Case : A 39-Year-Old Pregnant Woman with Fever after a Trip to Africa

Transcription

1 The new england journal of medicine Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor Case : A 39-Year-Old Pregnant Woman with Fever after a Trip to Africa Patrick Duff, M.D., William H. Barth, Jr., M.D., and Miriam D. Post, M.D. Presentation of Case From the Department of Obstetrics and Gynecology, University of Florida, Gainesville (P.D.); and the Division of Maternal Fetal Medicine (W.H.B.) and the Department of Pathology (M.D.P.), Massachusetts General Hospital, and the Departments of Obstetrics, Gynecology, and Reproductive Biology (W.H.B.) and Pathology (M.D.P.), Harvard Medical School both in Boston. N Engl J Med 2009;360: Copyright 2009 Massachusetts Medical Society. A 39-year-old woman in the first trimester of her first pregnancy was seen in the obstetrics and gynecology clinic of this hospital at 14 weeks of gestation because of a recent febrile illness. She had been well until approximately 9 weeks before this evaluation, when daily fevers with temperatures of up to 38.3 C developed, accompanied by rigors, malaise, myalgias, and fatigue. She took ibuprofen every 6 hours, with some improvement. One week later, she saw her primary care provider. She reported no headache, stiff neck, nasal congestion, sore throat, cough, nausea, abdominal pain, or diarrhea. Four months before the onset of fever, she had traveled to East Africa, where she worked for 6 weeks with her husband in an orphanage while awaiting completion of adoption procedures. Approximately 12 weeks before the onset of fevers, she returned to the United States with her adopted child. She had first traveled to East Africa 10 months earlier. Before this travel, she had received vaccinations for yellow fever, polio, hepatitis A and B viruses, Neisseria meningitidis, and typhoid. She took mefloquine daily during each trip and for 3 weeks after returning from each trip. After the first trip, she had prolonged fatigue, intermittent diarrhea, flatulence, and bloating. Testing of the stool for ova and parasites was negative; the symptoms persisted for 5 months, and metronidazole was administered for a presumptive diagnosis of giardiasis. During the more recent visit, she and her husband had episodes of diarrhea; she had had intermittent diarrhea since returning but otherwise felt well. On examination, the temperature was 37.7 C; the remainder of the examination was normal. Urinalysis, tests of renal function, and levels of serum electrolytes, glucose, and total bilirubin were normal; cultures of the blood were sterile. Other laboratory-test results are shown in Tables 1 and 2. On follow-up examination 4 days later, the temperature was 36.6 C and a diffuse macular rash was present on the trunk and extremities. A tuberculin skin test was negative. Two days later, 7 weeks before this evaluation, she saw an infectious-disease specialist at another hospital. She felt better but was still fatigued. She reported that during her recent trip to Africa, she had stayed in a large city but had traveled briefly to an area where malaria is endemic; she had had a rash, which she attributed to hives, that had spontaneously resolved. On her return, she was treated for scabies. 508

2 Table 1. Results of Hematologic, Serum Chemical, and Immunologic Laboratory Tests.* Variable Reference Range, Adult, at the Other Hospital 8 Wk before Evaluation at the Primary Care Physician s Office 7 Wk before Evaluation 3 Wk before Evaluation Hematocrit (%) Hemoglobin (g/dl) White-cell count (per mm 3 ) ,000 5,130 6,190 7,800 Differential count (%) Neutrophils Band forms Lymphocytes Atypical lymphocytes 0 4 Monocytes Eosinophils Basophils Platelet count (per mm 3 ) 150, , , , ,000 Mean corpuscular volume (μm 3 ) Albumin (g/dl) Globulin (g/dl) Alkaline phosphatase (U/liter) Aspartate aminotransferase (U/liter) Alanine aminotransferase (U/liter) Lactate dehydrogenase (U/liter) Iron (μg/dl) Iron-binding capacity (μg/dl) Ferritin (μg/ liter) IgG (mg/dl) ,920 IgA (mg/dl) IgM (mg/dl) Serum protein electrophoreses (g/dl) Albumin α 1 globulin α 2 globulin Beta globulin Gamma globulin ; M spike present, concentration 0.96 Human chorionic gonadotropin, quantitative (IU/liter) <5 (nonpregnant) 11,767 49,256 * To convert values for iron and iron-binding capacity to micromoles per liter, multiply by Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital and the other hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients. 509

