Amin J. Barakat, MD, FAAP

Thousands of years ago, when variola (smallpox) virus emerged, it caused illness and deaths among humans across the globe. Although the earliest evidence of skin lesions resembling those of smallpox is found on faces of mummies in Egypt (1570-1085 BCE), the earliest written description of a disease resembling smallpox appeared in China in the fourth century.

Although the technique of variolation (deliberate inoculation of an uninfected person with the smallpox virus to prevent smallpox disease) had been practiced in China, India, parts of Africa and the Middle East before it was introduced into England and North America in the 1720s, it was Edward Jenner, a country doctor in Great Britain, who, by creating the smallpox vaccine, pioneered the modern day concept of vaccination.

 On May 14, 1796, Jenner took fluid from a cowpox blister on the hand of Sarah Nelmes, a dairy maid who had fresh cowpox lesions on her hands and scratched it onto the skin of 8-year-old James Phipps, who had never had cowpox or smallpox. James contracted cowpox; when his fever subsided, Jenner inoculated him with live smallpox, and the child never contracted smallpox.

 The use of vaccination spread rapidly in England; however, the United States was slower in its implementation of the vaccination. Nevertheless, severe smallpox outbreaks in the 1700s helped the public accept vaccination.

In the early 1950s, an estimated 50 million smallpox cases occurred every year throughout the world. The disease killed about 300 million people worldwide in the 20th century.

 The risk of related death was reported to be 30%.

 Thanks to the success of the vaccine, the last natural outbreak of smallpox in the United States occurred in 1949, according to the Centers for Disease Control and Prevention (CDC). On May 8, 1980, the 33rd World Health Assembly declared the world free of smallpox.

Almost 100 years after Jenner, French physician Louis Pasteur pioneered vaccine science by illustrating the phenomenon of attenuation. He demonstrated that disease could be prevented by infecting humans with weakened germs.7 His subsequent work on anthrax and rabies confirmed his hypothesis.

 In 1885, he used a vaccine to successfully prevent rabies in a child who had been bitten by a rabid dog, starting the era of modern immunization.

At its peak in the 1940s and 1950s, poliomyelitis (polio) killed and paralyzed more than half a million people worldwide every year. During the epidemic in the northeastern United States in 1916, more than 27,000 people were reported to have been paralyzed and 6000 died.

 The development of vaccines against polio (the formalin-inactivated poliovirus vaccine [IPV] by Jonas Salk in 1953 and the live-attenuated oral poliovirus vaccine [OPV] by Albert Sabin in 1956) was adopted throughout the United States in 1955 and 1961, respectively.

 Following use of the vaccine, the US incidence of paralytic polio decreased from 13.9 cases per 100,000 in 1954 to 0.8 cases per 100,000 in 1961.

 Because of the polio vaccination, reported cases of wild poliovirus decreased by over 99% since 1988, from an estimated 350,000 cases then to 33 reported cases in 2018, according to the World Health Organization. The polio vaccine saved millions of children worldwide from polio, and according to the CDC, polio was eliminated from the United States in 1979. It was clear that people at risk of infection were those who had never been vaccinated or had not received the recommended doses of the vaccine.

During the 1920s, 100,000 to 200,000 cases of diphtheria (140-150 cases per 100,000) and 13,000 to 15,000 deaths were reported each year.

 These figures dropped dramatically after implementation of a universal childhood vaccination program including diphtheria toxoid beginning in the late 1940s. From 1996 through 2018, 14 cases of diphtheria—an average of less than 1 case per year—were reported in the United States.

In 1912, measles became a nationally notifiable disease in the United States, according to the CDC. In the 1950s, a decade before the measles vaccine became available in 1963, nearly all children got measles by the time they were 15 years old. It is estimated that measles affected 3 million to 4 million people in the United States each year with an estimated 400 to 500 deaths, 48,000 hospitalizations, and 1000 cases of encephalitis. A highly effective vaccination program is the reason measles was eliminated from the United States in 2000.

