Prenatal medicine: development, current status and future perspectives

Prenatal diagnosis and therapy are based mainly on the progress of diagnostic ultrasound and laboratory methods in genetics. There is a general tendency to replace second trimester fetal diagnoses by first trimester approaches. Transvaginal sonography and chorionic villus sampling in particular have been proven helpful in this context. The aim of all prenatal diagnostic measures is fetal therapy in time to prevent untreatable abnormalities. There has been some progress in this area; in particular, the application of stem cells for the correction of single cell diseases seems to be promising. Because all prenatal interventions involve a risk to the mother and especially the fetus, there is a concentrated effort to develop non-invasive screening or diagnostic methods. Extensive work on the isolation of fetal cells from the maternal circulation has revealed that such cells are present physiologically in pregnancy, but further trials need to show whether this method is safe enough for routine diagnostic use.     

Three consecutive pregnancies in a patient with glycogen storage disease type IA (von Gierke's disease)

Glycogen storage disease type IA is associated with metabolic abnormalities that can compromise fetal outcome. Normal outcome can be achieved by maintaining euglycemia throughout gestation. We report three consecutive pregnancies in a patient with glycogen storage disease type IA. The patient, a 35-year-old woman, has been maintained on a regimen of nightly nasogastric or cornstarch feedings for the past 12 years with improving metabolic control, reduced liver size, and no progression of multiple hepatic adenomas. On confirmation of each pregnancy, early in the first trimester nightly feeding was changed from cornstarch ingestion to Polycose by nasogastric intubation, with good metabolic control. During the last trimester of each pregnancy metabolic control showed further improvement, with lowering of lactate, urate, and triglyceride levels. During the first pregnancy unexpected fetal death occurred at 33 weeks. During the last two pregnancies, the patient was admitted at 33 and 34 weeks, respectively, for closer supervision of metabolic status and fetal monitoring. She underwent a cesarean section at 35 weeks 4 days of gestation and was delivered of a girl. She underwent a repeat cesarean section at 35 weeks 2 days for the subsequent gestation and was delivered of a boy. Both infants are healthy and appear to be unaffected by von Gierke's disease. Hepatic adenomas did not enlarge during the pregnancies. Meticulous management resulted in normal pregnancy outcomes in two consecutive gestations. Rapid fetal growth late in the third trimester may require particularly careful supervision to maintain euglycemia.     

Prenatal diagnosis of congenital cytomegalovirus infection

We report here the results of a study on the prenatal diagnosis of congenital cytomegalovirus (CMV) infection. The study was carried out by both PCR and virus isolation from amniotic fluid (AF) for 82 pregnant women at risk of transmitting CMV for the detection of (i) seroconversion to CMV immunoglobulin G (IgG) positivity during the first trimester of pregnancy, (ii) symptomatic CMV infection in the mother during the first trimester of pregnancy or intrauterine growth retardation detected by ultrasound or abnormal ultrasonographic findings suggestive of fetal infections, and (iii) seropositivity for CMV-specific IgM. For 50 women, fetal blood (FB) was also obtained and tests for antigenemia and PCR were performed. The results indicate that AF is better than FB for the prenatal diagnosis of CMV infection. PCR with AF has a sensitivity (SNS) of 100%, a specificity (SPE) of 83.3%, a positive predictive value (PPV) of 40%, and a negative predictive value (NPV) of 100%; rapid virus isolation with the same material has an SNS of 50%, an SPE of 100%, a PPV of 100%, and an NPV of 94.7%. Fewer than 10% of the women positive for IgM by enzyme immunoassay (EIA) had a congenitally infected fetus or newborn infant. When EIA IgM positivity was confirmed by Western blotting (WB) and the WB profile was considered, the percent transmission detected among women with an "at-risk" profile was higher than that observed among IgM-positive women and was the same as that among women who seroconverted during the first trimester of pregnancy (transmission rates of 29 and 25%, respectively).     

Syphilis management and treatment

Syphilis poses a serious health problem in many developing countries and in some areas of North America and Europe, especially Eastern Europe. This article initially addresses the state of the art regarding the interaction between syphilis and HIV infection and its consequences for management and treatment. Further attention is given to laboratory diagnosis of syphilis and false-positive and false-negative serologic reactions. The diagnosis and management of neurosyphilis, ocular, cardiovascular, and congenital syphilis are addressed, as well as management of syphilis patients allergic to penicillin and the Jarisch-Herxheimer reaction. Finally, the role of partner(s) and contact tracing is discussed.     

