Lilja Stefansson and Susan M. Lanni
History of present illness
A 31-year-old healthy gravida 2, para 1-0-0-1 woman at 10 weeks’
gestation presents to the emergency department complaining of a one-week history of flu-like symptoms. She works as a nurse in a pediatrics clinic and states that she is only con- cerned about this illness because she is pregnant and wants to
“make sure everything is ok.”She reports that she received the flu vaccine and waited this long to present as she thought the illness would be short-lived, but is now interested in obtaining a workup because a coworker told her to ask about cyto- megalovirus (CMV) testing. She states that herfirst pregnancy was uncomplicated and she delivered vaginally at term. This pregnancy has been uncomplicated to date and she has had a first-trimester dating ultrasound confirming a singleton gesta- tion with no abnormalfindings.
Physical examination
General appearance: Woman appears ill and fatigued, but awake, alert, and oriented × 3
Vital signs:
Temperature: 38.0°C Pulse: 102 beats/min
Blood pressure: 118/76 mmHg Respiratory rate: 16 breaths/min Oxygen saturation: 99% on room air HEENT: Cervical lymphadenopathy
Cardiovascular: Mild tachycardia, no murmurs, rubs, or gallops
Respiratory: Clear to auscultation bilaterally allfields Abdomen: Soft, nontender, nondistended
Laboratory studies:
WBCs: 11 000/μL Hb: 11.0 g/dL AST: 60 U/L ALT: 80 U/L
Other tests were all within normal range
Imaging: Bedside transabdominal ultrasound showed single living intrauterine pregnancy, consistent with 10 weeks’ gestation, fetal heart tones 150 beats/min. Normal appearing placenta
You discuss the findings with the patient and counsel her regarding the various diagnoses in the differential. She agrees to viral testing. You perform influenza, Epstein–Barr virus,
and CMV immunoglobulin M/immunoglobulin G (IgM/IgG) studies, which are all negative. She is diagnosed with a likely viral-illness and prior to sending her home, you counsel her to notify her obstetrician regarding this presentation to the emer- gency department. You inform her that she could potentially still have a diagnosis of CMV despite negative results, as antibody testing is variable and a negative IgM result does not rule out CMV. You explain to her that CMV can result in neurologic deficits in the fetus, most commonly sensori- neural hearing loss.
The patient informs her obstetrician about her illness and reports that her condition has improved. She has opted for close monitoring with serial ultrasounds. One month later she had a normal scan, and two months later she presented for her anatomy ultrasound scan (Fig. 61.1) with the following findings:
Gestational age:
Composite gestational age: 19 weeks 1 day Clinical gestational age: 19 weeks 1 day Estimated weight: Normal (276 g ± 40 g)
Amnioticfluid: Maximum vertical pocket 52 mm Morphology evaluation: Hyperechogenic bowel noted.
Otherwise, unremarkable fetal anatomic survey, nasal bone present, normal humerus length
Summary: A single living intrauterine pregnancy with normal fetal growth andfluid for given gestational age;
normal placenta; normal cervix. No additional aneuploidy
ECHOGENIC BOWEL
Fig. 61.1 Transabdominal ultrasound.
Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
markers were noted on the scan. Differential includes: CMV aneuploidy versus cysticfibrosis versus bleeding in early pregnancy
The patient underwent genetic counseling. She reports that she has not had any bleeding during this pregnancy. She was offered and accepted the recommended testing: maternal serum CMV antibody and avidity testing, cystic fibrosis screening, and amniocentesis. The results of the tests were:
Routine prenatal serum studies:
Cysticfibrosis 32 mutation panel screen: Negative Maternal serum analyte screen: Negative
Additional studies after echogenic bowel diagnosed:
CMV IgG: Positive CMV IgM: Positive Avidity testing: 0.47
(Reference values for avidity testing: Low avidity index,
≤0.50; intermediate avidity index, 0.51–0.59; high avidity index,0.60)
Amniocentesis results:
CMV PCR of amnioticfluid: Positive Karyotype: 46XY, normal male karyotype
How will you now manage this patient and how will you answer her questions regarding fetal effects of CMV exposure?
