USG pada infeksi intrauterin

CME A RTICLE

Ultrasound Markers of Fetal Infection, Part 2

Bacterial, Parasitic, and Fungal Infections

  Luiz Antonio Baila˜o, MD, PhD, Newton G. Osborne, MD, PhD,Þ Maria Christina S. Rizzi, MD,þ Fernando Bonilla-Musoles, MD, PhD,§ Geraldo Duarte, MD,¶ and Teresa Cristina R. Sicchieri Baila˜o, RN||

  Maternal morbidity is increased with intra-amniotic infection;

  Abstract: Up to 1 of all pregnancies have clinically overt intra-

  although maternal mortality is extremely rare in developed countries,

  amniotic bacterial infections, and an even larger percentage of

  this is not the case in societies where pregnant women have limited or

  pregnant women may be affected by silent infections. Although most pregnant women with overt intra-amniotic bacterial infection have

  no access to medical care. Although infected women who are treated

  experienced prolonged rupture of membranes (PROM), sympto-

  early and aggressively with wide-spectrum antibiotics do well, more

  matic and most silent nonviral intra-amniotic infections may occur

  than 10 of these women develop bacteremia and up to half of them

  with intact membranes.

  will require cesarean delivery because of poor uterine contractions and

  The etiology of intra-amniotic infection after PROM is

  arrest of labor.

  almost always polymicrobial and consists of genital tract patho-

  The overwhelming majority of term neonates exposed to intrauterine infection after PROM do well, but up to 30 of these

  gens, such as group B streptococci, Chlamydia trachomatis,

  neonates require treatment of neonatal pneumonia or bacteremia.

  Neisseria gonorrhoeae, mycoplasmas, aerobic Gram-negative

  Outcomes for preterm neonates or for neonates who experienced silent

  bacilli, such as the coliforms, and facultative and anaerobic

  fetal infections are more severe. Morbidity and mortality rates in these

  endogenous organisms, such as peptococci, peptostreptococci, and

  cases are high, and survivors may have long-term devastating sequelae.

  Bacteroides species. These organisms gain access to the uterine

  The ability to identify ultrasound markers of fetal infection

  cavity by the ascending route. Organisms such as Treponema

  will help clinicians identify etiologic agents with greater accuracy

  pallidum, Listeria monocytogenes, Toxoplasma gondii, trypano-

  and correlate these infections with specific antepartum and

  somes, and plasmodia are capable of gaining access to the amniotic

  postpartum syndromes. The recognition of markers of intrauterine

  cavity by transplacental hematogenous spread, and cause devastat-

  infection will also reduce unexpected adverse outcomes that result

  ing fetal infections.

  from undiagnosed fetal infections.

  Symptomatic intra-amniotic infection is usually a diagnosis of exclusion. Diagnostic criteria based on both clinical and laboratory

  Key Words: fetal infection, placental calcifications, fetal hydrops

  findings lack sensitivity and are nonspecific. It is difficult to obtain

  (Ultrasound Quarterly 2006;22:137 Y151)

  uncontaminated intra-amniotic samples, especially when there is PROM. The problem is even greater with silent infections. In most cases, fetal infection is suspected after an unexplained and

  LEARNING OBJECTIVES

  unexpected adverse outcome.

  After reading the article and completing the posttest, the reader should be able to

  Received for publication February 18, 2006; accepted March 29, 2006.

  list ultrasound markers associated with nonviral infections;

  Professor and Co-Director, DIAGNOSIS, Ribeira˜o Preto, SP, Brazil and

  describe placental calcification patterns associated with

  Department of Obstetrics and Gynecology, University of Sa˜o Paulo School of Medicine, Ribeira˜o Preto, SP, Brazil; †Professor and Chief of

  intrauterine infection;

  Gynecology, Department of Obstetrics and Gynecology, Howard

  describe fetal anatomical alterations that may result from

  University College of Medicine, Washington, DC; ‡Co-Director,

  fetal bacterial, parasitic, and fungal infections;

  DIAGNOSIS, Ribeira˜o Preto, SP, Brazil; §Professor and Chairman,

  identify alterations in blood flow patterns of the umbilical

  Department of Obstetrics and Gynecology, University of Valencia School

  cord and of the fetal circulation that may occur when there

  of Medicine, Valencia, Spain; ¶Professor, Department of Obstetrics and Gynecology, University of Sa˜o Paulo School of Medicine, Ribeira˜o Preto,

  is fetal infection; and

  SP, Brazil; ||Ultrasonography Instructor, DIAGNOSIS, Ribeira˜o Preto,

  identify the sonographic features of the placenta, fetal

  SP, Brazil.

  anatomy, and fetal circulation associated with intrauterine

  The authors have disclosed that they have no interests in or significant

  bacterial, parasitic, and fungal infection.

  relationships with any commercial companies pertaining to this educational activity.

  M

  Lippincott Continuing Medical Education Institute, Inc. has identified and

  any pregnant women are affected by overt or silent

  resolved all faculty conflicts of interest regarding this educational activity.

  bacterial, fungal, or parasitic infections. Infections may

  Reprints: Newton G. Osborne, MD, PhD, Professor and Chief of Gynecology,

  account for as much as 20 of fetal and neonatal diseases and

  Department of Obstetrics and Gynecology, Howard University College of Medicine, 2041 Georgia Ave, NW, Washington, DC 20060 (e-mail:

  may, in fact, be one of the most frequent causes of perinatal

  NewtonOsborneaol.com).

  mortality. Estimates of infections of embryos and fetuses and their effects on the health of the gestation are very

  Copyright 2006 by Lippincott Williams Wilkins

  difficult to obtain. Maternal signs and symptoms are

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  Ultrasound Quarterly Volume 22, Number 2, June 2006

  frequently nonspecific. In addition, acquisition of appro- priate samples may be problematic and, at times, even if

