Neonatology

June 4, 2024
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Module 3. Neonatology. Lesson 11. Topics:

Intrauterine infections of newborn (TORCH-infections). Diagnostic, treatment and prophylaxis of HIV ieonates). Classification, etiology, pathogenesis, clinical manifestations, diagnosis, differential diagnosis, treatment, prevention, prognosis.

Embryo- and fetopathies.

Diagnosing deviations from normal intrauterine development requires a detailed knowledge of the normal developement. Here fetal pathology closely coresponds with embryology. The duration of normal gestation is 280 days (which equals 40 weeks) counted from the first day of the last menstruation. Intrauterine development is traditionally divided into the folowing stage

embryonal: 18th week of the fetal developement (equals 310th week of gestation (w.g.)

fetal: from 9th week of the fetal development, i.e. from 11th week of gestation.

 

Furthermore, fetal period can be theoretically divided into a prevailable> (0 to 20 w.g.) and a viable period (over 20 w.g.).

It is necessary to emphasise that this classification is only formal and does not reflect the actual ability to survive after the premature delivery. This ability depends especially on the stage of development of the respiratory tract and lung tissue in particular. Infants born before 28th w.g. suffer of serious health complications caused by insufficient production of aleveolar surfactant by aleveolar type 2 pneumocytes.

 

Note: gestational age of the fetus is calculated from the first day of the last menstruation. However, the actual age of the fetus as approximately 2 weeks less (due to the usual date of conception) To make things clearer, the gestational age terminology is usualy used.

Congenital anomalies (CA) follow disorders during uterine development and can have various degrees of seriousness on a gradual scale from minor to very serious defects. Congenital anomalies can be either structural or functional.

Structural congenital anomalies vary from hypoplasia to agenesis and include also malformations, disruptions and deformations and their combinations. These congenital defects can be detected during the intrauterine development and if such a child is born the anomalies are usually recognizable at first sight.

Functional congenital anomalies usually do not manifest themselves right after the birth. The majority of them are metabolic disorders.

The science studying congenital anomalies their causes, pathogenesis, morfolology and prevention is calledteratology.

The global occurance of congenital anomalies is about 5% of stillborn infants, 23% newborn infants (anomalies detected right after birth) and another 23% are diagnosed during the first year of life.

 

Factors participating on the congenital anomalies genesis:

genetic factors: responsible for approximately 1015% of CAs, are associated with chromosomal aberrations or originate in gene mutations

environmental factors: so-called teratogens, cause another 1015% of CAs

multifactorial causes and factors not yet known: (7080%)

Teratogens and genetic factors can interfere with normal morphogenesis of the fetus on several levels. For example: cell migration, proliferation, interaction, apoptosis etc. can all be affected.

The sensitivity of the fetus to damage causing factors changes during its development. The first trimester of gravidity is the time, when the embryo is highly sensitive to teratogens, while in the second and third trimester (with organogenesis practically finished) the sensitivity decreases. This means that the sooner the damage occures, the more serious the consequences are. The co-called critical stage of the fetus is from the 3rd to the 9th week of gestation.

Critical stages of the organs are specific for each organ and slightly vary from one another:

Central nervous system and cardiovascular system: 36th week of gestation.

Senseseyes and ears 49th week of gestation.

Limbs: from the end of 4th week to the middle of 8th week of gestation.

Palate and teeth: 68th week of gestation.

External genitalia: 79th week of gestation.

The stage of gravidity is not the only important factor. Intensity of the teratogenic agent is important as well. Strong agents usually cause death of the fetus, therefore malformations are more likely to be caused by less intensive insults. During the first 2 weeks of development, the embryo is not very sensitive to teratogens, so there is either no damage at all, or the whole conceptus dies (which is less frequent).

 

Fetopathies

 

Fetopathies are fetal damages occurring after embryogenesis has ended and up to the time of birth. Compared with the vulnerability during organogenesis in the embryonic phase the sensibility to substances that can cause abnormalities is less pronounced in the fetal period.

 

 

Teratogenic factors

Environmental factors (also called teratogens) can be divided into these groups: physical, chemical and biologic.

Classification:

Physical agents:

One of the most serious is ionizing radiation, which causes growth retardation and defects of the central nervous system. Also it is necessary to mention the negative effects of vibrations.

Chemical agents:

Pharmacs: cytostatics, antibiotics (especially tetracyclines and streptomycin), hormones (progesteron, androgens), antiepileptics, anticoagulants etc.

Drugs: alcoholwith a 40% probability, chronic alcohol abuse during pregnancy causes fetal alcohol syndrome (characterised by brain damagemicrocephaly, hydrocephaly, leptomeningeal heterotopy, corpus callosum agenesis, arinencephaly; heart defectsespecially atrio-ventricular septal defects; growth retardation, congenital malformations of eyes and joints.)LSD, marijuana

Smoking: leads to disorders in afterbirth adaptation, lower birth weight and increases the risk of pre-term delivery. Children whose mothers smoked during pregnancy also develop asthma more often.

Biologic agents:

The fetus can be negatively affected by any illness the mother undergoes during her pregnancy. Etiologic agents with the most serious effects on the fetus are listed below (however, the listing is not complete).

Viruses: cytomegalovirus, herpes simplex, varicella-zoster, EBV, influenza, mumps

Bacteria: treponema pallidum

Parasites: toxoplasmosis

Metabolic disease of the mother

 

Fig. 22 Sensibility to teratogenic substances with the
          vulnerability maxima of a few organs

 

 

A
B

Embryonic period
Fetal period


 

 

 

During the embryonic period (A) the degree of sensibility to teratogenic substances is much greater than in the subsequent fetal period (B).

 

The observation that a substance has teratogenic effects for one species and not for another one or that even within a species differences in sensitivity occur leads one to suspect that there is still another, namely genetic, component to be taken into account. So, for example, the relationship betweeicotine abuse and fetal deformities is not a simple, linear one. The chance for abnormalities due to severe nicotine abuse in the normal population is only slightly elevated. If the fetus, though, has a special allele of the gene for the TGF- growth factor, the damaging substances in the tobacco smoke, which are transferred to the baby via the placenta, can elevate the risk for cleft lip and fusion disorders of the palate 10 fold. Nutrition also plays thereby an important role This example illustrates that teratology is by far not so simple and the research about possible teratogenic substance is much more complex than perhaps commonly thought. Great efforts must be undertaken to research, to understand and possibly eliminate the damaging effects of artificially manufactured substances and their decomposition products that our society produces.

 

Chemical substances

Teratogenic substances, consumed by the mother during pregnancy, can damage the embryo in its development. Medicines and environmental toxins comprise the largest class of teratogenic substances. After the thalidomide catastrophe deformities induced by medications have become much rarer. Caution must, though, be exercised before taking any unsupervised medicine during the pregnancy because only very little is known about the interactions of various medications in the embryo. The trend to alternative medicines such as the use of a harmless-appearing phyto-therapeutica can have disastrous consequences to the fetus. Ginko biloba, for example, contains a large concentration of cholchicine that is known to be poisonous for dividing cells.
The consumption of alcohol must also be mentioned – it is known with certainty to be a teratogenic substance.

 

Possible mechanisms for the fetal alcohol syndrome are:

The alcohol induced production of superoxide-radicals that oxidize the cell membranes and thereby can cause cytolysis.

The neural ridge cells are disturbed in their emigration.

Alcohol directly hinders cellular adhesion.

Nicotine abuse during the pregnancy mainly leads to deformities if a genetic predisposition is present. Under certain circumstances nicotine is also a neuro-teratogenic substance. Furthermore, nicotine probably has an influence on placental vessels, which in turn can have negative effects on fetal nourishment.

Animal models show that nicotine is a neuro-teratogenic substance. It disturbs the functioning of specific neurotransmitter receptors in the brain, altering their activity. However, because there exists a close relationship between the cholinergic and the catecholaminergic systems in the brain, nicotine affects various nerve-transmitter systems and thus not only on the momentary development in the fetal brain but, further, also on the beginning programming of entire transmitter systems. These changes happeot only in the CNS (central nerve system) but also in the peripheral autonomic nerve system. A consequence is that through deficient reaction to hypoxia the brain also experiences increased hypoxic damage retroactively. Probably some of the SIDS and perinatal difficulties can be derived from this mechanism.

 

In addition to the chemical substances just mentioned, new chemical combinations (200 – 500 substances) to be used as pesticides, cosmetics, etc. are being produced constantly and reliable information about toxicity is not available for many of them.

We must not only speak about the possible toxicity of new substances, but also about the excessive consumption of substances, such as vitamin A that, in themselves, are necessary for life. Of vitamin A one knows that when taken excessively during pregnancy it can lead to damage of the embryo/fetus. Thanks to its excellent effects on severe acne, it is employed in the treatment of this condition and can thereby cause severe damage to the baby, if an unplanned pregnancy occurs

 

Damages that result from excessive consumption of retinol (vitamin A) during a pregnancy:

Missing or deformed ears

Missing jaw or one that is too small

Disorders of jaw formation (split jaw)

Disorders of formation of the aortic arch

Missing thymus

Deformities in the CNS

 

Ionizing radiation and hyperthermia

Ionizing radiation can break chromosomes apart and so alter the DNA structure. This is the reason why unnecessary x-ray examinations during a pregnancy are actively discouraged even though today, thanks to technical advances, the risk of damage to an embryo/fetus by an x-ray examination is estimated to be very small.
It is possible that hyperthermia (from high fever) can have teratogenic effects.

 

The root cause of the disorder in an infection of the embryo/fetus is a primary infection of the mother. The type and severity of the embryonic/fetal disorder is influenced by the severity and mainly the time of pregnancy in which the infection occurs. It is primarily virus infections that show a large teratogenic potency. The most well known example for this is the rubella embryopathy. An infection with the rubella virus in the first month of pregnancy leads to abnormalities in roughly 50% of the embryos. The morbidity sinks in the second month of pregnancy to 25% and in the third, to 15%. After infection in the third or fourth month only hearing loss (damage to the inner ear) is observed. In principle a series of further viral infections during pregnancy can have similar consequences for the embryo/fetus like a rubella infection. The teratogenic potency of most viruses appears to be lower, but this is not known for certain. One does not yet precisely know, for example, the teratogenic potency of a HIV infection, although it is transferred to the still unborn baby

.

 

 

 

 

Fig. 24 Sensibility to infectious and medicinal teratogenic substances

 

 

A
B

Embryonic period
Fetal period


 

 

 

 

Fig.24
During the embryonic period (A) the degree of sensibility to teratogenic substances is much higher than in the subsequent fetal period (B).
The bars above the graph show the vulnerable time for various infectious diseases and other teratogenic conditions: thalidomide (orange), rubella (green), cytomegaly(magenta) and HIV infection (purple).

 

Maternal metabolic diseases

Fundamentally, one distinguishes between pregnancy-specific and pregnancy-unspecific diseases of the mother.
Pregnancy-specific illnesses are frequently summarized under the concept of gestosis. It is therewith emphasized that the pregnancy is the cause of these diseases without going into greater detail concerning the pathogenesis. One distinguishes between early gestosis (occurring during early pregnancy) and late gestosis (in the later stages of pregnancy).

In the pregnancy-unspecific diseases it must be kept in mind that today a coincidence of pregnancy and general diseases is much more frequent than earlier since possibilities for improved therapy of the basic disease not only improve the fertility of the ill woman (e.g., with diabetes mellitus), but also, in almost all cases, permit pregnancies to go full-term.