Value and limits of complementary investigations in cases of toxoplasmosis seroconversion during pregnancy. A case report and review of the literature]

We report a case of acute toxoplasmosis during the first trimester of pregnancy in which antenatal diagnosis was negative. Except for non-specific signs of liver failure, assessment by repeated ultrasound scans, testing of fetal blood for toxoplasmic specific antibodies and competitive PCR to isolate the parasite, had ruled out fetal infection. In spite of early treatment with spiramycin, and although the infant was assumed to be non-contaminated, severe hydrocephalus was noted at 3 and half months of life, arising soon after therapy had been stopped. This case focuses attention on the problem of the shortcomings of the diagnostic techniques currently used, and leads us to question our practical course of action. Several questions are thus raised: how reliable are indirect signs of fetal compromise, what is the real sensitivity of the PCR test and how useful are repeated amniocentesis and inoculation of the amniotic fluid to mice.     

Human immunodeficiency virus seropositivity in adolescents with syphilis

OBJECTIVE: The purpose of this study was to assess the relationship between syphilis and human immunodeficiency virus (HIV) infection among inner-city, minority group adolescents. METHODS: From August 1989 through June 1990, serum from all positive serologic tests for syphilis, obtained from patients attending a comprehensive adolescent health center in an acquired immunodeficiency syndrome epicenter and its two school-based clinics, were frozen without patient identifiers and were subsequently screened for HIV by enzyme-linked immunosorbent assay with confirmatory Western blot for positives. In addition, a retrospective chart review was performed for all patients with a positive serologic test for syphilis during the study period. RESULTS: Of the 59 specimens with a positive syphilis serologic test, 9 (15.3%) were HIV seropositive. Of the patients with syphilis, 57.4% were black and 42.6% were Hispanic; 16.4% were male (mean age 18.1) and 83.6% were female (mean age 17.8). Only 1 subject (female) was an injection drug user; 4 of the male subjects self-identified as having had sex with other males. Of the subjects, 27.8% had primary, 19.7% had secondary, and 52.5% had latent syphilis at the time of diagnosis. A prior or concurrent sexually transmitted disease was present in 90% of the males and 80% of the females; gonorrhea was the most prevalent sexually transmitted disease in the males (89%) and chlamydia was most prevalent in the females (35%). A history of chancroid and/or herpes was present in 16.4% of the subjects. CONCLUSIONS: It is concluded that the diagnosis of syphilis in an adolescent is a risk factor for HIV infection. All sexually active adolescents should be routinely screened for syphilis, regardless of sexual practices. Those with syphilis should be specifically counseled about their increased risk for HIV infection and the importance of consistent condom use, and they should be referred for formal HIV pretest counseling.     

Clinical picture of cardioborreliosis: from AV block to perimyocarditis

The third degree A-V heart block with severe Adams-Stokes attacks in nine patients with Lyme borreliosis was described. All patients had similar clinical picture: previously healthy with syncope as abrupt onset of the disease. Data on skin changes--erythema migrans--were obtained subsequently although the patients did not recall being bitten by a tick. Diagnosis was based on clinical manifestation, and on positive serologic tests to Borrelia. After the administered therapy (on admission atropine 0.5 mg i.v., and/or isoproterenol 0.02 mcg/kg/min, temporary pace-maker in two patients; and after proved diagnosis penicillin 20 mil. unit per day 10 days, and tetracyclin 2.0 gr per day 20 days A-V block returned to sinus rhythm with normal A-V conduction, and all biochemical parameters returned to normal limits. Perimyocarditis is not rare during Lyme borreliosis, but in this case infection syndrome is dominant.     

Treponemal specific tests for the serodiagnosis of syphilis. Syphilis and HIV Study Group

OBJECTIVES: To determine the rate of concordance of the Microhemagglutination Assay for Antibodies to T. pallidum (MHA-TP) and the Fluorescent Treponemal Antibody-Absorption test (FTA-ABS) prior to therapy in patients with early stage syphilis and to assess the incidence of and associated risk factors for seroreversion of these treponemal specific tests during the first year after therapy for early syphilis. DESIGN: Multicenter, prospective, cohort treatment study of patients with early syphilis. METHODS: Five hundred twenty-five patients were enrolled in a study to evaluate the response of early syphilis to either benzathine penicillin 2.4 million units intramuscularly once or this therapy plus amoxicillin 2 g and probenecid 500 mg orally both three times daily for 10 days. Serologic and clinical follow-up was conducted at intervals over 1 year. MHA-TP and FTA-ABS tests were performed on serologic specimens from each patient visit. RESULTS: Enrollment specimens showed 5% discordant MHA-TP and FTA-ABS results with 85% of these demonstrating a nonreactive MHA-TP. This occurred most commonly in primary syphilis. In patients who had a 1-year serologic follow-up with FTA-ABS or MHA-TP, seroreversion occurred in 9% and 5% of cases, respectively. No association between HIV-seropositivity and TST seroreversion was demonstrated. CONCLUSION: The MHA-TP may be less sensitive than the FTA-ABS for identifying patients with primary syphilis. Treponemal specific tests may become nonreactive during the first year after therapy for early syphilis.     