  TABLE 1. Common Ultrasound Findings Associated with

  samples are obtained, accurate interpretation of the results

  Specific Fetal Infections

  may be difficult. To make matters more difficult, many

  Infection

  Ultrasonography Findings

  newborn neonates with malformations or functional impair-

  Syphilis

  Placentitis; IUGR; bone deformities; cardiac, retinal,

  ment are discharged without ever establishing an etiology

  intracranial, hepatic, and placental calcifications;

  because, in some cases, if infection occurred early in the

  hydrops; IUFD.

  gestation, diagnostic serological alterations may no longer

  Listeriosis

  Hydrops, intracranial calcifications, IUFD.

  be detectable by the time of birth. About 7 to 10 of

  Tuberculosis

  Hepatomegaly; echogenic bowel; IUGR; hepatic, renal,

  newborn neonates harbor an agent of infection, many of placental, and intracranial calcifications; chronic

  hypoxemia; IUFD; bone deformities.

  whom have no clinical signs that would lead to a suspicion

  Gonococcal

  IUGR; ophthalmic and intracranial calcifications.

  of congenital infection.

  Fungal

  Placental calcifications, umbilical cord anomalies, IUFD.

  The factors that allow pathogens to invade the fetus are

  Toxoplasmosis

  Hydrocephaly; microcephaly; chronic hypoxemia;

  probably related to the severity of maternal contamination or

  hydrops; microophthalmia; placental, hepatic, retinal,

  infection, to the state of maternal cellular and humoral

  and intracranial calcifications; IUFD.

  mechanisms of defense against infection, to the presence of

  Malaria

  Placental calcifications, hydrops, chronic hypoxemia.

  subclinical co-infections, and, maybe, to certain exclusive

  Trypanosomal

  IUGR; hydrops; chronic hypoxemia; IUFD;

  properties of the specific pathogenic invader. It is almost

  placental, hepatic, and intracranial calcifications.

  universally accepted that placental villi, the amniotic

  IUFD indicates intrauterine fetal death.

  membrane, and the maternal mucosal surfaces, along with Note: Although IUFD can occur with any fetal infection, it is more common with

  the infections where it is listed.

  their secretions, act as a protective barrier against fetal infection. In addition, there are evidences that certain microbicidal and bacteriostatic agents in the amniotic fluid

  will help clinicians correlate these markers with etiologic

  inhibit the growth of pathogens that gain access to the

  agents of infection and with specific antepartum and

  amniotic cavity and, at times, effectively prevent fetal

  postpartum syndromes (Table 1). In some cases, physicians

  infection. 1 Y3

  Unfortunately, under certain conditions, patho-

  will be able to take measures to reduce the risk of fetal

  gens are able to breach these barriers and initiate devastating or

  and maternal adverse outcomes. 8 Y10 Furthermore, prenatal

  lethal fetal infections, which may result in overt maternal signs

  identification of ultrasound markers of intrauterine infec-

  and symptoms or may be completely silent. Conditions that

  tion is likely to reduce the problem of unexpected adverse

  predispose to infection are more common in poor, under-

  outcomes that result from undiagnosed, silent intrauterine infection.

  nourished, or malnourished women. 4 Y6

  A few organisms can breach the placental barrier and infect the fetus by way of the umbilical cord, regardless of the

  BACTERIAL INFECTIONS

  nutritional or health status of the mother. Some organisms, like Treponema pallidum, Listeria monocytogenes, and

  Syphilis

  Toxoplasma gondii, to name a few, have developed effective

  Syphilis is a systemic disease caused by T. pallidum.

  ways of crossing the placental barriers.

  Although the incidence rate of syphilis in pregnancy is not

  Other microorganisms, such as Streptococcus agalac-

  accurately known, it is estimated that the incidence of 15

  tiae (group B streptococcus), unencapsulated Hemophilus

  cases per 100,000 persons in the general population probably

  influenzae, Trypanosoma cruzi, plasmodia, and a few fungi,

  applies also to pregnant women. There are approximately 2

  occasionally breach the placental barrier and gain access to

  cases of early congenital syphilis per hundred cases of

  the fetus by the hematogenous route. Many other organisms

  primary or secondary syphilis in women of childbearing age.

  produce a chronic placentitis, with eventual destruction of

  Untreated syphilis in pregnancy may result in the birth of a villi, which then provides the opportunity for other organisms 7 neonate with congenital syphilis. In fact, almost all pregnant

  to gain access to the fetus.

  women with untreated primary syphilis, 90 with untreated

  The fetal immune system is immature. The fetal levels

  secondary syphilis, and 30 with untreated early latent

  of immunoglobin M (IgM) produced in response to microbial

  syphilis will infect their fetuses.

  invasion are relatively low; phagocytic function is not fully

  At the onset of congenital syphilis, T. pallidum is

  competent; the levels of complement are low; and T

  released directly into the fetal circulation, resulting in

  lymphocytes are still immature. These factors render the

  spirochetemia with widespread dissemination of the pathogen

  fetus vulnerable to infections acquired through the ascending

  to all fetal organs. Congenital syphilis presents as fetal

  or transplacental routes. Some of these fetal infections (eg,

  hydrops, unexplained stillbirth, or neonatal hepatosplenome-

  group B streptococcosis, syphilis, toxoplasmosis) may be

  galy with or without jaundice. Hemolytic anemia, pneumonia,

  preventable or treatable in utero. Fetal damage may be

  and multiple-bone involvement, snuffles, skin lesions, and

  avoided in some cases if health care professionals are able to

  testicular masses are common. The stillborn syphilitic neonate

  recognize incipient infection and start timely and effective

  is often macerated with a protuberant abdomen. Dermal

  antimicrobial prophylaxis or therapy.

  bullous vesicular lesions contain large numbers of treponemes.