Malnutrition and starvation of the mother can also lead to damage of the embryo/fetus.

Diabetic embryopathy

The incidence of congenital malformations in infants of diabetic mothers is increased 2 to 4 times compared to general population. These malformations are frequently multiple.

Macroscopic appearance:

Typical congenital malformations reported in diabetic embryopathy:

heart defects: double outlet right ventricle, transposition of the great vessels, tetralogy of Fallot

skeletal defects: caudal regression anomaly agenesis/dysgenesis of caudal vertebrae, hypoplasia of lower limbs; caudal regression has the strongest association with diabetes (occuring more than 200 times more frequently in infants of diabetic mothers than in other infants):

femoral hypoplasia

upper limb defects

amelia

neural tube defects (anencephaly, spina bifida)

Etiology:

Teratogenic effect of diabetes occurs during the critical 2 to 6 weeks after conception. The exact cause of the teratogenic effect is not known. Specialized preconceptional and prenatal care with strict glycemic control reduce the likelihood of congenital defects. There is close correlation between the incidence of congenital malformations and glykosylated hemoglobin HbA1c values. If optimal glycemic control is achieved prior conception and maintained during the gestation, the malformation rates decrease similar to those in the healthy population.

This risk is the same for diabetes mellitus of type 1 and 2.

Peroral antidiabetics are contraindicated during pregnancy.

Diabetic fetopathy

Diabetic fetopathy presents as fetal macrosomia in the 3rd trimestr of gestation.

The accelerated growth (exactly fetal obesity) results from fetal hyperinsulinemia when more glucose and other nutritions reach the fetus.

Clinical signs:

The birthweight is greater than 4000g. Fat is stored preferentionally in the abdominal and interscapular region, abdominal and shoulder circumference is increased. Complications durign labor (shoulder dystocia) are common and there is an increased risk of birth injury and asphyxia.

The early postnatal period complications include:

transient hypoglycemia

transient hypertrophic cardiomyopathy with subaortic stenosis, congestive heart failure

polycythemia

hyperbilirubinemia

respiratory distress syndrome (pulmonary maturity in infants of diabetic mothers is achieved 3 to 4 week later)

Pancreas pathology: hyperplasia of the islet cells. This finding returns to normal within the first few days after birth.

Strict glycemic control during the pregnancy and labor prevents these complications.

Intrauterine growth retardation.

Etiology: surround, factors, and maternal factors; medical, and obstetric complications of pregnancy.

Pathogenesis: the main pathogenetical factor is fetoplacental insufficiency with uteroplacental blood circulation problems as a background. Then developed chronic fetal hypoxia and metabolism changes. IUGR occurs when gas exchange and nutrient delivery to the fetus are not sufficient to allow it to thrive in utero. This process can occur primarily because of maternal disease causing decreased oxygen-carrying capacity (eg, cyanotic heart disease, smoking, hemoglobinopathy), a dysfunctional oxygen delivery system secondary to maternal vascular disease (eg, diabetes with vascular disease, hypertension, autoimmune disease affecting the vessels leading to the placenta), or placental damage resulting from maternal disease (eg, smoking, thrombophilia, various autoimmune diseases).

Evaluation of causative factors for intrinsic disorders leading to poor growth may include a fetal karyotype, maternal serology for infectious processes, and an environmental exposure history.

Intrauterine growth restriction (IUGR) refers to a condition in which an unborn baby is smaller than it should be because it is not growing at a normal rate inside the womb.

Delayed growth puts the baby at risk of certain health problems during pregnancy, delivery, and after birth. They include:

Low birth weight

Difficulty handling the stresses of vaginal delivery

Decreased oxygen levels

Hypoglycemia (low blood sugar)

Low resistance to infection

Low Apgar scores (a test given immediately after birth to evaluate the newborn’s physical condition and determine need for special medical care)

Meconimum aspiration (inhalation of stools passed while in the uterus), which can lead to breathing problems

Trouble maintaining body temperature

Abnormally high red blood cell count

In the most severe cases, IUGR can lead to stillbirth. It can also cause long-term growth problems.

Causes of Intrauterine Growth Restriction

IUGR has many possible causes. A common cause is a problem with the placenta. The placenta is the tissue that joins the mother and fetus, carrying oxygen and nutrients to the baby and permitting the release of waste products from the baby.

The condition can also occur as the result of certain health problems in the mother, such as:

Advanced diabetes

High blood pressure or heart disease

Infections such as rubella, cytomegalovirus, toxoplasmosis, and syphilis

Kidney disease or lung disease

Malnutrition or anemia

Sickle cell anemia

Smoking, drinking alcohol, or abusing drugs

Other possible causes include chromosomal defects in the baby or multiple gestation (twins, triplets, or more).

Classification:

Etiological: maternal, placental, fetal, combined factors.

Clinical types: a) hypotrophic (antenatal hypotrophy): after delivery body weight deficit is seen with normal length and head circumference (pathologic factors influenced during 3 trimester of pregnancy).

b) hypoplastic – after delivery body weight, length, head circumference are less theormal (pathologic factors influenced during II and III trimester of pregnancy).

c) dysplastic – retardation of weight, growth, head circumference are accompanied by dysembriogenesis.

By severity: I (mild), II (moderate), III (severe)

By duration: without complications, with complications and accompanied pathology.

 Perinatal Implications

IUGR causes a spectrum of perinatal complications, including fetal morbidity and mortality, iatrogenic prematurity, fetal compromise in labor, need for induction of labor, and cesarean delivery. In a cohort study in Sweden, a 10-fold increase in late fetal deaths was found among very small fetuses. Fetuses with IUGR who survive the compromised intrauterine environment are at increased risk for neonatal morbidity. Morbidity for neonates with IUGR includes increased rates of necrotizing enterocolitis, thrombocytopenia, temperature instability, and renal failure. These are thought to occur as a result of the alteration of normal fetal physiology in utero.

With limited nutritional reserve, the fetus redistributes blood flow to sustain function and to help in the development of vital organs. This is called the brain-sparing effect and results in increased relative blood flow to the brain, heart, adrenals, and placenta, with diminished relative flow to the bone marrow, muscles, lungs, GI tract, and kidneys. The brain-sparing effect may result in different fetal growth patterns.

In 1977, Campbell and Thoms introduced the idea of symmetric versus asymmetric growth. Symmetrically small fetuses were thought to have some sort of early global insult (eg, aneuploidy, viral infection, fetal alcohol syndrome). Asymmetrically small fetuses were thought to be more likely small secondary to an imposed restriction iutrient and gas exchange. Investigators since then have disagreed on the importance of this differentiation.

Table. Perinatal Events and Outcomes

Event

Asymmetrically SGA

Symmetrically SGA

Appropriate for Gestational Age

Anomalies

14%

4%

3%

Survivors – No serious morbidity

86%

95%

95%

Labor induction (< 36 wk)

12%

8%

5%

Intrapartum high blood pressure (< 32 wk)

7%

2%

1%

Cesarean delivery for nonreassuring fetal heart rate

15%

8%

3%

Intubated in delivery room

6%

4%

3%

Neonatal ICU admission

18%

9%

7%

Respiratory distress syndrome

9%

4%

3%

Intraventricular hemorrhage (grade III or IV)

2%

< 1%

< 1%

Neonatal death

2%

1%

1%

Gestational age at delivery

36.6 wk ± 3.5 wk

37.8 wk ± 2.9 wk

37.1 wk ± 3.3 wk

Preterm birth ≤ 32 wk

14%

6%

11%

The symmetrically grown infants who were SGA had outcomes very similar to the infants who were appropriate for gestational age and very different prognoses than the asymmetrically SGA fetuses, thus reinforcing the concept of using growth parameters for diagnostic and outcome counseling.

The stress that results in IUGR has been postulated to also result in advanced maturation of the fetus, resulting in decreased perinatal morbidity compared with age-matched normally groweonates.

Relative risks associated with IUGR using morbidity and mortality parameters, from the study by Bernstein et al, are as follows:

  • Relative risk of death

  • Relative risk of respiratory distress syndrome

  • Relative risk of intraventricular hemorrhage

  • Relative risk of severe intravascular hemorrhage

  • Relative risk of necrotizing enterocolitis

Increasingly, data support the idea that long-term consequences of IUGR last well into adulthood. Several authors have noted that these individuals have a greater predisposition to develop a metabolic syndrome later in life, manifesting as obesity, hypertension, hypercholesterolemia, cardiovascular disease, and type 2 diabetes.

Authors found that prepubertal individuals who had IUGR at birth show a greater insulin response than prepubertal individuals who had healthy growth as infants. This suggests that the increased risk of type 2 diabetes in adults who had restriction as infants stems, instead, from increased peripheral insulin resistance allowing the brain-sparing physiology to occur but with a permanent reduction in skeletal-muscle glucose transport. This ultimately results in beta-cell burnout. Although the causative pathophysiology is uncertain, the risk of a metabolic syndrome in adulthood is clearly increased among individuals who had IUGR at birth.

Organ system specific morbidity, as a result of growth restriction, is now being evaluated using different animal species and models. Human studies have clearly show organ specific sequelae of IUGR. Kaijser et al, using a large cohort, were able to demonstrate an association between low birth weight and adult risk of ischemic heart disease. Hallan et al demonstrated that adult kidney function is adversely affected by restricted intrauterine growth.

In addition to an increased risk for physical sequelae, mental health problems have been found more commonly in children with growth restriction. In a study performed in Western Australia, Zubrick et al showed that children born below the second percentile for weight were at significant risk for mental health morbidity, academic impairment and poorer general health . Specifically, Tideman et al have shown that impaired fetal circulation, as demonstrated by Doppler studies, in association with IUGR, results in worsened cognitive function in adulthood.

Diagnostic features of the intrauterine growth retardation

1.     Anamnesis: pathologic ethyological factors;

2.     Weight – length coefficient (in mature newborns), trophic index, percentage of the weight deficiency (in premature newborns).

3.     Clinical features: wrinkled and dry skin, desquamation or epidermis, soft tissues pressure is decreased, leak of subcutaneous fat.  

Two newborns with the same term of gestation

Table 1. Grades of the intrauterine growth and development retardation.

Diagnostic features

Normal

I Grade

II Grade

III Grade

 

Weight/length coefficient

60-64

59-55

54-50

<50

mature

Weight deficiency

 

10-20 %

20-30 %

>30 %

mature

Throphic index

0 cm

1 cm

2 cm

3 cm

premature

Body weight deficiency

 

10-20 %

20-30 %

>30 %

premature

Diagnosis and Surveillance

Criteria for diagnosis of IUGR

For most purposes, an EFW at or below the 10th percentile is used to identify fetuses at risk. Importantly, however, understand that this is not a definitive cutoff for uteroplacental insufficiency. A certaiumber of fetuses at or below the 10th percentile may be constitutionally small. In these cases, short maternal or paternal height, the neonate’s ability to maintain growth along a standardized curve, and a lack of other signs of uteroplacental insufficiency (eg, oligohydramnios, abnormal Doppler findings) can be reassuring to the clinician and parents. Customized growth curves for ethnicity, parental size, and gender are in development so as to improve sensitivity and specificity of diagnosing IUGR.

