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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Congenital and Maternal Syphilis

Stephen W. Leslie ; Ruben Vaidya .

Authors

Affiliations

Last Update: August 17, 2024 .

Continuing Education Activity

Congenital syphilis is caused by transmission of the spirochete Treponema pallidum from mother to fetus, resulting in diverse clinical presentations. Congenital syphilis in a fetus is sometimes associated with a full-term, seemingly healthy infant, but it can also cause prematurity or stillbirth. Rates of congenital syphilis are increasing around the world, and 2022 had the greatest number of cases since 1997.

The diagnosis of congenital syphilis can be difficult due to maternal antibodies in newborns, so the diagnosis is often focused on maternal syphilis. Syphilis serological testing is recommended at the first prenatal visit, at 28 weeks gestation, and at delivery. Screening pregnant patients and treating syphilis as early as possible can decrease significant infant morbidity and mortality.

This activity is designed to provide healthcare professionals with the comprehensive knowledge and skills necessary to effectively manage and prevent syphilis in both pregnant women and their newborns. Participants gain insights into the epidemiology, pathophysiology, clinical manifestations, diagnosis, treatment, and prevention strategies related to congenital and maternal syphilis. This course also emphasizes the pivotal role of an interprofessional team necessary for caring for affected patients and mitigating the impact of congenital and maternal syphilis on maternal and child health outcomes.

Implement appropriate treatments for all pregnant patients with abnormal prenatal testing for syphilis.

Coordinate an interprofessional approach and perinatal monitoring plan for the effective management of congenital and maternal syphilis.

Introduction

Congenital and maternal syphilis is caused by the transmission of the spirochete Treponema pallidum from the mother to the fetus, resulting in a multitude of clinical presentations ranging from asymptomatic healthy babies to premature infants with a wide array of clinical signs and symptoms, at times resulting in stillbirth and perinatal death.[1] The incidence of this disease is rising, with 2022 having the most cases since 1997.[2][3] Congenital and maternal syphilis is a nationally reportable disease, with each case being detailed to the Centers for Disease Control (CDC) by all 50 states. Appropriate prenatal care and early treatment are vital to avoiding the manifestations of congenital syphilis.

Etiology

The causative organism of syphilis was first identified by Fritz Schaudinn and Erich Hoffmann in 1905.[4] Congenital syphilis, like all other forms of the disease, is caused by Treponema pallidum (T Pallidum), which is a motile spirochete that is a helically coiled, corkscrew-shaped bacterium 6 to 15 μm long and 0.1 to 0.2 μm wide.[5] The first recorded outbreak of syphilis was in Europe in 1494 in modern-day Naples, Italy.[6] It is thought to have been brought to Naples by Columbus on his return from the New World. Subsequently, the disease spread throughout Europe.[6] Treponemal bacteria have only recently (2017) been successfully cultured in vitro using rabbit epithelial cells, but humans remain the only known host for T pallidum.[7][8][9]

Missed public health opportunities for reducing maternal syphilis include lack of proper antibiotic treatment despite an early diagnosis (30% to 40%), lack of prenatal care (20% to 30%), failure to perform prenatal syphilis testing (10% to 15%), and late identification of positive serology (10%).[10][11][12][13] As many as two-thirds of patients are lost to follow-up in some parts of the US, leading to preventable complications.[14][12][15][16][17][18]

Adding repeat prenatal syphilis testing early in the third trimester (at or around week 28 of gestation) has proven effective in reducing the incidence of congenital syphilis, especially since women can be infected or reinfected during pregnancy.[19][20] Besides early detection and adequate treatment of both the mother and infant, sexual partners of the mother should be tested and properly treated as well. Syphilis screening is part of the routine standard of care for all pregnant women in the United States, which has been shown to decrease rates of congenital syphilis significantly.[21] Most cases of the disease in neonates are seen in women without proper prenatal care or in those who received inadequate treatment.

Epidemiology

Researchers estimate that congenital syphilis is a complicating factor in about one million pregnancies every year worldwide.[22] Congenital syphilis has largely contributed to infant death and is responsible for 305,000 perinatal deaths around the world annually, making it the second leading cause of global perinatal mortality (prematurity being first).[10][23][24] As syphilis remains an easily treatable disease, most cases of congenital syphilis are seen in women who did not receive proper prenatal care or who received improper treatment.