This patient had exposure to CMV early in her pregnancy, which can have lasting neurologic fetal effects. Exposure in the first trimester can have more serious health implications for the pregnancy and serial ultrasounds are indicated to monitor growth and progression of findings. Currently there is no approved therapy for CMV, but there is a developing body of evidence for the use of CMV-specific hyperimmune gamma- globulin infusion therapy to mitigate fetal damage.
Cytomegalovirus exposure in the first trimester
Cytomegalovirus (CMV) is the most common congenital infection, affecting 0.2 –2.0% of neonates. It is a double- stranded DNA herpes virus that is transmitted by contact with bodilyfluids such as saliva, urine, blood, or sexual contact [1].
Children in daycare centers commonly acquire this infection and can transmit it to family members. One feature common to the herpesviridae family is that they cause a primary infec- tion that becomes quiescent, but can reactivate in the future.
Primary infections may have only minorflu-like symptoms or reactive adenopathy as their only manifestations. Reactivated CMV is typically asymptomatic, but is hallmarked by active viral shedding. Acute primary infection has an incubation period of 28–60 days and results in an IgM response usually 2–3 weeks following exposure. However, the IgM response is
variable and resolves in approximately 30–60 days, followed by an IgG response, which persists. Due to the inconsistency of the IgM response, serologic testing may be unreliable. When infection occurs, adults are generally asymptomatic, but approximately 15% may present with flu-like symptoms including fever, chills, and malaise, and abnormal laboratory findings such as leukocytosis and abnormal liver function tests.
Primary maternal infection prevalence ranges between 0.7 and 4.0%, with the risk of transmission to the fetus as high as 40%
[1]. The rate of vertical transmission increases proportional to the gestational age at time of infection; however, transmission that occurs earlier in the pregnancy is associated with worse outcomes [2]. If infection occurs in thefirst trimester, approxi- mately 25% of fetuses will be infected [3]. The prevalence of recurrent infection can be as high as 13.5%, but the risk of vertical transmission to the fetus with maternal CMV recur- rence decreases to 0.15–2.00%. Vertical transmission to the fetus occurs transplacentally and is more likely to occur in thefirst half of pregnancy; fetal infection can also occur during delivery or postpartum through breast-feeding [1]. Most infants are asymptomatic at birth; however, 10% will have symptoms, and of these, approximately one-third will die and a majority of the remainder will develop sequelae, the most common being sensorineural hearing loss [1,2,4]. Manifest- ations of infection vary, including jaundice, thrombocyto- penia, hepatosplenomegaly, and nonimmune hydrops.
Infection via intrapartum exposure from cervical fluids or postpartum from breast-feeding tends to be asymptomatic at birth and remains so, reiterating the clinical significance of exposure earlier in the pregnancy and via transplacental pas- sage to the fetus.
There are several ways to diagnose a primary infection in the pregnant patient if clinical suspicion of CMV infection arises. In several European countries, CMV testing is done as part of routine prenatal care. Of the 4 million babies born in the United States every year, only 5–6% of the approximately 40 000 infected will exhibit signs of infection. Antenatal testing is not routine here and is generally only performed when concern for infection is raised. Maternal CMV can be detected via serologic testing for IgG antibodies approximately four weeks apart if exposure is known. Evidence of a primary CMV infection is confirmed when an initial negative IgG seroconverts to positive over the intervening four weeks, or if titers increase greater than fourfold [1]. IgM titers are not as reliable to use as an indicator for primary infection as these may not be positive in an acute infection or they can persist for several months afterwards. Avidity testing is only performed if the IgG antibody is positive but can provide information regarding the timing of the infection. Avidity testing is an index of the specificity of the IgG antibody for its antigen.
A low avidity (values are lab. dependent) is indicative of a primary infection, and likely occurred in the past six months.
Higher avidity index values, greater than 0.7–0.8, generally occurs with more long-standing infections [5]. The fetal com- partment can be tested directly for CMV infection using Case 61: First-trimesterflu-like symptoms in a 31-year-old woman
amnioticfluid via PCR (sensitivity 77–100%) or culture (sen- sitivity 50–69%). In the first half of pregnancy, the utility of diagnosing CMV infection via fetal serologies is questionable, as the fetal immune system has not matured enough to develop antibodies, therefore minimizing the effective diagnosis of CMV infection. In addition, it requires Percutaneous Umbil- ical Cord Blood Sampling (PUBS), a procedure that has a higher rate of fetal loss than amniocentesis. In the newborn, urine can be PCR tested as the primary organ of replication in the fetus is the kidney; testing can also be performed on infected bodilyfluids including saliva and blood [1].