Importantly, review the dating criteria before offering intervention to treat growth restriction in a fetus. If dates are uncertain or unknown, obtaining a second growth assessment over a 2- to 4-week interval may be of value unless strong supportive data or risk factors warrant an immediate change in management plans.

Screening the fetus for growth restriction

Although no single biometric or Doppler measurement is completely accurate for helping make or exclude the diagnosis of growth restriction, screening for IUGR is important to identify at-risk fetuses. Dependent upon the maternal condition associated with IUGR) patients may undergo serial sonography during their pregnancies. An initial scan may be obtained in the middle of the second trimester (at 18-20 wk) to confirm dates, evaluate for anomalies, and identify multiple gestations. A repeat scan may be scheduled at 28-32 weeks’ gestation to assess fetal growth, evidence of asymmetry, and stigmata of brain-sparing physiology (eg, oligohydramnios, abnormal Doppler findings).

Screening for IUGR in the general population relies on symphysis–fundal height measurements. This is a routine portion of prenatal care from 20 weeks’ until term. Although recent studies have questioned the accuracy of fundal height measurements, particularly in obese patients, a discrepancy of greater than 3 cm between observed and expected measurements may prompt a growth evaluation using ultrasound. The clinician should be aware that the sensitivity of fundal height measurement is limited, and he or she should maintain a heightened awareness for potential growth-restricted fetuses. In an unselected hospital population, only 26% of fetuses that were SGA were suggested to be SGA based on clinical examination findings.

Biometry and amniotic fluid volumes

Most ultrasonographic machines report aggregate gestational age measurements and individual parameters. Assessing individual values is important to identify a fetus that is growing asymmetrically. In the presence of normal head and femur measurements, abdominal circumference (AC) measurements of less than 2 standard deviations below the mean appear to be a reasonable cutoff to consider a fetus asymmetric.

Supporting evidence of a hostile intrauterine environment can be obtained by specifically looking at amniotic fluid volumes (AFVs). Authors showed an increased rate of IUGR among fetuses with decreasing maximum vertical pocket (MVP) values. An MVP measurement of larger than 2 cm was associated with an IUGR rate of 5%, an MVP value smaller than 2 cm was associated with an IUGR rate of 20%, and an MVP measurement of smaller than 1 cm was associated with an IUGR rate of 39%. Chamberlain et al concluded that decreased AFI may be an early marker of declining placental function.

Uterine artery Doppler measurement

Both arterial Doppler and venous Doppler have been used in recent literature to support expectant management or delivery of IUGR fetuses and to identify fetuses at risk. Doppler velocimetry has been shown to contribute to the identification of fetuses at risk of IUGR. To follow is an overview of the various Doppler techniques and their clinical applications.

Flow patterns of maternal uterine arteries have been shown to reflect the impact of placentation on maternal circulation. Albaiges et al suggest that a one-stage uterine artery screening at 23 weeks’ gestation is effective in identifying pregnancies that will have poor perinatal outcomes prior to 34 weeks’ gestation related to uteroplacental insufficiency. In their study of 1751 women who were seen at 23 weeks’ gestation for any reason, an abnormal uterine artery study result included bilateral uterine artery notches or a mean pulsatility index (PI) of greater than 1.45 in both arteries.

These criteria were observed in approximately 7% of the population. Within this 7% were 90% of the women who later developed preeclampsia and required delivery before 34 weeks’ gestation, 70% of women with a fetus below the 10th percentile who required delivery before 34 weeks’ gestation, 50% of placental abruptions, and 80% of fetal deaths. Importantly, the negative predictive value for these adverse events prior to 34 weeks’ gestation was higher than 99%.

Authors conducted an overview of published studies on the efficacy of uterine artery Doppler findings as a predictor of preeclampsia, IUGR, and perinatal death.

Although these measurements appear promising, the sensitivity and specificity of uterine artery Doppler measurements is relatively low, and, because no proven interventions are available to prevent IUGR, uterine artery blood flow measurements are not included in routine surveillance protocols.

Umbilical artery Doppler measurement

Iormal pregnancies, umbilical artery (UA) resistance shows a continuous decline; however, this may not occur in fetuses with uteroplacental insufficiency. The most commonly used measure of gestational age–specific UA resistance is the systolic-to-diastolic ratio of flow, which changes from a baseline value to an elevated value with worsening disease. As the insufficiency progresses, end-diastolic velocity is lost and, finally, reversed. The status of UA blood flow corroborates the diagnosis of IUGR and provides early evidence of circulatory abnormalities in the fetus, enabling clinicians to identify the high-risk status of these fetuses and to initiate surveillance

UA Doppler measurements may help the clinician decide whether a small fetus is truly growth restricted.

Among all 138 identified fetuses with an elevated UA systolic-to-diastolic ratio, a 10-fold increase occurred in the rate of admission to and the duration of stay ieonatal ICUs and in the frequency and severity of respiratory distress syndrome. Equally importantly, no fetus with normal Doppler measurements was delivered with documented metabolic acidemia.

Venous Doppler waveforms

Venous Doppler has been measured at the ductus venosus (DV), umbilical vein (UV), inferior vena cava (IVC), and 7 other sites. This provides information about fetal cardiovascular and respiratory responses to its intrauterine environment. These measurements have been reported to become consistently abnormal when a fetus is severely compromised, thus providing evidence in support of an expedited delivery. While the optimal vessel for use for venous Doppler evaluations has not been identified, the knowledge gained from these measurements may provide additional information for the timing of delivery, especially in extremely premature (< 32 wk) gestations.

Three-dimensional ultrasonography

With the introduction and use of obstetrical 3-dimensional ultrasonography, many new applications for this technology are constantly explored. The use of these techniques in the evaluation of the growth-restricted fetus has been evaluated as well. As fetal femur dysplasia is associated with IUGR, Chang et al used 3-dimensional ultrasonography to measure fetal femur volume as a predictor of IUGR. They found a 10th percentile femur volume threshold, which differentiates growth-restricted fetuses from normal fetuses.

Therapeutic options    

Principles of treatment:

1.     Peculiarities of feeding.

2.     Medicine which includes: ferments of the gastro-intestinal tract, adaptogens, immune modulators; parenteral feeding, plasma.

3.     Vitamins.

4.       Antioxidants and anabolics (cartritin, tocopherol).

 

Although multiple therapeutic strategies have been tested to promote intrauterine growth and decrease perinatal morbidity and mortality, limited, if any, success has been achieved in this area. First, behavioral strategies to quit smoking result in a lower rate of low birth weight in babies at term among mothers who smoke. Second, balanced nutritional supplements in undernourished women and magnesium and folate supplementation (in some studies) decrease the rate of SGA newborns. Third, if malaria is the etiologic agent, maternal treatment of malaria can increase fetal growth.

Other options have been considered with a goal of decreasing perinatal morbidity and mortality. In 2003, Say et al reviewed maternal estrogen administration, maternal hyperoxygenation, and maternal nutrient supplementation as therapies for suspected impaired fetal growth. They concluded that evidence to evaluate the risks and benefits of these therapies was lacking. However, they did suggest that further trials of maternal hyperoxygenation seem warranted.

Additional therapies that have been proposed and may warrant further study are maternal hemodilution and intermittent abdominal negative pressure. These are also poorly studied, carry potential maternal and fetal harm, and should be considered experimental.

The only intervention that has been shown to decrease neonatal morbidity and mortality is the administration of steroids to premature fetuses when delivery is anticipated. Bernstein et al described the effect of maternal prenatal glucocorticoid administration in growth-restricted fetuses and found the benefits to be similar to those found in gestational age–matched, normally grown fetuses.

Recently, several studies have questioned the metabolic and cardiovascular response of IUGR fetuses to maternal glucocorticoid administration. Authors found a divergent response between the 2 groups of fetuses as measured by UA Doppler. Almost 45% of these fetuses had transient improvement in their Doppler waveforms, and these fetuses had significantly better outcomes than their counterparts who had no improvement of their waveforms, even transiently. These authors suggest that daily Doppler-based monitoring after the administration of steroids can help delineate a group of fetuses at extremely high risk of acidosis and mortality. They also suggest that further work is needed to elucidate the efficacy of steroids versus immediate delivery in this very high-risk subset of IUGR fetuses.

Management and Delivery Planning

Once IUGR has been detected, the management of the pregnancy should depend on a surveillance plan that maximizes gestational age while minimizing the risks of neonatal morbidity and mortality. This should include steroid administration when at all feasible, based on the monitoring and delivery strategies discussed below (see image below and Harman and Baschat’s integrated fetal testing for IUGR). Fetal lung maturity studies by amniocentesis, in fetuses greater than 34 weeks’, may additionally influence delivery timing.

The goal in the management of IUGR, because no effective treatments are known, is to deliver the most mature fetus in the best physiological condition possible while minimizing the risk to the mother. Such a goal requires the use of antenatal testing with the hope of identifying the fetus with IUGR before it becomes acidotic. Developing a testing scheme, following it, and having a high index of suspicion in this population when results of testing are abnormal is important. The positive predictive value of an abnormal antenatal test result in fetuses with IUGR is relatively high because the prevalence of acidemia and chronic hypoxemia is relatively high.

Although numerous protocols have been suggested for antenatal monitoring of IUGR fetuses, the mainstay includes a weekly nonstress test (NST). Additional modalities may include amniotic fluid volume determination, biophysical profiles, and/or Doppler assessments. Other more complex protocols have been proposed.

Peculiarities of adaptation: Adaptation is long and changed; large percentage and long duration of prime weight loss; long umbilical wound epithelization; decreased neonatal reflexes; low resistance to the illnesses; continued jaundice.

Ambulatory care and prevention

1.     After body weight has beeormalized – observation of pediatrician once a month during one year; neurologist, orthopedist ophthalmologist – once during one year.

2.     Rehabilitation therapy: two courses 2-3 weeks duration

a)     simulative drugs (apical, pentoxyl, metyluracyl, natrii nucleinatis), antioxidants;

b)    vitamins;

c)     aromatic bathes, massage, gymnastics.

3.     Antenatal diagnosis of the intrauterine grows retardation;

Treatment of the pregnant women, pregnancy complications preventions. Preventing Intrauterine Growth Restriction

Although IUGR can occur even when a mother is perfectly healthy, there are things mothers can do to reduce the risk of IUGR and increase the odds of a healthy pregnancy and baby.

Recommendatoins to the mother

          Keep all of your prenatal appointments. Detecting potential problems early allows you treat them early.

  • Be aware of your baby’s movements. A baby who doesn’t move often or who stops moving may have a problem. If you notice changes in your baby’s movement, call your doctor.

  • Check your medications. Sometimes a medication a mother is taking for another health problem can lead to problems with her unborn baby.

  • Eat healthfully.  Healthy foods and ample calories help keep your baby well nourished.

  • Get plenty of rest. Rest will help you feel better and it may even help your baby grow. Try to get eight hours of sleep (or more) each night. An hour or two of rest in the afternoon is also good for you.

  • Practice healthy lifestyle habits. If you drink alcohol, take drugs, or smoke, stop for the health of your baby.

 

Intrauterine infections (TORCH-syndrome).

Toxoplasmosis

Other (Chlamydial infections, congenital syphilis, lysteria infection)

Rubella

Cytomegaloviral (CMV) infection

Herpes simplex viral (HSV) infection

Congenital Infections so-called TORCH infections (toxoplasmosis, other, rubella, Cytomegalovirus infection, and herpes simplex infection). The newborn infant is more vulnerable than the older child to certain infections.  The preterm baby is even less able to withstand infection and more liable to suffer serious complications. Infection of the fetus can result in embryonic death, stillbirth, prematurity, intrauterine growth retardation, developmental abnormalities or congenital disease.