3 The new england journal of medicine Table 2. Results of Microbiologic and Serologic Laboratory Tests.* Variable Reference Range, Adult, at the Other Hospital 8 Wk before Evaluation at the Primary Care Physician s Office Hepatitis A virus IgM antibody screen Negative Negative Hepatitis B core virus IgM antibody screen Negative Negative Hepatitis C virus IgG antibody screen Negative Negative Schistosoma antibody (EIU) <1.00 Cytomegalovirus IgG antibody (EIU) Cytomegalovirus IgM antibody (EIU) Cytomegalovirus viral load hybrid-capture assay (pg/ml) Negative, <0.8; equivocal, ; positive, >0.99 Negative, <0.9; equivocal, ; positive, >1.09 Negative, <0.75; equivocal, ; positive, Wk before Evaluation Varicella zoster virus screen Negative Positive Infectious mononucleosis heterophile-antibody screen Negative Epstein Barr viral-capsid early antigen (titer) Negative, < Wk before Evaluation Negative Epstein Barr antiviral-capsid-antigen IgG (titer) Negative, < Epstein Barr antiviral-capsid-antigen IgM (titer) Negative, <10 <10 Epstein Barr antinuclear antigen (titer) Negative, <5 >5 Herpes simplex virus IgG enzyme immunoassay (EIU) Negative, < Toxoplasma IgG antibody (EIU) Negative, < Toxoplasma IgM antibody (EIU) Negative, < Parvovirus IgM antibody (EIU) Parvovirus IgG antibody (EIU) Negative, <0.89; equivocal, ; positive, >1.11 Negative, <0.89; equivocal, ; positive, >1.11 Strongyloides antibody (EIU) <1.00 Treponema pallidum IgG screen Negative Negative * EIU denotes enzyme immunounit. Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital and the other hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients Her last menstrual period was 5 weeks earlier, and a home pregnancy test the previous day was positive. Tests in the preceding 18 months for antibody to rubella were positive, and tests for the human immunodeficiency virus (HIV) were negative. She had had a mononucleosis-like illness as an adolescent, herpes simplex vulvovaginitis, exposure to diethylstilbestrol in utero, an abnormal Papanicolaou smear of the cervix that led to a loop electrosurgical excision procedure, meningitis while in college, and infertility, for which she had received in vitro fertilization treatments without success. She was married and lived in New England. She did not smoke or use illicit drugs. Her medications included valacyclovir as needed for genital herpes and ibuprofen every 6 hours for fever. She had no known allergies. Her newly adopted, 17-month-old child had had diarrhea without fever and had been treated for gastrointestinal parasites and salmonella infection. On examination, the temperature was 36.7 C; other vital signs were normal. There was mild conjunctival erythema; a faint maculopapular rash over the arms, hands, and torso; and a mildly enlarged liver, with no tenderness or splenomegaly. The remainder of the examination was normal. The blood type was A Rh-positive, and an antibody screen and a rapid plasma reagin test were negative. Testing for antinuclear antibody and anti smooth-muscle antibody were negative. 510

4 Analysis of the stool disclosed no ova or parasites, and a culture was negative for pathogens. A urine specimen for shell-vial isolation of cytomegalovirus (CMV) was negative. Culture of the urine and nucleic acid testing for chlamydia and gonorrhea were negative. Other laboratory-test results are shown in Tables 1 and 2. One week later, transvaginal ultrasonography of the uterus revealed a single live fetus at 7.4 weeks of gestation. Testing for antibody to hepatitis B e antigen was negative. The patient s symptoms gradually resolved. Repeat ultrasonography 1 month before this evaluation revealed a live fetus at 11.4 weeks of gestation. Results of laboratory tests performed 3 weeks before this evaluation are shown in Tables 1 and 2. The patient was referred to the obstetrics and gynecology clinic of this hospital. She felt well and was taking no medications. She and her husband greatly desired this unexpected pregnancy and declined termination after discussion of the risks of fetal CMV infection. Twelve days later, testing of blood for CMV-specific IgG avidity was 0.60 (positive result, 0.60). Repeat ultrasonography of the pelvis 3 weeks and 5 weeks later showed a single active fetus with no identifiable anatomical abnormalities and a size consistent with the gestational age. At 21 weeks of gestation, a diagnostic procedure was performed. Differential Diagnosis Dr. Patrick Duff: May we see the ultrasound studies? Dr. William H. Barth, Jr.: Multiple ultrasound studies performed at the other hospital showed an active fetus at the expected gestational age. There was normal intracranial anatomy with no ventriculomegaly, calcifications, echogenic bowel, ascites, or hydrops. The heart was normal, and there was no evidence of pleural or pericardial effusions. Dr. Duff: Several disorders should be