  The ability to identify ultrasound markers of infec-

  Hepatomegaly with fibrosis and persistent extramedullary

  tion in the placenta, in the embryo, and in fetal organs

  hematopoiesis are present. 11,12 Pancreatitis may be severe.

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  Glomerular injury caused by antigen-antibody complex deposi- tion may be present. Meningeal involvement is commonly found around the brain stem and optic chiasma. Syphilitic endocarditis may be present. Osteochondritis, periostitis, and osteomyelitis are characteristic. Severe anemia leads to fetal hydrops.

  A neonate’s VDRL test titer of more than 4 times higher than the maternal level is strongly suggestive of congenital disease. The presence of fluorescent treponemal antibody IgM in the neonate’s serum confirms the diagnosis. False-positive IgM may occur by cross-reaction with other IgM antibodies. False-negative IgM may occur if maternal IgG levels are very high.

  The syphilitic placenta is large, sometimes massively, but without much edema. An abnormally thick placenta is

  detectable with ultrasound 13 (Fig. 1). The placental-fetal

  FIGURE 2. Spectral Doppler analysis of the umbilical arteries of

  weight ratios in congenital syphilis are usually at least 0.5.

  the placenta shown in Figure 1 reveals an elevated RI, which

  There is a triad of changes consisting of focal villitis, vascular

  indicates a risk of malnutrition and hypoxia in addition to the

  changes (including endothelial proliferation and perivascular

  other risks associated with fetal infection with syphilis.

  inflammation), and immature villi. These changes predispose to fetal malnutrition and hypoxia (Figs. 2 Y5). The decidua at the base of the placenta may have plasma cells and lymphocytes,

  Listeria Monocytogenes

  particularly around maternal vessels. Scarring of villi occurs

  L. monocytogenes is a small, Gram-positive coccoba-

  with chronic infections.

  cillus that is widely distributed in nature and in a variety of

  Unlike adult syphilis, which passes through stages, fetal

  animal reservoirs. Most L. monocytogenes isolates that cause

  or congenital syphilis has simultaneous development of lesions

  human disease belong to serovars 1a, 1b, and 4b. 14

  similar to those found at all 3 classic stages. The skin may have

  Human infection with L. monocytogenes has protean

  bullous lesions, characteristically extending to the palms and

  manifestations, of which meningitis is the most frequent form in

  soles. Focal destruction of bony tissue between the diaphysis

  adults. The most unique clinical form of infection with L.

  and epiphysis may produce characteristic bone lesions.

  monocytogenes is infection of the genital tract of pregnant

  Granulation tissue may be exuberant, producing saber shin

  women with subsequent infection of the fetus or of the newborn

  and bossing of the forehead. BCelery stalk lesions may occur.

  neonate at the time of delivery. Pregnant women with genital

  There may be ultrasound evidences of encephalitis, chorio-

  tract infection are usually asymptomatic. Symptomatic, sys-

  retinitis, bone deformities, hepatosplenomegaly, endocarditis,

  temic maternal infection is characterized by an acute febrile

  or fetal hydrops. Perivascular cuffing, deep within the tissue

  illness, which may be followed by spontaneous abortion,

  of the central nervous system, is a characteristic finding.

  stillborn delivery, delivery of a seriously ill premature or term

  Many of these changes are detectable with ultrasonography

  neonate, or delivery of an unaffected term neonate. The case

  (Figs. 6 Y11).

  fatality rate for liveborn neonates of infected mothers is 27.

  FIGURE 1. Chronic hypertrophic placentitis. Observe the marked heterogeneous echogenic thickening of the chorionic plate (small vertical arrow), along with hypoechogenic areas of

  FIGURE 3. Spectral Doppler analysis of the ductus venosus of a

  the villous mass (large horizontal arrow). Maternal workup

  16-week infected fetus showing fetal hemodynamic alteration.

  demonstrated infection with T. pallidum.

  Observe the abnormal reflux with atrial contractions (arrows).

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  FIGURE 6. Chronic encephalitis with collar-of-pearl formations (arrow) along the walls of the third ventricle.

  neonates that acquired the infection in utero, and may be

  FIGURE 4. Spectral Doppler analysis of the middle cerebral

  associated with diarrhea, pneumonitis, seizures, and maculo-

  artery of infected fetus revealing vasodilatation with reduced

  papular skin lesions of the trunk and legs. Not surprisingly,

  flow impedance.

  these neonates have an increased risk of neonatal mortality.

  14 Y17

  If neonatal infection results from contamination at the

  Fetal infection can occur with intact membranes.

  Fetal

  time of delivery, the symptoms of neonatal listeriosis appear

  infection may result in nonimmune hydrops andor in fetal

  after the fifth day of life. As is the case with survivors of

  meningitis. Fetuses that survive an intrauterine infection

  intrauterine infection, infection with L. monocytogenes

  with L. monocytogenes are likely to be born prematurely and

  acquired at birth causes meningitis, widespread granuloma-

  to have low birth weight. Surviving fetuses usually have

  tous lesions, microabscesses, and septicemia.

  evidence of distress during labor and develop postnatal granulomatosis infantiseptica. When there is fetal infection,

  Chlamydia trachomatis, Mycoplasma hominis, and

  symptoms of septicemia usually develop within a few hours

  Ureaplasma urealyticum

  of birth. If evidences of infection are not obvious at birth,

  Although C. trachomatis infection in neonates results

  septicemia definitely presents within 2 days of birth in all

  from perinatal exposure to the mother’s infected cervix in the overwhelming majority of cases, 18 C. trachomatis, M. hominis, and U. urealyticum may also cause intrauterine infection. 19 Y26 Intrauterine infection with these pathogens may be associated with intrauterine growth restriction, preterm delivery, low birth

  FIGURE 5. Spectral Doppler analysis of the descending aorta shows absent end-diastolic flow, indicative of visceral and

  FIGURE 7. Fetal chorioretinitis. Observe the calcifications of

  placental alterations.

  the retina and the choroids (arrow).