 

Tabl. 2. Effect of Infection on the Fetus and Newborn Infant

Organism or disease

Prematurity

In utero Growth Retardation and Low Birth Weight

Developmental Anomalies

Congenital Disease

Persistant Postnatal Infection

Viruses

Rubella

+

+

+

+

CMV

+

+

+

+

+

HSV

+

+

+

VZV

(+)

+

+

+

Enteroviruses

(+)

+

Hepatitis B

 +

+

+

HIV

(+)

(+)

(+)

+

+

Erythrovirus B19

(Parvovirus B19)

+

Bacteria

Treponema pallidum

+

+

+

Mycobacterium tuberculosis

+

+

+

Listeria monocytogenes

+

+

Campylobacter fetus

+

+

Salmonella typhosa

+

+

B. burgdorferi

+

Parasites

Toxoplasma gondii

+

+

+

+

Plasmodium spp.

(+)

+

+

+

Trypanosoma cruzi

+

+

+

+ = evidence for effect; – = no evidence for effect; (+) = association of effect with infection has been suggested and is under consideration.

Clinical findings are rarely disease specific but include (Tabl. 3):

·                   Low birthweight for gestational age.

·                   Prematurity.

·                   Seizures

·                   Chorio-retinitis

·                   Purpura

·                   Chronic rash

·                   Cerebral calcification

·                   Micro-ophthalmia

·                   Jaundice

·                   Anaemia

·                   Hepatosplenomegaly

·                   Pneumonitis

Tabl 3. Clinical features of congenital infections.

Microorganism

Signs

Toxoplasma gondii

Hydrocephalus, diffuse intracranial calcification, chorioretinitis

Rubella virus

Cardiac defects, sensorineural hearing loss, cataracts

Cytomegalovirus

Microcephalus, periventricular calcification

Herpes Simplex Virus

Vesicular lesions, keratoconjunctivitis

Treponema pallidum

Bullous, macular, and eczematous skin lesions involving the palms and the soles; rhinorrhea, dactylitis and other signs of osteochrondritis and periostitis

Varicella-zoster virus

Limb abnormalities, cicatricial lesions

Erythrovirus B19 (Parvovirus B19)

Diffuse edema (in utero hydrops fetalis)

Human Immunodeficiency virus

Severe thrush, failure to thrive, recurrent bacterial infections, calcification of the basal ganglia

 

Cytomegalovirus (CMV) infection Of all the human herpesviruses described to date, infection with cytomegalovirus (CMV) arguably is the most important cause of morbidity and mortality. Although primary infection with this agent generally is asymptomatic in healthy adults, CMV has emerged in recent years as the most important cause of congenital infection in the developed world, commonly leading to mental retardation and developmental disability.

Causes CMV is a member of the family of 8 human herpesviruses, designated as human herpesvirus 5 (HHV-5). Transmission of CMV infection may occur throughout life, chiefly via contact with infected secretions (saliva, urine, and fomites). Acquisition of CMV in the newborn period is common. Approximately 1% (range 0.5-2.5%) of all newborns are infected congenitally with CMV. Most of these infections occur in infants born to mothers with preexisting immunity and are clinically silent at birth.

The route of congenital infection is presumed to be transplacental. CMV also may be transmitted perinatally, both by aspiration of cervicovaginal secretions in the birth canal and by breastfeeding. More than 50% of infants fed with breast milk that contains infectious virus become infected with CMV.

CLINICAL Congenital CMV infection may be present as Cytomegalic inclusion disease:

·                   Approximately 10% of congenitally infected infants have clinical evidence of disease at birth. The most severe form of congenital CMV infection is referred to as cytomegalic inclusion disease (CID).

·                   CID almost always occurs in women who have primary CMV infection during pregnancy, although rare cases are described in women with preexisting immunity who presumably have reactivation of infection during pregnancy.

·                   CID is characterized by intrauterine growth retardation, hepatosplenomegaly, hematological abnormalities (particularly thrombocytopenia), and a variety of cutaneous manifestations, including petechiae and purpura (ie, blueberry muffin baby). However, the most significant manifestations of CID are those involving the central nervous system. Microcephaly, ventriculomegaly, cerebral atrophy, chorioretinitis, and sensorineural hearing loss are the most common neurological consequences of CID.

·                   Intracerebral calcifications typically demonstrate a periventricular distribution and commonly are encountered by CT scan. The finding of intracranial calcifications is predictive of cognitive and audiologic deficits in later life and predicts a poor neurodevelopmental prognosis.

·                   Overall, 90% of infants who survive symptomatic CID have significant long-term neurological and neurodevelopmental sequelae. Indeed, it has been estimated that congenital CMV may be second only to Down syndrome as an identifiable cause of mental retardation in children.

Asymptomatic congenital CMV

·                     Most infants with congenital CMV infection are born to women who have preexisting immunity to CMV. These infants appear clinically normal at birth; however, even though infants with congenital CMV infection appear well, they may have subtle growth retardation compared to uninfected infants. Although asymptomatic at birth, these infants, nevertheless, are at risk for neurodevelopmental sequelae.

·                     The major consequence of inapparent congenital CMV infection is sensorineural hearing loss. Approximately 15-20% of these infants will have unilateral or bilateral deafness. Routine newborn audiologic screening may not detect cases of CMV-associated hearing loss because this deficit may develop months or even years after delivery.

Acquired CMV infection:

·                     Perinatal acquisition of CMV usually occurs secondary to exposure to infected secretions in the birth canal or via breastfeeding. Most infections are asymptomatic. Indeed, in some reviews, CMV acquired through breast milk has been referred to as a form of natural immunization.

·                     Some infants who acquire CMV infection perinatally may have signs and symptoms of disease, including lymphadenopathy, hepatitis, and pneumonitis, which may be severe on occasion. Interestingly, these infections do not appear to carry any risk of neurological or neurodevelopmental sequelae.

Investigations

·                   Urine culture for CMV (must be in first two weeks of life to confirm congenital infection). Urine must be chilled and transported immediately to the lab on melting ice.

·                   Cord or infant blood for CMV PCR .

·                   Head ultrasound.

·                   Long term: serial audiology and developmental assessment, head circumference, ophthalmology.

TREATMENT  Medical care consists of good nutritional support, vigorous supportive care for end-organ syndromes (particularly pneumonia in immunocompromised patients), and specific antiviral therapy.

Currently, 3 antiviral therapies are approved for prophylaxis and/or therapy of CMV infection. Experience with these agents is limited in children.

Ganciclovir (Cytovene) Pediatric Dose <3 months: Not established; >3 months: Administer as in adults. Adult Dos:

·                   Induction: 5 mg/kg IV bid for 2-3 wk, followed by maintenance dose;

·                   IV maintenance: 5 mg/kg IV qd for the duration of therapy; 2.5 mg/kg/dose IV q8h has been used in some patients with CMV pneumonitis

·                   PO maintenance: 1 g PO q8h limited to HIV-positive individuals ieed of long-term anti-CMV therapy for CMV retinitis

Relatively little information exists concerning the use of GCV in the setting of congenital CMV infection. Because some of the neurological sequelae of congenital CMV, particularly sensorineural hearing loss, progress postnatally, the presentation of results from a recently terminated nationwide collaborative trial are of interest. Intravenous GCV led to improvement or stabilization of hearing in a significant number of 6-month-old infants. Case reports have suggested the efficacy of GCV for acutely ill neonates with life-threatening CMV disease (eg, pneumonia).

Cidofovir (Vistide) — Nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viruses. Pediatric Dose not established.

Foscarnet (Foscavir) — Organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. Pediatric Dose <12 years: Not established; >12 years: Administer as in adults. Adult Dose 90 mg/kg IV q12h infused over a minimum of 1 h for 14-21 d.

 Immunoglobulins — Used as passive immunization for the prevention of symptomatic CMV disease. Have been useful in the control of CMV disease.

Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin, Gammar-P) Adult Dose 500 mg/kg IV qod for 10 doses in combination with GCV, followed by 500 mg/kg IV 2 times per wk for 8 additional doses. Pediatric Dose Not established.

CMV-Ig (CytoGam) — A CMV hyperimmunoglobulin has been shown to decrease incidence of CMV disease when administered posttransplant to high-risk transplant recipients.

Prevention:Until the goal of a CMV vaccine is realized, educating women of childbearing age about the risks of CMV and about how to avoid disease transmission are the only control strategies available.

 

 

Tabl 4. Differential diagnosis of different  congenital infections.

Clinical Sign

Rubella virus

CMV

HSV

Toxoplasma gondii

Treponema pallidum

Streptococcus agalactiae (Grp B) or E. coli

Hepatosplenomegaly

+

+

+

+

+

+

Jaundice

+

+

+

+

+

+

Adenopathy

+

+

+

Pneumonitis

+

+

+

+

+

+

Skin Lesions Petechiae/purpura

+

+

+

+

+

+

Vesicles

+

++

+

Maculopapular exanthems

+

+

++

CNS Lesions
Meningoencephalitis

+

+

+

+

+

+

Microcephaly

++

+

+

Hydrocephalus

+

+

+

++

Intracranial calcifications

++

++

Paralysis

Hearing deficits

+

+

+

Heart lesions
Myocarditis

+

+

+

Congenital defects

++

Bone lesions

++

+

++

Eye Lesions
Glaucoma

++

+

Chorioretinitis or retinopathy

++

+

+

++

+

Cataracts

++

+

+

Optic atrophy

+

+

Microphtalmia

+

+

Uveitis

_

+

+

Conjunctivitis or keratoconjunctivitis

_

_

++

 

Rubella Rubella and congenital rubella syndrome are caused by rubella virus. The major complication of rubella is its teratogenic effects when pregnant women contract the disease, especially in the early weeks of gestation. The virus can be transmitted to the fetus through the placenta and is capable of causing serious congenital defects, abortions, and stillbirths. Congenital rubella occurs in about 90% of women with confirmed rubella infection during the first 20 weeks of pregnancy. 

Pathophysiology: Congenital rubella syndrome Fetal infection occurs transplacentally during the maternal viremic phase, but the mechanisms by which rubella virus causes fetal damage are poorly understood. The fetal defects observed in congenital rubella syndrome are likely secondary to vasculitis resulting in tissue necrosis without inflammation. Another possible mechanism is direct viral damage of infected cells. Studies have demonstrated that cells infected with rubella in the early fetal period have reduced mitotic activity. This may be the result of chromosomal breakage or due to production of a protein that inhibits mitosis. Regardless of the mechanism, any injury affecting the fetus in the first trimester (during the phase of organogenesis) results in congenital organ defects.

CLINICAL Congenital rubella history focuses on the following:

·                   The number of weeks of pregnancy when maternal exposure to rubella occurred (The risk of congenital rubella syndrome is higher if maternal exposure occurs during the first trimester.)

·                   Maternal history of immunization or medical history of rubella

·                   Evidence of intrauterine growth retardation during pregnancy

·                   Manifestations suggestive of congenital rubella syndrome in a child

Physical: The classic triad presentation of congenital rubella syndrome consists of the following:

·                     Sensorineural hearing loss is the most common manifestation of congenital rubella syndrome. It occurs in approximately 58% of patients. Studies have demonstrated that approximately 40% of patients with congenital rubella syndrome may present with deafness as the only abnormality without other manifestations. Hearing impairment may be bilateral or unilateral and may not be apparent until the second year of life.