considered in the differential diagnosis in this patient, who presented with fever after a trip to Africa (Table 3). Three of these malaria, an intestinal parasitic infection, and hepatitis are of particular interest because of the patient s travel history. Although the patient took appropriate malaria prophylaxis (mefloquine), prophylaxis is not uniformly effective in preventing malaria. Nevertheless, the patient had thin and thick blood Table 3. Risk of Various Infections to Mother and Fetus. Condition Relative Risk of Complications Mother smears that were negative for malaria on at least one occasion. In addition, patients with malaria usually have more than 10% atypical lymphocytes in the peripheral blood; this patient had 4%. Therefore, I do not think that malaria is the most likely diagnosis. A second consideration related to foreign travel is that of a parasitic or bacterial intestinal infection. The patient had been treated presumptively for giardiasis several months before the present illness developed. Her newly adopted child had more recently been treated for intestinal parasites and salmonellosis. The patient herself had had intermittent episodes of diarrhea. However, during the course of the present evaluation, she had negative tests for ova, parasites, and pathogenic bacteria in the stool. Therefore, this diagnosis seems unlikely. Viral hepatitis is a possibility, since she had traveled to an area of the world where both hepatitis A and B are prevalent. However, she was vaccinated for these infections. Serologic tests for hepatitis A, B, and C antibody were negative, although I would like to have confirmed that the tests for hepatitis B surface antigen, in addition to those for hepatitis B e antigen, were negative. Moreover, the serum aminotransferase concentrations were not in the range usually associated with acute viral hepatitis. Parvovirus Infection Parvovirus infection is another consideration in an obstetrical patient with a persistent fever and Fetus Malaria High Low Intestinal parasite Moderate Low Viral hepatitis A, B, or C Moderate Low for hepatitis A, moderate for hepatitis B and C Parvovirus Low High Rubeola High Low Human immunodeficiency virus High High Mononucleosis Low Low Toxoplasmosis Cytomegalovirus Low (unless immunosuppressed) Low (unless immunosuppressed) High High 511

5 The new england journal of medicine rash. However, parvovirus is usually a mild, selflimited disorder. The infection typically presents as erythema infectiosum and is characterized by low-grade fever, myalgias, arthralgias, and a prominent slapped cheek rash. 1 In this patient, the rash spared the face and, therefore, is not typical for parvovirus infection. In addition, serologic tests showed evidence of previous infection with parvovirus that was not acute. Lifelong immunity is usual, and recurrent infection is extremely rare. Rubella and Rubeola Rubella also needs to be considered. This infection is particularly important to diagnose because the virus has extremely injurious effects on the fetus. However, persistent fever is unusual with rubella, as is hepatitis. The rash usually includes the face, rather than affecting only the extremities and trunk, as in this patient. In addition, the patient had evidence of serologic immunity to rubella, and second infections are unlikely. In adults, rubeola (measles) can have a prolonged clinical course, and hepatitis, pneumonia, and encephalitis are possible complications. However, the rash in rubeola usually does not spare the face. Evidence of rubeola infection could be documented by serologic tests, although it was not tested for in this patient. Acute Retroviral Illness Another important consideration in the differential diagnosis is acute retroviral illness. 2 This illness typically develops within several weeks after exposure to HIV. It is characterized by fever, malaise, generalized lymphadenopathy, and nonspecific gastrointestinal symptoms. Affected patients may have a transient rash, and signs of hepatitis may develop. This patient had a negative test for HIV infection in the past 18 months and apparently had not been tested again more recently. Early in the course of acute retroviral illness, the antibody test for HIV can be negative. However, a polymerase-chain-reaction (PCR) test could be performed to document low levels of virus in the patient s serum. Mononucleosis The patient s clinical findings and some of the laboratory studies raise the possibility of mononucleosis caused by Epstein Barr virus. For example, the patient had evidence of atypical lymphocytes and a borderline leukocytosis in the peripheral-blood smear. In addition, mild-to-moderate elevations in the