In the United States, the rate of congenital syphilis peaked at roughly 100 cases per 100,000 live births in 1991, then declined dramatically with 334 total annual cases (8.4 cases per 100,000 live births) in 2012, and since then has steadily increased.[11][25] Since 2012, the incidence of congenital syphilis has been on the rise.[2][3][10][11] Between 2017 and 2022, the incidence rates of maternal and congenital syphilis increased in the US by over 2.5 times (from 87.2 to 280.4 per 100,000 live births, according to the National Center for Health Statistics (NCHS). The annual incidence in the US has significantly increased, with 5,726 cases reported and an annual rate of 77.9 cases per 100,000 live births in 2023.

The incidence of congenital syphilis in the US has increased over 10-fold between 2012 and 2022, with the fastest rate of increase in maternal syphilis being found in women younger than 24 years of age, according to the CDC.[3] This corresponds to a 40% decrease in federal funding in the US for preventive programs for sexually transmitted infections since 2000.[10] This is mirrored by a similar rise in Canada, where the incidence more than doubled between 2016 and 2020.[26][27] Regional distribution of congenital syphilis in the United States varies, with the highest incidence in the South, followed by the West and Midwest, with the lowest incidence in the Northeast.[11]

Significant racial disparity is seen in the incidence of congenital syphilis in the US. In 2014, the CDC reported that congenital syphilis was 10 times more prevalent in mothers who were Black compared to mothers who were White (38.2 versus 3.7 cases per 100,000 births).[28] They also reported a 3-fold higher prevalence in Black mothers compared to Hispanic mothers (38.2 versus 12.2 cases per 100,000 live births).[11] The NCHS reported that the ethnic groups with the greatest rise in incidence of maternal syphilis between 2017 and 2022 were Native Americans, while the lowest increase was in White and Asian Americans.[3]

Globally, the World Health Organization (WHO) has estimated that 7 in 1000 pregnant women have a maternal syphilis infection. This has caused over 200,000 annual neonatal deaths and 1.5 million cases of infected newborns reported worldwide in 2023, with almost two-thirds of all cases being found in Africa.[6][10][26] Without early diagnosis and treatment, up to 40% of pregnant women with syphilis will give birth to stillborn neonates, and 33% will deliver infants of low birth weight.[29][30] Untreated maternal and congenital syphilis costs nearly $310 million yearly.[10][14]

Overall, the worldwide incidence of congenital syphilis increased by 500% between 2011 and 2020.[31] The global rate of congenital syphilis was 473 cases per 100,000 live births in 2020 and 661,000 total cases worldwide, as estimated by the WHO.[32][33] These include 355,000 adverse birth outcomes (clinical or symptomatic congenital syphilis, early fetal demise, low birth weight, neonatal mortality, prematurity, or stillbirths).[33] Despite increasing worldwide prevalence, some countries have essentially eliminated congenital syphilis, including Cuba, Malaysia, Maldives, Sri Lanka, and Thailand.[10][26]

Pathophysiology

In adults, syphilis initiates an infection after local infiltration through subcutaneous tissues to cause a local immune response and establish an initial ulcerative lesion.[6] As the bacteria easily cross the placental barrier, the fetus of an infected mother is likely also to become infected. This may occur at any time during the pregnancy but most often during the third trimester.[10][34]

Congenital syphilis differs from adult disease in that T pallidum is released straight into the bloodstream of the fetus, causing spirochetemia with early fetal spread to most organs, including the bones, kidneys, spleen, liver, and heart. This leads to widespread inflammation throughout these organ systems, resulting in various clinical manifestations.

