and obstetrical history should be obtained. It is also important to obtain a detailed three-generation pedigree and ascertain exposures such as sick contacts or drugs. A physical examination should be performed paying particular attention to evidence of preeclampsia, abruption placentae or evidence of fetal growth restriction. A bedside ultrasound should be performed to evaluate for oligohydramnios, placental abnormalities, and to obtain fetal growth parameters. The presence of fetal scalp edema and overlapping cranial bones (Spalding sign) may indicate fetal demise occurred more than 48 hours ago. 

An appropriate evaluation of stillbirth is extremely important. For the patient and her family, ascertaining a cause for the adverse pregnancy outcome can help them to cope with the loss. For the physician, an identifiable cause can be helpful in counseling about the recurrence risk and management in subsequent pregnancies. That said, the patient should be offered fetal autopsy, placental evaluation, and fetal karyotype analysis. Many couples are reluctant to consent to autopsy due to emotional or cultural reasons. It is important to address their specific concerns and educate them regarding the procedure (eg, the face is not touched) and clarify the importance of autopsy. An assessment of fetal-maternal hemorrhage, maternal serology for parvovirus B-19 infection (B19), antiphospholipid syndrome, and toxicology screen is recommended. Additional studies can be performed if indicated and these will be addressed in more detail in the next section. 

It is reasonable to offer the patient the opportunity to choose the timing of delivery provided she is clinically stable without evidence of abruption, preeclampsia, infection, or other indications that preclude waiting. The patient may elect immediate induction of labor, await spontaneous labor, or choose an alternate delivery date provided she understands the risks associated with expectant management. After delivery, gross examination of the baby and placenta should be performed and abnormalities noted. The patient should be offered the opportunity to hold her baby and allow for religious ceremonies to be performed if desired. A supportive environment should be provided so that the patient and her family can spend the appropriate time they feel is needed with their baby. A referral to a peer support group, bereavement counselor, or mental health professional should be offered to assist the patient in dealing with grief and depression. The physician should notify the patient of the results from the evaluation in a timely manner and discuss their significance. A copy of the results and excluded diagnoses should also be provided.


Stillbirth is defined as in utero fetal death after 20 weeks’ gestation. If gestational age is unknown, a birth weight of ≥ 350 to 500 g is used depending on state reporting guidelines.1 The stillbirth rate (number of stillborn neonates/1000 total births, including live births and stillbirths) in the United States has been relatively unchanged over the past 20 years, remaining at approximately 6.2/1000 in 2003 to 20052 (Level II-3). Approximately half of all stillbirths are of undetermined cause making it difficult for physicians to optimize management in a subsequent pregnancy.

Risk Factors and Causes

There are very few conditions that can unequivocally be established as directly causing fetal death and many more that have been associated with stillbirth. For example, numerous maternal demographic risk factors have consistently been associated with stillbirth. These include lower socioeconomic status and education level, as well as, lack of prenatal care. Even when controlling for these confounders, significant racial disparities exist between race and pregnancy outcome. The rate of stillbirth in African American women is double that of whites, 11.13 versus 4.79, respectively2 (Level II-3). Hispanics are also at increased risk of stillbirth compared to whites.

Due to the rise in obesity and delayed childbearing, recent data has become available regarding these maternal characteristics and pregnancy outcome. Obesity defined as prepregnancy BMI greater than 30 kg/m2 confers a twofold increased risk of stillbirth even in an otherwise uncomplicated pregnancy.3 In the absence of age-related maternal complications, age alone also confers an increased risk of stillbirth. Fretts and colleagues established an increased odds ratio (OR) for women age 35 to 39 and for those greater than 40 of 1.9 (95% confidence interval [CI] 1.3-2.7) and 2.4 (95% CI 1.3-4.5), respectively(Level II-2). Although less established, maternal stress has also been associated with stillbirth. The underlying mechanisms for why obesity, maternal age, and stress increase the risk of stillbirth have not been well elucidated.

Cocaine and tobacco use during pregnancy also increase the risk of stillbirth, sixfold and twofold, respectively5 (Level II-2). Interestingly, women who stop smoking in the first trimester decrease their risk of stillbirth to that of nonsmokers5 (Level II-2). Obesity, smoking, and cocaine use are all modifiable risk factors.

