Intrauterine infection

Intrauterine infection is a disease of the fetus and newborn that occurs as a result of ante- and/or intranatal infection, manifested in the intrauterine period or in the first days (months) after birth.

The incidence of intrauterine infection among sick newborns is 3-5%.

[ 1 ], [ 2 ], [ 3 ]

What causes intrauterine infection?

Previously, intrauterine infection was designated by the term “TORCH infections” based on the first letters of the names of nosologies: toxoplasmosis, other, rubella, cytomegalia, herpes.

Currently, congenital or intrauterine infection is a numerous disease of various etiologies.

Among the pathogens of this group of diseases, the most significant are viruses that, due to their small size, can easily pass through the placenta. These include representatives of the families Herpesviridae [cytomegalovirus (CMV), herpes simplex viruses (HSV) types 1 and 2], Retroviridae [human immunodeficiency virus (HIV)], Parvoviridae (group B viruses), Togaviridae (rubella virus), Paramyxoviridae (measles virus), Hepadnoviridae (hepatitis B virus), Flaviviridae (hepatitis C virus), Picornaviridae (enteroviruses). The pathogens of acute respiratory viral diseases are not so important etiologically, since they are quite large in size, which does not allow them to penetrate the placenta, and due to the presence of specific antibodies in the mother, they are eliminated from the body.

The second most important pathogen in the etiological structure of these diseases is the protozoan, toxoplasma, and a representative of the Treponematoceae family, pale treponema. An even smaller role is given to listeria and pathogenic fungi.

So, the etiology of intrauterine infections is as follows.

Viruses:

• family Herpesviridae (CMV, HSV types 1 and 2);
• family Retroviridae (human immunodeficiency virus);
• Parvoviridae family (group B viruses);
• family Togaviridae (rubella virus);
• family Paramyxoviridae (measles virus);
• family Hepadnoviridae (hepatitis B virus);
• family Flaviviridae (hepatitis C virus);
• family Picomaviridae (enteroviruses).

Protozoa (Toxoplasma).

Bacteria:

• streptococci groups B and D;
• staphylococci;
• pale treponema;
• chlamydia;
• mycoplasmas (mycoplasma and ureaplasma);
• listeria.

Pathogenic fungi (representatives of the genus Candida).

Pathogenesis and routes of infection of the fetus and newborn

• Depending on the gestational period at which the infectious factor is exposed, various outcomes are possible.
• During the period of embryogenesis, in response to the impact of a pathological factor, alteration of organ rudiments occurs, causing a disruption of morphogenesis. An infectious agent can have a dual effect.
• Embryotoxic mechanism: damage to the endothelium, blockage of the lumen of the vessels, leading to hypoxia of the embryo. As a result, a slowdown in the development of the embryo is observed up to its death. Frozen pregnancy or miscarriages are diagnosed in the early stages.
• Teratogenic mechanism: disruption of organ and tissue formation, leading to developmental defects (CM); miscarriages are possible (both early and late).

Thus, exposure to an infectious agent in the embryonic period (16-75 days) can result in the formation of congenital malformations, frozen pregnancy, and miscarriages.

During early fetogenesis (76-180 days), the fetus exhibits an inflammatory reaction in response to damaging agents. The reaction is imperfect, as it is non-specific, and consists of alteration and excessive development of the mesenchyme, leading to the formation of fibrous changes in the organs. In the case of a severe course of the disease, the fetus dies (late miscarriage; stillbirth). In a mild course, changes in the fetus's organs may occur. In this case, several outcomes can be expected.

Formation of congenital defects of inflammatory genesis due to the proliferation of connective tissue. For example, in the case of hepatitis, as a result of compression of the bile ducts, atresia of the biliary tract occurs. In the case of encephalitis, underdevelopment of the gray matter, gliosis of the brain and, as a consequence, microcephaly occur.

In the case of a very mild inflammatory reaction, only a slowdown in the increase in the weight and length of the fetus can be observed, resulting in intrauterine growth retardation (IUGR).

When an infectious agent comes into contact with fetal tissue before the 12th week of gestation, when the antigen is not recognized by the immune system and is not eliminated (formation of immunological tolerance); a slow infection occurs, which may manifest itself at a later age.

Thus, exposure to an infectious agent during early fetogenesis may result in stillbirth, intrauterine growth restriction, the formation of congenital malformations, and immunological tolerance.

When infected in the third trimester of pregnancy, the fetus produces antibodies (Th-2 response). The Th-1 response of the immune system is weak. It is the basis for the elimination of any antigen, and if it were not for the placenta, the fetus would be rejected during pregnancy.

This is why the immune response of the fetus is formed mainly by the Th-2 type, which is more associated with humoral immunity, which also underlies the atopic response. Sensitization rather than protection of the fetus occurs.

The consequences of an intrauterine infection will depend on the severity of the infectious process.

In severe infectious processes, fetal death and stillbirth are possible.

In moderate cases, fetal disease develops, i.e. intrauterine infection.

In mild cases, IUGR is possible, mainly of the hypotrophic (asymmetric) type.