The placentas in fetuses with maternal syphilis tend to become significantly enlarged beyond normal due to a localized inflammatory response.[35][36][37] In addition to its large size and a general pallor, histological examination of the placenta may exhibit signs of enlarged hypercellular villi, necrotizing funisitis ("barber's pole" appearance), proliferative vascular changes, and acute and chronic villitis.[35]

Over 75% of the neonates born with a placenta heavier than the 90th percentile for the infant's birth weight have been found to have congenital syphilis. This finding is so common that serological testing for syphilis is suggested for all mothers and neonates when placental weight reaches the 90th percentile or higher.[38]

Histopathology

Treponema pallidum is 6 to 15 μm long and 0.1 to 0.2 μm wide.[5] Because of its limited width, it cannot be easily seen by direct microscopic examination and requires darkfield microscopy for visualization.[39] Darkfield microscopy allows visualization of live treponemes, which are active, thin, corkscrew spiral-shaped organisms enveloped by a cytoplasmic membrane and a loosely associated outer membrane that may appear to be moving forward and backward.[39][40] The overall sensitivity of darkfield microscopy in primary syphilis is about 80%.[40] The main advantage of dark-field microscopy is that it can allow a diagnosis even before serological testing becomes positive or where such testing is unavailable.[40][41]

Treponema pallidum may also be visualized using immunofluorescent staining and special silver stains, which also demonstrate the characteristic corkscrew-shaped spiral organisms.[42]

History and Physical

High-risk factors for congenital syphilis include maternal drug abuse, homelessness, incarceration, domestic violence, lack of health insurance, poverty, lower education levels, having sex with multiple partners, as well as failure to receive prenatal care, STD testing, or treatment during pregnancies.[10][28][43][44][45] Mental health issues, cultural factors, social stigma associated with sexually transmitted infections, and lack of monitoring after testing also contribute to an increased risk.[10][46]

Physical findings of maternal syphilis are the same as for any woman of similar age.[14] One of the most common findings is a painless indurated chancre at the site of inoculation (see Image. Primary Syphilis Chancre). Other common findings on physical examination include lymphadenopathy and a maculopapular rash that affects the palms of the hands, the soles of the feet, and possibly the buccal mucosa (see Image. Keratotic Lesions on the Palms).[6] These signs will disappear even without treatment and lead to latent syphilis in 70% of cases but will progress to tertiary syphilis in the remainder.[6][14][44] See StatPearls' companion reference, "Syphilis," for more information.[6]

If a mother tests serologically positive for syphilis, the newborn should receive a careful physical examination looking for any early signs or symptoms of congenital disease as well as a nontreponemal (Venereal Disease Research Laboratory [VDRL] or Rapid Plasma Reagin [RPR]) assay.[14][44] A follow-up examination of the neonate in 3 months is also recommended.[14][44]

While congenital syphilis can cause severe illness and fetal demise, most neonates (70%) born with the disease are asymptomatic at birth.[10][47] If the fetus becomes infected during the second or third trimester, the neonate is typically born without symptoms and may appear healthy.[48] Worse outcomes (prematurity, spontaneous abortion, stillbirths, and perinatal demise) in neonates with congenital syphilis are associated with early transmission of T pallidum to the fetus from the mother during the first trimester.[48]

Symptoms of early congenital syphilis usually will be seen within the first 3 months after birth but may present up to 2 years of age.[10][48] Untreated infants typically begin to show clinical symptoms by 3 months of age. Late congenital syphilis would include those cases that only appear after the infant is 2 years old.[48]

Early symptoms of congenital syphilis in a neonate or infant will most commonly include 1 or more of the following: [6][14][44][49]

The rhinitis produces a copious, persistent white discharge, which is continuous, unresponsive to treatment, and persistent.

The highly contagious discharge contains active spirochetes that can be visualized under darkfield microscopy.

Small red or pink-colored maculopapular lesions may be commonly seen on the back, buttocks, posterior thigh, and especially the palms and the soles of the feet.

If congenital syphilis is not diagnosed early, persistent inflammation may lead to scarring and gumma formation, as well as many other possible symptoms.[50]

Additional clinical findings in congenital syphilis may include any of the following: [6][7][14][44][49][50][51][52][53][54][55][56][57][58][59][60]

Clavicle enlargement (Higoumenakis sign is the enlargement of the sternoclavicular region of the clavicle.)

Eye involvement may include unexplained changes in vision, interstitial keratitis, secondary glaucoma, chorioretinitis, uveitis, and corneal scarring.

Hutchinson teeth (Hypoplastic notched or peg-shaped permanent teeth, usually of the upper central incisors)

Hutchinson triad (Hutchinson teeth, interstitial keratitis, and sensorineural hearing loss) is relatively specific for congenital syphilis.

Pneumonia alba (X-ray findings may include classic, complete opacification of both lungs or a generalized diffuse, fluffy infiltrate.)