aminotransferase levels can occur in the course of mononucleosis. However, this patient had a history of a mononucleosis-like illness in adolescence, a screen for heterophile antibody was negative, and the results of tests for antibodies to Epstein Barr virus were indicative of past infection. Toxoplasmosis The patient s clinical manifestations are consistent with toxoplasmosis. Her foreign travel almost certainly exposed her to improperly cooked meat and possibly to feral cats, both of which are important sources of transmission of toxoplasmosis. However, serologic testing was negative for IgM and IgG antibody to Toxoplasma gondii. CMV infection The patient s clinical course and laboratory studies are most consistent with a diagnosis of CMV infection. Hepatitis is a well-recognized complication of CMV infection. Although CMV can be acquired through sexual transmission, most pregnant women probably acquire it through exposure to children through contact with contaminated saliva, urine, or toys. This woman had worked in an orphanage for several weeks while awaiting adoption of her child, and she probably acquired the infection in that setting. The patient had both IgM and IgG antibody to CMV. 3 Of perhaps greatest importance, she had clear evidence of viremia, because the hybridcapture assay on the buffy-coat test was positive for CMV. The most important question at this point is whether the infection has been transmitted to the fetus, since about 40% of women with primary CMV infection during pregnancy transmit it to the fetus, and 20% of fetuses infected in the first trimester have serious sequelae, including death or severe disability (Table 4). 4 This patient clearly had CMV infection, but we do not know whether this was a primary infection in someone previously seronegative for CMV, reactivation of latent CMV infection, or a second infection in a previously immune woman with a new strain of CMV. The risk of transmission to the fetus is greater in primary CMV infection than in reactivation, although in rare instances, 512

6 Table 4. Principal Manifestations of Severe Congenital CMV Infection. Abnormality Approximate Frequency (%) Hepatosplenomegaly 50 Petechiae 50 Intracranial calcifications 45 Intrauterine growth restriction 40 Jaundice 40 Microcephaly 25 Chorioretinitis 15 Hearing loss 15 Mental retardation 15 Seizures 10 even reactivated infection can result in severe fetal injury. Infection of a previously seropositive woman by a new strain may also result in CMV infection of the fetus. 5 If this patient was seronegative before pregnancy, her risk of transmitting CMV infection to her child would be markedly increased as compared with that of a woman who was seropositive before pregnancy. 6 The most useful laboratory test for the diagnosis of maternal CMV infection is assessment for the presence of IgM and IgG antibodies. This patient had both IgG and IgM antibodies, but because the IgM antibody can remain positive for an extended period after an acute infection has resolved and can even reappear in the serum in the presence of a recurrent infection, there is still some ambiguity regarding her prepregnancy immune status. Determination of immunoglobulin avidity can be valuable in this setting in distinguishing between acute and reactivated infection, with the presence of low-avidity antibody indicating acute infection. 3 In this case, the avidity testing was also ambiguous, with a borderline level of avidity. The most valuable test for the diagnosis of CMV infection of the fetus is amniocentesis. 7-9 Although ultrasound examination showed no evidence of fetal injury as a result of CMV infection, I believe that the most appropriate diagnostic test is amniocentesis. A sample of amniotic fluid should be assessed by PCR or culture to determine whether CMV infection is present. If virus is identified in the amniotic fluid, a detailed ultrasound examination should be performed to assess for evidence of fetal injury. Possible abnormalities that can easily be identified on ultrasonography include intrauterine growth restriction, microcephaly, ventriculomegaly, isolated serous effusions, echogenic bowel, and placental thickening. 