·                     Ocular abnormalities including cataract, infantile glaucoma, and pigmentary retinopathy occur in approximately 43% of children with congenital rubella syndrome. Both eyes are affected in 80% of patients, and the most frequent findings are cataract and rubella retinopathy. Rubella retinopathy consists of a salt-and-pepper pigmentary change or a mottled, blotchy, irregular pigmentation, usually with the greatest density in the macula. The retinopathy is benign and nonprogressive and does not interfere with vision (in contrast to the cataracts) unless choroid neovascularization develops in the macula.

·                     Congenital heart disease including patent ductus arteriosus (PDA) and pulmonary artery stenosis is present in 50% of infants infected in the first 2 months of gestation. Cardiac defects and deafness occur in all infants infected during the first 10 weeks of pregnancy and deafness alone is noted in one third of those infected at 13-16 weeks of gestation.

Other findings in congenital rubella syndrome include the following:

·                     Intrauterine growth retardation, prematurity, stillbirth, and abortion

·                     Central nervous system abnormalities, including mental retardation, behavioral disorders, encephalographic abnormalities, hypotonia, meningoencephalitis, and microcephaly

·                     Hepatosplenomegaly

·                     Jaundice

·                     Hepatitis

·                     Skin manifestations, including blueberry muffin spots that represent dermal erythropoiesis and dermatoglyphic abnormalities

·                     Bone lesions, such as radiographic lucencies

·                     Endocrine disorders, including late manifestations in congenital rubella syndrome usually occurring in the second or third decade of life (eg, thyroid abnormalities, diabetes mellitus)

·                     Hematologic disorders, such as anemia and thrombocytopenic purpura

Investigations  Mother: Check antenatal serology and perform if result not available (mother may have IgG from infection very early in pregnancy, so documented seropositivity from a previous pregnancy is more reliable). Baby:  Infection of the fetus is CHRONIC, so congenitally infected infants will shed virus at high titre for many months.

·                   Urine and CSF for rubella virus PCR.

·                   White blood cells (cord blood or infant blood) for rubella PCR.

·                   Serum (cord or infant blood) for rubella IgM.

TREATMENT Medical Care: Treatment is supportive. Provide vision screening and hearing screening for asymptomatic newborns.

Treatment of symptomatic newborns is as follows:

·                   Provide careful evaluation of the eyes and ophthalmology referral for babies with corneal clouding, cataract, and retinopathy. Corneal clouding may indicate infantile glaucoma.

·                   Babies with congenital rubella syndrome who develop respiratory distress may require supportive treatment in the intensive care unit.

·                   Hepatosplenomegaly is monitored clinically. No intervention is required.

·                   Patients with hyperbilirubinemia may require phototherapy or exchange transfusions if jaundice is severe to prevent kernicterus.

·                   True hemorrhagic difficulties have not been a major problem; however, IVIG may be considered in infants who develop severe thrombocytopenia. Corticosteroids are not indicated.

·                   Infants who have a rubella-related heart abnormality should be carefully observed for signs of congestive heart failure. Echocardiography may be essential for diagnosis of heart defects.

Contact isolation is required for patients with congenital rubella during hospitalizations because babies are infected at birth and usually are contagious until older than 1 year unless viral cultures have produced negative results.

Drug therapy is currently not a component of the standard of care for rubella.

Further Outpatient Care: Careful follow-up care after discharge from the hospital for patients with congenital rubella syndrome is composed of the following:

·                   Hearing evaluation

·                   Vision screening

·                   Developmental screening

·                   Monitor blood sugar levels and perform thyroid function tests when clinically indicated.

·                   Education and rehabilitation follow-up care are important for children with congenital rubella.

Prophylaxis Care of women who are pregnant and exposed to rubella virus

·                     If a pregnant woman is exposed to rubella virus in the first trimester of gestation, serologic investigation should be performed promptly.

·                     A blood sample should be obtained as soon as possible and tested for rubella antibody. An aliquot of frozen serum should be stored for possible repeated testing later to determine any rise in titers. If the woman has rubella-specific IgG antibody in a properly performed test at the time of exposure, she is immune. It is highly unlikely that her pregnancy will be complicated with congenital rubella syndrome. However, some authorities would retest her in 2-3 weeks because maternal reinfection complicated with congenital rubella syndrome has been very rarely reported in the literature.

·                     If antibody is not detectable in the initial sample, a second serum specimen should be collected 2-3 weeks later and tested concurrently with the first serum sample in the same laboratory. If the second test result is again negative, another serology is warranted 6 weeks after exposure and is tested concurrently with the first specimen. A negative test result in both specimens indicates that infection has not occurred. A positive test result in the second and not the first (seroconversion) indicates recent infection.

·                     The options for a woman exposed to rubella in early pregnancy include pregnancy termination for confirmed infection or administration of IG if termination is not acceptable under any circumstances.

Postexposure prophylaxis during pregnancy

·                   IG administered to a pregnant woman following exposure to rubella is controversial and may not prevent infection of the fetus. The IG may modify the clinical manifestations in the mother without diminishing the viral replication and, therefore, leave the fetus unprotected.

·                   Because infants with congenital rubella syndrome have been born to women who received passive immunoprophylaxis shortly after exposure, rubella IG postexposure prophylaxis in pregnancy is not recommended.

·                   The CDC recommends that IG be used only if a susceptible pregnant woman who has been exposed to rubella will not consider pregnancy termination under any circumstances.

·                   Whether a higher dose of IG given intravenously is useful to prevent congenital rubella syndrome is unknown.

Toxoplasmosis Toxoplasma gondii is a widely distributed protozoan that usually causes an asymptomatic infection in the healthy host. In Fig. 1 and Fig. 2 is shown simplified life-cycle of Toxoplasma gondii. Toxoplasmosis refers to a symptomatic infection by T gondii and can be acute or chronic. Apart from disease in immunocompromised individuals, congenital toxoplasmosis is the most serious manifestation of infection, resulting from vertical transmission of T gondii from a parasitemic mother to her offspring. The severity of disease depends on the gestational age at transmission. Ophthalmologic and neurologic disabilities are the most important consequences of infection and can be present even when the congenital infection is asymptomatic. Congenital toxoplasmosis is a preventable disease. Prepregnancy screening accompanied by serial titers and appropriate counseling in women with initial negative titers would minimize cases.

Fig. 1. Toxoplasma life-cycle.

 

Fig. 2. Toxoplasma life-cycle.

Pathophysiology: T gondii is an obligate intracellular protozoan. It has an intestinal and an extraintestinal cycle in cats but only an extraintestinal cycle in other hosts, including herbivores, omnivores, and carnivores.

Vertical transmission is the cause of congenital toxoplasmosis. The infection can occur in utero or during a vaginal delivery. Transmission by breastfeeding has not been demonstrated. In general, only primary infection during pregnancy results in congenital toxoplasmosis. Infections that occur before but within 6 months of conception may result in transplacental transmission. Intrauterine exposure can result in an uninfected infant or infection that ranges from being asymptomatic to causing stillbirth. Approximately 30% of exposed fetuses acquire the infection, but most of the infants are asymptomatic. The severity of infection in the fetus depends on the gestational age at the time of transmission.

In general, earlier infection is more severe but less frequent. As a consequence, 85% of live infants with congenital infection appear normal at birth. Very early infections (ie, occurring in the first trimester) may result in fetal death in utero or in a newborn with severe central nervous system (CNS) involvement, such as cerebral calcifications and hydrocephalus.

Mortality/Morbidity: Fetuses and immunocompromised individuals are at particularly high risk for severe sequelae and even death. Infection acquired postnatally is usually much less severe.

·                   Newborns with acute congenital toxoplasmosis often die in the first month of life.

·                   Subacute congenital disease may not be observed until some time after birth, when symptoms start to appear.

CLINICAL History: Pediatric toxoplasmosis can be acute or chronic, asymptomatic or symptomatic, and congenital or postnatally acquired.

Congenital toxoplasmosis is the consequence of transplacental hematogenous fetal infection by T gondii during primary infection in pregnant women. Primary infection in an otherwise healthy pregnant woman is asymptomatic in 60% of cases. Symptoms during pregnancy are frequently mild. The most common manifestations are fatigue, malaise, a low-grade fever, lymphadenopathy, and myalgias. Latent Toxoplasma infection with reactivation during pregnancy may lead to congenital infection only in immunocompromised women (most commonly, those with AIDS).

The classic triad of chorioretinitis, hydrocephalus, and intracranial calcifications cannot be used as a strict diagnostic criterion for congenital toxoplasmosis because a large number of cases would be missed. Congenital toxoplasmosis may occur in the following forms:

·                   Neonatal disease

·                   Disease occurring in the first months of life

·                   Sequelae or relapse of previously undiagnosed infection

·                   Subclinical infection

When clinically recognized in the neonate, congenital toxoplasmosis is very severe. Signs of generalized infection are usually present, such as intrauterine growth retardation, jaundice, hepatomegaly, splenomegaly, lymphadenopathy, and a rash. Neurologic signs are severe and always present. They include microcephaly or macrocephaly, bulging fontanelle, nystagmus, abnormal muscle tone, seizures, and delay of developmental milestone acquisition.

·                   Most cases of chorioretinitis result from congenital infection, although patients are often asymptomatic until later in life. Symptoms include blurred vision, scotoma, pain, photophobia, and epiphora. Impairment of central vision occurs when the macula is involved, but vision may improve as inflammation resolves. Relapses of chorioretinitis are frequent but rarely accompanied by systemic signs or symptoms.

·                   Latent toxoplasmosis may reactivate in women with human immunodeficiency virus (HIV) and result in congenital transmission. Congenital toxoplasmosis in the infant with HIV appears to run a more rapid course than in infants without HIV.

Physical:

·                   Lymphadenopathy is the most common form of symptomatic acute toxoplasmosis in immunocompetent individuals.

·                   Patients typically present with painless firm lymphadenopathy that is confined to one chain of nodes, which are most commonly cervical. The suboccipital, supraclavicular, axillary, and inguinal groups may also be involved.

·                   Other physical manifestations include a low-grade fever, occasional hepatosplenomegaly (Fig. 3), and a rash.

·                   Ophthalmologic examination reveals multiple yellow-white cottonlike patches with indistinct margins located in small clusters in the posterior pole.

·                   Characteristically, a focal necrotizing retinitis develops that may atrophy and generate black pigment, or it may be associated with panuveitis. Papillitis is usually indicative of CNS disease. Flare-up of congenitally acquired chorioretinitis is often associated with scarred lesions in proximity to the fresh lesions.

·                   Because of multifocal involvement of the CNS, clinical findings vary widely. They include alterations in mental status, seizures, motor weakness, cranial nerve disorders, sensory abnormalities, cerebellar signs, meningismus, movement disorders, and neuropsychiatric manifestations in patients with immunocompromise.

Fig. 3. Toxoplasma gondii Infections (Toxoplasmosis). Infant girl with congenital toxoplasmosis with hepatosplenomegaly.

 

Investigation of babies born to toxoplasma IgM positive mothers

The following samples will enable search for toxoplasma DNA (by PCR) in baby’s blood, placenta and amniotic fluid.