Chromosomal abnormalities are the best studied genetic causes of fetal death and are reported in 6% to 12% of stillbirths1,6 (Level III). This may very well be an underestimation since genetic testing is not always performed or when it is performed, cell culture may not be successful in up to 50% of cases7 (Level II-2). Congenital anomalies account for up to 15% to 20% of stillbirths6(Level III). That said, fetuses with anomalies identified on antenatal sonogram, postmortem examination or those noted to be small for gestational age have a higher rate of chromosomal abnormalities than those without these findings. In the absence of these abnormalities, the risk of aneuploidy is thought to be less than 2%. The most common specific abnormalities include monosomy X (23%), trisomy 21 (23%), trisomy 18 (21%), and trisomy 13 (8%)6 (Level III). Stillborn infants who have a normal karyotype but have dysmorphic features on autopsy may have genetic conditions not detectable by routine cytogenetic analysis. Autosomal recessive metabolic disorders (eg, hemoglobinopathies, amino acid disorders, glycogen storage diseases) and X-linked disorders (lethal in male fetuses) have also been reported as causes of stillbirth. Confined placental mosaicism in which the fetal karyotype is normal may also be associated with fetal death and intrauterine growth restriction5 (Level II-2).

Maternal disease contributes to approximately 10% of all stillbirth cases8(Level III). Many diseases have been linked to stillbirth with the most common being pregestational diabetes (type 1 and 2) and chronic hypertension. Others include thyroid disease, cardiovascular disease, kidney disease, antiphospholipid syndrome, and systemic lupus erythematosus. In most cases, however, stillbirth occurs only in the setting of overt clinical disease.

Despite improvements in care, pregestational diabetes mellitus (type 1 and 2) have an increased risk of stillbirth, more commonly in the second and third trimesters than those without diabetes. Women with type 2 diabetes mellitus have a 2.5-fold increased risk for stillbirth than nondiabetic women9 (Level II-2). Maternal comorbidities, fetal anomalies, and growth disorders may play a role in the risk of stillbirth, however, even when controlling for these, the stillbirth risk is increased. The exact factors that account for the increased risk of stillbirth in pregestational diabetics are not fully understood and the glycemic threshold that places them at risk is also not well established. Data suggest that the risk of stillbirth can be reduced in pregestational diabetics by identifying and treating their disease.

Maternal infections comprise approximately 10% to 25% of stillbirth cases in developed countries8(Level III). Infection is more common in early cases of stillbirth compared to those occurring at term (19% vs 2% at term)10 (Level III). Direct infection, placental damage, and systemic maternal illness are all thought to be possible mechanisms. However, the relationship between maternal infection and stillbirth is not always clear since serologic and histologic isolation of a particular organism does not always prove causation. The most common ascending bacterial infections are caused by Escherichia coli, group B streptococci, Ureaplasma urealyticum, Mycoplasma hominis and Bacteroides while, Listeria monocytogenes can reach the fetus by hematogenous route.

Parvovirus B19 (B19) is the virus with the strongest association with stillbirth. Less than 1% of stillbirths in this country are reported to be due to parvovirus although this may be an underestimation due to the lack of systematic testing10 (Level III). B19 crosses the placenta attacking both the fetal erythropoietic tissue and myocardium resulting in severe fetal anemia and cardiac damage. This in turn may lead to subsequent nonimmune hydrops and stillbirth if in utero fetal transfusion is not performed. Interestingly, half of all pregnant women in the United States have been exposed to parvovirus and are considered to be immune. Of those who are susceptible, approximately 25% will have acute infection with exposure. Thirty percent of those mothers with acute infection will pass the infection to the fetus. Fetal hydrops or other associated findings occur in only 10% of those affected and stillbirth occurs in about 1% of infected fetuses10 (Level III). The majority will not result in stillbirth with intrauterine transfusion. The risk of stillbirth is highest when infection occurs at less than 20 weeks gestation.