In addition, rejection of the fetus, miscarriage and premature birth are possible. This is due to the fact that as a result of the infectious process, interferons are released, which in turn induce a Th-1 immune response. The pregnant woman also has an increased Th1-1 immune response, which increases the likelihood of rejection.

When an infectious agent enters the fetus's body, intrauterine infection occurs. This is not yet a disease, and various outcomes are possible:

• absence of intrauterine disease of the fetus (in the presence of natural resistance to the pathogen, for example, anthrax);
• formation of immunological tolerance (depends on the timing of infection during the fetogenesis period);
• infectious process, i.e. disease.

Fetal infection can occur both in the antenatal and intranatal periods. In the antenatal period, two routes of infection are possible: transplacental and ascending. The first is more typical for viruses that can penetrate the intact placental barrier. However, when exposed to other microorganisms (listeria, chlamydia, ureaplasma, etc.), placentitis and fetal infection may develop. In ascending infection, the integrity of the amniotic membranes is compromised and the infectious agent enters as a result of aspiration of infected amniotic fluid and/or secretions from the mother's birth canal. Contact infection through damaged skin is possible. Intranatal infection occurs during childbirth and can be realized with all types of pathogens.

The source of infection for the fetus in most cases is the mother. However, the widespread use in recent years of invasive methods of prenatal diagnostics and treatment, as well as prolongation of pregnancy due to premature rupture of the membranes, creates conditions for iatrogenic intrauterine infection.

Symptoms of intrauterine infection

Almost all intrauterine infections are characterized by a similar clinical picture, including the following symptom complexes:

• IUGR;
• skin changes of various nature, jaundice;
• hepatosplenomegaly (possibly in combination with hepatitis);
• CNS damage from minimal manifestations to meningitis or meningoencephalitis;
• respiratory tract damage;
• cardiovascular disorders;
• kidney damage;
• hematological abnormalities in the form of anemia, thrombocytopenia or hyperthrombocytosis, neutropenia, blood clotting disorders.

Congenital cytomegalovirus infection

One of the most common intrauterine infections (0.2-0.5%). The high frequency of intrauterine CMV infection is due to its widespread distribution in the human population, which is 20-95% depending on age, social status, level of material well-being and sexual activity.

The source of infection is a sick person or a virus carrier. Transmission occurs mainly by contact, less often by airborne droplets and alimentary. Congenital cytomegalovirus infection develops as a result of antenatal (transplacental) or intranatal infection. In most cases of intrauterine infection, the source of the pathogen is the mother, who is sick with CMV. Transfusion transmission of the pathogen is possible when administering CMV-infected blood products to the fetus. The highest risk of intrauterine infection of the fetus with CMV and the development of severe forms of the disease is noted in cases where the pregnant woman is sick with primary CMV. The incidence of primary diseases during pregnancy is approximately 1%. Intrauterine infection of the fetus occurs in 30-50% of cases. At the same time, 5-18% of infected children have a manifest form of intrauterine infection with a severe course and, often, a fatal outcome.

In the case of development of a secondary infectious disease (reactivation of latent persistent CMV or infection with a new strain of the virus in women seropositive for CMV), the risk of infection of the fetus and development of severe forms of congenital cytomegalovirus infection is significantly lower (does not exceed 2%), which is due to the formation of specific immunity.

Reasons

The causative agent of this intrauterine infection is Cytomegalovirus hominis. It is a DNA-containing virus of the Herpesviridae family, belonging to the "Human Herpesvirus-5" group.

Pathogenesis

In the fetus's body, the virus spreads unhindered, penetrates into cells, where it actively replicates and forms daughter viral particles. The daughter virions, having left the infected cell, affect neighboring undamaged cells. Cells affected by CMV hypertrophy, their nuclei increase in size. Such a cell with a large nucleus and a narrow strip of protoplasm is called an "owl's eye". The degree of damage to the fetus depends on the intensity of virus reproduction. In this case, both minimal manifestations of the disease (asymptomatic, subclinical forms) and severe lesions are possible: embryo- and fetopathy, generalized inflammatory changes.

Classification

Generalized form.

Localized forms:

• cerebral;
• liver;
• pulmonary;
• renal;
• mixed.

Asymptomatic form.

Symptoms

In case of antenatal infection, the clinical picture of the disease may manifest itself already at birth. The following symptoms are observed:

• thrombocytopenic purpura (76%);
• jaundice (67%);
• hepatosplenomegaly (60%);
• microcephaly (53%);
• hypotrophy (50%);
• prematurity (34%);
• hepatitis (20%);
• interstitial pneumonia;
• encephalitis;
• chorioretinitis.

In rare cases, when secondary cytomegalovirus infection in a pregnant woman is accompanied by intrauterine infection of the fetus, congenital CMV is asymptomatic. However, in the future, 5-17% of children may develop neurological changes such as sensorineural deafness, delayed psychomotor development, minor brain dysfunction, etc.