If suspected after delivery:

·                   Maternal serum for toxoplasma IgG and IgM

·                   Infant serum (red top) for toxoplasma IgG, IgM and infant blood (CPD or EDTA tube) for PCR

·                   Head ultrasound, CT-scan (Fig.4)

·                   CSF for M, C and S, protein, glucose and toxoplasma PCR

·                   Tissue culture (Fig. 5)

Click to see larger picture

Fig. 4. Cranial CT scan of infant born with symptomatic congenital cytomegalovirus infection. Neurological involvement is evident, manifest as ventriculomegaly and periventricular calcifications.

Click to see larger picture

Fig. 5. Toxoplasmosis. Toxoplasma gondii trophozoites in tissue culture.

Treatment

·                   prenatal treatment of the mother in preventing adverse fetal outcomes with spiramycin. If documented fetal infection is noted in the prenatal period (via amniotic PCR), consider treatment with pyrimethamine and sulfadiazine.

·                   Treat infant for clinically, serologically, or maternally apparent disease with pyrimethamine and sulfadiazine for 1 year. Folinic acid should be given to prevent bone marrow suppression. A year of treatment allows the infant to become immunocompetent and will reduce neurologic sequelae compared to a shorter course of treatment. A pediatric infectious disease (ID) consultation should be obtained.

·                   Corticosteroid for ocular disease and CNS infection (high level of CSF protein), add prednisone 1mg/kg/d divided q 12 hours until CSF protein is normal and/or ocular inflammation resolves.

MEDICATION

·                   Sulfadiazine (Microsulfon) Pediatric Dose: Acquired toxoplasmosis: >1 year: 75 mg/kg/d PO once, followed by 50 mg/kg/d for 2-4 wk; Congenital toxoplasmosis: 100 mg/kg/d PO once, followed by 100 mg/kg/d divided q12h for 2-6 mo.

·                   Dapsone (Avlosulfon) Pediatric Dose: >1 month: 1 mg/kg/d PO; not to exceed 25 mg/d.

·                   Clindamycin (Cleocin) Pediatric Dose: 8-20 mg/kg/d PO as hydrochloride (cap) or 8-25 mg/kg/d PO as palmitate (susp) divided tid/qid; not to exceed 1.8 g/d. 20-40 mg/kg/d IV/IM divided tid/qid; not to exceed 4.8 g/d/

·                   Pyrimethamine (Daraprim) Pediatric Dose: 2 mg/kg/d PO divided q12h for 2-4 d initially, then 1 mg/kg/d PO qd or divided q12h for 1 mo; not to exceed 25 mg/d.

·                   Azithromycin (Zithromax) Pediatric Dose: 10 mg/kg as single dose on day 1, not to exceed 500 mg/d; followed by 5 mg/kg on days 2-5, not to exceed 250 mg/d.

·                   Spiramycin (Rovamycine) Pediatric Dose: 50-100 mg/kg/d PO divided bid/qid for 3-4 wk.

·                   Leucovorin (Wellcovorin) — Also called folinic acid. Derivative of folic acid used with folic acid antagonists, such as sulfonamides and pyrimethamine. Pediatric Dose: 5-10 mg PO 3 times/wk

Prevention:

Preventing the infection is particularly important for women who are pregnant and for patients who are seronegative and immunocompromised.

·                   Avoid consuming raw or undercooked meat, unpasteurized milk, and uncooked eggs.

·                   Wash hands after touching raw meat and after gardening or having other contact with soil.

·                   Wash fruits and vegetables.

·                   Avoid contact with cat feces.

·                   To attempt to prevent congenital toxoplasmosis, routine serologic screening of pregnant women has been performed in order to identify fetuses at risk of becoming infected.

Table 3. Prophylaxis to Prevent First Episode and Recurrence of Toxoplasmosis in Children

Prevention of

Indication

First Choice

Alternatives


 

First episode of toxoplasmosis1

Severe immunosuppression and presence of IgG antibody to Toxoplasma

TMP-SMX, 150–750 mg/m2 per day in 2 divided doses, orally, every day


Dapsone (children
≥1 mo of age), 2 mg/kg or 15 mg/m2 (max 25 mg), orally, every day, PLUS pyrimethamine, 1 mg/kg, orally, every day, PLUS leucovorin, 5 mg, orally, every 3 days
Atovaquone, children 1–3 mo and >24 mo of age: 30 mg/kg, orally, every day; children 14–24 mo of age: 45 mg/kg, orally, every day

Recurrence of toxoplasmosis2

Prior toxoplasmic encephalitis

Sulfadiazine, 85–120 mg/kg per day in 2–4 divided doses, orally, every day, PLUS pyrimethamine, 1 mg/kg or 15 mg/m2 (max 25 mg), orally, every day, PLUS leucovorin, 5 mg, orally, every 3 days

Clindamycin, 20–30 mg/kg per day in 3 divided doses, orally, every day, PLUS pyrimethamine, 1 mg/kg, orally, every day, PLUS leucovorin, 5 mg, orally, every 3 days


 

Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-exposed and infected children. MMWR Recomm Rep. 2004;53(RR–14):1–63

1 Protection against toxoplasmosis is provided by the preferred antipneumocystis regimens and possibly by atovaquone. Atovaquone may be used with or without pyrimethamine. Pyrimethamine alone probably provides little, if any, protection (for information about severe immunosuppression, see Table 3.50, p 540).

2 Only pyrimethamine plus sulfadiazine confers protection against Pneumocystis jiroveci pneumonia as well as toxoplasmosis. Although the clindamycin plus pyrimethamine regimen is recommended in adults, this regimen has not been tested in children. However, these drugs are safe and are used for other infections.

 

Herpes Simplex infection Approximately 1500-2000 new cases of neonatal HSV infection are diagnosed each year. Neonatal HSV infection often leads to long-term neurologic impairment and eveeonatal death.

Despite strategies designed to prevent perinatal transmission, the number of cases of neonatal HSV infection continues to rise, mirroring the rising prevalence of genital herpes infection in women of childbearing age.

Etiology HSV is a DNA virus. HSV has 2 subtypes: herpes simplex virus 1 (HSV-1) and HSV-2. Although each is a distinct virus, they share some antigenic components (eg, antibodies that react to one type may “neutralize” the other).

HSV-1 infections were traditionally associated with the oral area (fever blisters), whereas HSV-2 infections occurred in the genital region.

PERINATAL TRANSMISSION OF HSV HSV can be vertically transmitted to the infant during the antenatal, intranatal, or postnatal periods.

Antenatal Five percent of all cases of neonatal HSV infection result from in utero transmission. With primary infection, transient viremia occurs. HSV has a potential risk for hematogenous spread to the placenta and to the fetus. Hematogenous spread can produce a spectrum of findings similar to other TORCH  infections, eg, microcephaly, microphthalmia, intracranial calcifications, and chorioretinitis.

Intranatal Intranatal infection accounts for the majority of infected infants and occurs from passage of the infant through an infected birth canal. Seventy-five to 90% of infants with neonatal HSV are born to asymptomatic mothers who have no history of HSV infection.

Postnatal Postnatal transmission of HSV can occur through contact with infected parents or health care workers.

Clinical findings

·                   Average incubation 6 days; can be up to 20.

·                   Disseminated disease may mimic fulminate sepsis with seizures, jaundice, hepatitis, encephalitis, DIC, or pneumonia. If untreated, up to 90% mortality.

·                   Local mucocutaneous disease may be mild. Conjunctivitis, keratitis, or chorioretinitis can result in vision loss and blindness.

Investigations

·                   Skin vesicles: swab for viral culture and HSV PCR

·                   Swabs from eyes, mouth/nasopharynx for HSV culture.

·                   WBCs (CPD or EDTA tube) for HSV PCR

·                   CSF – cells, protein, glucose, culture, viral culture and HSV PCR.

·                   Head CT/EEG may localise disease but not essential.

·                   Subtype specific (HSV1 and 2) serology may be useful on mother and baby.

·                   Ophthalmic consultation.

Prevention and treatment.

·                   Any active lesions during pregnancy should be cultured to confirm disease. Active disease at delivery mandates C-section. Routine use of PCR to identify asymptomatic shedders is not yet standard of care.

·                   If vaginal delivery occurs over active lesions or >4 hours, begin acyclovir 30 mg/kg/d IV Q8h for 14-21 days. doses as high as 45-60 mg/kg/d divided q8h have been used in full-term infants. Premature infants: 20 mg/kg/d PO/IV divided q12h for 14-21 d.

·                   Infected mother and infant should be kept in contact isolation.

Chlamydial Infections Chlamydia can cause diseases of many systems. The most frequent disease, caused by Chlamydia trachomatis, is a sexually transmitted.

Pathophysiology: C trachomatis is an obligate intracellular bacterium that infects the urethra and cervix. The bacterium usually is spread through sexual activity and can be spread vertically, causing conjunctivitis and pneumonia iewborns. The transmission rate from infected mother to newborn is 50%, causing conjunctivitis (most cases) or pneumonia (10-20%). The incubation period is 1-5 weeks.

CLINICAL History:

·                   Symptoms for pneumonia begin in children aged 1-3 months and for conjunctivitis in children aged 1-2 weeks.

·                   Cough, fever in pneumonia (classic description is afebrile)

·                   Eye discharge, swelling in conjunctivitis

·                   Mother with diagnosed or suspected chlamydial infection during pregnancy

Physical:

·                   Fever, cough, wheezing, and pulmonary crackles in pneumonia

·                   Conjunctival erythema, mucoid discharge, and/or periorbital swelling in conjunctivitis

Lab Studies:

Nonculture tests that detect antigens or deoxyribonucleic acid (DNA) of chlamydia using molecular techniques

·                   Direct immunofluorescent antibody (DFA, MicroTrak), enzyme immunoassay (EIA, Chlamydiazyme), and DNA probes (PACE Gen-Probe) all are approximately 80% sensitive and 95% specific.

·                   Polymerase chain reaction (PCR) and ligase chain reaction (LCR) have sensitivity and specificity approaching 100% but still are very expensive to perform on a routine basis.

Infants with suspected pneumonitis

·                   Perform a nasopharyngeal (NP) swab for chlamydia culture. Currently available rapid tests are not approved for use on NP-derived specimens.

·                   In severe or complicated cases, bronchoalveolar lavage fluid can be sent for chlamydia culture as well. A CBC that demonstrates peripheral eosinophilia in the right clinical situation offers additional supportive evidence for C trachomatous pneumonia.

Infants with suspected chlamydia conjunctivitis

·                   Perform an antigen/DNA detection test and/or chlamydia culture by scraping of palpebral conjunctiva.

·                   If the mother has had documented chlamydial infection during pregnancy that went untreated, treat the infant presumptively, even without confirmation of infection.

TREATMENT

·                   Erythromycin (E.E.S., Eryc, E-Mycin) Newborns with chlamydia conjunctivitis or pneumonia: Erythromycin (base) 50 mg/kg/d PO divided qid for 14 d.

·                   Amoxicillin (Trimox, Amoxil)30-40 mg/kg/d PO divided tid for 7-10 d.

·                   Sulfisoxazole — Less effective than most other regimens. Pediatric Dose: 120-150 mg/kg/d PO divided qid.

Syphilis Syphilis is a communicable disease caused by Treponema pallidum, which belongs to the Spirochaetaceae family.