Cytomegalovirus (CMV) is the most common congenital viral infection. Primary maternal infection during pregnancy occurs in approximately 1% of pregnant women with a 50% risk of transmission to the fetus10 (Level III). The risk of congenital infection increases with increasing gestational age and is greatest when maternal infection occurs in the third trimester. However, the risk of severity of disease and resulting fetal injury is highest when infection occurs in the first trimester. The presence of maternal antibodies does not confer absolute immunity, therefore pregnant women remain at risk, albeit low, for recurrent infection with fetal infection occurring in only 5% to 10% of cases. Congenital infection is manifested by intrauterine fetal growth, restriction, ventriculomegaly, and intracranial calcifications while neonatal sequelae include central nervous system abnormalities and multiorgan failure. CMV rarely results in fetal death; however, it has been described in case reports. Other viruses less commonly associated with stillbirth include Coxsackie A and B, echoviruses, enterovirus, chickenpox, measles, rubella, mumps, polio, rubeola, herpes simplex virus, and HIV.

Maternal primary infection with the parasite Toxoplasma gondii occurs in 1 per 1000 susceptible pregnancies in the United States. Like CMV, the fetus is most likely to be infected if maternal infection occurs in the third trimester; however, fetuses infected in the first trimester are associated with the greatest risk of injury10 (Level III). Clinical manifestations of infection include ventriculomegaly, increased placental thickness, hepatomegaly, ascites, intracranial calcifications, microcephaly, and hydrocephalus. Stillbirth from Toxoplasma occurs in 5% of cases after the first trimester as a result of direct infection from transplacental passage but it is considered to be an uncommon cause of stillbirth overall8 (Level III). Other organisms such as Treponema pallidum,

Borrelia burgdorferi (Lyme disease), Leptospira interrogans (leptospirosis), Plasmodium falciparum (malaria), Coxiella burnetii (Q fever), and Trypanosoma brucei (trypanosomiasis) while rare in this country should be considered in those with potential travel exposures.

Antiphospholipid syndrome (APS) is an acquired thrombophilia that is characterized by the presence of at least one clinical feature and at least one laboratory criteria of antiphospholipid antibodies levels (anticardiolipin antibodies, lupus anticoagulant, anti–beta-2 glycoprotein-I). APS has been identified as the cause of pregnancy loss in women with recurrent spontaneous abortion and stillbirth5 (Level II-2). Anembryonic pregnancy loss has not been associated with antiphospholipid antibodies. The exact mechanism(s) that leads to fetal loss are uncertain but it is hypothesized that thrombosis and inflammation may lead to infarction in the placenta resulting in second or third-trimester fetal deaths. Treatment with heparin or low-molecular-weight heparin and low-dose aspirin may improve obstetrical outcomes in women with APS.

Heritable thrombophilias have been associated with an increased risk of vascular thrombosis and are strongly associated with losses greater than 10 weeks rather than early pregnancy losses although this association is not always consistent across studies. In a meta-analysis of 31 studies, however, only factor V Leiden, prothrombin G20210A gene mutation and protein S deficiency were associated with late nonrecurrent fetal loss after 19 weeks (odds ratio [OR] 3.26, 95% confidence interval [CI] 1.82-5.83, OR 2.30, 95% CI 1.09-4.87, and OR 7.39, 95% CI 1.28-42.63, respectively).11 Protein C deficiency, antithrombin III, and methylenetetrahydrofolate mutation associated with hyperhomocysteinemia were not associated with pregnancy loss.11 A retrospective study of a cohort of women participating in The European Prospective Cohort on Thrombophilia (EPCOT) trial demonstrated a slight increased risk of stillbirth in women with combined inherited thrombophilia defects and those with antithrombin deficiency12 (Level II-2). In contrast, a recent prospective cohort study did not show an association between the factor V Leiden mutation and pregnancy loss13 (Level II-2). Therefore, the clinician must be cautious in attributing the cause of stillbirth to heritable thrombophilias as most individuals with these thrombophilias will have a normal outcome.

Fetal-maternal hemorrhage (FMH) is reported in 3% to 14% of cases of stillbirths5(Level II-2). While occult FMH during pregnancy is common, the volume transfused is often very small. Excessive FMH (> 30 mL) occurs in 1 in 1000 deliveries. Acute hemorrhage greater than 40% of fetal blood volume often results in fetal death. Evidence of fetal anemia and tissue hypoxia by autopsy and placental examination support the diagnosis of FMH as a cause of stillbirth. FMH in the absence of placental abruption is a rare cause of stillbirth.