In case of intranatal infection, the course of the disease is largely determined by the characteristics of the premorbid condition of the newborn (maturity, full-term status, perinatal lesions, the degree of expression of functional changes during the adaptation period, etc.). At the same time, in premature weakened children with a burdened perinatal history, clinical manifestation of CMV is possible already by the 3rd-5th week of life. Most often, interstitial pneumonia is noted, the development of prolonged jaundice, hepatosplenomegaly, anemia and other hematological disorders is possible.

Diagnostics

Virological methods. Molecular - detection of the CMV genome using DNA hybridization and PCR. The material for the study can be any biological environment of the body (blood, saliva, urine, tracheal lavage, cerebrospinal fluid, etc.).

Serological (ELISA) is used to detect anti-CMV antibodies and determine antibody avidity.

Absolute criteria for verifying the diagnosis of "congenital CMV" are the detection of the pathogen itself (viremia), its genome (DNA) or antigens in the blood. Detection of the CMV genome in the blood and cerebrospinal fluid can be interpreted as a sign of the active period of intrauterine CMV. If the DNA of the virus is detected in cells of other biological environments, then it is impossible to judge the period of the disease unambiguously.

Serological markers of this intrauterine infection are less reliable. However, detection of IgM antibodies in cord blood, as well as in the blood of a newborn, is one of the important diagnostic criteria. Confirmation of the active period of congenital CMV is also confirmed by detection, along with anti-CMV IgM, of an increase in the titer of low-avidity anti-CMV

Detection of specific anti-CMV IgM, as well as detection of a 4-fold increase in the titer in paired anti-CMV sera or detection of low-avidity ones indicates an active (acute) period of infection.

Treatment

The indication for etiotropic treatment is the active period of the manifest form of the disease.

Due to high toxicity, the use of virostatic drugs (ganciclovir, valganciclovir) in newborns is unacceptable.

The drug of choice for the etiotropic treatment of intrauterine infection is human anti-cytomegalovirus immunoglobulin (NeoCytotect). Release form: 10 ml in a bottle, ready-to-use solution. NeoCytotect cannot be mixed with other drugs.

Method of administration: intravenously using a perfusion pump. A single dose is 1 ml/kg every 48 hours until clinical symptoms disappear (usually 3-5 infusions). The initial infusion rate is 0.08 ml/(kg h), after 10 minutes, if the drug is well tolerated, the rate can be gradually increased to a maximum of 0.8 ml/(kg h).

Contraindications for use:

• intolerance to human immunoglobulin;
• hereditary immunodeficiency conditions accompanied by the absence or sharp decrease in the concentration of IgA. The question of the need for etiotropic treatment of newborns
• with asymptomatic congenital CMV infection has not been finally resolved.

Features of care and feeding:

• Seronegative pregnant women should not be allowed to care for a child with congenital CMV;
• Feeding a seronegative newborn with donor milk from a seropositive woman is not permitted;
• In case of development of CMV, a seropositive woman should not stop breastfeeding her child.

[ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ]

Outpatient observation

Children with congenital CMV infection, as well as children from the risk group, are subject to dispensary observation. The risk group includes newborns from infected mothers and women with a burdened obstetric history. Dispensary observation is carried out by a local pediatrician and a neurologist, and, if necessary, other specialists.

Children with this intrauterine infection are observed for a year, in the chronic form - for 3 years, in the residual form, when developmental defects are detected - until the transition to the adolescent office. Frequency of examinations: at birth, at 1, 3, 6 months, then - every 6 months.

For children at risk, dispensary observation is carried out throughout the year with examinations at birth, 1, 3, 6 and 12 months of life.

Clinical and laboratory monitoring includes neurological and audiological examination, ultrasound of the brain and parenchymal organs, assessment of hematological parameters, biochemical blood analysis, determination of specific antibodies to CMV, and immunogram examination.

Preventive vaccinations for children with CMV are not recommended for one year.

[ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ], [ 20 ]

Congenital herpes infection

The incidence of neonatal herpes ranges from 1/2500 to 1/60,000 newborns, with the prevalence of herpes infection among the adult population being 7-40%. Clinical symptoms of genital herpes are observed in only 5% of those infected. In premature infants, congenital herpes infection (CHI) occurs 4 times more often than in full-term infants. The highest risk of developing herpes infection in a newborn is observed in cases of genital herpes in a pregnant woman shortly before delivery (within 1 month).

The source of this intrauterine infection for a pregnant woman is a sick person or a virus carrier. Transmission routes: contact, sexual and airborne. Antenatal infection is possible (about 5% of cases), more often - intranatal infection through contact with secretions from the mother's genital tract. Women with a primary clinical episode of herpes less than 6 weeks before delivery should be delivered by cesarean section. The incubation period for intranatal infection is 3-14 days.

Reasons

This intrauterine infection is caused by HSV type 1 (labial) or 2 (genital). HSV type 2 is of great importance in the etiological structure, and type 1 accounts for about 10-20%.

Pathogenesis

When HSV enters the body, circulating in the blood, it penetrates into erythrocytes and leukocytes. It actively multiplies in the cells of internal organs, bypassing the capillary barrier by diapedesis. The virus has the property of causing tissue necrosis. The disease often becomes recurrent with long-term persistence of the pathogen in the body. In the absence of specific antiviral therapy, high mortality is noted in newborns: in generalized forms it is 80-90%, with damage to the central nervous system 50%. The disability rate is up to 50%.