10 Until recently, there was no proven prenatal therapy for congenital CMV infection. In one study, 11 immunotherapy with hyperimmune globulin for congenital CMV infection significantly decreased the risk of delivering CMV-infected infants, and in some patients, therapy with hyperimmune globulin reversed abnormal ultrasonographic findings. Nonetheless, prevention of maternal and fetal infection is the standard. At present, there is no effective vaccine for CMV. Therefore, appropriate preventive measures include safe sexual practices, careful hand washing and cleansing of environmental surfaces, and transfusion of only CMVnegative blood to obstetric patients or their fetuses. In this patient, if the amniocentesis were positive for CMV, I would recommend treatment with hyperimmune globulin. If the initial amniocentesis were negative, I would recommend repeating the study in approximately 4 weeks, because an initially negative CMV culture or PCR assessment may convert to positive over time. Of course, at the time of each amniocentesis, a targeted ultrasound examination should be performed to assess for anomalies. Dr. Nancy Lee Harris (Pathology): Dr. Riley, will you give us your impressions from when you cared for this patient? Dr. Laura E. Riley (Obstetrics and Gynecology): The patient clearly had active CMV infection. The issue was whether there was any possibility that this could be reactivation rather than a primary infection. This patient had a long history of infertility and was committed to this pregnancy by the time I saw her. She did not want to terminate the pregnancy without a clear indication that the baby was going to be sick. If this was reactivated disease as opposed to primary infection, the baby was at much less risk. We performed the CMV avidity test in the hope that it would help us distinguish between acute infection and reactivated infection. In fact, the test showed borderline high avidity, suggesting that this could be reactivated disease, and the ultrasound was nor- 513

7 The new england journal of medicine A B C D Figure 1. Pathological Examination of the Fetus and Placenta. Histologic examination of the placenta (Panel A, hematoxylin and eosin) shows a lymphoplasmacytic infiltrate involving chorionic villi (chronic villitis) and stromal expansion, characteristic of CMV placentitis. Immunohistochemical staining with antibody to CMV (Panel A, inset; immunoperoxidase) highlights infected cells. Histologic examination of the fetal liver (Panel B, hematoxylin and eosin) shows hepatic parenchyma with a prominent focus of necrosis involving and surrounding a centrally located portal tract. At the interface between the portal tract and hepatic parenchyma, there are enlarged, basophilic cells. At higher magnification (Panel C, hematoxylin and eosin), there are basophilic, circular, glassy, owl s eye intranuclear inclusions of CMV within markedly enlarged hepatocytes. A section of fetal lung (Panel D, hematoxylin and eosin) shows a CMV-infected cell with a large intranuclear inclusion. mal. The diagnostic test was a repeat ultrasound examination with amniocentesis and testing of the fluid for karyotype and the presence of CMV. Dr. Barth: Ultrasound examination at 21 weeks of gestation again showed appropriate biometry, with no evidence of early-onset growth restriction. The placenta was normal, and the volume of amniotic fluid was normal. The intracranial anatomy was again normal, with no evidence of ventriculomegaly or calcifications. Similarly, there was no evidence of hepatic calcifications, echogenic bowel, ascites, or hydrops fetalis, and the four-chamber view of the heart including the lung fields showed no evidence of pleural or pericardial effusions. Amniocentesis was performed. Clinical Diagnosis Cytomegalovirus infection. Dr. Patrick Duff s Diagnosis Cytomegalovirus infection. 514

8 Pathological Discussion Dr. Miriam D. Post: PCR testing of the amniotic fluid revealed the presence of CMV DNA, and the shell-vial culture was positive for CMV. The karyotype was 46,XX. Dr. Riley: On learning the results of the amniotic-fluid culture and the PCR, the patient believed that she could not cope with an infant who was likely to be very sick, so she ultimately chose to terminate the pregnancy. Dr. Post: The female fetus was phenotypically normal and weighed 420 g, with a foot length of 3.7 cm (22 weeks of gestation, based on foot length). On histologic examination, the placenta showed widespread chronic (lymphoplasmacytic) villitis and villi with stromal expansion and karyorrhectic debris (Fig. 1A), characteristic of CMV infection. 12 Other findings included calcification of villous trophoblasts and necrotizing lymphocytic vasculitis. In endothelial cells and stromal macrophages, enlarged cells showed intranuclear, glassy, owl s eye inclusions, which stained positively with CMV antibody (Fig. 1A, inset). There was massive periportal necrosis of the fetal liver (Fig. 1B) with prominent CMVinfected cells (Fig. 1C); similar cells were found in the lungs (Fig. 1D). Calcifications, which may be found in a variety of organs in patients with congenital CMV infection, were not found. 