Pathophysiology: Congenital syphilis is caused by transplacental transmission of spirochetes; the transmission rate approaches 100%. Perinatal death may result from congenital infection in more than 40% of affected, untreated pregnancies. Among survivors, manifestations traditionally have been divided into early and late stages. Manifestations are defined as early if they appear in the first 2 years of life and late if they develop after age 2 years.

Because inflammatory changes do not occur in the fetus until after the first trimester of pregnancy, organogenesis is unaffected. Nevertheless, all organ systems may be involved. With early-onset disease, manifestations result from transplacental spirochetemia and are analogous to the secondary stage of acquired syphilis. Congenital syphilis does not have a primary stage. Late-onset disease is seen in patients older than 2 years and is not considered contagious.

CLINICAL History: Most recognized syphilitic disease in children is congenital. A pregnant woman with syphilis who has not received therapy or who has received inadequate therapy may transmit the infection to the fetus at any clinical stage of the disease.

Early-onset congenital syphilis

·                   Most affected infants are asymptomatic at birth and are identified only by routine prenatal screening. If untreated, symptoms develop within weeks or months. The typical stillborn or highly symptomatic newborn is born prematurely with an enlarged liver and spleen, skeletal involvement, and often pneumonia and bullous skin lesions.

·                   The earliest signs of congenital syphilis may be poor feeding and snuffles (ie, syphilitic rhinitis).

Physical: Early-onset congenital syphilis

·                   Early manifestations of congenital infection are varied and involve multiple organ systems. The most striking lesions affect the mucocutaneous tissues and bones. Mucous patches, rhinitis, and condylomatous lesions are highly characteristic features of mucous membrane involvement in congenital syphilis.

·                   Nasal fluid is highly infectious. Snuffles are followed quickly by a diffuse maculopapular desquamative rash that involves extensive sloughing of the epithelium, particularly on the palms and soles and about the mouth and anus. In contrast to acquired syphilis, a vesicular rash and bullae may develop. These lesions are highly infectious.

·                   Hepatomegaly is reported in almost 100% of cases, and biochemical evidence of liver dysfunction usually is observed.

Late-onset congenital syphilis

·                   Scarring from the early systemic disease causes late manifestations of congenital syphilis.

·                   Manifestations include neurosyphilis and involvement of the teeth, bones, eyes, and the eighth cranial nerve.

Investigations

·                   Peripheral blood counting, liver function tests and syphilis serology on infant blood

·                   Maternal syphilis serology.

·                   CSF for VDRL, cells protein and glucose.

·                   Long bone xrays.

·                   Darkfield microscopy of skin lesions, nasal discharge, placental tissue or amniotic fluid may show spirochaetes (but majority of cases have none of these).

TREATMENT  

·                   Congenital syphilis iewborns: Aqueous crystalline penicillin G is recommended if congenital syphilis is proved or highly suspected. The recommended dosage is 100,000-150,000 U/kg/d IV q8-12h to complete a 10- to 14-day course.

·                   Congenital syphilis in older infants and children: Treat diagnosed infants older than 4 weeks with aqueous crystalline penicillin (200,000-300,000 U/kg/d IV q6h for 10-14 d).

·                   Neurosyphilis: The recommended treatment is aqueous crystalline penicillin G, 200,000-300,000 U/kg/d IM (50,000 U/kg q4-6h) for 10-14 days, followed by a single dose of benzathine penicillin 50,000 U/kg/dose in 3 weekly doses.

Further Outpatient Care:

·                     Follow up congenital syphilis with evaluation at ages 1, 2, 4, 6, and 12 months. Obtaiontreponemal titers at ages 3, 6, and 12 months after conclusion of treatment. Nontreponemal antibody titers should decline by age 3 months and should be nonreactive by age 6 months. Consider retreatment for patients with persistently stable titers, including low titers.

·                     Infants who are treated for congenital neurosyphilis should undergo repeat clinical evaluation and CSF examination at 6-month intervals until their CSF examination result is normal. A positive CSF VDRL result at age 6 months is an indication for retreatment.

Prevention: Indications for syphilis screening include the following:

·                     All women at first prenatal visit and high-risk women again at 28 weeks’ gestation

·                     All women delivering a stillborn infant

·                     All newborns older than 22 weeks’ gestation whose mothers were not screened

Listeria Infection Listeriosis is an infection caused by a gram-positive motile bacterium, Listeria monocytogenes. Listeriosis is relatively rare and occurs primarily in newborn infants, elderly patients, and patients who are immunocompromised.

Pathophysiology: Ingestion of Listeria by pregnant women can result in a flulike illness. Many pregnant women can carry Listeria asymptomatically in their GI tract or vagina. Maternal infection with Listeria can result in chorioamnionitis, premature labor, spontaneous abortion, or stillbirth. Fetal infection can occur via transplacental transmission. Vertical transmission also can occur from mother to infant via passage through an infected birth canal or ascending infection through ruptured amniotic membranes.

Two clinical presentations of neonatal infections occur, early onset (<5 d) and late onset (>5 d). Early-onset neonatal listeriosis usually is associated with sepsis or meningitis. Late-onset neonatal listeriosis frequently presents with purulent meningitis. Listeriosis often involves many organs with microabscesses or granulomas.

Mortality/Morbidity: Early-onset neonatal listeriosis has a 20-30% mortality rate. Late-onset neonatal listeriosis has a 0-20% mortality rate. Hydrocephalus, mental retardation, and other CNS sequelae have been reported in survivors of Listeria meningitis.

CLINICAL

·                   Early-onset neonatal infections (<5 d) begin at the mean age of 1.5 days.

·                   Late-onset neonatal infections (>5 d) begin at the mean age of 14 days.

Physical: Listeriosis presents in the same manner as other more commoeonatal pathogens, such as group B streptococci and Escherichia coli.

·                   Respiratory distress – Tachypnea, grunting, apnea, and retractions

·                   Temperature instability

·                   Poor feeding

·                   Lethargy/irritability

·                   Seizures

·                   Granulomatous rash – Disseminated small pale nodules

Lab Studies:

1.                   Blood culture

2.                   Cerebrospinal fluid culture

3.                   Respiratory tract culture

4.                   Histopathology and culture of rush

5.                   Culture of other infected tissues: (Joint, Pericardial fluid, Pleural fluid, Amniotic fluid, Placenta, Gastric aspirate).

Imaging Studies: CT scan or MRI may be useful to detect abscesses in brain or liver.

TREATMENT Medical Care: Care of a newborn includes antibiotics as well as careful monitoring of the patients temperature, respiratory system, fluid and electrolyte balance, nutrition, and cardiovascular support.

Ampicillin alone or in combination with an aminoglycoside is the therapy of choice. Listeria is not susceptible to cephalosporins of any generation.

Drug Name

Ampicillin (Marcillin, Omnipen, Polycillin, Principen)

Pediatric Dose

Ampicillin dosing based on 25-100 mg/kg/dose slow IV push (higher doses typically used for meningitis)
Gestational age <29 weeks
Postnatal age of 0-28 days: Interval 12 h
Postnatal age of >28 days: Interval 8 h
Gestational age 30-36 weeks
Postnatal age of 0-14 days: Interval 12 h
Postnatal age of >14 days: Interval 8 h
Gestational age 37-44 weeks
Postnatal age of 0-7 days: Interval 12 h
Postnatal age of >7 days: Interval 8 h
Gestational age >44 weeks
All postnatal ages: 6 h

Drug Name

Gentamicin (Garamycin, Gentacidin) — Useful in combination with ampicillin against listeria.

Pediatric Dose

Usual neonatal maintenance dosage for treatment of septicemia or meningitis depends upon gestational and postnatal age
Gentamicieonatal dosing scheme: Loading dose of 4 mg/kg can be given
Maintenance dose: 2.5-3 mg/kg/dose IV over 30 min (consider using 3 mg/kg/dose)
Gestational age <29 weeks
Postnatal age of 0-28 days: Interval 24 h
Postnatal age of >28 days: Interval 24 h (consider using 3 mg/kg/dose)
Gestational age 30-36 weeks
Postnatal age of 0-14 days: Interval 24 h (consider using 3 mg/kg/dose)
Postnatal age of >14 days: Interval 24 h
Gestational age >37 weeks
Postnatal age of 0-7 days: Interval 12 h
Postnatal age of >7 days: Interval 8 h

 

Drug Name

Penicillin G (Pfizerpen) — Can be used as an alternative to ampicillin.

Pediatric Dose

250,000-400,000 U/kg/d IV divided q4-6h

Tratment of TORCH-infection you can find although here.

Prevention: Advice for all persons:

·                   Wash hands, knives, and cutting boards after handling uncooked food.

·                   Cook all meat thoroughly.

·                   Wash all vegetables thoroughly.

·                   Keep raw meats separate from other foods during preparation to avoid cross-contamination.

Advice for pregnant patients or patients with immunocompromised:

·                   Avoid soft cheeses such as feta, Brie, blue cheese, Mexican-style cheese, and Camembert.

·                   Thoroughly reheat leftovers.

·                   Avoid deli foods unless thoroughly heated.

Prognosis: Prognosis is guarded depending on whether meningitis or shock is present. Hydrocephalus, mental retardation, and other CNS sequelae have been reported following meningitis.

HIV Infection in Infants and Children

NIAID has a lead role in research devoted to children infected with HIV, the virus that causes AIDS. NIAID-supported researchers are developing and refining treatments to prolong the survival and improve the quality of life of HIV-infected infants and children.

In this era of antiretroviral therapy, epidemiologic studies such as NIAID’s Women and Infant’s Transmission Study (WITS) are examining risk factors for transmission as well as the course of HIV disease in pregnant women and their babies. Researchers have helped illuminate the mechanisms of HIV transmission, the distinct features of pediatric HIV infection, and how the course of disease and the usefulness of therapies can differ in children and adults.

A Global Problem

According to UNAIDS (The Joint United Nations Programme on HIV/AIDS) at the end of 2003, an estimated 2.5 million children worldwide under age 15 were living with HIV/AIDS. Approximately 500,000 children under 15 had died from the virus or associated causes in that year alone. As HIV infection rates rise in the general population, new infections are increasingly concentrating in younger age groups.

December 2003 UNAIDS/World Health Organization (WHO) worldwide statistics show

  • 700,000 children under age 15 were newly infected with HIV

  • Thirteen percent of all new HIV infections were in children under age 15

  • Three million children in sub-Saharan Africa, the region with the highest number of cases, are living with HIV

More than 95 percent of all HIV-infected people now live in developing countries, which have also suffered 95 percent of all deaths from AIDS. In those countries with the highest prevalence, UNAIDS predicts that, between 2000 and 2020, 68 million people will die prematurely as a result of AIDS. In seven sub-Saharan African countries, mortality due to HIV/AIDS in children under age five has increased by 20 to 40 percent. Life expectancy for a child born in Botswana, the country with the highest HIV prevalence in the world, has dropped below 40 years—a level not seen in that country since before 1950.

The United States has a relatively small percentage of the world’s children living with HIV/AIDS. From the beginning of the epidemic through the end of 2002, 9,300 American children under age 13 had been reported to the Centers for Disease Control and Prevention (CDC) as living with HIV/AIDS. The vast majority of HIV-infected children acquire the virus from their mothers before or during birth or through breast feeding. Because of the widespread use of AZT and other highly active antiretroviral therapy in HIV-infected pregnant women in the United States, only 92 new cases of pediatric AIDS were reported in 2002. More than three times that number are infected with HIV but have not yet developed AIDS.