Classification

• Localized form with lesions of the skin and mucous membranes of the mouth and eyes.
• Generalized form.
• Herpetic lesion of the central nervous system (meningoencephalitis, encephalitis).

Symptoms

The localized form with lesions of the skin and mucous membranes of the mouth and eyes occurs in 20-40% of patients with neonatal herpes and is characterized by the presence of single or multiple vesicular elements on various parts of the body in the absence of signs of a systemic inflammatory reaction. Most often, they appear on the 5th-14th day of life, but in case of antenatal infection, the elements are detected from birth. The reverse development of the vesicles and the process of their healing lasts 10-14 days.

In herpetic eye lesions, keratoconjunctivitis, uveitis, chorioretinitis, and retina dysplasia are observed. Complications of herpetic eye infection: corneal ulcer, optic nerve atrophy, blindness.

In the absence of specific treatment, in 50-70% of newborns the localized cutaneous form can lead to generalization of the process or to damage to the central nervous system.

The generalized form occurs in 20-50% of cases. Clinical signs usually appear on the 5th-10th day of life and earlier.

Progressive deterioration of the child's condition and severe microcirculation disorders are noted. Liver and adrenal gland damage is typical. Also noted is an enlarged spleen, hypoglycemia, hyperbilirubinemia, and DBC syndrome. Herpetic meningoencephalitis occurs in 50-65% of cases. Specific rashes on the skin and mucous membranes appear on the 2nd-8th day from the onset of the disease; 20% of patients have no rashes.

Herpetic CNS infection (meningoencephalitis, encephalitis) accounts for about 30% of cases. Symptoms usually appear in the 2nd-3rd week of life. Characterized by a rise in temperature, loss of appetite, lethargy, followed by episodes of increased excitability and tremor. Poorly controlled focal and generalized seizures develop rapidly. Cerebrospinal fluid indices may initially be within normal limits, then an increase in protein and lymphocytic or mixed cytosis is observed.

In 40-60% of patients with this form, there are no specific herpetic rashes on the skin and mucous membranes.

Diagnostics

• The cultural method is the isolation of the virus from blood, cerebrospinal fluid, and vesicle contents. The sensitivity of the method is 80-100%, and the specificity is 100%.
• Detection of HSV antigens by direct immunofluorescence method during examination of the contents of vesicles and scrapings from suspicious areas of the skin.
• PCR (with blood and cerebrospinal fluid samples) for detection of the HSV genome. The sensitivity of the method is 95%, specificity is 100%.
• ELISA for the detection of viral antigens in blood, cerebrospinal fluid, urine, nasopharyngeal contents, etc.
• ELISA for the determination of specific antiherpetic antibodies in blood serum.

Treatment

For all forms of neonatal herpes infection, specific antiviral therapy with acyclovir is indicated.

Drug: acyclovir.

• Method of administration: intravenous drip, slow infusion.
• Frequency of administration: 3 times a day every 8 hours.
• Doses: for localized form - 45 mg/kg x day); for generalized and meningoencephalitis - 60 mg/kg x day).
• The duration of treatment for the localized form is 10-14 days, for the generalized form and meningoencephalitis - at least 21 days.
• Multicenter studies conducted in recent years have shown the advisability of using a dose of 60 mg/kg/day for the treatment of the localized form.

[ 21 ], [ 22 ], [ 23 ]

Features of feeding

If the disease develops in a woman, it is necessary to continue breastfeeding, since even with a primary infection, the penetration of HSV into milk is unlikely. The exception is cases when herpetic eruptions are located on the mother's chest.

[ 24 ], [ 25 ], [ 26 ], [ 27 ], [ 28 ]

Outcomes

In the case of early administration of antiviral therapy for intrauterine infection, mortality in generalized forms is less than 50%, in meningoencephalitis - 14%, the frequency of neurological complications ranges from 10-43%, relapses of skin manifestations in the first 6 months are observed in 46% of children.

[ 29 ], [ 30 ], [ 31 ]

Congenital rubella

The frequency of fetal lesions depends on the gestational age. In the period up to the 8th week of gestation, the infectious process develops in 50-80% of fetuses. If the pregnant woman is infected in the second trimester, then no more than 10-20% are infected; in the third trimester, fetal lesions are rare.

A pregnant woman can become ill through contact with a sick person. The virus is transmitted by airborne droplets. The virus reaches the embryo or fetus transplacentally.

Reasons

The causative agent of intrauterine infection is the rubella virus, which belongs to the togaviruses.

Pathogenesis

The cytodestructive effect of the virus is manifested only in the lens of the eye and the cochlea of the inner ear. In most organs and tissues affected by the rubella virus, significant morphological changes are not observed. These pathological manifestations are associated with the suppression of mitotic activity of cells and the slowing of the growth of cell populations. Disruption of cell growth occurs either with the direct action of the reproducing virus or with damage to the genetic apparatus of the cell.