Reviewing the history of vaccination and showing parents a historical timeline (Figure) are strong tools for convincing them, especially those with vaccination hesitancy, of the safety and efficacy of childhood vaccines in preventing serious illness and death in children, as well as protecting the public.

Although adherence to childhood vaccination scheduled by age 24 months in the United States is high, pediatricians continue to be challenged by vaccine hesitancy. In my pediatric practice, I have presented historical facts regarding pre- and postvaccination morbidity and mortality reports to parents in my prenatal sessions. These presentations persuaded many, if not most, vaccine-hesitant parents to accept vaccination for their children. Having used this method successfully in my 50 years of pediatric practice, I recommend that pediatricians try to make a serious effort to present this information to parents (Table) to convince them that vaccines can safely prevent serious and deadly infections in their children and community.

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2. Willis NJ. Edward Jenner and the eradication of smallpox. 

. 1997;42(4):118-121. doi:10.1177/003693309704200407

3. Henry EH. Experience in Massachusetts and a few other places with smallpox and vaccination. 

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4. Henderson DA. The eradication of smallpox—an overview of the past, present, and future. 

. 2011;29:D7–D9. doi:10.1016/j.vaccine.2011.06.080

6. World Health Assembly, 33. Thirty-third World Health Assembly, Geneva, May 5-23, 1980: verbatim records of plenary meetings, reports of committees. World Health Organization. Accessed August 23, 2021, 

https://apps.who.int/iris/handle/10665/154894

7. Plotkin SA. Vaccines: past, present and future. 

. 2005; 11(suppl 4):S5-S11. doi:10.1038/nm1209

8. Pasteur L, Chamberland C-E. Sur la vaccination charbonneuse. C.R. Acad. Sci. Paris. 1881; 92:1378-1383.

9. Centers for Disease Control and Prevention. Historical Perspectives A Centennial Celebration: Pasteur and the Modern Era of Immunization. 

10. Baicus A. History of polio vaccination. 

l 2012;1(4):108-114. doi:10.5501/wjv.v1.i4.108

11. Strebel PM, Sutter RW, Cochi SL, et al. Epidemiology of poliomyelitis in the United States one decade after the last reported case of indigenous wild virus-associated disease. 

.1992;14(2):568–579. doi:10.1093/clinids/14.2.568

12. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases, 11th Edition (The Pink Book). Updated April 15, 2019. Accessed August 23, 2021. 

http://www.cdc.gov/vaccines/Pubs/pinkbook/downloads/dip.pdf

Articles

Sharing how vaccinations first began and were implemented can be a useful tool in educating families of their importance.

The history of vaccination

A pragmatic and clinically focused approach to these issues should facilitate the pediatrician in their treatment of infants with prenatally detected hydronephrosis.

The use of routine fetal ultrasound has increased the diagnosis of ANH. ANH, which is dilation of the fetal renal collecting system, is one of the most common fetal anomalies, occurring in 1% to 5% of pregnancies.

 However, Hamilton et al reported an incidence of 1% to 2% of pregnancies in the United States, or 40,000 to 80,000 cases annually based on an estimated annual birth rate of 4 million.

 Prenatal ultrasound, which can visualize the kidneys at 12 to 13 weeks’ gestation and identify distinct renal architecture by week 20, has the advantage of allowing follow-up without invasive testing or radiation exposure. Fetal magnetic resonance imaging may be indicated in select cases to further delineate the structural abnormalities of the fetal urinary tract.

ANH may be a sign of underlying severe fetal urinary system anomalies or chromosomal aneuploidies and also may be associated with impaired renal development and fetal renal parenchymal injury.

 ANH may be transient in 50% to 70% of cases. It also may be secondary to ureteropelvic junction (UPJ) obstruction in 10% to 30% of cases, vesicoureteral reflux (VUR) in 10% to 40% of cases, ureterovesical junction (UVJ) obstruction in 5% to 15% of cases, multicystic dysplastic kidney in 2% to 5% of cases, posterior urethral valves (PUV) in 1% to 5% of cases, and other anomalies.