  • The U.S. city with the highest rate of pediatric AIDS through 2002 was New York City, followed by Miami, Florida, and Washington, DC.

  • The disease disproportionately affects children in minority groups, especially African Americans. Out of 9,300 cases in children under 13 reported to the CDC through December 2002, 59 percent were black/non-Hispanic, 23 percent were Hispanic, 17 percent were white/non-Hispanic, and less than 1 percent were in other minority groups.

New anti-HIV drug therapies and promotion of voluntary testing continue to positively effect the death rate.

Transmission

Almost all HIV-infected children get the virus from their mothers before or during birth or through breastfeeding. In the United States, approximately 25 percent of pregnant HIV-infected womeot receiving AZT therapy have passed on the virus to their babies. The rate is significantly higher in developing countries.

Prior to 1985 when screening of the nation’s blood supply for HIV began, some children as well as adults were infected through transfusions with blood or blood products contaminated with HIV. A small number of children also have been infected through sexual or physical abuse by HIV-infected adults.

Pregnancy and Birth

Most MTCT, estimated to cause more than 90 percent of infections worldwide in infants and children, probably occurs late in pregnancy or during birth. Although the precise mechanisms are unknown, scientists think HIV may be transmitted when maternal blood enters the fetal circulation or by mucosal exposure to virus during labor and delivery. The role of the placenta in maternal-fetal transmission is unclear and the focus of ongoing research.

The risk of MTCT is significantly increased if the mother has advanced HIV disease, increased levels of HIV in her bloodstream, or fewer numbers of the immune system cells-CD4+ T cells-that are the main targets of HIV.

Other factors that may increase the risk are maternal drug use, severe inflammation of fetal membranes, or a prolonged period between membrane rupture and delivery. A study sponsored by NIAID and others found that HIV-infected women who gave birth more than 4 hours after the rupture of the fetal membranes were nearly twice as likely to transmit HIV to their infants, as compared to women who delivered within 4 hours of membrane rupture.

Breastfeeding

HIV also may be transmitted from a nursing mother to her infant. Studies have suggested that breastfeeding introduces an additional risk of HIV transmission of approximately 10 to 14 percent among women with chronic HIV infection. In developing countries, an estimated one-third to one-half of all HIV infections are transmitted through breastfeeding.

WHO recommends that all HIV-infected women be advised about both the risks and benefits of breastfeeding for their infants so they can make informed decisions. In countries where safe alternatives to breastfeeding are readily available and economically feasible, this alternative should be encouraged. In general, in developing countries where safe alternatives to breastfeeding are not readily available, the benefits of breastfeeding in terms of decreased illness and death due to other infectious diseases greatly outweigh the potential risk of HIV transmission.

Preventing Mother-to-Child Transmission

In 1994, a landmark study demonstrated that AZT, given to HIV-infected women who had very little or no prior antiretroviral therapy and CD4+ T-cell counts above 200/mm3, reduced the risk of MTCT by two-thirds, from 25 percent to 8 percent. In the study, AZT therapy was initiated in the second or third trimester and continued during labor, and infants were treated for 6 weeks following birth. AZT produced no serious side effects in mothers or infants. Long-term follow up of the infants and mothers is ongoing.

A few years later, another study found that the risk of transmitting HIV from an HIV-positive mother to her newborn infant could be reduced to 1.5 percent in those women who received antiretroviral treatment and appropriate medical and obstetrical care during pregnancy.

Combination therapies have been shown to be beneficial in treating HIV-infected adults, and current guidelines have been designed accordingly. In HIV-infected pregnant women, the safety and pharmacology of these potent drug combinations need to be better understood, and NIAID is conducting studies in this area.

The AZT regimen is not available in much of the world because of its high cost and logistical requirements. The cost of a short-course AZT regimen is substantially lower, but is still prohibitive in many countries. International agencies are studying whether there may be innovative ways to provide AZT at lower cost, for example, through reductions in drug prices to developing countries or partnerships with industry. As a result, NIAID continues to evaluate other strategies that may be simpler and less costly to prevent MTCT in various settings.

Because a significant amount of MTCT occurs around the time of birth, and the risk of maternal-fetal transmission depends, in part, on the amount of HIV in the mother’s blood, it may be possible to reduce transmission using drug therapy only around the time of birth. NIAID has planned other studies that will assess the effectiveness of this approach as well as the role of new antiretrovirals, microbicides and other innovative strategies in reducing the risk of MTCT of HIV.

Diagnosis

HIV infection is often difficult to diagnose in very young children. Infected babies, especially in the first few months of life, often appear normal and may show no telltale signs allowing for a definitive diagnosis of HIV infection. Moreover, all children born to infected mothers have antibodies to HIV, made by the mother’s immune system, that cross the placenta to the baby’s bloodstream before birth and persist for up to 18 months. Because these maternal antibodies reflect the mother’s but not the infant’s infection status, the test for HIV infection is not useful iewborns or young infants.

In recent years, investigators have demonstrated the utility of highly accurate blood tests in diagnosing HIV infection in children 6 months of age and younger. One laboratory technique, called polymerase chain reaction (PCR), can detect minute quantities of the virus in an infant’s blood. Another procedure allows physicians to culture a sample of an infant’s blood and test it for the presence of HIV.

Currently, PCR assays or HIV culture techniques can identify at birth about one-third of infants who finally and ultimately prove to be HIV infected. With these techniques, approximately 90 percent of HIV-infected infants are identifiable by 2 months of age, and 95 percent by 3 months of age. One innovative new approach to both RNA and DNA PCR testing uses dried blood spot specimens, which should make it much simpler to gather and store specimens in field settings.

Progression of HIV Disease in Children

Researchers have observed two general patterns of illness in HIV-infected children. About 20 percent of children develop serious disease in the first year of life; most of these children die by age 4. The remaining 80 percent of infected children have a slower rate of disease progression, many not developing the most serious symptoms of AIDS until school entry or even adolescence.

The factors responsible for the wide variation observed in the rate of disease progression in HIV-infected children are a major focus of the pediatric AIDS research effort. Study found that maternal factors, including Vitamin A level and CD4+ T-cell counts during pregnancy, as well as infant viral load and CD4+ T-cell counts in the first several months of life, can help identify those infants at risk for rapid disease progression who may benefit from early aggressive therapy.

Signs and Symptoms

Many children with HIV infection do not gain weight or grow normally. HIV-infected children frequently are slow to reach important milestones in motor skills and mental development such as crawling, walking, and talking. As the disease progresses, many children develop neurologic problems such as difficulty walking, poor school performance, seizures, and other symptoms of HIV encephalopathy (a brain disorder).

Like adults with HIV infection, children with HIV develop life-threatening opportunistic infections (OIs), although the incidence of various OIs differs in adults and children.

Toxoplasmosis (a parasitic disease) is seen less frequently in HIV-infected children than in HIV-infected adults, while serious bacterial infections occur more commonly in children than in adults.

Pneumocystis carinii pneumonia (PCP) is the leading cause of death in HIV-infected children with AIDS. PCP, as well as cytomegalovirus disease, usually are primary infections in children, whereas in adults these diseases result from the reactivation of latent infections.

A lung disease called lymphocytic interstitial pneumonitis, rarely seen in adults, occurs more frequently in HIV-infected children. This condition, like PCP, can make breathing progressively more difficult and often results in hospitalization.

Severe candidiasis, a yeast infection that can cause unrelenting diaper rash and infections in the mouth and throat that make eating difficult, is found frequently in HIV-infected children.

As children with HIV become sicker, they may suffer from chronic diarrhea due to opportunistic pathogens.

Children with HIV suffer the usual childhood infections more frequently and more severely than uninfected children. These infections can cause seizures, fever, pneumonia, recurrent colds, diarrhea, dehydration, and other problems that often result in extended hospital stays and nutritional problems.

Treatment

While the basic principles that guide treatment of pediatric HIV infection are the same as for an HIV-infected adult, there are a number of unique scientific and medical concerns that are important to consider in treating children with HIV infection. These range from differences in age-related issues such as CD4+ T-cell counts and drug metabolism to requirements for special formulations and treatment regimens that are appropriate for infants through adolescents. As in adults, treating HIV-infected children today is a complex task of using potent combinations of antiretroviral agents to maximally suppress viral replication.

Researchers are focusing not only on the development of new antiretroviral products but also on the critical question of how to best use the treatments that are currently available, especially in resource-poor nations. Treatment strategy questions should be designed to identify, for example, the best initial therapy, when failing regimens should be modified, and strategies to address the antiretroviral needs of children with advanced disease. Another high priority is the long-term assessment of these strategies to determine sustained antiretroviral benefits as well as to monitor for potential adverse consequences of treatment.

Problems in Families

A mother and child with HIV usually are not the only family members with the disease. Often, the mother’s sexual partner is infected, and other children in the family may be infected as well. Frequently, a parent with AIDS does not survive to care for his or her HIV-infected child.

In the countries hardest hit by the AIDS epidemic, some 14 million children under 15 around the world have been orphaned by AIDS—80 percent of them (11 million) in sub-Saharan Africa alone. The rate is expected to increase. One in three of these orphans is under age five. Communities and extended families are struggling with and often overwhelmed by the vast number of children orphaned by AIDS. Many orphans and other children from families devastated by AIDS face multiple risks, such as forced relocation, violence, living on the streets, drug use, and even commercial sex. Other children suffer because sexuality education and services are not available to them or not effectively communicated to them. Living in a country undergoing political turmoil or can also raise the risk of a child becoming HIV-infected.

In the United States, most children living with HIV/AIDS live in inner cities, where poverty, illicit drug use, poor housing, and limited access to and use of medical care and social services add to the challenges of HIV disease.

One encouraging note is, according to UNAIDS, that where information, training, and services to help prevent HIV infection are made available and affordable, young people are more likely to make use of them than their elders.

Management of the complex medical and social problems of families affected by HIV requires a multidisciplinary case management team, integrating medical, social, mental health, and educational services. NIAID provides special funding to many of its clinical research sites to provide for services, such as transportation, day care, and the expertise of social workers, crucial to families devastated by HIV.

 

References:

1.     Averys neonatology: pathophysiology and management of the newborn / G. B. Avery, M. G. MacDonald, M. M. K. Seshia [et al.]. – 6th ed. – Philadelphia : Lippincott Williams and Wilkins, 2005. – 354 p.

2.     Nelson Textbook of Pediatrics, 19th Edition. – Expert Consult Premium Edition – Enhanced Online Features and Print / by Robert M. Kliegman, MD, Bonita M.D. Stanton, MD, Joseph St. Geme, Nina Schor, MD, PhD and Richard E. Behrman, MD. – 2011. – 2680 p.

3.     Pediatrics / Edited by O.V. Tiazhka, T.V. Pochinok, A.M. Antoshkina/ – Vinnytsa: Nova Knyha Publishers, 2011. – 584 p.

4.     Baschat AA, Galan HL, Ross MG, Gabbe SG. Intrauterine growth restriction. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: Normal and Problem Pregnancies. 6th ed. Philadelphia, PA: Elsevier Saunders; 2012:chap 31. 

5.     Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, June 2003.

6.     Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States, June 2003.

 

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http://www.neonatology.org/neo.clinical.html

 

 

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