Symptoms

The classic congenital rubella syndrome, Gregg's triad, is characteristic:

• deafness develops in 50% of newborns if the mother was ill in the first month of pregnancy, in 14-25% if in the second or third month of pregnancy, and in 3-8% if at a later stage;
• eye damage (cataract, microphthalmia);
• heart disease, congenital defects (patent ductus arteriosus, pulmonary artery stenosis, aortic stenosis, septal defects).

In addition to the classic syndrome, there is an extended rubella syndrome, which includes microcephaly, brain damage (meningoencephalitis), glaucoma, iridocyclitis, the presence of areas of depigmented retina, interstitial pneumonia, hepatosplenomegaly, hepatitis, etc. Petechial rash on the skin (due to thrombocytopenia) and anemia are typical.

Diagnostics

Virological method - isolation of the virus from pathological material.

ELISA is performed to detect specific antibodies. The material for PCR is amniotic fluid, chorionic villus tissue, umbilical cord blood, and fetal tissue.

Treatment

There is no specific treatment for intrauterine infection. Symptomatic therapy is performed.

[ 32 ], [ 33 ], [ 34 ], [ 35 ], [ 36 ], [ 37 ], [ 38 ]

Congenital toxoplasmosis

The number of infected people varies between 10-90% depending on the place of residence and age. According to different authors, 10-40% of people aged 18 to 25 are infected. During pregnancy, about 1% of women are initially infected with toxoplasmosis. In 30-40% of cases, they transmit the pathogen to the fetus. Thus, 1 in 1000 fetuses is infected.

Human infection most often occurs through the alimentary route when eating raw or insufficiently cooked meat of domestic and wild animals. Less often - by contact (for example, from a cat). Infection is also possible through blood transfusion or organ transplantation. Fetal infection occurs through the placenta. Cases of infection through mother's milk have been described.

Reasons

The causative agent of intrauterine infection is an intracellular parasite from the class Sporozoa, Toxoplazma gondii.

Pathogenesis

Infection of a woman with toxoplasmosis in the first 2 months of pregnancy does not lead to infection of the fetus, while the disease in the 3rd-6th months is accompanied by infection of the fetus in 40% of cases, and in the 6th-8th months - in 60% of cases. When the fetus is infected in the 3rd month of gestation, the disease occurs in a clinically expressed form in 50% of cases, with infection in the 3rd-6th months - in 25%, and in the 6th-9th months it almost always occurs erased or subclinically. When toxoplasma enters the fetus's body, it mainly affects the central nervous system: underdevelopment of the cerebral hemispheres with microcephaly, ependymal damage, the occurrence of an adhesive process with the development of hydrocephalus. The development of thrombovasculitis with foci of aseptic necrosis is noted, in place of which multiple cavities and cysts are formed during resorption. Sometimes calcification of inflammation foci with the formation of scattered calcifications is observed. In case of eye damage, focal necrosis, productive inflammation of the retina and vascular membrane are noted. Liver damage in the form of interstitial hepatitis is typical. The pathological process affects the spleen, lungs, lymph nodes and other organs.

Classification

• Acute generalized form with hepatosplenomegaly and jaundice.
• Subacute with signs of encephalitis or meningoencephalitis.
• Chronic form, manifested by postencephalic defects.

Symptoms

Congenital toxoplasmosis is characterized by:

• prolonged jaundice;
• febrile conditions;
• skin rashes of various nature;
• hepatosplenomegaly;
• picture of meningitis, meningoencephalitis;
• convulsions;
• hydrocephalus;
• microphthalmia, chorioretinitis, uveitis;
• calcifications in the brain tissue (upon additional examination);
• lymphadenitis;
• cardiomyopathy of unknown genesis.

Diagnostics

Direct detection of toxoplasma in stained blood smears, cerebrospinal fluid centrifugate, and in smears of lymph node puncture or biopsy.

Serological test (ELISA) - detection of specific anti-toxoplasma antibodies.

Treatment

• Drugs: combination of pyrimethamine and sulfonamides. Doses: pyrimethamine 1 mg/kg/day).
• Short-acting sulfonamides: sulfadiazine 0.1 g/kg x day); sulfadimethoxine 25 mg/kg x day); sulfadimidine 0.1 g/kg x day).
• Frequency: pyrimethamine - 2 times a day; sulfadiazine - 2 times a day; sulfadimethoxine - 1 time a day; sulfadimidine - 4 times a day.
• Application scheme: pyrimethamine 5 days + sulfanilamide 7 days, 3 cycles with breaks of 7-14 days. In case of exacerbation of chorioretinitis, chronic form in immunodeficiency state, the course is repeated after 1-2 months.

Alternative scheme

• Drugs: combination (sulfadoxine + pyrimethamine) - fansidar.
• Doses: calculated based on pyrimethamine - 1 mg/kg/day).

