http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–3 ! 2013 Informa UK Ltd. DOI: 10.3109/14767058.2013.853288

SHORT REPORT

Fetal anemia as a signal of congenital syphilis J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/18/14 For personal use only.

Guillaume Mace´1, Vanina Castaigne2, Aurore Trabbia3, Virginie Guigue4, Evelyne Cynober5, Anne Cortey5, Vale´rie Lalande6, and Bruno Carbonne2 1

Department of Obstetrics and Gynecology, Bocage Hospital, Burgundy University, Dijon, France, 2Department of Obstetrics and Gynecology, Armand Trousseau Hospital, Paris, France, 3Department of Obstetrics and Gynecology, Esquirol Hospital, Saint-Maurice, France, 4Department of Obstetrics and Gynecology, Hopital Couple-Enfant, Grenoble, France, 5Centre National de Re´fe´rence en He´mobiologie Ne´onatale, Armand Trousseau Hospital, Centre National de Re´fe´rence en He´mobiologie Pe´rinatale, Paris, France, and 6Department of Virology, Saint-Antoine Hospital, Paris, France Abstract

Keywords

An upsurge in syphilis has been observed almost everywhere over the past decade. The mother’s clinical presentation is often uninformative. The diagnosis of maternal syphilis infection is most often based on serologic tests that allow early Extencilline treatment. Syphilis ultrasound findings are non-specific, and delay before treatment can be decisive for prognosis. Fetal anemia is a physiological consequence of severe infection. We confirmed that syphilis can be suggested non-invasively by MCA-PSV measurements in a context of ascitis or atypical hydrops in the absence of usual causes. It is therefore important to perform maternal TPHA/ VDRL serology if fetal anemia is suspected. In association with Extencilline treatment, intra uterine transfusion can limit consequences of infection. Reduced fetal movements and nonreactive fetal heart rate may prefigure acute perinatal complications or stillbirth.

Anemia, congenital syphilis, fetal movements, intra uterine transfusion, prenatal

Introduction An upsurge in syphilis rates is reported in numerous countries [1]. Prevalence in France [2] has grown substantially since 2000, although congenital syphilis (CS) remains rare. Because primary syphilis often goes unnoticed, maternal-fetal transmission most frequently takes place at the stage of secondary syphilis, and its clinical signs can also be discreet and polymorphous [3]. We present here two cases of CS discovered prenatally by findings of ascites and anemia associated with a reduction in fetal heart rate (FHR) reactivity. First case A 17-year-old woman from Cameroon, of low socioeconomic status, primigravida, with no medical or surgical history, was referred at 33 weeks’ gestation for suspected fetal anemia. Her blood group was O RhD positive. The serology testing, routinely performed in France during the first trimester, showed that she was immunized against toxoplasmosis and rubella and was seronegative for hepatitis B and C, HIV and syphilis. The pregnancy was unremarkable until 33 weeks, when she came at her maternity unit because of a reduction in perceived fetal movements. At admission, FHR was normal, Address for correspondence: Dr Guillaume Mace´, Department of Obstetrics and Gynecology, Bocage Hospital, Burgundy University, 14 rue Gaffarel, Dijon 21000, France. E-mail: [email protected]

History Received 23 February 2013 Accepted 6 October 2013 Published online 7 November 2013

but ultrasound findings included a strip of ascites and a middle cerebral artery peak systolic velocity (MCA-PSV) measured at 1.6 MoM. The Coombs test was negative; the Kleihauer–Betke test could not be interpreted because of sickle-cell trait, and the maternal CMV and parvovirus B19 serology results suggested past infections. Successive FHR readings were not reactive; they showed a baseline heart rate of 150 bpm with phases of reduced variability (55 bpm) for more than 40 min. Corticosteroid treatment and close in-patient monitoring followed. During the ultrasound surveillance, MCA-PSV remained at 1.5 MoM and the volume of ascites increased; hepatomegaly appeared, together with minor pericardial effusion. The amniotic fluid volume was normal, and no other effusion or subcutaneous edema was visualized. At 34 weeks, amniocentesis was performed and a fetal blood sample was taken. It confirmed fetal anemia at 8.4 g/dL and allowed an in utero transfusion that raised fetal hemoglobin to 16.2 g/dL. The karyotype was normal; fetal thrombocytopenia, at 30 000 platelets, led to testing for platelet incompatibility, with negative results. Given the negativity of usual causes of fetal anemia (i.e. fetomaternal allo-immunization, parvovirus or cytomegalovirus infection, fetomaternal hemorrhage), maternal TPHA/ VDRL serology was tested, and amniotic fluid was analyzed to look for metabolic diseases. Fetal cerebral MRI and echocardiography were also performed. At 35 weeksþ 2 days, as the FHR variability was still reduced (Figure 1), and fetal movements grew still less

J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/18/14 For personal use only.