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  FIGURE 8. Two-dimensional ultrasound image of fetal femur

  FIGURE 10. Marked fetal splenomegaly. The splenic

  with local bone destruction (arrow).

  parenchyma shows soft hypoechogenic areas that indicate edema.

  weight, or neonatal death. It is likely that these pathogens are etiologic agents of these complications, particularly when the

  of time in the contaminated environment. There may be

  IgM antibody against them is present in fetal blood or in the

  multiple skin abscesses, gastrointestinal abscesses, or severe

  blood of newborn neonates. 19 Y25

  genital infections. There is risk of fetal septicemia that may lead to meningoencephalitis, intrauterine growth retardation

  Neisseria gonorrhoeae

  (IUGR), lesions in multiple joints, disseminated intravascular

  N. gonorrhoeae may infect the cervix and contaminate

  coagulopathy, and fetal death. Acute intra-amniotic infection

  the vagina of pregnant women. 26 The gonococcus can invade

  can also lead to preterm, premature rupture of membranes

  the amniotic cavity and cause fetal infection. 27 More

  (pPROM), premature labor, prematurity, and congenital

  commonly, the uterus and the neonate become infected

  conjunctivitis and ophthalmitis. In these cases, neonates

  during labor and delivery. Exposed neonates who remain

  may be born with pharyngeal, tracheal, stomach, or skin

  untreated may develop gonococcal conjunctivitis and

  infections. They may also have vulvar, vaginal, urethral, or

  pharyngitis. 26

  anal infection with the gonococcus.

  Intra-amniotic infection may lead to grave conse-

  Intrauterine infections during the first trimester may

  quences. Fetal damage is directly proportional to the length

  lead to septic abortion. Hematogenous fetal infection is rare, but when it occurs, there may be placentitis with eventual

  FIGURE 9. Liver of 32-week infected fetus. Observe the cluster of echogenic lesions. The absence of acoustic shadowing

  FIGURE 11. Twenty-nine-week fetus with group B

  suggests that these echogenic foci most likely represent

  streptococcal infection. Observe the marked fetal ascites (lower

  specular reflections from the walls of microabsceses rather

  vertical arrow). The bowel with marked echogenicity (middle

  than true microcalcifications. The liver is the first organ to

  horizontal arrow) is floating free in fluid, and the liver (upper

  be affected by infections that gain access by the

  downward arrow) is clearly visible, separated from the

  transplacental route.

  abdominal wall.

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  fetal infection via umbilical cord blood, with development of liver abscesses and septicemia.

  Group B Streptococcus (Streptococcus agalactiae)

  Group B streptococci are frequently cultured from the vagina and the cervical canal. Colonized pregnant women are at risk of ascending infection that may lead to pPROM and premature labor. 28,29 Fetal infection can occur with intact membranes. 30,31 When fetal infection occurs without pre- mature delivery, the fetus may develop skin infection. By breathing in contaminated amniotic fluid, pharyngeal and pulmonary infection may follow. The fetus may develop pleural effusions and other lesions that can be detected by ultrasonography, such as pulmonary microabscesses and areas of lung necrosis (Figs. 12, 13). On rare occasions, there may be hematogenous infections of the placenta leading to placentitis, placental infarction, and placental abscesses. Infection of the fetus by the hematogenous route is rare.

  FIGURE 13. Pregnancy at 36th week of gestation with

  When it occurs, the liver is primarily affected. Liver

  maternal history of nonspecific febrile illness. There are

  abscesses, septicemia, and ascites may follow, with involve-

  pulmonary hyperechogenic foci that most likely represent

  ment of multiple other organs (Fig. 9).

  microabscesses and hypoechogenic areas that suggest focal

  Mycobacterium tuberculosis parenchymal destruction. The fetus shows cardiomegaly with

  signs of cardiac insufficiency.

  Although uncommon in developed countries, congeni- tal tuberculosis is frequently underdiagnosed. Delayed

  reason, early diagnosis is desirable. Mortality rate is high with 33

  diagnosis and treatment results in up to 50 mortality rate.

  untreated disease.

  Infected fetuses may develop hepatomegaly and splenome-

  The criteria for diagnosis of congenital tuberculosis 34,35

  galy. Neonates with congenital tuberculosis usually do not

  are the following:

  manifest signs of disease for days or weeks after delivery. The

  1. M. tuberculosis must be proved to be present;

  signs and symptoms of infection may be nonspecific. The

  2. The neonate has a primary complex in the liver;

  neonates may develop respiratory distress, fever, poor

  3. The lesions are present within the first few days of life;

  feeding, failure to thrive, lethargy, lymphadenopathy, and

  and

  abdominal distention. 32 Hepatosplenomegaly may be

  4. If the neonate has neither a proved hepatic primary

  detected on physical examination. Congenital tuberculosis

  complex nor lesions in the first few days of life,

  has an excellent prognosis if treated at an early stage. For this

  extrauterine infection must be excluded. The liver is the principal site of fetal infection after the

  hematogenous spread of infection from the umbilical veins.

  FIGURE 12. Fetus with pleural effusion. Observe the calcifications in the heart. Cardiac calcifications are a direct sign of an inflammatory process. Pleural effusion can result from several conditions, but its association with cardiac

  FIGURE 14. Liver of 18-week fetus with hyperechogenic ring

  calcifications in this case makes pleural effusion an indirect sign

  structures suggestive of granulomas. The mother had

  of fetal infection.

  tuberculosis.