Alternative scheme

• Drugs: macrolides (spiramycin, roxithromycin, azithromycin) - in the absence of CNS damage.
• Doses: spiramycin 150,000-300,000 IU/kg/day); roxithromycin 5-8 mg/kg/day); azithromycin 5 mg/kg/day).
• Frequency: spiramycin - 2 times a day; roxithromycin - 2 times a day; azithromycin - 1 time a day.
• Dosage regimen: spiramycin - 10 days; roxithromycin - 7-10 days; azithromycin for 7-10 days.

[ 39 ], [ 40 ], [ 41 ], [ 42 ], [ 43 ], [ 44 ], [ 45 ]

Congenital listeriosis

The incidence of congenital listeriosis is 0.1%. In the human population, the carriage of listeria is on average 2.1%. Perinatal mortality from listeriosis ranges from 0.7 to 25%.

The pathogen is widespread in some types of soil, especially in agricultural areas. Soil is a source of the pathogen for animals, which become infected through contaminated water and feed. Listeria enters the human body mainly through the alimentary route through contaminated products (milk and dairy products, meat of animals and birds, vegetables, seafood, etc.). Listeria can multiply in products stored in the refrigerator.

There are transplacental and intranatal routes of fetal infection.

Reasons

Intrauterine infection is caused by Listeria monocytogenes, a gram-positive rod belonging to the Corynebacterium family.

Pathogenesis

If a pregnant woman is infected with Listeria, the fetus is also infected, inflammation with the development of a septic-granulomatous process is observed. In case of transplacental infection, the fetus is affected by lung damage or a generalized form of intrauterine infection. In case of intranatal infection, CNS damage is most often diagnosed. Specific granulomas are found in almost all organs.

Symptoms

Clinical symptoms of intrauterine infection appear on the 2nd-4th day of life (in case of transplacental infection) or after the 7th day (in case of intranatal infection). The general condition of children is severe. Manifestations of pneumonia, severe respiratory distress syndrome and meningitis or meningoencephalitis are typical. Skin rashes of various nature are typical: nodules, papules, roseola, less often - hemorrhages. Similar elements can be in the pharynx; ulcers on the oral mucosa are also determined. Jaundice, hepatosplenomegaly, cardiac disorders are possible.

• Diagnostics
• Biological test. Animals are infected with material from patients (currently almost never used).
• Bacteriological method - sowing of amniotic fluid, umbilical cord blood, meconium, cerebrospinal fluid, and newborn blood on nutrient media.
• Serological methods (RSC, RPGA) - determination of the titer of specific anti-listeriosis antibodies, study of the titer over time.
• Detection of Listeria monocytogenes RNA in biological fluids using PCR is a highly specific diagnostic method.

Treatment

• Medicines: ampicillin.
• Doses: 200-400 mg/kg/day).
• Frequency of administration: 3 times a day.
• Duration of therapy: 2-3 weeks.

In severe cases, ampicillin + aminoglycosides (gentamicin) are used.

• Doses: ampicillin 200-400 mg/kg/day); gentamicin 5-8 mg/kg/day).
• Frequency of administration: ampicillin - 3 times a day; gentamicin - 2 times a day.
• Duration of therapy: ampicillin for 2-3 weeks; gentamicin for 7-10 days.

Alternative scheme:

• Benzylpenicillin 100,000-200,000 IU/kg x day) + gentamicin 7.5 mg/kg x day); azlocillin 50-100 mg/kg x day); amoxicillin + clavulanic acid 25-35 mg/kg x day).
• Frequency of administration: benzylpenicillin - 4-6 times a day; azlocillin - 2-3 times a day; amoxicillin + clavulanic acid - 2-3 times a day.
• Duration of therapy: 3-4 weeks.

Or:

• Medicines: macrolides (spiramycin, roxithromycin, azithromycin) - for CNS damage.
• Doses: spiramycin 150,000-300,000 IU/kg/day); roxithromycin 5-8 mg/kg/day); azithromycin 5-10 mg/kg/day).
• Frequency: spiramycin and roxithromycin - 2 times a day; azithromycin - 1 time a day.
• Duration of treatment: 3-4 weeks.

[ 46 ], [ 47 ], [ 48 ], [ 49 ]

Congenital chlamydia

The causative agent of intrauterine infection is widespread in nature. Chlamydia infects 6-7% of children. Intrauterine fetal death due to congenital chlamydia is observed in 5.5-14.4% of cases. The frequency of infection in pregnant women is 10-40%.

Infection occurs mainly intranatally, rarely - antenatally in the last weeks of pregnancy. Infection probably occurs when amniotic fluid is swallowed or when it enters the respiratory tract of the fetus.

Reasons

The disease is caused by microorganisms; isolated in a separate order Chlamydiaceae, genus Chlamydia. The latter includes four species.

• Chlamydia psittaci usually causes pneumonia, encephalitis, myocarditis, arthritis, and pyelonephritis in humans.
• Chlamydia pneumonia causes acute respiratory infections and mild pneumonia in adults.
• Chlamydia trachomatis is found only in humans, 18 antigenic variants (serotypes) of the microbe have been identified. Serotypes A, B, C are the causative agents of trachoma.
• Chlamydia ресоrum - described in sheep, cattle. Similar to Chlamydia psittaci. Role in pathogenesis of human diseases is unknown.