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J Matern Fetal Neonatal Med, Early Online: 1–3

Figure 1. Poor variability (55 bpm, more than 1 h), no fetal movement. Fetal heart rate (1 cm.s).

frequent, spontaneous labor began. An emergency cesarean delivered a girl weighing 2300 g. The Apgar score at 1 min was 1 and required emergency tracheal intubation and adrenaline administration at 3 and 5 min, after external cardiac massage. At 10 min, the clinical examination found a non-reactive and fixed stare as well as major hepatomegaly. As neurological status improved progressively, the newborn was transferred to the neonatal intensive care unit. Laboratory results showed a C Reactive Protein at 156 mg/L and ASAT at 117 IU/L, Hemoglobin at 11 g/L and platelets at 23 000/mm3. The antenatal maternal VDRL/TPHA serology was obtained on day 3. The results were strongly positive: 5120/ 32. Therefore, Extencillin treatment was instituted without awaiting the neonatal serology results, which subsequently confirmed the diagnosis of CS. The pediatric course indicated a severe form combining moderate axial hypotonia, bone lesions, a nephrotic syndrome with kidney failure, cholestasis, anemia and thrombocytopenia that required a transfusion of packed red blood cells and platelets on D2. Mechanical ventilation was stopped on D9 and peritoneal dialysis was performed with a favorable outcome. Reviewing the maternal serum samples during pregnancy made it possible to date the syphilis infection between 10 and 18 weeks. Second case A 27-year-old woman, of Moroccan origin, was referred for fetal hydrops and intra-uterine growth retardation (IUGR) at 26 weeks. MCA-PSV was elevated at 1.5 MoM suggesting fetal anemia. At her booking visit, at 17 weeks, TPHA/VDRL was strongly positive with a 81920/512 rate. Positive Immunoglobulin M suggested a recent maternal syphilitic infection. However, no maternal symptoms were noticed and

fetal ultrasound revealed no morphologic anomaly. For unknown reasons, treatment was not initiated at this time. Other usual blood tests showed acquired immunization for CMV, toxoplasmosis and rubella. The patient’s blood group was A RhD positive with a negative Coombs test. At 23 weeks, the ultrasound examination showed a normal growth without morphological anomalies. At 26 weeks, the surveillance of fetal growth by ultrasound scan revealed a severe IUGR below the 3rd centile for cephalic and femoral measurements, absence of fetal movements, ascitis, hyperechogenic bowel, hepato-splenomegaly and elevated MCAPSV at 2 MoM. The Kleihauer–Betke test and Parvovirus B19 serology were negative. She was therefore referred to our National Reference Center. Upon arrival, an intra-uterine fetal death was observed. An amniocentesis was performed before induction of labor and it confirmed the presence of Treponema pallidum by Polymerase Chain Reaction. A 720 g stillborn girl was delivered without visible external anomaly. Karyotype was normal and fetopathological examination was denied by the parents.

Discussion An upsurge in syphilis has been observed almost everywhere over the past decade. The mother’s clinical presentation is often uninformative, and the 3-phase kinetics of T. pallidum can be misleading. The diagnosis of maternal syphilis infection is most often based on serologic tests that allow early and appropriate treatment. Because a delay in the beginning of Extencillin treatment can be decisive for prognosis, diagnosis must be evocated largely in non-specific situations. Thus, it is essential to recognize the clinical picture and course of fetal infection. In the absence of screening or in cases of asymptomatic infection during the second

Fetal anemia as a signal of CS

J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 06/18/14 For personal use only.

DOI: 10.3109/14767058.2013.853288

trimester, the ultrasound signs of fetal disease are nonspecific: ascites with or without fetal hydrops, placental thickening, hydramnios, hepatosplenomegaly, and dilated or echogenic bowel. Approximately 35% of newborns with fetal infection have clinical signs [4]. IUGR and stillbirth are observed, related perhaps to chronic villitis and damage to the vascular walls. The risk of perinatal mortality is 40%, but Gust [5] reports that first-trimester screening followed by treatment that begins before 16 weeks appears to reduce the risk by 90%. Contrary to other well-described fetal infections, such as CMV or toxoplasmosis, few prenatal diagnoses of syphilis have been reported in the literature [6,7]. It is therefore difficult to assess the prognosis of fetal infection from simple antenatal observations. Chen et al. [6] reported a case of fetal syphilis diagnosed from hydrops and positive IgM, which led to an early treatment with Extencillin. Secondary anemia was detected at 28 weeks by MCA-PSV monitoring. An intrauterine transfusion was performed successfully and the newborn, delivered at 35 weeks, had no stigmata of infection. This case suggests that implementing anti-treponema treatment at the fetal hydrops stage, combined with an intrauterine transfusion if secondary anemia is found, can lead to sequel-free recovery. Moreover, several studies agree that MCA-PSV is effective for monitoring non-immune fetal anemia, especially in fetal infections, by parvovirus B19 or CMV, for example [8,9]. In a series of 32 pregnancies, Hollier et al. [7] performed amniocenteses and cordocenteses systematically when the mother was known to have syphilis. The results found proven fetal infection in 66%, 88% of which with elevated transaminases, 66% with hepatomegaly, 26% with anemia, 35% with thrombocytopenia and 12% with ascites. Treatment appeared most effective when begun early and in the absence of ascites. The sequence of fetal syphilitic damage appears to begin with the elevation of transaminases and hepatomegaly and continues with hematologic changes. Ascites and then fetal hydrops complete the clinical picture. In our first case, as Chen et al. [6], we confirmed that CS sequence can be suggested non-invasively by MCAPSV and liver length measurements in a context of ascitis or atypical hydrops in the absence of usual causes (CMV and parvovirus serologies, Coombs test and Kleihauer– Betke test negative). In case of elevated MCA-PSV, a fetal blood sampling and, if necessary, an intrauterine transfusion should be performed without waiting for the results of the etiological work-up. Otherwise, the severity of anemia may lead to fetal death or cerebral lesions [10] when sequel-free cure is possible.

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It is therefore important to perform maternal TPHA/VDRL serology in cases of unexplained ascites with hepatomegaly, especially if there is a fetal anemia. The second case shows that, if syphilitic serology is not taken into account by mistake, the entire physiological sequence can appear, with severe anemia and hydrops on late preterminal evolution. A particular attention should be paid to fetal reactivity. The reduction of fetal movements and the non-reactive FHR seem more marked than would be expected for the level of fetal anemia, and the moderate ascitis identified in the first case. Altogether with fetal immobility of the second case, this symptom could be related to the pseudoparalysis of Parrot, explained by pain that induces refusal to move the extremities [5]. These reports suggest that reduced fetal movements, associated with ultrasound signs of infection, may be of important diagnostic guidance in these infrequent situations. It may also prefigure acute perinatal complications or stillbirth at worst.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

References 1. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 2007. Available from: http://www.cdc.gov/std/ stats11/syphilis.htm [last accessed 27 Oct 2013]. 2. Bouyssou A, Janier M, Dupin N, et al. La syphilis en France: analyse des donne´es de surveillance sur 10 ans, 2000–2009. Bull Epidemiol Hebd 2011:26–28. 3. Nathan L, Bohman VR, Sanchez PJ, et al. In utero infection with Treponema pallidum in early pregnancy. Prenat Diagn 1997;17: 119–23. 4. Walker GJ, Walker DG. Congenital syphilis: a continuing but neglected problem. Semin Fetal Neonatal Med 2007;12:198–206. 5. Gust DA, Levine WC, St Louis ME, et al. Mortality associated with congenital syphilis in the United States, 1992–1998. Pediatrics 2002;109:E79. 6. Chen I, Chandra S, Singh A, et al. Successful outcome with intrautetrine transfusion in non-immune hydrops fetalis secondary to congenital syphilis. J Obstet Gynaecol Can 2010;32:861–5. 7. Hollier LM, Harstad TW, Sanchez PJ, et al. Fetal syphilis: clinical and laboratory characteristics. Obstet Gynecol 2001;97:947–53. 8. Hernandez-Andrade E, Scheier M, Dezerega V, et al. Fetal middle cerebral artery peak systolic velocity in the investigation of nonimmune hydrops. Ultrasound Obstet Gynecol 2004;23:442–5. 9. Mace´ G, Audry G, Cortey A, et al. Congenital hypoplasia of abdominal wall muscles following fetal ascitis due to Parvovirus B19 infection. Ultrasound Obstet Gynecol 2011;37:497–8. 10. Carbonne B, Nguyen A, Cynober E, et al. Prenatal diagnosis of anoxic cerebral lesions caused by profound fetal anemia secondary to maternal red blood cell allo-immunization. Obstet Gynecol 2008; 112:442–4.

Fetal anemia as a signal of congenital syphilis.

An upsurge in syphilis has been observed almost everywhere over the past decade. The mother's clinical presentation is often uninformative. The diagno...
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