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  decidual plate are involved. Chorioamnionitis is commonly seen. Fetal infection has been associated with premature delivery and fetal death. There may be nonspecific ultrasound abnormalities of the placenta and umbilical cord. 39,40

Coccidioides immitis

  C. immitis, the etiologic agent of coccidioidomycosis, is

  a dimorphic fungus that lives in the soil of highly restricted geographic areas. The organism is restricted to the south- western United States and contiguous areas of northern Mexico. This fungus can also be found in a few areas of Central and South America that have semiarid climate, alkaline soil, and characteristic plants and rodents of this type of semidesert environment. The risk of C. immitis dissemina- tion is higher in the third trimester of pregnancy, probably because of an intrinsic susceptibility of the mother and the fetus when levels of estradiol are higher. 41,42

  FIGURE 15. Foci of chronic placentitis in a grade I placenta.

  Placental infection with C. immitis leads to microscopic

  Observe the peripheral echogenic clusters of microabscesses

  foci of necrosis. The necrotic foci contain dead villi, fibrin

  and areas of ring formation (arrow) typical of mature

  deposits, and granulomatous reactions. Fetal demise may

  granulomas.

  accompany severe maternal disease and placental damage. The placental barrier seems to be efficient in preventing fetal

  Hepatic and placental granulomas can be observed with

  disease. The necrotic villi may lead to infarction of placental

  ultrasonography (Figs. 14, 15). The lungs may be infected by

  cotyledons. These changes are detectable with ultrasound and

  hematogenous spread or by inhalation of infected amniotic

  by the absence of flow when observed with color Doppler

  fluid. The central nervous system is seldom infected, but long

  echocardiography. The infection-induced, chronic, atrophic

  bones, kidneys, spleen, the gastrointestinal tract, skin, and

  placentitis provokes IUGR and chronic hypoxemia, and may

  lymph nodes may be involved. Infection with M. tuberculosis

  cause perinatal death.

  causes characteristic caseating lesions. Hepatic granulo- mata are detectable with ultrasound. Severe fetal infection

  Cryptococcus, Blastomyces, and

  causes IUGR and encephalitis that may result in postnatal

  Sporothrix species

  microcephaly.

  Cryptococcus neoformans is one of the few organisms of the genus Cryptococcus that is pathogenic to humans. C. neoformans is an encapsulated yeast that is normally found in

  FUNGAL INFECTIONS

  soil and avian feces. Cryptococcosis, the disease that results

  Fungi may cause fetal infection by an ascending route

  from infection with C. neoformans after airborne exposure

  (eg, Candida species) or by systemic spread (eg, Cocci-

  and inhalation of the yeast, initially affects the lungs. The

  dioides, Cryptococcus, Blastomyces, and Sporothrix species).

  organism may metastasize from the lungs to virtually any

  Systemic mycoses are extremely uncommon in immunocom-

  organ in the body. This organism is ubiquitous in nature, yet

  petent pregnant patients. Maternal systemic mycoses are seen

  the incidence rate of cryptococcosis is low.

  in otherwise healthy patients who are first exposed in endemic

  Blastomyces dermatitidis, a thermally dimorphic fun-

  areas during pregnancy or in immunosuppressed patients.

  gus, is the causative agent of blastomycosis, a chronic lung

  Fortunately, fungi are rarely cultured in surveys of fetal or

  infection characterized by granulomatous and suppurative

  placental pathology.

  lesions that occurs after inhalation of the organism. Most infections are subclinical and resolve spontaneously. Calci-

  Candida species

  fication is uncommon; therefore, there is little radiological or

  Although vaginal candidiasis is common in pregnancy,

  histopathologic evidence of residual blastomycotic lesions.

  systemic maternal disease, fetal infection, and placental

  Although there is preferential spread from the lungs to the

  colonization are extremely rare. 36 Y38 Placental and fetal

  skin and bones in subclinical infections, dissemination may

  infection, when they occur, seem to occur by the ascending

  occur to any organ with severe infections.

  route. The infection is usually restricted to the placenta,

  Sporothrix schenckii is a thermally dimorphic fungus

  umbilical cord, amniotic membrane, and fetal skin.

  that causes sporotrichosis, a chronic infection of the

  Microscopic examination of the umbilical cord reveals

  lymphatics and cutaneous and subcutaneous tissues. The

  multiple yellow circular plates spanning the length of the

  infection follows traumatic implantation of the organism into

  umbilical cord and, occasionally, appears histologically as

  the skin. Secondary spread may involve lymph nodes,

  superficial microabscesses comprised of neutrophil polymor-

  underlying muscle, bone, and, occasionally, lungs, central

  phonuclear cells, lymphocytes, and large mononuclear cells.

  nervous system, and the genitourinary tract. Sporotrichosis is

  The lesions penetrate Wharton jelly but do not invade deeper

  considered an occupational disease of forest rangers,

  vascular structures. Neither the chorionic villi nor the

  horticulturists, and other agricultural workers.

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  C. neoformans, B. dermatitidis, and S. schenckii are

  known to be able to cause systemic maternal infection. However, placental involvement and fetal infection have not been well documented with these organisms. It is likely that the scant documentation of the effects of fetal infection with these organisms is due to a low incidence rate of maternal infection, along with a low index of suspicion when there is unexplained IUGR, fetal flow centralization, fetal organ calcification, or abnormal placental calcification.

  PARASITIC INFECTIONS

  Toxoplasma gondii

  T. gondii is an obligate intracellular parasite of, primarily, domestic cats and other felines. However, the organism is known for its lack of host specificity. It may be found in several primates, carnivores, ungulates, birds, and rodents. The organism causes toxoplasmosis in humans.

  FIGURE 17. Fetus at 22th week of gestation with toxoplasmosis.