Fetal growth restriction is an important cause of stillbirth with a reported incidence of approximately 4% to 5%14 (Level III). This estimate is difficult to ascertain due to dating inaccuracies and the use of population-based charts for weight percentiles that may not accurately reflect an individual’s inherent growth potential. Available evidence supports the risk of stillbirth increases when fetal weight declines below the 10th percentile for gestational age. The risk of stillbirth is 1.5% and almost 2.5% when estimated fetal weight is less than 10th percentile and less than fifth percentile for gestational age, respectively.1 Findings consistent with chronic placental dysfunction are seen in cases of stillbirths related to growth restriction.

Stillbirths are often attributed to umbilical cord or placental abnormalities. Umbilical cord accidents due to cord occlusion from true knots, nuchal cords, or body cords may be associated with stillbirths, especially those occurring at term. Of note, up to 30% of normal pregnancies may have cord entanglement(Level III). Before attributing cord accident as the cause of stillbirth, it is important to exclude other causes and confirm the presence of cord occlusion and fetal tissue hypoxia. Other placental/umbilical cord abnormalities that can cause stillbirth include placental abruption (10%-20% cases), placental infarction, umbilical cord thrombosis, cord prolapse, velamentous cord insertion, vasa previa, and amniotic band syndrome.

Finally, the risk of stillbirth is increased with multiple gestations compared to singletons 0.5%, twins 1.8%, triplets 2.4%, and quadruplet 3.7%15 (Level II-2). The reason for fetal death may be associated with obstetrical complications which occur more often with multiple gestations such as preeclampsia, intrauterine growth restriction, preterm labor, and placental abruption. Unique complications that may results in stillbirth include twin-twin transfusion syndrome complicating 10% to 15% of monochorionic/diamniotic gestations and cord entanglement complicating approximately half of monoamniotic gestations.

Several classification systems have been proposed to aid in reducing the number of unexplained cases of fetal deaths. No single system has been universally accepted and comparison between systems is difficult. The goal in the evaluation is to focus on individual risk factors, common conditions, and those that may be associated with an increase risk of recurrence.

The optimal evaluation of stillbirth is controversial and primarily based on expert opinion1,5 (Level II-2). Most would agree that fetal autopsy, gross and microscopic evaluation of the placenta including the membranes and umbilical cord, and fetal karyotype are the most important part of the evaluation (Table 27–1). If the parents decline autopsy, a partial autopsy, photography,
whole body x-rays, or postmortem MRI should be offered as they may provide valuable information. Gross examination of the fetus by a pathologist or geneticist can also be useful. Successful culture of fetal cells can be difficult especially with a long interval between fetal death and delivery. To improve the yield of obtaining a reliable karyotype, amniocentesis or chorionic villus sampling can be performed prior to delivery. If the patient declines these invasive


Fetal autopsy
Placental evaluation
Fetal karyotype
Generally accepted in addition to recommended
Antibody screen (if negative on initial prenatal screen, does not require repeat testing)
Serologic screen for syphilis in high-risk patients
Screen for fetal-maternal hemorrhage (Kleihauer-Betke or other)
Toxicology screen
Parvovirus B19 screen
Lupus anticoagulant screen
Anticardiolipin antibodies
Anti–beta-2 glycoprotein-I
Useful if clinically suspected
Factor V Leiden mutation
Prothrombin G20210A mutation
Protein C, protein S, and antithrombin III deficiency screen
Generally not recommended
TORCH titers
• Placental cultures

procedures or resources to perform them are lacking, tissues such as placenta, fascia lata, skin from the nape of the neck, and tendons can be collected after delivery for fetal karyotype5 (Level II-2). The placental sample should consist of 1 cm3 from the fetal surface near the cord insertion (chorionic plate) including the membranes. It is important to avoid placing placental or fetal tissue in formalin as they will not grow in culture. If cell culture for fetal karyotype is unsuccessful, the physician should investigate whether comparative genomic hybridization is available.

Although additional testing is controversial, screening for FMH (eg, Kleihauer-Betke or flow cytometry) is advised as it is a common cause of stillbirth and is inexpensive as well as noninvasive. Ideally, evaluation for FMH should be undertaken before induction of labor because small amounts of fetal blood may enter the maternal circulation with delivery. Antibody screen (indirect Coombs test) to exclude red cell alloimmunization is also recommended. If it was previously performed during pregnancy, repeat testing is unnecessary since sensitization during pregnancy rarely results in stillbirth. Serologic testing for B19 and toxicology screen is also recommended while repeat serologic testing for syphilis can be reserved for high-risk women.