Lung function changes among recycling workers exposed to organic dust

OBJECTIVE: To describe the feasibility of diagnosing fetal congenital heart defects by transvaginal ultrasonography during the first trimester of pregnancy. METHODS: Pregnant women presenting to the Ultrasonographic Unit at the Chaim Sheba Medical Center who had a diagnosis of fetal heart defects were reviewed retrospectively. Attention was paid to prenatal ultrasound studies, karyotype, and pathologic examinations. RESULTS: Using high-resolution transvaginal ultrasonography, we were able to detect fetal tachycardia (one case), ectopia cordis with ventricular septal defect (one case), atrioventricular septal defect (two cases), ventricular septal defect with persistent truncus arteriosus (one case), tetralogy of Fallot (two cases), and large right atrium with unguarded tricuspid valve (Uhl disease) (one case). Seven of these fetuses had normal karyotypes and all showed additional sonographic abnormalities, including septated cystic hygroma (three cases), hydrops (ascites and pericardial effusions) (two cases), omphalocele (one case), and bilateral agenesis of kidneys (one case). Only one fetus with an abnormal karyotype (45,XO) showed a combination of septated cystic hygroma with hydrops. CONCLUSIONS: High-resolution duplex Doppler transvaginal ultrasonography during the first trimester of pregnancy seems to be a useful diagnostic method for detecting some congenital heart diseases.     

Congenital syphilitic skeletal manifestations in a premature infant revisited

Increasing rates of congenital syphilis have been reported in recent years despite the availability of adequate therapy. In our perinatal-neonatal center, approximately 1.5% of newborns have reactive serologic tests for syphilis. Untreated or partly treated maternal syphilis can adversely affect neonatal outcome since the treponeme can cross the placenta at any time during pregnancy. As a result of hematogenous placental transmission, neonatal manifestations are usually systemic and similar to the secondary stage of syphilis, and include hepatosplenomegaly, jaundice, neurosyphilis, and skeletal changes. A case of early congenital syphilis in an extremely premature infant with primary skeletal involvement is presented.     

Ovarian tumors and pregnancy

Ovarian tumors during pregnancy are a rare event. In most cases the tumors are detected accidentially during routine examination, ultrasound or a caesarean section at term. The incidence of malignant ovarian tumors is about 1:10,000 to 1:40,000 pregnancies. Histologic subtypes and prognosis do not differ from tumors not associated with pregnancy, it seems however, that there are more lesions of borderline malignancy and of low grade. Therapy depends mostly on the age of gestation and tumor stage. Conservative surgery is recommended only in stage IA disease. Radical surgery and if necessary adjuvant therapy is recommended during the first trimester. In the third trimester a caesarean section can be followed by radical surgery, provided that there is a close cooperation between gynecologists and pediatricians. In the second trimester this regimen is possible only as an exception which includes a critical maternal risk-benefit assessment.     

Ocular syphilis and neurosyphilis in a patient with human immunodeficiency virus infection

A patient who presented with severely decreased bilateral vision was found to have syphilis and neurosyphilis that responded well to a 14-day course of penicillin and prednisone. The patient tested positive for HIV, which can alter the natural course of syphilis, often making the diagnosis and treatment difficult. Conventional therapy for syphilis may not be effective in patients with HIV. Any patient with syphilis who is in a high-risk group should be tested for HIV; conversely, any patient with HIV should be tested for syphilis if signs or suspicions exist.     

Treatment of inflammatory rheumatic disorders in pregnancy: what are the safest treatment options?

The interaction of pregnancy and the rheumatic diseases varies, ranging from life-threatening conditions such as thromboembolic events and progressive renal disease in some autoimmune disorders, to minor flares of peripheral arthritis in inflammatory rheumatic disease. As a consequence, treatment strategy will vary according to the maternal or fetal compromise expected. All nonsteroidal anti-inflammatory drugs (NSAIDs), including high dose aspirin (acetylsalicylic acid), can cause adverse effects during pregnancy related to the inhibition of prostaglandin synthesis. Prolongation of gestation and labour, constriction of the ductus arteriosus, persistent fetal circulation, impairment of renal function and bleeding are risks of third trimester exposure of pregnant women to all inhibitors of cyclo-oxygenase. Most of these adverse effects can be prevented by discontinuing NSAIDs 8 weeks prior to delivery. Low dose aspirin has not been associated with fetal or neonatal toxicity. Some corticosteroids such as prednisone and prednisolone do not readily cross the placenta and can be safely used during pregnancy as immunosuppressive drugs. Maternal complications related to corticosteroids may occur and close monitoring is therefore mandatory. There is limited information on the safety of disease-modifying antirheumatic drugs including gold, antimalarials, penicillamine (D-penicillamine), sulfasalazine and cyclosporin. Of these agents, sulfasalazine has the best record for tolerability and can be used by pregnant patients. Gold compounds and penicillamine should be discontinued when pregnancy is recognised. Hydroxychloroquine has not been associated with congenital malformations and seems preferable to chloroquine in patients requiring treatment with antimalarials. Use of cyclosporin may be an alternative to other therapy in pregnant patients with severe rheumatic disease. Indications for treatment with colchicine during pregnancy are few, except for familial Mediterranean fever. Azathioprine can be used when the maternal condition requires a cytotoxic drug during the first trimester. Cyclophosphamide, chlorambucil and methotrexate are contraindicated during pregnancy because of their teratogenic potential. Their use may be considered in late pregnancy if the mother has a life-threatening condition.     