13 Methods for detecting fetal CMV infection include CMV antigenemia assay, testing for IgG and IgM antibodies, the shell-vial assay, hybrid-capture assay, and avidity testing. 14,15 The antigenemia assay is a quantitative measure of CMV present in white cells by means of indirect immunofluorescence for immediate early phosphoprotein 65 antigen. IgM antibody peaks during the first 1 to 3 months after infection but may be detectable for up to 1 year. The shell-vial assay is an indirect, qualitative measurement performed by inoculating exogenous cells with serum or urine. Cytopathic effects are visible within 24 hours after inoculation and are detectable by indirect immunofluorescence of immediate early antigens. Hybrid-capture testing is based on formation of a DNA RNA hybrid, which is detectable with the use of enzyme-linked immunosorbent assay. Avidity testing is used to determine the interval since maternal infection. Initially, the IgG antibody has relatively weak reactivity (low avidity) with CMV antigens; however, after approximately 4 months of infection, there is strong reactivity (high avidity). Even with detection of CMV in the mother, it is not possible to predict whether transmission to the fetus will occur. 14 In this case, testing of the mother for IgG and IgM was positive, as was the initial hybrid capture. IgG avidity testing returned a result of 0.60 (positive result, 0.60). Thus, it could not be determined when maternal infection occurred. Dr. Harris: Dr. Duff, should testing for antibodies to CMV be part of the prenatal evaluation of a pregnant woman, as rubella testing is? Dr. Duff: I would selectively screen health care workers, day-care workers, preschool teachers, and mothers of small children, who are at high risk for exposure during pregnancy. In that way, the health care provider can reassure those who have IgG antibody and no IgM antibody that they have been exposed to this virus and their risk of an acute infection with fetal injury is quite low. Those without antibodies should be advised to take appropriate precautions to avoid infection during pregnancy. Anatomical Diagnosis Systemic congenital cytomegalovirus infection and cytomegalovirus placentitis. No potential conflict of interest relevant to this article was reported. References 1. Markenson GR, Yancey MK. Parvovirus B19 infections in pregnancy. Semin Perinatol 1998;22: Hammer SM. Management of newly diagnosed HIV infection. N Engl J Med 2005;353: Guerra B, Simonazzi G, Banfi A, et al. Impact of diagnostic and confirmatory tests and prenatal counseling on the rate of pregnancy termination among women with positive cytomegalovirus immunoglobulin M antibody titers. Am J Obstet Gynecol 2007;196(3):221.e1-221.e6. 4. Duff P. Immunotherapy for congenital cytomegalovirus infection. N Engl J Med 2005;353: Boppana SB, Rivera LB, Fowler KB, Mach M, Britt WJ. Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med 2001;344: Fowler KB, Stagno S, Pass RF. Maternal immunity and prevention of congenital cytomegalovirus infection. JAMA 2003; 289: Azam AZ, Vial Y, Fawer CL, Zufferey J, Hohfeld P. Prenatal diagnosis of congeni- 515

9 tal cytomegalovirus infection. Obstet Gynecol 2001;97: Lipitz S, Yagel S, Shalev E, Achiron R, Mashiach S, Schiff E. Prenatal diagnosis of fetal primary cytomegalovirus infection. Obstet Gynecol 1997;89: Donner C, Liesnard C, Content J, Busine A, Aderca J, Rodesch F. Prenatal diagnosis of 52 pregnancies at risk for congenital cytomegalovirus infection. Obstet Gynecol 1993;82: La Torre R, Nigro G, Mazzocco M, Best AM, Adler SP. Placental enlargement in women with primary cytomegalovirus infection is associated with fetal and neonatal disease. Clin Infect Dis 2006;43: Nigro G, Adler SP, La Torre R, Best AM. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353: Baergen R. Manual of Benirschke and Kaufmann s pathology of the human placenta. New York: Springer, Gilbert-Barness E, ed. Potter s pathol- ogy of the fetus, infant and child. 2nd ed. Philadelphia: Elsevier, Hassan J, Connell J. Translational mini-review series on infectious disease: congenital cytomegalovirus infection: 50 years on. Clin Exp Immunol 2007;149: Munro SC, Hall B, Whybin LR, et al. Diagnosis of and screening for cytomegalovirus infection in pregnant women. J Clin Microbiol 2005;43: Copyright 2009 Massachusetts Medical Society. Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends, shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens, and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced, averaging slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the Case Record. The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA (telephone ) or Pathphotoslides@partners.org. 516