Tibial deformities (Anterior bowing or "saber shins" and localized demineralization of the proximal medial tibia [Wimberger sign])

Congenital syphilis that is untreated or undiagnosed during the neonatal period may progress during the first 4 years following birth to a state similar to a severe form of secondary syphilis in adults. Bulging fontanels, cranial nerve palsies, condyloma lata, hepatosplenomegaly, rashes, seizures, and unexplained fevers are typical findings in late congenital syphilis.[6] Untreated neonates may also develop a latent form of the disease. As adults, these patients can progress to develop symptoms of tertiary or neurosyphilis such as nerve-related deafness (otosyphilis), ocular syphilis with visual disturbances possibly resulting in blindness, syphilitic paresis, and tabes dorsalis.[6][53][61][62][63]

Evaluation

Congenital syphilis can be difficult to diagnose at birth as most infants born with the disease are asymptomatic at the time of delivery.[6][44] Maternal IgG antibodies are transferred to the fetus until delivery, which interferes with serological testing of the neonate and makes interpretation of treponemal tests on neonatal serum difficult.[14][44] This effect can persist for 15 months or more, during which time specific treponemal serological testing on the infant is not recommended.[44]

Nontreponemal tests (VDRL or RPR) may be performed on the neonate instead, as they utilize IgM antibodies, which do not cross the placenta.[14][44][64][65] Nontreponemal IgA and IgG maternal antibodies may passively cross the placental barrier, which reduces their sensitivity, but they are still clinically useful.[14][66] If the results are positive, the neonate should be followed by serial nontreponemal testing every 2 to 3 months. Most neonates with elevated titers at birth who are uninfected will normalize their serology by the age of 6 months.[14][44] Persistently elevated nontreponemal titers suggest infection or inadequate treatment.[14][44]

Initial serological testing is focused on the mother. It includes nontreponemal serum assays (RPR or VDRL), which can be used for disease tracking, and treponemal antibody tests—fluorescent treponemal antibody absorption assay (FTA-ABS), T pallidum particle agglutination assay (TPPA), T pallidum hemagglutination assay (TPHA)—which are considered confirmatory.[6][44][53][67]

Maternal screening for syphilis in early pregnancy at the first prenatal visit is of prime importance in preventing congenital syphilis.[6][14][44][68] Standard nontreponemal screening assays for maternal syphilis (VDRL, RPR) require confirmation with an antibody treponemal-specific test, but rapid point-of-care screening tests (see below) can be used to allow immediate treatment for high-risk populations who test positive where follow-up is uncertain and resources are limited.[6][44][53][68][69][70][71][72][73][74]

Routine screening for maternal syphilis with a nontreponemal test (VDRL, RPR) is recommended by the CDC, the American Academy of Pediatrics, the American Association of Family Physicians, the US Preventive Services Task Force, the World Health Organization (WHO), and the American College of Obstetrics and Gynecology during the first prenatal visit.[6][14][44][68]

Patients at higher risk, such as those who live in a geographic area with a high incidence of syphilis (defined by the WHO as an endemic prevalence of 5% or higher), should have additional testing sometime during the pregnancy (28 weeks of gestation is suggested) and at the time of delivery. This is especially important as many women can be infected with syphilis during pregnancy.[6][14][44][75]

Reverse sequence screening for syphilis is now being performed by some laboratories. Standard serological testing has traditionally begun with a nontreponemal test (VDRL, RPR), followed by a treponemal antibody test for confirmation if positive. However, automated treponemal immunoassays have made it reasonable for some laboratories to perform the treponemal test first, followed by the nontreponemal assay for confirmation and quantification. Either method is considered acceptable by the CDC. Which protocol to follow depends on laboratory resources, logistics, and local standards of care.[76]

Rapid point-of-care screening tests for syphilis that provide results in less than 20 minutes are now commercially available, allowing for immediate treatment of pregnant women at risk at their first prenatal visit.[6][77] Most rapid point-of-care tests are antibody-based (treponemal) tests and optimally require confirmation with a nontreponemal assay, although a few combine the two, which is preferred.[6][69][70][71][72][73][74][77]