Most authorities would agree that routine testing for APS (lupus anticoagulant, anticardiolipin antibodies, and anti–beta-2 glycoprotein-I) is recommended1,5 (Level II-2). Testing for heritable thrombophilias is acceptable in cases with severe placental pathology, fetal growth restriction, or a personal or family history of thromboembolic disease. The usefulness of “TORCH titers” (serology for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex) remains debatable and routine testing is not recommended1,5,8 (Level II-2; Level III). These titers almost never aid in the diagnosis of congenital infection in the absence of autopsy and placental findings of infection. In the absence of data suggesting subclinical disease associated with stillbirth, routine testing for thyroid disease or diabetes in asymptomatic women is unnecessary.

Patients should be given the option of proceeding with delivery at the time of diagnosis although expectant management is reasonable as long as there are no medical indications for immediate delivery. Patients may elect for expectant management to allow them an opportunity to cope with the news or if they desire to avoid induction of labor. Within 2 weeks of the stillbirth 80% to 90% of women will enter labor spontaneously. The risks of expectant management include intrauterine infection and maternal coagulopathy. It is difficult to quantify the risk of coagulopathy because most women elect delivery at the time of diagnosis. Older literature suggests the risk of coagulopathy (due to thromboplastin release from the placenta into the maternal circulation) is approximately 25% after 4 weeks of fetal death8 (Level III). If the patient opts for expectant management it is important to arrange for weekly outpatient follow-up for assessment of temperature, abdominal pain, bleeding, and labor symptoms. Weekly assessment of complete blood count, platelet count, and fibrinogen are not necessary unless there is clinical suspicion of coagulopathy(Level III).

Delivery options include surgical and medical management depending on the gestational age, experience of the clinician, and patient preference taking into consideration her desire to see the baby. Dilation and evacuation (D&E) is considered equally safe as medical induction in centers where clinicians have the training and expertise to perform this surgical procedure. This surgical approach limits the ability to perform a full fetal autopsy and is generally not performed after 24 weeks’ gestation. On the other hand, medical induction of labor can be accomplished at any gestational age with oxytocin, prostaglandins E (PGE) or E1 (PGE1) or dilators such as laminaria (osmotic) or Foley bulb (mechanical). Higher doses of prostaglandin E1 and oxytocin can be used if gestational age is less than 28 weeks16 (Level II-2). For women with prior documented or suspected low transverse cesarean delivery, the use of prostaglandins is not recommended if the gestational age is greater than 28 weeks. For these women, low-dose oxytocin and transcervical Foley bulb are reasonable alternatives. Cesarean delivery should be reserved for unusual circumstances since there are potential maternal risks with absolutely no fetal benefits.

Recurrence Risk and Subsequent Pregnancy
The reported recurrence risk of stillbirth is 2-to 10-fold, depending on maternal race (higher in African Americans), maternal disease (diabetes, hypertension), and characteristics of the prior stillbirth17 (Level III). The risk is higher for those with earlier losses (< 24 wk) compared to term stillbirths. Moreover, losses associated with placental insufficiency, abruption or genetic conditions are more likely to recur than due to infection or twinning. Importantly, women with a prior preterm, live birth associated with growth restriction have a stillbirth rate (21.8 per 1000) in a subsequent pregnancy that is higher than those with a prior stillbirth.1 Women with a prior stillbirth also have an increased risk of fetal growth restriction, abruption, and preterm birth in subsequent pregnancies.

Patients should be counseled prior to subsequent pregnancies to address all modifiable risk factors such as obesity and cocaine and tobacco use. A large metaanalysis suggested an association between perinatal death and interpregnancy interval, with increased risk at short (< 6 mo) and long intervals (> 50 mo).18 Although waiting 6 months is reasonable for some, maternal age and psychological stability are important considerations. The patient should be encouraged to continue with therapy as well as antidepressant medications as needed. 