 Due to the increase in the detection of ANH, pediatricians had increased responsibility in administering parental prenatal counseling and pre- and postnatal diagnostic and treatment plans. The rationale for early diagnosis of ANH is to treat urinary tract obstruction and prevent pyelonephritis, renal calculi, loss of renal function, and chronic kidney disease.

Three systems are used to classify the degree of ANH: renal pelvic diameter (RPD), Society for Fetal Urology (SFU) criteria, and urinary tract dilation (UTD) classification. Although not uniformly accepted, the most common method to determine RPD is measurement of the maximum anteroposterior diameter of the renal pelvis in a transverse plane.

 RPD of less than 4 mm at less than 28 weeks’ gestation and less than 7 mm at 28 weeks’ gestation is usually transient and does not usually require postnatal workup or future intervention.

 These authors found that an anteroposterior diameter (APD) of 4 mm or greater before 33 weeks’ gestation or 7 mm or greater after 33 weeks’ gestation was 100% accurate in identifying patients with abnormal renal function or those who might require intervention postnatally. However, many of these patients will demonstrate spontaneous improvement without surgical intervention. Others have classified RPD as mild, moderate, or severe according to specific measurement criteria (Table 1

). An RPD of greater than 10 mm in the second trimester is associated with increased risk for the presence of congenital anomalies of the kidney and urinary tract (CAKUT). However, a clear cutoff value for defining obstruction requiring surgical intervention has not been determined.

In 1993, the SFU proposed a classification based on the appearance of the calices, renal pelvis, and renal parenchyma to determine the grade of ANH (Table 2

). The SFU grading system is probably the most commonly used system of classification for both pre- and postnatal grading of UTD.

In 2014, a multidisciplinary work group proposed a revision to the SFU classification, using “UT dilation” as a common terminology that would lead to a more standardized reporting of abnormal findings. This classification requires more extensive modifiers to determine the level of urinary tract obstruction than the SFU system. In the normal fetus, calyceal dilation is absent, the renal parenchyma has normal thickness and appearance, the ureter is not seen, the bladder is normal, and there is no unexplained oligohydramnios (Table 3

). According to the new UTD system, the renal pelvis is considered to be not dilated if the APD measures less than 4 mm at less than 28 weeks’ gestation, less than 7 mm at 28 weeks’ gestation or greater, and less than 10 mm postnatally. A fetus is considered to be at increased risk of postnatal uropathy if the APD of the renal pelvis is 7 mm or greater at less than 28 weeks’ gestation, or 10 mm or greater at 28 weeks’ gestation or greater, or if there is 1 of the following: dilation of peripheral calyces, abnormal parenchymal thickness, appearance of visibly dilated ureter, abnormal bladder, or the presence of oligohydramnios.

Patients with pathological ANH have high SFU and APD grades, and both grading systems may be used as relatively reliable predictors for the outcome of ANH, including ANH regression and postpartum surgery.

These authors found that the sensitivity and specificity of the SFU and that of the APD grading system are very similar, indicating that both grading systems have a relatively high diagnostic accuracy. However, they noted that the combination of both grading systems seems to have a higher diagnostic value compared with that of each system alone regarding the discrimination of pathological ANH from physiological ANH.

Management of ANH depends on the risk assessment. A fetus categorized as low risk based on ultrasound prior to 32 weeks’ gestation will require only 1 further repeat ultrasound at starting at 32 weeks’ gestation. However, ANH (APD > 4 mm in the second trimester, > 7 mm in the third trimester) requires further follow-up. Findings suspicious of PUV (oligohydramnios, dilated bladder, or bilateral ANH) warrant monitoring every 2 to 4 weeks throughout pregnancy, and any comorbid fetal abnormality also should be investigated.

 If increasing oligohydramnios is seen after 20 weeks’ and before 32 weeks’ gestation, bladder outlet obstruction is suspected and fetal intervention such as vesicoamniotic (VA) shunting may be considered. This will allow for the return of amniotic fluid in an effort to promote fetal lung development. The middle of the second trimester is the ideal time period to offer prenatal intervention.