Rapid screening tests are not intended as a replacement for standard laboratory testing, but they allow for immediate therapy and are suggested for global use in high-risk populations, as well as where the syphilis prevalence rate is elevated, healthcare resources are stretched thin, follow-up is unreliable, and where it is cost-effective.[44][77][78][79][80][81][82][83][84][85][86][87]

The FDA has approved an over-the-counter treponemal antibody test for syphilis that can be performed at home in the US. This is a treponemal antibody test (with a control) on a test strip designed to use just a few drops of blood, and the results are available in about 15 minutes. In clinical trials, this test showed a negative predictive value of 99.5% and a positive predictive value of 93.4%. Like other treponemal antibody tests, once the test becomes positive, it remains that way for life, so patients will require additional nontreponemal testing for confirmation.[88] See the companion StatPearls' reference article on "Point-of-Care Testing."[77]

Ultrasonography may be able to identify intrauterine fetal syphilis starting at 18 weeks of gestational age.[14] Findings include hepatomegaly (80% of cases), anemia (33%), placental enlargement (27%), polyhydramnios (12%), and hydrops fetalis (10%).[14][89][90][91][92][93][94][95][96][97] Various gastrointestinal abnormalities, fetal growth restriction, and increased middle cerebral artery peak systolic velocity (suggesting fetal hydrops) may also be found on prenatal fetal ultrasonography in affected fetuses.[98] Aggressive therapy with IM benzathine penicillin G and IV aqueous penicillin G for 10 to 14 days has been suggested, with some successes reported, but no established standardized protocol exists.[99][100][101] The lack of any abnormal ultrasonographic findings does not preclude a fetal treponemal infection, as 12% to 15% of neonates born with congenital syphilis will have normal prenatal ultrasounds.[14][89][90]

Evaluation of an infant or neonate suspected of possible congenital syphilis is primarily based on the finding of material syphilis (positive serology in the mother) or suspicious clinical findings. Initial workup for an infant born to a woman with reactive nontreponemal and treponemal testing should follow the recommendations of the CDC or the American Academy of Pediatrics.[44][78]

The key diagnostic test is a quantitative nontreponemal serological assay (RPR or VDRL) on the serum of any newborn infant where the mother tests positive for syphilis or where the child is otherwise considered suspicious for having the disease.[44][102] The same nontreponemal test, and preferably the same laboratory, should be used for testing both mother and child sera.[44] The umbilical cord blood should not be used for serological testing for syphilis. Any newborn at risk for congenital syphilis should also be tested for HIV.[44]

The laboratory, histologic, and radiographic abnormalities in a newborn can aid in the diagnosis of congenital syphilis as follows: [6][49][98]

Histologic examination of the placenta and cord for the typical pathological changes and presence of spirochetes.

Long bone radiographs may show findings of pathologic fractures, metaphyseal serration, localized demineralization, and osseous destruction. Moth-eaten lesions in the long bones due to demineralization are highly characteristic of congenital syphilis.[49]

Specific serological treponemal tests include fluorescent treponemal antibody absorption (FTA-ABS), hemagglutination test for antibodies to T pallidum (TPHA), or T pallidum particle agglutination assay (TPPA).

Polymerase chain reaction (PCR) assays, darkfield microscopic examinations, and direct fluorescence antibody testing are not readily available in the US or many other parts of the world, and silver staining is not considered reliable.[6][14][31][103] Nucleic acid amplification tests (NAATs) are available with a sensitivity of 75% to 100%.[14] These tests can be clinically useful, but the FDA currently approves none for use in the US.[14][44] This means that serological testing is the primary diagnostic testing modality for both maternal and congenital syphilis.[6][31][44][53]

The CDC recommends that any woman who has had a fetal demise beyond 20 weeks of gestation receive a serological test for syphilis. They also recommend that no new mother or infant should be permitted to leave the hospital without at least 1 documented serological test result for syphilis recorded for the mother.[44]

Neurosyphilis in neonates and infants is usually asymptomatic. However, up to 60% of neonates born with symptoms of congenital syphilis will also have neurosyphilis.[14][98][104][105]