Of primary epidemiological significance is Chlamydia trachomatis, less commonly Chlamydia pneumoniae. Under microscopy, chlamydia appear as small gram-negative cocci. They are unable to grow on artificial media, so bacteriological diagnostics of the disease is impossible. Chlamydia have an affinity for cylindrical epithelium (urethra, cervical canal, conjunctiva, bronchi, lungs), as well as squamous epithelial cells, lymphocytes, and neutrophilic leukocytes.

Pathogenesis

When chlamydia enters the fetus's body, it multiplies rapidly. Increased secretion of tumor necrosis factor (TNF), destruction of damaged epithelial cells, increased metabolism of arachidonic acid, and changes in prostaglandin synthesis contribute to disruption of microcirculation in the brain, lungs, and other organs. Due to the peculiarities of the biological cycle of chlamydia (the duration of the full reproduction cycle is 48-72 hours) and the morphofunctional maturity of the newborn, the development of a local inflammatory reaction often occurs slowly, only after 2-3 weeks of life.

Symptoms

Symptoms of intrauterine infection usually appear on the 5th-10th day of life. In this case, predominant damage to the respiratory tract is noted. Nasal congestion, difficulty breathing through the nose, and scant mucous discharge from the nose are observed. Respiratory chlamydia can often occur as pneumonia, less often as atelectasis, bronchiolitis, and croup. Lymph node swelling and damage to the mucous membranes are also characteristic. Common features of clinical manifestations of congenital chlamydia:

• bilateral pneumonia;
• pleurisy;
• purulent conjunctivitis;
• encephalopathy of vascular genesis;
• vulvovaginitis, urethritis;
• myocarditis;
• enteropathy.

Clinical manifestations do not disappear for a long time with conventional treatment regimens and increase with the child's age. The general blood test shows normochromic anemia, a tendency to thrombocytopenia, neutrophilic leukocytosis, monocytosis, and eosinophilia.

Chlamydial conjunctivitis of newborns appears in the first, less often in the second week after birth and is manifested by sticking of the eyelids after sleep, abundant purulent discharge from the conjunctival sac, redness and swelling of the conjunctiva. In the absence of therapy, the disease acquires a protracted course with alternating periods of attenuation and exacerbation of the inflammatory process.

Chlamydial pneumonia in newborns develops in the 1st to 4th month of life. It occurs without an increase in body temperature and is characterized by the child's lethargy, loss of appetite, attacks of whooping cough-like (convulsive, spasmodic) cough, shortness of breath, cyanotic skin, and the presence of wet and dry wheezing in the lungs. Often, pleurisy develops along with pneumonia. The disease has a protracted course. In half of the cases, pneumonia is combined with conjunctivitis.

Otitis media is an inflammation of the middle ear. In newborns, it manifests itself as ear pain against the background of elevated body temperature. The pain increases during sucking, which is manifested by the child's sudden crying during feeding. Acute otitis in newborns often goes unnoticed by others, up to the appearance of purulent discharge from the external auditory canal. With severe otitis, the child sleeps poorly, wakes up often, is restless, screams, turns his head, refuses to breastfeed.

Chlamydial gastrointestinal tract lesions in newborns are caused by the entry of microorganisms when they swallow infected amniotic fluid. After birth, children experience increased regurgitation of food, vomiting, bloating, and diaper rash.

Diagnostics

ELISA and PCR are performed.

Treatment

Drugs: macrolides.

• Doses: spiramycin 150,000-300,000 IU/kg/day); roxithromycin 5-8 mg/(kg/day); azithromycin 5-10 mg/(kg/day); josamycin 30-50 mg/(kg/day); midecamycin 30-50 mg/(kg/day); clarithromycin 7.5-15 mg/(kg/day).
• Frequency: spiramycin - 2 times a day; roxithromycin - 2 times a day; azithromycin - 1 time a day; josamycin - 3 times a day; midecamycin - 2-3 times a day; clarithromycin - 2 times a day.
• Dosage regimen: at least 3 weeks.
• Combination with immunocorrective therapy.

[ 50 ], [ 51 ], [ 52 ], [ 53 ]

Congenital mycoplasmosis

Currently, there are 6 known species of mycoplasma that cause human diseases: Mycoplasma pneumoniae, Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma species, Ureaplasma urealyticum, Mycoplasma incognitus (isolated in AIDS patients). Currently, the number of diseases caused by mycoplasmas has increased significantly. Mycoplasma genitalium has the most pronounced pathogenic potential. With the help of a special structure (organelle), mycoplasma cells attach to erythrocytes and other cells. Mycoplasma genitalium is detected more often in homosexuals (30%) than in heterosexual men (11%). Mycoplasma hominis is less pathogenic, but is found much more often in infectious processes of the genitourinary system. It is detected much more often in inflammatory processes in women than in men. Mycoplasma pneumoniae is the causative agent of primary pneumonia in humans, causing intrauterine infection. Infection occurs ante- and intranatally. The pathogen is detected in pregnant women in 20-50% of cases.