Fetal intervention of VA shunting may improve postnatal outcome in fetuses with lower urinary tract obstruction who have favorable fetal renal function parameters. Fetal renal function can be evaluated by combining fetal urinary biochemistry profiles with ultrasound characteristics of fetal kidneys according to gestational age.

 Increased levels of sodium, calcium, chloride, β2 microglobulin, and decreased levels of creatinine after 18 weeks’ gestation measured in fetal urine in patients with bilateral obstructive uropathy and oligohydramnios are associated with poor neonatal outcomes and may serve as adjuvants to decide on the need for antenatal intervention.

 reported higher survival in the fetuses receiving VA shunting, whereas Spiro et al

 reported that prenatal interventions do not improve renal function prognosis of patients with oligohydramnios associated with CAKUT.

Because there is no consensus on the postnatal approach to ANH, fetuses with persistent antenatal renal pelvis measurements 7 mm or greater in the third trimester should be investigated postnatally. Because physiologic dehydration of the newborn can lead to underestimation of hydronephrosis, an early normal postnatal ultrasound, if done in the first 72 hours of life, does not preclude the presence of urinary tract abnormality.

 screened 1645 citations, of which 17 studies met inclusion criteria and created a data set of 1308 participants. There was a significant increase in risk of any postnatal pathology per increasing degree of ANH (11.9% for mild, 45.1% for moderate, and 88.3% for severe). The risk of VUR was similar for all degrees of antenatal hydronephrosis.

Most cases of ANH are transient and resolve spontaneously with increasing gestational age or soon after birth. Maayan-Metzger et al found that 97.5% of mild prenatal ANH resolved or remained mild on follow-up, although 80% of the moderate and only 20% of the severe cases improved.

 Barbosa et al showed that 25% of ANH resolved prenatally, including 90%, 75%, and 28% of mild, moderate, and severe ANH cases, respectively.

Because hydronephrosis could be underestimated on an early postnatal ultrasound, newborns with persistent or worsening ANH should be evaluated with a postnatal ultrasound after at least 48 to 72 hours of life. Ultrasound findings (SFU grade 1-2) after 48 to 72 hours of life in patients associated with low risk for postnatal uropathy should be followed up with an ultrasound in 3 to 6 months. If the hydronephrosis improves, longer-term imaging is not necessary, based on the very low risk of progression. Patients with higher-risk (SFU grades 3-4) hydronephrosis should undergo more frequent ultrasounds and, when indicated, a MAG-3 Lasix renal scan to rule out obstruction at the UPJ or UVJ. This allows for the evaluation of both differential renal function and drainage of the dilated collecting system. Consultation with a pediatric urologist or nephrologist should also be considered in these higher-risk patients.

Opinions differ on the indication for VCUG in patients with ANH. Many centers screen all patients with grades 3 to 4 hydronephrosis to look for clinically significant dilating VUR (grade > 3). However, more specific selection criteria for VCUG have been proposed, including ureteral dilation, duplication of the collecting system, and/or renal dysmorphia, which were shown to have the same yield for detection of dilating VUR but with only approximately half as many patients requiring VCUG.

Patients with risk of more severe postnatal uropathy, such as those with suspected PUV, bilateral severe hydronephrosis, or solitary hydronephrotic kidney, should be routinely evaluated with a VCUG and MAG-3 Lasix renal scan during the first 1 to 2 weeks of life to determine renal function, renal drainage, and the possible need for early neonatal surgical intervention versus close serial monitoring with renal function studies and ultrasounds.

 Prophylactic antibiotics may be considered at this stage. Unfortunately, there are not enough data to support strong recommendations in many instances, and some decisions are left to the discretion of the specialist. An algorithm of the postnatal management of ANH is shown in Figure 2.