The diagnosis is made by laboratory evaluation of the cerebrospinal fluid (CSF) in high-risk neonates. These findings include increased protein (>0.15 g/L), elevated cell count (>25 cell/mm 3 ), and a positive VDRL of the CSF.[1][106] CSF VDRL is highly specific (90% specificity) but has a sensitivity of only 50%.[14][98][104][105] For these reasons, some experts have suggested omitting the CSF examination, making the diagnosis based on other evidence, and treating the infant for neurosyphilis regardless.[107] PCR testing is only marginally sensitive (about the same as VDRL), but with a 97% specificity, it may be useful where it is available in the laboratory evaluation of the CSF to help diagnose neurosyphilis.[108][109][110]

Symptomatic neurosyphilis in infants is rare except for patients with untreated congenital syphilis.[7] Symptoms may include bulging fontanelles, cerebral infarctions, cranial nerve palsies, fever, hydrocephalus (progressive), increased cranial circumference, neurodevelopmental delay or regression, papilledema, seizures, visual and optical problems, vomiting, and widening of the cranial suture lines. Pituitary abnormalities may also occur, which would include diabetes insipidus and hypoglycemia.[111][112]

Treatment / Management

Maternal syphilis (syphilis infection in pregnant women) is treatable with 2.4 million units of benzathine penicillin G, which is extremely effective in eliminating congenital syphilis in the fetus, but the optimal dosing regimen and timing have not been definitively established.[11][44][113] A single IM dose of 2.4 million units of benzathine penicillin G administered before the 28th week of gestation has been effective in Africa.[114][115][116][117] However, there is evidence that a second equivalent IM dose of benzathine penicillin G given 1 week later is beneficial, especially if there is any evidence of fetal involvement.[44][115][118][119][120] In general, maternal syphilis should be treated based on the stage of the disease as outlined by the CDC and summarized in StatPearls' companion reference on "Syphilis."[6][44]

Factors that interfere with the early diagnosis and treatment of maternal syphilis include the lack of timely prenatal care, lack of rapid point-of-care tests, inadequate antibiotic supplies, drug dispensing failures, poor monitoring of pregnant women and their partners by the regional healthcare system, logistical delays in receiving the first penicillin dose, poor postnatal care especially within 1 month of delivery, and the low treatment compliance of sexual partners.[10][121][122][123][124] More than a third of maternal syphilis patients with resultant stillbirths will have received no prenatal care.[125]

A fourfold reduction in nontreponemal titers compared to baseline six months following antibiotic therapy for syphilis generally indicates a good response.[126] However, during pregnancy, the lack of such a response by the date of delivery in patients who received antibiotic treatment between 16 and 22 weeks gestation is not associated with any adverse outcomes for the newborn.[126]

In high-risk areas where medical follow-up is uncertain—such as in Tanzania, where 6% of pregnant women have syphilis—it is recommended that pregnant patients who test positive on a rapid point-of-care screening test immediately receive benzathine penicillin G without waiting for any confirmatory testing.[114][115][116][117] Treatment of maternal syphilis with benzathine penicillin is 98% effective at preventing congenital syphilis.[11][114][115][116][127]

For latent infections or when the duration of the syphilitic infection is unknown, 3 weekly IM doses of 2.4 million units of benzathine penicillin G are recommended.[14][44] Any delay in therapy of 10 days or more requires complete retreatment.[14][44]

In cases of penicillin-allergic mothers, testing to determine the extent of the allergy and desensitization is recommended, as it is the most effective treatment for maternal syphilis.[44] Many patients labeled as penicillin allergic may have only a mild intolerance.

Maternal reinfection or therapeutic failure is suggested by a fourfold or greater increase in a nontreponemal (VDRL, RPR) assay titer maintained for at least 2 weeks after antibiotic treatment.[44] As these nontreponemal titers tend to increase right after antibiotics are given, a follow-up serological assay should wait until about 2 months after therapy is completed.[44]

Treatment of the neonate with congenital syphilis depends on the diagnostic likelihood of the disease. Various healthcare organizations and medical societies may have slightly different recommendations.

A summary of the 2021 guidelines from the CDC is as follows: [1][44]

Proven or Highly Likely Neonatal Disease

This applies to infants where the mother is positive serologically with both a treponemal test and a nontreponemal assay, PLUS any of the following:

The neonate's serum has 4 times or greater nontreponemal titer (VDRL or RPR) than the mother's serum level at delivery.

Positive identification of T pallidum by darkfield microscopy, silver staining, or PCR of bodily fluids, lesions, or the placenta.

Additional Recommended Tests: