Sandbox:Reddy 2

Overview

Congenital Syphilis is caused by Treponema pallidum, its transmitted to the fetus in utero from an infected mother via the placenta. The severity of the disease is dependent on the stage of maternal infection and the duration of exposure to the fetus. Transmission is typically in the second trimester and the highest rates of transmission are seen in women with primary syphilis. The rates of transmission decrease with the increasing duration of the maternal infection, as the concentration of spirochetes in the blood stream decreases. Syphilis infection to the fetus in utero can result in stillborn, miscarriage and a live birth with severe manifestations of hydrops. Prenatal screening for syphilis during the first trimester is recommended to all pregnant women and adequate treatment with penicillin prevents the transmission to the fetus.

Historical Perspective

• In the 19th century congenital syphilis was believed to be transmitted during conception by the father’s sperm, during delivery in the birth canal, or from infected milk or breasts.
• In 1905, Schaudinn and Hoffmann identified Spirochaeta pallida.
• Transplacental transmission from an asymptomatic infected mother was first described in 1906.
• In 1943, Lentz and Ingraham reported penicillin as treatment for congenital syphilis.
• In 2006, the WHO launched a global effort to eliminate congenital syphilis.

Classification

Congenital Syphilis is classified based on the timing of appearance of signs and symptoms into:

• Early congenital Syphilis: If the signs and symptoms are identified in children aged less than 2 years. It is usually diagnosed in new born or in the first few weeks after birth.
• Late congenital Syphilis: If the signs and symptoms of the disease are identified in children aged more than 2 years. The signs are usually non-specific and more than half the children are asymptomatic. They can present with interstitial keratitis, eighth nerve deafness or clutton's joints.
• Stigmata: These are the scars resulting from early or late congenital syphilis. The features of stigmata in early congenital syphilis include saddle nose deformity, Hutchinson's teeth, rhagades, choriod scarring and onychia. Stigmata secondary to late congenital syphilis include perforation of the palate, corneal opacities, optic atrophy and periosteal changes of tibia.

Causes

The causative pathogen for Congenital syphilis Treponema pallidum.

Pathophysiology

Pathogenesis

• Transmission to the fetus is transplacental, it can also occur during delivery in the presence of maternal genital lesions.
• The risk of transmission to the fetus is dependent on the stage of the maternal disease(dependent on the spirochete concentration in the blood stream) and the duration of exposure to the fetus in utero.
• The risk of vertical transmission of syphilis from an infected untreated mother decreases as maternal disease duration progresses: transmission risk of 70–100% for primary syphilis and 40% for early latent syphilis to 10% for late latent disease. The variation in the percentages with the duration of infection is because the concentration of spirochetes in the blood stream decrease with the duration of maternal syphilis infection.
• Kassowitz's law describes the an inverse relationship of interval between the disease and pregnancy. Longer the interval between infection and pregnancy more benign is the outcome.
• Transmission of infection typically takes place between the 16th and 28th week of pregnancy, however the transmission can be as early as the first trimester of pregnancy.</nowiki><ref name="pmid17675391">{{cite journal| author=Zhou H, Chen XS, Hong FC, Pan P, Yang F, Cai YM et al.| title=Risk factors for syphilis infection among pregnant women: results of a case-control study in Shenzhen, China. | journal=Sex Transm Infect | year= 2007 | volume= 83 | issue= 6 | pages= 476-80 | pmid=17675391 | doi=10.1136/sti.2007.026187 | pmc=2598725 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17675391 }} </ref><ref name="pmid15247352">{{cite journal| author=Hook EW, Peeling RW| title=Syphilis control--a continuing challenge. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 2 | pages= 122-4 | pmid=15247352 | doi=10.1056/NEJMp048126 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15247352 }} </ref><ref name="pmid16205297">{{cite journal| author=Buchacz K, Greenberg A, Onorato I, Janssen R| title=Syphilis epidemics and human immunodeficiency virus (HIV) incidence among men who have sex with men in the United States: implications for HIV prevention. | journal=Sex Transm Dis | year= 2005 | volume= 32 | issue= 10 Suppl | pages= S73-9 | pmid=16205297 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16205297 }} </ref><ref name="pmid25514173">{{cite journal| author=Solomon MM, Mayer KH| title=Evolution of the syphilis epidemic among men who have sex with men. | journal=Sex Health | year= 2015 | volume= 12 | issue= 2 | pages= 96-102 | pmid=25514173 | doi=10.1071/SH14173 | pmc=4470884 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25514173 }} </ref><ref name="pmid24927712">{{cite journal| author=Hakre S, Arteaga GB, Núñez AE, Arambu N, Aumakhan B, Liu M et al.| title=Prevalence of HIV, syphilis, and other sexually transmitted infections among MSM from three cities in Panama. | journal=J Urban Health | year= 2014 | volume= 91 | issue= 4 | pages= 793-808 | pmid=24927712 | doi=10.1007/s11524-014-9885-4 | pmc=4134449 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24927712 }} </ref><ref name="newell">Newell, J., et al. "A population-based study of syphilis and sexually transmitted disease syndromes in north-western Tanzania. 2. Risk factors and health seeking behaviour." Genitourinary medicine 69.6 (1993): 421-426.</ref>
• Inadequate antenatal care
• Multiple sexual partners
• Prostitution
• Illicit drug use
• Unprotected sex
• Residence in highly prevalent areas
• HIV infection
• Presence of other STIs
• Previous history of STIs
• Intravenous drug use
• Health care professionals who are predisposed to occupational risk
• Low socioeconomic status