Management of subsequent pregnancies is individualized and based on whether a cause of fetal death was identified. Interestingly, the decline in stillbirth rates over the past three decades coincides with increased surveillance; however, it remains unclear whether increased surveillance reduces the risk of recurrent stillbirth. Antenatal testing at 32 to 34 weeks is appropriate in healthy women with a history of prior stillbirth.1 It is reasonable to start fetal surveillance earlier (26-28 wk) if the patient has additional risk factors for stillbirth such as hypertension, renal disease, or fetal growth restriction. Initiating fetal testing several weeks before the gestational age of the prior stillbirth for patients who are very anxious is also acceptable. Fetal surveillance with non-stress test (NST), contraction stress test (CST), biophysical profile (BPP), or modified BPP is appropriate. The reported stillbirth rate (per 1000) within 1 week of a normal test is 1.9, 0.3, 0.8, and 0.8, respectively for NST, CST, BPP, and modified BPP, with a negative predictive value of 99.8% to 99.9%.19 Trials evaluating fetal kick counting have revealed conflicting results and the effectiveness in preventing stillbirth remains uncertain. 

Timing of delivery should be discussed with the couple in advance and factors such as maternal anxiety, cervical status, and cause of prior stillbirth should be considered. If fetal surveillance remains reassuring, and in the absence of other risk factors that may increase the risk of stillbirth, elective induction at 39 weeks is reasonable. If elective delivery is undertaken between 37 and 38 completed weeks, amniocentesis for documentation of fetal lung maturity profile is recommended. Throughout pregnancy, the patient is likely to be anxious and will require ongoing support and reassurance, especially around the time of the prior stillbirth.

Comprehension Questions

27.1 A patient with uncomplicated prenatal care now presents with preeclampsia at 26 weeks, IUGR, and stillbirth. In addition to offering fetal autopsy, genetic evaluation, and placental examination which of the following laboratory tests do you believe would be the next most important to order as a part of this evaluation?
A. HgA1c
B. TORCH titers
C. Lupus anticoagulant, anticardiolipin antibodies, anti–beta-2 glycoprotein-I
D. Thyroid-stimulating hormone (TSH)

27.2 A 28-year-old woman has recently delivered vaginally and asks about the length of time recommended between delivery and the next pregnancy, because she had read something on the internet about too short a pregnancy interval being associated with stillbirth. Which of the following is the most accurate statement?
A. There is no proven pregnancy interval associated with stillbirth.
B. There is an increased risk associated with pregnancy interval shorter than 3 months, but normal risk after this duration.
C. There is an increased risk associated with pregnancy interval shorter than 6 months, but normal risk after this duration.
D. There is an increased risk associated with pregnancy interval shorter than 9 months, but normal risk after this duration.


27.1 C. Uteroplacental insufficiency and early onset preeclampsia provide strong clinical suspicion for antiphospholipid syndrome. Therefore, maternal testing with lupus anticoagulant, anticardiolipin antibodies, and anti–beta-2 glycoprotein-I is an important part of this particular evaluation. Routine testing for diabetes, thyroid disease, and TORCH infections is generally not recommended.

27.2 C. There is evidence that a pregnancy interval less than 6 months is associated with an increased risk of stillbirth, but no increased risk after this duration.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1
➤ Fetal autopsy, placental evaluation, and karyotype are the most important tests in the evaluation of a stillbirth (Level II-2).
➤ Testing for lupus anticoagulant, anticardiolipin antibodies, and anti–beta-2 glycoprotein-I is recommended as treatment may improve outcome in subsequent pregnancy (Level II-2).
➤ “TORCH titers” (serology for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex) are rarely helpful and routine testing is not recommended (Level III).
➤ Antenatal testing at 32 to 34 weeks is recommended in healthy women with a history of prior stillbirth (Level III).


• Routine testing for inherited thrombophilias is controversial and should be reserved for selected cases where clinical suspicion is strong.


1. Management of stillbirth. ACOG Practice Bulletin No. 102. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2009;113:748-761. 

2. MacDorman MF, Kirmeyer S. Fetal and perinatal mortality, United States, 2005. Natl Vital Stat Rep. 2009;57:1-19 (Level II-3). 

3. Chu SY, Kim SY, Lau C, et al. Maternal obesity and risk of stillbirth: a metaanalysis. Am J Obstet Gynecol. 2007;197:223-228. A meta-analysis of nine high-quality studies identifying an increased risk of stillbirth in overweight and obese women (meta-analysis). 