  Acquisition of T. gondii follows the consumption of infected

  There is bilateral ophthalmitis with condensation of the vitreous

  undercooked meat or exposure to oocysts in cat excreta or

  humor, cataracts (upward arrow), and retinal calcifications infected soil. Most maternal infections are asymptomatic or 43 (downward arrow).

  result in a mild influenzalike illness. Y46

  Acute infection during pregnancy, accompanied by

  than 5. Fetal infection may result in encephalomyelitis,

  parasitemia, can lead to placental infection. Transmission to

  central nervous system necrosis and calcification, and

  the fetus depends on gestational age. In early pregnancy, the

  ophthalmic calcifications (Figs. 16 Y18).

  transmission rate is only about 10; however, severe lesions

  Severe neonatal manifestations are low birth weight,

  can affect 90 of infected fetuses. In the last trimester of

  jaundice, hepatomegaly, thrombocytopenia, meningoence-

  pregnancy, the rate of vertical transmission rises to about

  phalitis, and hydrocephalus. Hydrocephalus, intracranial

  45; however, the rate of severe fetal lesions drops to less

  calcification, and bilateral retinochoroiditis are the classical

  FIGURE 16. Fetus at 36th week of gestation with chronic encephalitis. Observe the asymmetric dilatation of the lateral ventricles and enlargement of the cisterna magna. There is also vascular calcification (arrow on vasculith) next to the fissure of Sylvius. This fetus also had splenomegaly.

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  Ultrasound Markers, Part 2

  of a chronic granulomatous lesion. Fetal disease results from placental compromise secondary to massive egg deposition and the associated inflammatory reaction. Direct fetal infection has not been documented. The observable ultra- sound changes occur in the placenta.

Trypanosomiasis

  T. cruzi, the agent of Chagas disease, is the most important cause of trypanosomal congenital infection. 52 Infected mothers are commonly asymptomatic during pregnancy. The incidence rate of congenital disease is higher if the mother is symptomatic, presumably because of greater parasitemia. Recurrent congenital disease is possible.

  The placenta becomes infected after maternal para- sitemia. Amastigotes are subsequently found in the chorionic villi and plate. Less frequently, they are found in the membranes. Villous edema and granulomatous reaction

  FIGURE 18. Pregnancy at 34th week of gestation with fetal

  may follow placental infection. Fetal infection occurs

  toxoplasmosis. The fetus has severe, chronic encephalitis.

  predominantly through the umbilical cord but may also

  Observe the asymmetric cerebral atrophy with calcifications of

  occur from contaminated amniotic fluid. Fetal infection

  the ventricular walls (horizontal arrow) and the cerebral

  involves the heart, skeletal muscle, brain, skin, the gastro-

  parenchyma (vertical upward arrow). There is great destruction

  intestinal tract, and the reticuloendothelial system. Infection

  of the parenchyma to the extent that the ventricle

  leads to severe anemia, fetal edema, hepatosplenomegaly,

  (downward arrow) is adjacent to the meninges (secondary

  jaundice, and encephalitis. Extramedullary hematopoiesis is

  schizencephaly).

  increased. The disease may resemble erythroblastosis fetalis. Infection may lead to abortion, stillbirth, prematurity, low

  triad of congenital toxoplasmosis. These common fetal and

  birth weight, or neonatal death.

  neonatal lesions are detectable with ultrasound. The accurate diagnosis of disease in pregnancy is desirable because antenatal therapy seems to reduce the severity of postnatal

  DISCUSSION

  manifestations. 45,46

  Although the advances in knowledge and the develop- ment of newer laboratory methods, such as the polymerase

  Malaria (Plasmodium falciparum)

  chain reaction and nucleic acid hybridization technique, have

  Congenital malaria has been documented with all major

  improved our ability to detect maternal infections, many (if

  species of plasmodia. Most diseases related to malaria in

  not most) infections that can cause serious fetal damage or

  pregnancy are secondary to placental involvement and its

  death remain undetected. Placental atrophy, amniotic volume

  subsequent effects upon the fetus. Pregnancy seems to be

  alterations, fetal growth restriction, depletion or failure of

  associated with increased maternal parasitemia. Prenatally

  development of fetal fat stores, chronic hypoxemia, mal-

  acquired malaria is found primarily in neonates of non-

  formations, and perinatal death are nonspecific events that

  immune women who contract malaria during pregnancy. It is

  can result from intrauterine infection. Intrauterine infection

  rare among the neonates of indigenous women of malarial

  may affect the brain, eyes, heart, lungs, liver, spleen, kidneys,

  areas, despite heavy infestation of the placenta. The incidence

  or bones of the fetus in ways that may not be clinically rate of abortion is inversely proportional to the degree of 47 obvious until weeks, months, or years after birth. 53

  maternal immunity. Y49

  Most of the anatomical malformations, placental

  Placental infection is often associated with severe

  structural alterations, and umbilical cord changes that occur

  maternal anemia, preterm labor, fetal growth restriction, and

  with fetal infection are detectable with good-quality ultra-

  low birth weight. Fever, anemia, and splenomegaly occur in

  sound machines. Our experience suggests that appropriate

  neonates with congenital infection. Reticulocytosis, jaundice,

  screening ultrasonography schedules can be used to identify

  and hyperbilirubinemia are frequently seen. Hepatomegaly is

  certain markers of fetal infection. We are proposing a

  less frequently seen.

  minimum of 4 ultrasound examinations (at the 13th, 22nd, 30th, and 36th gestational weeks) for the following reasons:

  Schistosomiasis

  1. Prenatal and postnatal clinical detection of congenital

  Schistosoma haematobium is likely to migrate preferen-

  silent infections is low.

  tially to the pelvic veins after penetration, in cercarial form,

  2. Many of the sequelae of silent chronic encephalitis

  through the skin. Excretion of eggs in the uterus and placenta

  become evident during the school years. At times, the

  can occur both with S. haematobium and with Schistosoma

  sequelae of silent fetal infection are erroneously attrib-

  mansoni. 50,51

  uted to events that occur during labor and delivery.

  Eggs are found in the intervillous spaces, with or

  3. Many conditions that occur later in the life of affected

  without an accompanying inflammatory response in the form

  individuals are late manifestations of undiagnosed

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  congenital infection categorized as idiopathic or attrib-

  from the placenta, are causally related to hydrops. Obstruc-

  uted to postnatal events. Late manifestations of chronic

  tion to venous return from the placenta leads to increased

  inflammation in organs such as the heart, lungs, liver,

  venous pressure, which, in turn, leads to placental edema,

  kidneys, and other organs may, in fact, be sequelae of

  impaired gas exchange, fetal hypoxia, fetal capillary damage,

  undetected congenital infection that could have been

  loss of plasma proteins, and, eventually, to fetal hydrops.

  detected prenatally by identification of ultrasound

  The so-called TORCH infections (toxoplasmosis, other

  markers and confirmation with appropriate prenatal

  infections, rubella, cytomegalovirus infection, and herpes

  laboratory tests.

  simplex), syphilis, coxsackie virus infection, Parvovirus

  4. At the 13th week of gestation, we can identify abnormal

  infection, malaria, and infection from organisms that cause

  nuchal translucency, abnormal ductus venosus flow, and

  fetal myocarditis can initiate the changes that ultimately

  several fetal anomalies. Besides being a marker for

  result in fetal hydrops. In cases of fetal hydrops (Fig. 11), the

  certain chromosomal anomalies and recognized syn-

  placenta is often extremely thick and may weigh more than

  dromes, nuchal translucency and abnormal ductus

  1 kg (Fig. 1). In addition, there may be marked edema of the

  venousus flow are also markers of fetal infection during

  umbilical cord.

  the first trimester and, especially, of infections that

  Placental edema suggests that the underlying cause

  compromise fetal cardiovascular function.

  induced severe fetal anemia andor obstruction to venous

  5. Ultrasound evaluation during the 22nd, 30th, and 36th

  return from the placenta. The 3 most important failures of

  gestational week will reveal signs of placentitis, altera-

  fetal homeostasis, which are associated with hydrops, are (1)

  tions of amniotic fluid volume, fetal dysmorphology,

  severe, chronic anemia, (2) hypoproteinemia, and (3) fetal

  hydrops, IUGR, and chronic hypoxemia.

  cardiac failure. Complications arise as fluid balance deterio- rates. Eventually, all 3 mechanisms may contribute to the

  Signs of chronic hypoxemia can be detected by

  worsening of the hydropic state.

  performance of a simplified fetal biophysical profile (respira-

  Placental edema interferes with maternal-fetal trans-

  tory movements, body movements, and cardiac reactivity),

  port. 54 Y56 This event contributes to the worsening of the fetal

  along with Doppler study of cerebral arteries. Doppler studies

  condition by contributing to a decrease in fetal plasma protein

  are also useful for the evaluation of cardiac, cerebral, renal,

  because of poor protein transport, and to hypoxic damage to

  and placental functions, and for evaluation of functional

  fetal capillaries caused by less efficient oxygenation, which,

  alterations caused by inflammatory processes. These studies

  in turn, leads to the loss of even more plasma proteins into the

  also help to evaluate calcifications, granulomas, and disrup-

  interstitial space.

  tions in the various tissues that are strong markers of infec-

  Although placental alterations may give a clue to the

  tion. In many of the ultrasound images, hyperechogenic foci

  etiology of fetal disorders, lesions such as villitis, atrophy,

  identified as Bcalcifications have no acoustic shadowing as

  and thickening are generally nonspecific. Frequently, pla-

  would be expected with truly calcified lesions (Figs. 9, 13, 15).

  cental lesions are markers of problems that may range from

  Without pathological correlation, it is impossible to state

  malformations and infection to serious metabolic disorders.

  unequivocally that these images are definite examples of

  Hydrops is one of the most common nonspecific

  microcalcification. These echogenic lesions most likely rep-

  disorders related to fetal abnormalities and acquired disease.

  resent specular reflections from the walls of microabscesses

  Besides certain viral infections, noninfectious fetal condi-

  that may eventually evolve into truly calcified lesions.

  tions, and a few maternal disorders, 57 syphilis, leptospirosis,

  Infections that reach the fetus by the placental route are

  S. agalactiae (group B streptococcus) septicemia, toxoplas-

  characteristically associated with inflammation of the placental

  mosis, and Chagas disease can start the chain reaction that

  villi. There may be focal infiltration of villi with lymphocytes

  results in hydrops fetalis.

  and histiocytes. This inflammatory reaction eventually leads to

  Abnormal placental size and inappropriate placental

  necrosis, granulation tissue formation, fibroblastic prolifera-

  calcifications are other indicators of an abnormal pregnancy.

  tion, and fibrosis. Vasculitis of villus stem arteries may cause

  Extravillous calcification is a common finding in full-term

  thrombosis and atrophy of villi. Villitis caused by subclinical

  pregnancies (Fig. 19). This phenomenon is most frequently

  infection can lead to progressive placental atrophy and

  seen during the summer months and is more common with 58

  abnormal calcification. These placental changes lead to

  primigravidas. Y60 The normal patterns of extravillous

  progressive restriction of fetomaternal exchange, to fetal

  placental calcification at term and of fetal-placental weight

  growth restriction, and to the most severe forms of chronic

  ratios for differing gestational ages are well documented. 61

  fetal hypoxia. The diagnosis of villositary atrophy can be made

  Intravillous calcification, in turn, is associated with

  with Doppler scanning by detection of an increase in the

  embryonic and fetal death, fetal infection, fetal cardiac

  resistive index (RI) of the umbilical arteries. Doppler scanning

  failure, and chronic placentitis (Fig. 20). We have also

  of fetal cerebral arteries, aorta, renal vessels, and venous

  observed this type of abnormal placental calcification in

  system can also be used to evaluate the necessary vascular

  pregnant smokers. This anomaly is probably caused by

  adjustments of the fetus to compensate for chronic hypoxemia.

  placental vascular alterations induced by toxic substances in

  Fetal hydrops and pathological calcification are 2

  tobacco smoke. If, in addition to intravillositary calcification,

  common sequelae of intrauterine infection. A variety of

  there is an abnormally small placenta with ultrasound

  structural abnormalities, which primarily interfere with the

  evidence of fibrosis and infarcts, we must rule out maternal

  fetoplacental circulation, usually obstructing venous return

  vascular diseases, such as hypertension or type 1 diabetes.

  146

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  Silent congenital infections can also cause nonspecific changes in the amniotic fluid. Volume may be reduced because of placental atrophy, chronic vascular lesions, a reduction in fetal pulmonary or renal perfusion or function, an alteration in fetal metabolism, or a reduction in fetal-maternal exchange. Infections are prominent among the many etiologies for polyhydramnios. Infection causes disturbances in the control of fetal blood levels of protein, interferes with placental venous return, and induces cardiovascular and hematological alterations. These disturbances interfere with the normal control of amniotic fluid volume. When there is intra-amniotic microbial invasion, the amniotic fluid density may increase because of the proliferation of microorganisms and because of the accumulation of debris that originates from meconium and from increasing desquamation of different epithelial tissues affected by the infection. As a consequence, the structural integrity and strength of the amniotic membranes may be compromised, and pPROM may follow. Therefore, ascending infection from the maternal genital tract is one of the most important causes of chorioamnionitis, amniorrhexis, and microbial invasion of the amniotic cavity. When pathogenic organisms invade the amniotic cavity across intact membranes and overwhelm the natural defense systems, the fetal brain, lungs, liver, gastrointestinal tract, kidneys, skin, or other fetal organs may be compromised.

  The brain is at risk of serious damage from intrauterine infection. Fetal and neonatal meningoencephalitis may have a benign transitory course without future consequences, or may affect brain tissue with varying degrees of damage. The process may end with simple edema andor with varying degrees of disruption, or it may follow a chronic, progressive course with extensive compromise because of severe destruction of cerebral parenchyma, ventriculitis, necrosis, meningitis, and fluid collection. The most severe form is schizencephaly, which consists of extensive destruction of parenchymal tissue and rupture of the ventricular wall so that there is physical contact between the ventricular cavities and the meninges (Fig. 18).

  There are 2 basic mechanisms by which brain lesions can occur: (1) they may occur by the effects of chronic

  hypoxia, and (2) they may be caused by a direct invasion of microorganisms into brain tissues. Both events may take place simultaneously in the most severe cases. Chronic hypoxia results from atrophy of placental villi after chronic villitis or placentitis. Chronic hypoxia induces adaptive vascular reactions that are active in all living individuals, starting from fetal life. These adaptive vascular changes are useful in situations of acute asphyxia because they preserve the heart and the brain from grave and irreversible damage, as is seen, for example, in cases of acute intrapartum hypoxia or in cases of postnatal recovery from acute asphyxia after drowning. In these cases, there is a redistribution of circulating blood to the brain, the heart, and the suprarenal glands due to vasodilatation, and a reduction of blood to the lungs, kidneys, the gastrointestinal tract, the skin, and the musculoskeletal system due to vasoconstriction. When there is timely rescue from acute asphyxia, there are no permanent sequelae.

  The blood redistribution that occurs in acute cases of hypoxia becomes a trap in cases of chronic hypoxia. If the conditions leading to chronic hypoxia remain for too long, there can be severe hypoxic-ischemic lesions in the organs affected by persistent vasoconstriction, and grave hypoxic- hemorrhagic lesions in organs affected by persistent vasodi- latation. In our experience, a situation of chronic fetal hypoxia can remain silent for up to 6 weeks. After this time, the risk of neonatal complications with permanent sequelae increases progressively with the duration of exposure to chronic hypoxia. Unfortunately, classical methods, such as fetal biophysical profile and fetal cardiac monitoring that are commonly used for diagnostic evaluation of fetal health, are only capable of detecting chronic hypoxia toward the end of the protective cardiovascular redistribution process, when fetal neurological and cardiac decompensation have already started. In these cases, the classical monitoring methods may prevent fetal andor neonatal death, but they may not prevent the sequelae of chronic hypoxia because the serious damage to the brain and the heart frequently occurs during the silent

  FIGURE 20. Abnormal echogenic foci within the placental cotyledons. These lesions may evolve into calcifications.

  FIGURE 19. Normal placental calcification.

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  phase. At times, the manifestations of undiagnosed chronic hypoxic damage during fetal life may only emerge as late in

  TABLE 3. Doppler Findings of Different Lesions that Result postnatal life as adulthood. 53 from Fetal Encephalitis

  It is possible to diagnose atrophy of placental villi

  Condition

  Impedance (RI)

  and to detect fetal adaptive vascular reactions to hypoxia with

  Acute encephalitis

  Normal or j

  Doppler studies of the venous and arterial flows of the

  Chronic sclerosing encephalitis

  fetoplacental unit. 62 Y64 Detection of compensated chronic

  Chronic vasculitis

  hypoxia will provide for earlier delivery and prevent the

  Hydrocephaly secondary to brain atrophy

  Normal

  most serious sequelae associated with decompensated chronic