Screening

Effective prevention and detection of congenital syphilis depends on the identification of syphilis in pregnant women and screening is a key component to decrease the incidence of congenital syphilis. The recommendations for screening are as follows:

	Screening Recommendations
Timing of Screening	Test all pregnant women at the first prenatal visit.
Screening Tests	Nontreponemal tests commonly used for initial screening include: Venereal Disease Research Laboratory (VDRL) Rapid Plasma Reagin (RPR) Confirmatory tests include: Fluorescent treponemal antibody absorbed (FTA-ABS) Treponema pallidum particle agglutination (TPPA)
High Risk Population	Most organizations recommend testing high-risk women again during the third trimester and at delivery. Groups at increased risk include: Uninsured women Women living in poverty Sex workers Illicit drug users Those diagnosed with other sexually transmitted diseases (STDs) Other women living in communities with high syphilis morbidity

Epidemiology, Demographics

Incidence

• It is estimated that every year 2 million pregnant women are infected with syphilis every year.
• In 2005, WHO reported that 460,000 abortions or still birth and 270,000 cases of congenital syphilis every year can be attributed to maternal syphilis.
• The incidence of congenital syphilis in United States in the year 2014 is 11.6 cases per 100,000 live births. The incidence of congenital syphilis has increased when compared to the numbers from 2008 to 2012 and the change is attributed to the increase in the number of women with primary and secondary syphilis.

Race

• Congenital syphilis is ten times and three times more prevalent in black population compared to whites and Hispanics respectively.

Natural History, Complications and Prognosis

Natural History

Syphilis is a sexually transmitted disease and is prevalent in high risk population. Women with syphilis infection can transmit the infection to the fetus in utero resulting in a wide spectrum of outcomes. The risk of transmission is higher in pregnant women who do not undergo regular antenatal screening or in women who are untreated or adequately treated during the period of gestation. The risk of transmission to the fetus is dependent on the stage of syphilis infection in the mother (primary, secondary, tertiary or latent), duration of maternal infection and the exposure to fetus in utero. The transmission of infection typically occurs during the second trimester but early transmission also occurs. Syphilis can complicate the outcome of pregnancy and is dependent on the severity of infection in the fetus, severe infection has adverse outcomes in the new born.<ref name="pmid6340889">{{cite journal| author=Charles D| title=Syphilis. | journal=Clin Obstet Gynecol | year= 1983 | volume= 26 | issue= 1 | pages= 125-37 | pmid=6340889 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6340889 }} </ref><ref name="QinFeng2014">{{cite journal|last1=Qin|first1=Jia-Bi|last2=Feng|first2=Tie-Jian|last3=Yang|first3=Tu-Bao|last4=Hong|first4=Fu-Chang|last5=Lan|first5=Li-Na|last6=Zhang|first6=Chun-Lai|last7=Yang|first7=Fan|last8=Mamady|first8=Keita|last9=Dong|first9=Willa|title=Risk Factors for Congenital Syphilis and Adverse Pregnancy Outcomes in Offspring of Women With Syphilis in Shenzhen, China|journal=Sexually Transmitted Diseases|volume=41|issue=1|year=2014|pages=13–23|issn=0148-5717|doi=10.1097/OLQ.0000000000000062}}</ref>

Complications

• Severe infection in the fetus can result in spontaneous abortion, stillbirth, non-immune hydrops, intrauterine growth restriction, and perinatal death, and serious sequelae in liveborn infected children.<ref name="pmid24275265">{{cite journal| author=Cohen SE, Klausner JD, Engelman J, Philip S| title=Syphilis in the modern era: an update for physicians. | journal=Infect Dis Clin North Am | year= 2013 | volume= 27 | issue= 4 | pages= 705-22 | pmid=24275265 | doi=10.1016/j.idc.2013.08.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24275265 }} </ref>

Prognosis

• Adequate treatment of infected mother during the period of gestation can prevent the transmission of disease significantly and treatment of the mother with one dose of pencillin is proven to improve outcomes in the fetus.<ref name="pmid12232835">{{cite journal |vauthors=Watson-Jones D, Gumodoka B, Weiss H, Changalucha J, Todd J, Mugeye K, Buvé A, Kanga Z, Ndeki L, Rusizoka M, Ross D, Marealle J, Balira R, Mabey D, Hayes R |title=Syphilis in pregnancy in Tanzania. II. The effectiveness of antenatal syphilis screening and single-dose benzathine penicillin treatment for the prevention of adverse pregnancy outcomes |journal=J. Infect. Dis. |volume=186 |issue=7 |pages=948–57 |year=2002 |pmid=12232835 |doi=10.1086/342951 |url=}}</ref>
• In newborns and infants with congenital syphilis treatment with penicillin has a good prognosis with normal development.<ref name="pmid21639965">{{cite journal| author=Caddy SC, Lee BE, Sutherland K, Robinson JL, Plitt SS, Read R et al.| title=Pregnancy and neonatal outcomes of women with reactive syphilis serology in Alberta, 2002 to 2006. | journal=J Obstet Gynaecol Can | year= 2011 | volume= 33 | issue= 5 | pages= 453-9 | pmid=21639965 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21639965 }} </ref>

Diagosis

History and Symptoms

A combination of maternal risk factors and symptoms in the baby are essential to suspect congenital syphilis. The most common symptoms in the new born include: <ref name="pmid3288424">{{cite journal| author=Wendel GD| title=Gestational and congenital syphilis. | journal=Clin Perinatol | year= 1988 | volume= 15 | issue= 2 | pages= 287-303 | pmid=3288424 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3288424 }} </ref><ref name="pmid16649151">{{cite journal| author=Kremenová S, Zákoucká H, Kremen J| title=[Issues of congenital syphilis in the past twenty years. II. Clinical picture]. | journal=Klin Mikrobiol Infekc Lek | year= 2006 | volume= 12 | issue= 2 | pages= 51-7 | pmid=16649151 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16649151 }} </ref>

• Skin rash occurs in 70% of affected cases
• Yellowish discoloration of the skin
• Abdominal distension
• Generalized edema
• Irritability
• Low birth weight
• Failure to thrive
• Fever
• Difficulty breathing

Late Syphilis: It is diagnosed in children aged greater than 2 years. The symptoms are non specific.

Physical Examination

The physical examination findings suggestive of congenital syphilis include:<ref name="EwingRoberts1985">{{cite journal|last1=Ewing|first1=C I|last2=Roberts|first2=C|last3=Davidson|first3=D C|last4=Arya|first4=O P|title=Early congenital syphilis still occurs.|journal=Archives of Disease in Childhood|volume=60|issue=12|year=1985|pages=1128–1133|issn=0003-9888|doi=10.1136/adc.60.12.1128}}</ref>

• Vesiculobullous or maculopapular rash occurring on the palms and soles is present in 70% of the children with congenital syphilis. Other patterns of rash such as vesiculobullous lesions, condylomata lata lesions, annular lesions, and erythema multiforme-like targetoid lesions are present in affected infants.<ref name="FerreiraCorreia2016">{{cite journal|last1=Ferreira|first1=Sara Tavares|last2=Correia|first2=Cátia|last3=Marçal|first3=Monica|last4=Tuna|first4=Madalena Lopo|title=Skin rash: a manifestation of early congenital syphilis|journal=BMJ Case Reports|year=2016|pages=bcr2016216148|issn=1757-790X|doi=10.1136/bcr-2016-216148}}</ref>
• Low birth weight with signs of prematurity
• Nonimmune hydrops : It is characteristic of congenital syphilis and the features of non-immune hydrops include ascites, pericardial effusion, pleural effusion and skin edema, however Rh incompatability should be ruled out as a cause of hydrops.<ref name="pmid8822333">{{cite journal| author=Barron SD, Pass RF| title=Infectious causes of hydrops fetalis. | journal=Semin Perinatol | year= 1995 | volume= 19 | issue= 6 | pages= 493-501 | pmid=8822333 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8822333 }} </ref>
• Jaundice
• Hepatosplenomegaly
• Rhinitis
• Lympadenopathy
• Pseudoparalysis of an extremities

Laboratory Findings

Prenatal Diagnosis

• Detection of IgM antibodies aganist T.pallidum in the blood collected by chordocentesis.<ref name="pmid1923218">{{cite journal |vauthors=Wendel GD, Sánchez PJ, Peters MT, Harstad TW, Potter LL, Norgard MV |title=Identification of Treponema pallidum in amniotic fluid and fetal blood from pregnancies complicated by congenital syphilis |journal=Obstet Gynecol |volume=78 |issue=5 Pt 2 |pages=890–5 |year=1991 |pmid=1923218 |doi= |url=}}</ref><ref name="pmid26753496">{{cite journal| author=Park JY, Han GH, Kwon DY, Hong HR, Seol HJ| title=Prenatal diagnosis of congenital syphilis presenting with transient pleural effusion in the fetus: a case report and rising incidence of congenital syphilis in South Korea. | journal=Clin Exp Obstet Gynecol | year= 2015 | volume= 42 | issue= 6 | pages= 822-4 | pmid=26753496 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26753496 }} </ref>
• PCR of the amniotic fluid to detect the T. pallidum DNA.<ref name="MullerEwert2006">{{cite journal|last1=Muller|first1=M|last2=Ewert|first2=I|last3=Hansmann|first3=F|last4=Tiemann|first4=C|last5=Hagedorn|first5=H J|last6=Solbach|first6=W|last7=Roider|first7=J|last8=Nolle|first8=B|last9=Laqua|first9=H|last10=Hoerauf|first10=H|title=Detection of Treponema pallidum in the vitreous by PCR|journal=British Journal of Ophthalmology|volume=91|issue=5|year=2006|pages=592–595|issn=0007-1161|doi=10.1136/bjo.2006.110288}}</ref>
• Antenatal ultrasound is commonly done and the findings suggestive of congenital syphilis include: hydrops fetalis characterised by scalp oedema, placental thickening, serous cavity effusion, and polyhydramnios. Other additional findings inlcude hepatosplenomegaly, placentomegaly, non-continuous gastrointestinal obstruction and dilatation of the small bowel.<ref name="pmid9565220">{{cite journal |vauthors=Levine Z, Sherer DM, Jacobs A, Rotenberg O |title=Nonimmune hydrops fetalis due to congenital syphilis associated with negative intrapartum maternal serology screening |journal=Am J Perinatol |volume=15 |issue=4 |pages=233–6 |year=1998 |pmid=9565220 |doi=10.1055/s-2007-993933 |url=}}</ref><ref name="Russell1974">{{cite journal|last1=Russell|first1=Peter|title=Placental Abnormalities of Congenital Syphilis|journal=American Journal of Diseases of Children|volume=128|issue=2|year=1974|pages=160|issn=0002-922X|doi=10.1001/archpedi.1974.02110270034007}}</ref><ref name="pmid7927729">{{cite journal |vauthors=Riley BS, Oppenheimer-Marks N, Radolf JD, Norgard MV |title=Virulent Treponema pallidum promotes adhesion of leukocytes to human vascular endothelial cells |journal=Infect. Immun. |volume=62 |issue=10 |pages=4622–5 |year=1994 |pmid=7927729 |pmc=303152 |doi= |url=}}</ref>

Postnatal Diagnosis

• Examination of the placenta or umbilical cord using a silver stain demonstrates spirochetes or a T. pallidum PCR test can be done.
• The use of serological tests to identify the infection in infants less than 15months of age born to infected mothers is not performed as passive transfer of IgG antibodies to the fetus occurs during the pregnancy.
• Other laboratory findings in the new born include:<ref name="pmid11384701">{{cite journal |vauthors=Hollier LM, Harstad TW, Sanchez PJ, Twickler DM, Wendel GD |title=Fetal syphilis: clinical and laboratory characteristics |journal=Obstet Gynecol |volume=97 |issue=6 |pages=947–53 |year=2001 |pmid=11384701 |doi= |url=}}</ref>
• Elevated liver enzymes
• Leucocytosis
• Coombs negative haemolytic anaemia
• Thrombocytopenia
• Hypoalbuminemia
• Hyperbilirubinemia

Imaging Studies

X-Ray

• Skeletal survey in a still born, typical osseous lesions are demonstrated in congenital syphilis.

Long Bone Radiographs

• Radiographs typically demonstrate bilateral, symmetric, and polyostotic lesions in femur, humerus, and tibia.<ref name="pmid2584243">{{cite journal| author=Rasool MN, Govender S| title=The skeletal manifestations of congenital syphilis. A review of 197 cases. | journal=J Bone Joint Surg Br | year= 1989 | volume= 71 | issue= 5 | pages= 752-5 | pmid=2584243 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2584243 }} </ref><ref name="pmid8609122">{{cite journal| author=Kocher MS, Caniza M| title=Parrot pseudoparalysis of the upper extremities. A case report. | journal=J Bone Joint Surg Am | year= 1996 | volume= 78 | issue= 2 | pages= 284-7 | pmid=8609122 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8609122 }} </ref>
• Common findings on radiographs include:
  • Metaphyseal lucent bands
  • Symmetric localized demineralization and osseous destruction of proximal tibial metaphysis
  • Metaphyseal serration

Ultrasound

Antenatal sonographic features include:<ref name="radiop2"> https://radiopaedia.org/articles/in-utero-syphilis-infection. Accessed on September 28th, 2016. </ref><ref name="pmid21844732">{{cite journal| author=Reyna-Figueroa J, Esparza-Aguilar M, Hernández-Hernández Ldel C, Fernández-Canton S, Richardson-Lopez Collada VL| title=Congenital syphilis, a reemergent disease in Mexico: its epidemiology during the last 2 decades. | journal=Sex Transm Dis | year= 2011 | volume= 38 | issue= 9 | pages= 798-801 | pmid=21844732 | doi=10.1097/OLQ.0b013e31821898ca | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21844732 }} </ref>

• Fetal hepatosplenomegaly
• Placentomegaly
• Fetal ascites
  

In severe cases findings include:

• Fetal hydrops
• Bent fetal long bones

Doppler Studies

Doppler ultrasound of the uterine and umbilical arteries show increases in the mean systolic to diastolic ratios in mothers infected with syphilis indicating an increased resistance to perfusion of the placenta secondary to vasculitis, placental villitis and obliterative arteritis caused by syphilis.<ref name="Genc2000">{{cite journal|last1=Genc|first1=M.|title=Syphilis in pregnancy|journal=Sexually Transmitted Infections|volume=76|issue=2|year=2000|pages=73–79|issn=13684973|doi=10.1136/sti.76.2.73}}</ref>

Other Diagnostic Studies

CSF Analysis

Indications : Lumbar puncture is indicated in the following situations.<ref name="Phiske2014">{{cite journal|last1=Phiske|first1=MeghanaMadhukar|title=Current trends in congenital syphilis|journal=Indian Journal of Sexually Transmitted Diseases and AIDS|volume=35|issue=1|year=2014|pages=12|issn=0253-7184|doi=10.4103/0253-7184.132404}}</ref>

• If the infant or child has signs and symptoms of congenital Syphilis.
• If there is no documentation of treatment for maternal infection during the period of gestation.
• If the mother was treated within 4 weeks of delivery.
• If the mother was inadequately treated or documentation of the treatment is incomplete.
• A four-fold decline in titer following therapy in the mother is not documented.

CSF Findings:<ref name="pmid26042815">{{cite journal| author=Workowski KA, Bolan GA, Centers for Disease Control and Prevention| title=Sexually transmitted diseases treatment guidelines, 2015. | journal=MMWR Recomm Rep | year= 2015 | volume= 64 | issue= RR-03 | pages= 1-137 | pmid=26042815 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26042815 }} </ref>

• Reactive CSF VDRL.
• CSF pleocytosis(>25 white blood cells [WBC]/microL for infants <1 month)
• Elevated CSF protein (>150 mg/dL in term infants <1 month of age and >170 mg/dL in preterm infants <1 month of age)

Treatment

Medical Therapy

Management during the period of gestation

	CDC Recommendations for management of pregnant woman with Syphilis infection
Approach during the Prenatal Period	All women should be screened serologically for syphilis early in pregnancy. Most states mandate screening at the first prenatal visit for all women;<ref name="pmid11384701">Hollier LM, Harstad TW, Sanchez PJ, Twickler DM, Wendel GD (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11384701 Fetal syphilis: clinical and laboratory characteristics.] ''Obstet Gynecol'' 97 (6):947-53. PMID: [http://pubmed.gov/11384701 11384701]</ref> antepartum screening by nontreponemal antibody testing is typical, but in some settings, treponemal antibody testing is being used. Pregnant women with reactive treponemal screening tests should have confirmatory testing with nontreponemal tests with titers to monitor treatment response. In populations in which use of prenatal care is not optimal, RPR test screening and treatment (if the RPR test is reactive) should be performed at the time that pregnancy is confirmed. For communities and populations in which the prevalence of syphilis is high and for patients at high risk, serologic testing should be performed twice during the third trimester (ideally at 28-32 weeks' gestation) and at delivery. Any woman who delivers a stillborn infant after 20 weeks' gestation should be tested for syphilis. No infant should leave the hospital without the maternal serologic status having been determined at least once during pregnancy. Quantitative maternal nontreponemal titer, especially if >1:8, might be a marker of early infection and bacteremia. However, risk for fetal infection is still significant in pregnant women with late latent syphilis and low titers. Seropositive pregnant women should be considered infected unless an adequate treatment history is documented clearly in the medical records and sequential serologic antibody titers have declined. Serofast low antibody titers might not require treatment; however, persistent higher titer antibody tests might indicate reinfection, and treatment might be required.
Recommended Regimen for Treatment	Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection.<ref name="urlSexually Transmitted Diseases Treatment Guidelines, 2010">{{cite web|url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5912a1.htm |title=Sexually Transmitted Diseases Treatment Guidelines, 2010 |format= |work= |accessdate=2012-12-19}}</ref> Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal infection.<ref name="pmid9916946">Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel GD (1999) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9916946 Efficacy of treatment for syphilis in pregnancy.] ''Obstet Gynecol'' 93 (1):5-8. PMID: [http://pubmed.gov/9916946 9916946]</ref> Evidence is insufficient to determine optimal, recommended penicillin regimens.<ref name="pmid11686978">Walker GJ (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11686978 Antibiotics for syphilis diagnosed during pregnancy.] ''Cochrane Database Syst Rev'' (3):CD001143. [http://dx.doi.org/10.1002/14651858.CD001143 DOI:10.1002/14651858.CD001143] PMID: [http://pubmed.gov/11686978 11686978]</ref>
Additional Considerations	Some evidence suggests that additional therapy can be beneficial for pregnant women in some settings (e.g., a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis).<ref name="pmid12353207">Wendel GD, Sheffield JS, Hollier LM, Hill JB, Ramsey PS, Sánchez PJ (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12353207 Treatment of syphilis in pregnancy and prevention of congenital syphilis.] ''Clin Infect Dis'' 35 (Suppl 2):S200-9. [http://dx.doi.org/10.1086/342108 DOI:10.1086/342108] PMID: [http://pubmed.gov/12353207 12353207]</ref> When syphilis is diagnosed during the second half of pregnancy, management should include a sonographic fetal evaluation for congenital syphilis, but this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis (i.e., hepatomegaly, ascites, hydrops, fetal anemia, or a thickened placenta) indicate a greater risk for fetal treatment failure;<ref name="pmid11384701">Hollier LM, Harstad TW, Sanchez PJ, Twickler DM, Wendel GD (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11384701 Fetal syphilis: clinical and laboratory characteristics.] ''Obstet Gynecol'' 97 (6):947-53. PMID: [http://pubmed.gov/11384701 11384701]</ref> such cases should be managed in consultation with obstetric specialists. Evidence is insufficient to recommend specific regimens for these situations. Women treated for syphilis during the second half of pregnancy are at risk for premature labor and/or fetal distress if the treatment precipitates the Jarisch-Herxheimer reaction.<ref name="pmid2304710">Klein VR, Cox SM, Mitchell MD, Wendel GD (1990) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=2304710 The Jarisch-Herxheimer reaction complicating syphilotherapy in pregnancy.] ''Obstet Gynecol'' 75 (3 Pt 1):375-80. PMID: [http://pubmed.gov/2304710 2304710]</ref> These women should be advised to seek obstetric attention after treatment if they notice any fever, contractions, or decrease in fetal movements. Stillbirth is a rare complication of treatment, but concern for this complication should not delay necessary treatment. Pregnant women taking treatment for late latent syphilis should not miss any dose, else she must repeat the whole course of therapy.<ref name="pmid8355931">{{cite journal| author=Nathan L, Bawdon RE, Sidawi JE, Stettler RW, McIntire DM, Wendel GD| title=Penicillin levels following the administration of benzathine penicillin G in pregnancy. | journal=Obstet Gynecol | year= 1993 | volume= 82 | issue= 3 | pages= 338-42 | pmid=8355931 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8355931 }} </ref> All patients who have syphilis should be offered testing for HIV infection.
In patients with Penicillin Allergy	For treatment of syphilis during pregnancy, no proven alternatives to penicillin exist. Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin. Oral step-wise penicillin dose challenge or skin testing may be helpful in identifying women at risk for acute allergic reactions. Tetracycline and doxycycline usually are not used during pregnancy. Erythromycin and azithromycin should not be used, because neither reliably cures maternal infection or treats an infected fetus.<ref name="pmid11686978">Walker GJ (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11686978 Antibiotics for syphilis diagnosed during pregnancy.] ''Cochrane Database Syst Rev'' (3):CD001143. [http://dx.doi.org/10.1002/14651858.CD001143 DOI:10.1002/14651858.CD001143] PMID: [http://pubmed.gov/11686978 11686978]</ref> Data are insufficient to recommend ceftriaxone for treatment of maternal infection and prevention of congenital syphilis.
Pregnant Woman with HIV Infection	Placental inflammation from congenital infection might increase the risk for perinatal transmission of HIV. All HIV-infected women should be evaluated for syphilis and receive treatment as recommended. Data are insufficient to recommend a specific regimen for HIV-infected pregnant women.
Follow Up	Coordinated prenatal care and treatment are vital. Serologic titers should be repeated at 28-32 weeks' gestation and at delivery as recommended for the disease stage. Providers should ensure that the clinical and antibody responses are appropriate for the patient's stage of disease, although most women will deliver before their serologic response to treatment can be assessed definitively. Inadequate maternal treatment is likely if delivery occurs within 30 days of therapy, if clinical signs of infection are present at delivery, or if the maternal antibody titer at delivery is fourfold higher than the pretreatment titer. Serologic titers can be checked monthly in women at high risk for reinfection or in geographic areas in which the prevalence of syphilis is high. <ref name="urlSexually Transmitted Diseases Treatment Guidelines, 2010">{{cite web|url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5912a1.htm |title=Sexually Transmitted Diseases Treatment Guidelines, 2010 |format= |work= |accessdate=2012-12-19}}</ref>

Management of a Neonate or an Infant with Congenital Syphilis

The diagnosis of congenital syphilis can be difficult, as maternal nontreponemal and treponemal IgG antibodies can be transferred through the placenta to the fetus, complicating the interpretation of reactive serologic tests for syphilis in neonates. Therefore, treatment decisions frequently must be made on the basis of:

• Identification of syphilis in the mother
• Adequacy of maternal treatment
• Presence of clinical, laboratory, or radiographic evidence of syphilis in the neonate
• Comparison of maternal (at delivery) and neonatal nontreponemal serologic titers using the same test, preferably conducted by the same laboratory.

Evaluation and Approach

• All neonates born to mothers who have reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal serologic test (RPR or VDRL) performed on the neonate's serum, because umbilical cord blood can become contaminated with maternal blood and yield a false-positive result, and Wharton's jelly within the umbilical cord can yield a false-negative result.
• Conducting a treponemal test (i.e., TP-PA, FTA-ABS, EIA, or CIA) on neonatal serum is not recommended because it is difficult to interpret.
• Any neonate at risk for congenital syphilis should receive a full evaluation and testing for HIV infection.
• The following scenarios describe the congenital syphilis evaluation and treatment of neonates born to women who have reactive serologic tests for syphilis during pregnancy. Maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the neonate for congenital syphilis in most scenarios, except when congenital syphilis is proven or highly probable.

	CDC Recommendations for management of neonates with Congenital Syphilis
Clinical senario 1	Infants with proven or highly probable disease and with any one of the following : An abnormal physical examination that is consistent with congenital syphilis or A serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer or A positive darkfield test of body fluid(s). Recommended Evaluation CSF analysis for VDRL, cell count, and protein Complete blood count (CBC) and differential and platelet count Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver-function tests, neuroimaging, ophthalmologic examination, and auditory brain stem response) Preferred regimen 1: Aqueous crystalline penicillin G 100,000-150,000 U/kg/day, administered as 50,000 U/kg/dose IV q12h during the first 7 days of life and q8h thereafter for a total of 10 days Preferred regimen 2: Procaine penicillin G 50,000 U/kg/dose IM q24h for 10 days Note: If more than 1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding the use of other antimicrobial agents (e.g., ampicillin). When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis. The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy. In all other situations, the maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the infant
Clinical senario 2	Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and with one of the following: Mother was not treated or inadequately treated, or has no documentation of having received treatment or Mother was treated with erythromycin or another non-penicillin regimen or Mother received treatment less than 4 weeks before delivery. Recommended Evaluation CSF analysis for VDRL, cell count, and protein** CBC, differential, and platelet count Long-bone radiographs Preferred regimen 1: Aqueous crystalline penicillin G 100,000-150,000 U/kg/day, administered as 50,000 U/kg/dose IV q12h during the first 7 days of life and q8h thereafter for a total of 10 days Preferred regimen 2: Procaine penicillin G 50,000 U/kg/dose IM q24h for 10 days Preferred regimen 3: Benzathine penicillin G 50,000 U/kg/dose IM single dose Note: If the mother has untreated early syphilis at delivery, 10 days of parenteral therapy can be considered Before using the single-dose benzathine penicillin G regimen, the complete evaluation (i.e., CSF examination, long-bone radiographs, and CBC with platelets) must be normal, and follow-up must be certain. If any part of the infant's evaluation is abnormal or not performed, if the CSF analysis is uninterpretable because of contamination with blood, or if follow-up is uncertain, a 10-day course of penicillin G is required. If the neonate's nontreponemal test is nonreactive and the provider determines that the mother's risk of untreated syphilis is low, treatment of the neonate with a single IM dose of benzathine penicillin G 50,000 units/kg for possible incubating syphilis can be considered without an evaluation. Neonates born to mothers with untreated early syphilis at the time of delivery are at increased risk for congenital syphilis, and the 10-day course of penicillin G may be considered even if the complete evaluation is normal and follow-up is certain.
Clinical senario 3	Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and Mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery and Mother has no evidence of reinfection or relapse. Recommended Evaluation' No evaluation recommended Preferred regimen: Benzathine penicillin G 50,000 U/kg/dose IM single dose
Clinical senario 4	Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and Mother's treatment was adequate before pregnancy and Mother's nontreponemal serologic titer remained low and stable before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4) Recommended evaluation No evaluation recommended No treatment is required Benzathine penicillin G 50,000 U/kg IM single dose might be considered, particularly if follow-up is uncertain
Follow up	All neonates with reactive nontreponemal tests should receive careful follow-up examinations and serologic testing (i.e., a nontreponemal test) every 2–3 months until the test becomes nonreactive. In the neonate who was not treated because congenital syphilis was considered less likely or unlikely, nontreponemal antibody titers should decline by age 3 months and be nonreactive by age 6 months, indicating that the reactive test result was caused by passive transfer of maternal IgG antibody. At 6 months, if the nontreponemal test is nonreactive, no further evaluation or treatment is needed; if the nontreponemal test is still reactive, the infant is likely to be infected and should be treated. Treated neonates that exhibit persistent nontreponemal test titers by 6–12 months should be re-evaluated through CSF examination and managed in consultation with an expert. Retreatment with a 10-day course of a penicillin G regimen may be indicated. Neonates with a negative nontreponemal test at birth and whose mothers were seroreactive at delivery should be retested at 3 months to rule out serologically negative incubating congenital syphilis at the time of birth. Neonates whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal Note: Treponemal tests should not be used to evaluate treatment response because the results are qualitative and passive transfer of maternal IgG treponemal antibody might persist for at least 15 months A reactive CSF Venereal Disease Research Laboratory (VDRL) test or abnormal CSF indices that persist and cannot be attributed to other ongoing illness requires retreatment for possible neurosyphilis and should be managed in consultation with an expert.
Penicillin Allergy	Infants and children who require treatment for congenital syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized and then treated with penicillin. Data are insufficient regarding the use of other antimicrobial agents (e.g., ceftriaxone) for congenital syphilis in infants and children.