4. Fretts RC, Schmittdiel J, McLean FH, Usher RH, Goldman MB. Increased maternal age and the risk of fetal death. N Engl J Med. 1995;333:483-489. Analysis of a large Canadian database over 30 years demonstrating the decline of stillbirth and the association of advanced maternal age (Level II-3). 

5. Silver RM, Varner MW, Reddy U, et al. Work-up of stillbirth: a review of the evidence. Am J Obstet Gynecol. 2007;196:433-444. A review article examining the evidence for the workup of stillbirth from the five centers involved in the Stillbirth Collaborative Research Network (Level II-2). 

6. Wapner RJ, Lewis D. Genetic and metabolic causes of stillbirth. Semin Perinatol. 2002;26:70-74 (Level III). 

7. Rodger CS, Creasy MR, Fitchett M, Maliszewska CT, Pratt NR, Waters JJ. Solid tissue culture for cytogenetic analysis: a collaborative survey for the Association of Clinical Cytogeneticists. J Clin Pathol. 1996;49:638-641 (Level II-2). 

8. Silver RM. Fetal Death. Obstet Gynecol. 2007;109:153-167. Clinical expert series reviewing fetal death in depth (Level III). 

9. Cundy T, Gamble G, Townend K, Henley PG, MacPherson P, Roberts AB. Perinatal mortality in type 2 diabetes mellitus. Diabet Med. 2000;17:33-39. Large observational study conducted in New Zealand over 12 years documenting the perinatal mortality on pregnancies complicated by type 2 diabetes mellitus (Level II-2). 

10. Goldenberg RL, Thompson C. The infectious origins of stillbirth. Am J Obstet Gynecol. 2003;189:861-873. Excellent review of the literature examining infectious causes related to stillbirth (Level III). 

11. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361:901-908. A meta-analysis of 31 prospective and retrospective observational studies, which found that FVL and PTGM were associated with a two-to threefold increase in both early recurrent pregnancy loss and late, nonrecurrent fetal loss (meta-analysis). 

12. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;361:913-916. A large multicenter prospective cohort evaluating inherited thrombophilias and fetal loss (Level II-2). 

13. Dizon-Townson D, Miller C, Sibai B, et al. The relationship of the factor V Leiden mutation and pregnancy outcomes for the mother and fetus. Obstet Gynecol. 2005;106:517-524. Prospective observational multicenter study conducted by the NICHD Maternal-Fetal Medicine Units Network which evaluated almost 5000 women and found no differences in pregnancy outcomes in heterozygous factor V Leiden carriers and a low-risk of venous thromboembolism in pregnancy (Level II-2). 

14. Fretts RC. Etiology and prevention of stillbirth. Am J Obstet Gynecol. 2005;193:1923-1935. Widely quoted review article on stillbirth (Level III). 

15. Salihu HM, Aliyu MH, Rouse DJ, Kirby RS, Alexander GR. Potentially preventable excess mortality among higher-order multiples. Obstet Gynecol. 2003;102:679-684. A retrospective cohort study of multiple gestations and mortality delivered in the United States from 1995 to 1997 (Level II-2). 

16. Dickinson JE. Misoprostol for second-trimester pregnancy termination in women with a prior cesarean delivery. Obstet Gynecol. 2005;105:352-356. A review of women with prior cesarean deliveries undergoing abortion at 14 to 28 weeks gestation for fetal anomaly using misoprostol with the most effective being 400 μg vaginally every 6 hours for a total of 48 hours (Level II-2). 

17. Reddy UM. Prediction and prevention of recurrent stillbirth. Obstet Gynecol. 2007;110:1151-1164 (Level III). 

18. Conde-Agudelo A, Rosas-Bermudez A, Kafury-Goeta AC. Birth spacing and risk of adverse perinatal outcomes: a meta-analysis. JAMA. 2006;295:1809-1823. A large meta-analysis of observational studies investigating the association between interpregnancy interval and untoward perinatal health events that are entwined with neonatal mortality (meta-analysis). 

19. Antepartum fetal surveillance. ACOG Practice Bulletin No. 9. American College of Obstetricians and Gynecologists. 1999.


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