Urinary tract infection and the use of prophylactic antibiotics

Female gender, uncircumcised males, high-grade UTD, and VUR were found to be independent high-risk predictors of febrile urinary tract infection (UTI) in patients with ANH.

 The benefits of continuous antibiotic prophylaxis in patients with ANH are controversial.

 In a systematic review of the literature, which included 3876 infants, UTI rates in patients with low-grade hydronephrosis were similar regardless of continuous antibiotic prophylaxis status: 2.2% on prophylaxis versus 2.8% not receiving prophylaxis.

 However, when looking at high-grade UTD, a significant decrease in the rate of UTI was seen (14.6% treated vs 28.9% untreated; 

 < .01). The estimated number of patients needed to treat to prevent 1 UTI in those with high-grade UTD was 7.

In a meta-analysis of prenatal UTD in 2008, Lee et al reported a 4%, 14%, 33%, and 40% incidence of UTI in SFU grades of 1 to 4, respectively, which indicated the presence of a linear relationship between the degree of UTD and risk of developing UTI.

 Higher rates of UTI in higher-grade UTD as compared with lower-grade UTD also were reported.

 It appears from these studies that the presence of moderate to severe UTD does place the neonate at risk of UTI. Prophylactic antibiotics may have to be considered to prevent UTI and risk for kidney damage.

Ureteral dilation has shown to be an independent risk factor for UTI.

 Herz et al in a 10-year retrospective experience in patients with prenatally detected UTD, reported the incidence of febrile UTI on prophylactic antibiotics to be 7.9% versus 18.7% without treatment.

 The authors found that ureteral dilation of more than 11 mm in patients not maintained on prophylactic antibiotics afforded a 5-fold higher risk of developing a febrile UTI. They also suggested that continuous antibiotic prophylaxis may play a significant role in reducing the risk of febrile UTI in children with ANH and risk factors (ureteral dilation, high-grade VUR, and UVJ obstruction), but otherwise seems unnecessary. Other reports showed that antibiotic prophylaxis did not reduce the risk of UTI, even in the high-risk groups; however, the authors did not specifically investigate the risk in cases associated with ureteral dilation.

Additionally, in an observational registry from 4 centers, Zee et al were unable to demonstrate an association between UTI and the use of prophylactic antibiotics, presence of VUR, dilated ureter, or renal duplication.

 Only 26% of their 213 patients had SFU grade 3 to 4 hydronephrosis and only 11% had ureteral dilation, 88% of whom were treated with antibiotic prophylaxis. Although the benefit of continuous antibiotic prophylaxis in infants with ANH is not proven, clinicians may decide to use them in patients with ANH associated with other high-risk predictors. Physicians should discuss the rationale of prophylactic antibiotics with the family prenatally and postnatally.

Newborn circumcision is associated with a significantly lower rate of UTI among infant boys with hydronephrosis and should be considered, particularly in newborns with higher risk of infection, including ureteral dilation, PUV, or dilating VUR.

 The evaluation/management of antenatal hydronephrosis needs to be tailored based on risk assessment. The use of routine continuous antibiotic prophylaxis in infants with ANH is controversial; however, it may have to be considered in cases associated with ureteral dilatation or dilating (Grade >3) VUR. Newborn circumcision is also an effective measure to reduce the risk of UTI in males.

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7. Corteville JE, Gray DL, Crane JP. Congenital hydronephrosis: correlation of fetal ultra-sonographic findings with infant outcome. 

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10. Timberlake MD, Herndon CDA. Mild to moderate postnatal hydronephrosis-grading systems and management. 

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Antenatal hydronephrosis (ANH), also referred to as urinary tract dilation, is one of the most confounding challenges to the practicing pediatrician. When dealing with newborns and children with ANH, pediatricians face understanding the significance of the degree of hydronephrosis, risk assessment, prenatal and postnatal management, and the use of prophylactic antibiotics.

Amin J. Barakat, MD, FAAP

Articles

The history of vaccination

A pediatrician’s dilemma: Understanding, diagnosing, and treating antenatal hydronephrosis