Most infections are diagnosed based on fetal ultrasound findings, which may include calcifications of the lateral border of the ventricles, echogenic bowel, hydrops, ascites, hepato- splenomegaly, and ventriculomegaly (Table 61.1). The severity of the disease is not correlated with the amount of CMV virus detected in amniotic fluid; rather, it can be determined by clinicalfindings such as sonographic evidence of central ner- vous system infection [1].
Currently, there are no approved therapies for CMV infec- tion. There is a developing body of literature regarding the
antenatal intravenous administration of hyperimmune globu- lin to the mother, and neonatal ganciclovir for reducing the occurrence of central nervous system damage and hearing loss in newborns [1,2].
It is important to counsel pregnant patients on appropriate prevention strategies, particularly in those patients at high risk for contracting CMV. Patients at high risk are those that work around or live with children or immunocompromised people, women from lower socioeconomic backgrounds, those born outside the United States, those with other sexually transmitted diseases, and women whosefirst pregnancy occurred below the age of 15. Prevention strategies include basic hygiene measures such as frequent hand washing, use of personal protective equipment such as gloves, gowns and goggles, caution when handling physiologic fluids from children including diapers, using condoms, and avoiding needle-sharing for intravenous drug abusers.
Key teaching points
Cytomegalovirus (CMV) is the most common congenital infection, affecting 0.2–2.0% of all neonates.
CMV is transmitted through bodyfluids.
Fetal infection has a poorer prognosis when it occurs earlier in the pregnancy.
The most common clinical sequelae from CMV infection in the neonate is sensorineural hearing loss.
Diagnosis is usually made after clinical suspicion arises from ultrasonographicfindings concerning for CMV infection. Testing can be performed through maternal serologies (IgM, IgG, avidity testing, PCR, and culture); on fetus through amnioticfluid (PCR, culture).
Prevention of CMV occurs primarily through methods such as hand washing and hygiene. There is no vaccine for CMV, but there is some developing evidence regarding CMV hyperimmune gamma-globulin given to the mother during pregnancy and ganciclovir administered to the neonate.
References
1. American College of Obstetricians and Gynecologists. Perinatal and parasitic infections. Practice Bulletin No. 20.Int J Gynaecol Obstet2002;76(1):95–107.
Reaffirmed 2011.
2. Visentin S, Manara R, Milanese L, et al.
Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at
1 year of age.Clin Infect Dis 2012;55:497–503.
3. Nigro G, Adler SP, Parruti G, et al.
Immunoglobulin therapy of fetal cytomegalovirus infection occurring in thefirst half of pregnancy–a case control study of the outcome in children.J Infect Dis2012;205:
215–27.
4. Lipitz S, Yinon Y, Malinger G, et al.
Risk of cytomegalovirus-associated
sequelae in relation to time of infection andfindings on prenatal imaging.
Ultrasound Obstet Gyneol2013;41:
508–14.
5. Leruez-Ville M, Sellier Y, Salomon LJ.
et al. Prediction of fetal infection in cases with cytomegalovirus immunoglobulin M in thefirst trimester of pregnancy: a retrospective cohort.Clin Infect Dis2013;56:
1428–35.
Table 61.1 Manifestations of CMV in the fetus and the neonate Ultrasonographicfindings
associated with CMV
Clinical sequelae of CMV in neonate
Fetal growth restriction Cerebral calcifications Ventriculomegaly Microcephaly Hepatomegaly Splenomegaly Hyperechogenic bowel Oligohydramnios Polyhydramnios Pleural effusion Hydrops
Placental enlargement (placental thickness>35 mm)
Asymptomatic Microcephaly Sensorineural loss Neurologic deficits Chorioretinitis Learning disabilities Psychomotor retardation Hepatomegaly
Splenomegaly Jaundice
Hemolytic anemia
Thrombocytopenic purpura Death
CMV, cytomegalovirus.