	CDC Recommendations for management of Infants and Children with Congenital Syphilis
Congenital Syphilis in infants and children	Infants and children aged ≥1 month who are identified as having reactive serologic tests for syphilis should be examined thoroughly and have maternal serology and records reviewed to assess whether they have congenital or acquired syphilis. Any infant or child at risk for congenital syphilis should receive a full evaluation and testing for HIV infection Recommended Evaluation CSF analysis for VDRL, cell count, and protein CBC, differential, and platelet count Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver function tests, abdominal ultrasound, ophthalmologic examination, neuroimaging, and auditory brain-stem response) Preferred regimen: Aqueous crystalline penicillin G 50,000 U/kg q4–6h for 10 days If the infant or child has no clinical manifestations of congenital syphilis and the evaluation (including the CSF examination) is normal, treatment with up to 3 weekly doses of benzathine penicillin G, 50,000 U/kg IM can be considered. A single dose of benzathine penicillin G 50,000 units/kg IM up to the adult dose of 2.4 million units in a single dose can be considered after the 10-day course of IV aqueous penicillin to provide more comparable duration of treatment in those who have no clinical manifestations and normal CSF. All of the above treatment regimens also would be adequate for children who might have other treponemal infections.
Follow Up	Careful follow-up examinations and serologic testing (i.e., a nontreponemal test) of infants and children treated for congenital syphilis after the neonatal period (30 days of age) should be performed every 3 months until the test becomes nonreactive or the titer has decreased fourfold. If the titers increase at any point for more than 2 weeks or do not decrease fourfold after 12–18 months, the infant or child should be evaluated (e.g., through CSF examination), treated with a 10-day course of parenteral penicillin G, and managed in consultation with an expert. Treponemal tests should not be used to evaluate treatment response, because the results are qualitative and persist after treatment; further, passive transfer of maternal IgG treponemal antibody might persist for at least 15 months after delivery. Infants or children whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal. After 2 years of follow-up, a reactive CSF VDRL test or abnormal CSF indices that persists and cannot be attributed to other ongoing illness requires retreatment for possible neurosyphilis and should be managed in consultation with an expert.
Penicillin Allergy	Infants and children who require treatment for congenital syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized and treated with penicillin

Prevention

Primary Prevention

Primary prevention of syphilis in women of reproductive age and men who have sex with women and prevention of mother to infant transmission in infected individuals plays a important role in decreasing incidence of congenital syphilis.Effective measures for the primary prevention of congenital syphilis include reducing the risk of mother having syphilis infection and also screening during the antenatal period:<ref name="pmid19805553">{{cite journal |author=Stamm LV |title=Global challenge of atibiotic-resistant Treponema pallidum |journal=[[Antimicrobial Agents and Chemotherapy]] |volume=54 |issue=2 |pages=583–9 |year=2010 |month=February |pmid=19805553 |pmc=2812177 |doi=10.1128/AAC.01095-09 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=19805553 |accessdate=2012-02-21}}</ref><ref name="pmid24135571">{{cite journal |vauthors=Cameron CE, Lukehart SA |title=Current status of syphilis vaccine development: need, challenges, prospects |journal=Vaccine |volume=32 |issue=14 |pages=1602–9 |year=2014 |pmid=24135571 |pmc=3951677 |doi=10.1016/j.vaccine.2013.09.053 |url=}}</ref><ref name=CDCsyphilis>http://www.cdc.gov/std/tg2015/syphilis.htm Accessed on September 27, 2016</ref><ref name="pmid27081586">{{cite journal| author=Lago EG| title=Current Perspectives on Prevention of Mother-to-Child Transmission of Syphilis. | journal=Cureus | year= 2016 | volume= 8 | issue= 3 | pages= e525 | pmid=27081586 | doi=10.7759/cureus.525 | pmc=4829408 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27081586 }} </ref>

• Routine screening in pregnant females, individuals with high risk behaviours, and those residing in highly prevalent areas.
• Abstinence from intimate physical contact with an infected person.
• Consistent use of latex condoms.
• Limiting no of sexual partners.
• Avoid sharing sex toys.
• Practising safe sex.

Secondary Prevention

• Regular follow up of infants with congenital syphilis to examine for the re-appearance of signs and symptoms of syphilis after recommended treatment has shown to improve outcomes.<ref name="pmid28146163">{{cite journal| author=Feliz MC, Prizybicien AR, Rossoni AM, Tahnus T, Pereira AM, Rodrigues C| title=Adherence to the follow-up of the newborn exposed to syphilis and factors associated with loss to follow-up. | journal=Rev Bras Epidemiol | year= 2016 | volume= 19 | issue= 4 | pages= 727-739 | pmid=28146163 | doi=10.1590/1980-5497201600040004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28146163 }} </ref><ref name="pmid26474815">{{cite journal| author=Wallace HE, Broomhall HM, Isitt CE, Miall LS, Wilson JD| title=Serological follow-up of infants born to mothers with positive syphilis serology - real-world experiences. | journal=Int J STD AIDS | year= 2016 | volume= 27 | issue= 13 | pages= 1213-1217 | pmid=26474815 | doi=10.1177/0956462415612394 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26474815 }} </ref><ref name="pmid27622443">Vallejo C, Cifuentes Y (2016). "Characterization and six-month follow-up on a cohort of newborns with congenital syphilis". Biomedica. 36 (1): 101–8. doi:10.7705/biomedica.v36i1.2661. PMID 27622443. </ref>