Reasons

Intrauterine infection is caused by mycoplasma, which belongs to the class Mollicutes of the family Mycoplasmataceae. This family is divided into 2 genera: the genus Mycoplasma, which includes about 100 species, and the genus Ureaplasma, which includes 2 species (ureaplasma urealyticum, ureaplasma parvum).

Pathogenesis

When mycoplasma enters the fetus's body, it affects almost all organs; specific changes are found in the central nervous system, lungs, liver, and kidneys. A generalized process often develops.

Symptoms

The disease is characterized by:

• interstitial bilateral pneumonia (cough, moderate dyspnea, few physical findings);
• hepatosplenomegaly;
• meningitis, meningoencephalitis;
• lymphadenopathy;
• fever.

Clinical signs appear as the child ages. A general blood test shows normochromic anemia, no leukocytosis and pronounced neutrophilia, there may be eosinophilia, monocytosis, thrombocytosis, alternating

Diagnostics

Isolation of mycoplasmas in material from pathological foci by light microscopy, phase-contrast microscopy or immunofluorescence. This method is highly accurate. However, the difficulty is that the conditions for culturing mycoplasmas are quite complex and require a special nutrient medium. In addition, it is necessary not only to establish the presence of mycoplasma in the patient's body (almost everyone has them in varying quantities), but also to determine the type and quantity of the pathogen, as well as the characteristics of its effect on the body of a particular person.

Serological reactions (ELISA, RSC, RPGA). A 4-fold increase in titer is considered diagnostic.

PCR diagnostics are carried out.

Treatment

Mycoplasma hominis

• Doses: josamycin and midecamycin 30-50 mg/(kg x day).
• Frequency: josamycin - 3 times a day; midecamycin - 2-3 times a day.
• Dosage regimen: at least 3 weeks.

Mycoplasma pneumoniae

Drugs: macrolides.

• Doses: erythromycin 20-40 mg/(kg/day); spiramycin 150,000-300,000 IU/kg/day); roxithromycin 5-8 mg/(kg/day); azithromycin 5 mg/(kg/day); josamycin 30-50 mg/(kg/day); midecamycin 30-50 mg/(kg/day); clarithromycin 15 mg/(kg/day).
• Frequency: erythromycin - 4 times a day; spiramycin - 2 times a day; roxithromycin - 2 times a day; azithromycin - 1 time a day; josamycin - 3 times a day; midecamycin - 2-3 times a day; clarithromycin - 2 times a day.
• Dosage regimen: at least 3 weeks.

In case of damage to the central nervous system, fluoroquinolones are used for vital indications.

[ 54 ], [ 55 ], [ 56 ], [ 57 ], [ 58 ], [ 59 ], [ 60 ], [ 61 ]

Diagnostics

Diagnosis of intrauterine infection is based on the isolation of the pathogen itself, determination of its genome, antigens or specific antibodies.

The cultural method (virological, bacteriological) is the isolation of the pathogen from the pathological material being studied and its identification. The virological method is almost never used in practice due to its labor intensity and the length of the study. It is not always possible to identify the bacterial pathogen.

The immunofluorescence method is based on the use of luminescence to detect the antigen-antibody reaction occurring on the surface of cells or tissue sections.

Direct immunofluorescence is used to detect pathogen antigens in the pathological material being studied.

Indirect immunofluorescence is used to detect antibodies to the pathogen in the test material.

Serological examination of the newborn should be carried out before the introduction of blood products with simultaneous serological examination of the mother using the paired serum method at intervals of 14-21 days. Seroconversion is observed after clinical manifestations of the disease and the appearance of direct markers of the pathogen (DNA or antigens) in the blood. When the fetus develops immunological tolerance to the pathogen antigens, an inadequate specific immune response is possible. The following methods are classified as serological.

Enzyme immunoassay (ELISA) is the most promising, it is used to detect specific antibodies and act as markers of the immune response. Detection of antibodies indicates an active course of the infectious process. Detection alone does not allow to characterize the period of the disease. Antibodies of this class, appearing after the acute phase of the infectious process, continue to be synthesized after recovery for a long time. In addition, they are able to penetrate the placental barrier and appear in the newborn. If the titer at birth corresponds to the maternal or below its level, and during a repeated study after 3-4 weeks decreases by 1.5-2 times, then those determined in the child were most likely maternal. ELISA is carried out with a parallel determination of the avidity of antibodies, since the degree of avidity can indirectly characterize the period and severity of the infectious process. The detection of low-avidity antibodies indicates a current or recently suffered disease, and the detection of high-avidity antibodies allows us to exclude the active phase of the infectious process.

The complement fixation reaction (CFR) allows one to determine an antibody by a known antigen or an antigen by a known antibody based on the ability of antibodies included in immune complexes to bind complement.

Passive hemagglutination reaction (PHA). It is performed using erythrocytes or neutral synthetic materials with adsorbed antigens or antibodies on their surface. Agglutination occurs when the corresponding serums or antigens are added.

Molecular methods. Identification of the pathogen genome using DNA hybridization and polymerase chain reaction (PCR).