Pregnancy and perinatality: biological follow-up

Blood and urinary tests which are necessary for pregnancy diagnosis and follow-up, for newborn and mother medical supervision, during the month following birthday, are today described in reglementary texts, laws, and recommendations such as advised medical references (RMO). These documents specify the nature of obligatory tests, the checking rhythm and the list of useless tests. hCG research remains necessary for pregnancy diagnosis, but hCG dosage is essential only in case of programmed medical assistance or pathological pregnancy (extrauterine pregnancy, hydatiform mole, choriocarcinoma). The obligatory follow-up of a pregnant woman includes determination of blood groups, research of infectious agents responsible for diseases (toxoplasmosis, rubeola, hepatitis B, syphilis), proteinuria and glycosuria research and blood count according to a given calendar. When the mother's condition is bad and reminiscent of a pathological pregnancy, when a genetic risk exists for the fetus or when fetal growth is abnormal as indicated by echographic control (intra-uterine growth retardation), laboratory tests are used to follow the maternal pathological course (arterial hypertension, diabetes mellitus, anemia, bacterial, viral or parasitic disease), to verify the existence of a genetic disease, to know about the fetal functional state (by amniocentesis or cordocentesis), to identify an erythrocyte fetomaternal incompatibility. Since last trimester pregnancy accidents are able to endanger mother's and fetus lives, the feto-maternal follow-up must be adjusted to pathological diagnosis types and requires a particular supervision of the delivery. Finally mother and child must undergo a post-natal follow-up during the four weeks after birthday (perinatality control).     

Listeriosis during pregnancy

Listeriosis is an uncommon infection that has a unique predilection for pregnant women and may result in pregnancy loss. Contaminated food is the usual source of infection, and increased federal surveillance of foodstuffs is the most effective strategy for prevention of disease. Although dramatic epidemics have received the most publicity, more cases of perinatal listeriosis are isolated. If Listeria chorioamnionitis is diagnosed preterm, in contrast to other types of chorioamnionitis, in utero therapy with high-dose penicillin or trimethoprim-sulfamethoxazole is possible, and preterm delivery may be avoided. The clinical characteristics of neonatal listeriosis are similar to neonatal Group B Streptococcus sepsis, with early and late onset forms of disease. The epidemiology, diagnosis, and management of Listeria infection in pregnancy are reviewed.     

Revascularization of internal iliac arteries during aortoiliac surgery: a multicenter study

Prenatal screening for fetal abnormalities in an accepted part of modern obstetric management. Improvements on current screening procedures need to address increased diagnostic efficacy and earlier diagnosis. This study evaluates diagnostic efficacy of PAPP-A and F beta-hCG in the detection of first trimester pregnancy abnormalities, including Down syndrome (DS). Of 731 pregnant volunteers, obtained from a mature age population undergoing chorionic villus sampling (CVS), 17 DS and 11 compromised (six numerical (excluding sex chromosome) aneuploidies, five spontaneously failed) pregnancies were detected. Application of an algorithm, which combines PAPP-A and F beta-hCG levels with material age, detected 66.6 per cent of DS pregnancies for a five per cent false positive rate. Similarly, for a 1-2 per cent recall rate, 72.2 per cent of compromised pregnancies were detected. This report supports the notion that prenatal screening at 9-12 weeks of pregnancy is achievable with PAPP-A and F beta hCG quantitation. Whereas mid-gestational screening targetted the detection of fetal abnormalities, screening earlier in pregnancy will detect other pregnancy-related abnormalities, in addition to aneuploidy.     

Laryngeal atresia or stenosis presenting as second-trimester fetal ascites--diagnosis and pathology in three independent cases

Congenital atresia of the larynx is a rare abnormality. We describe three cases where prenatal diagnosis during the second trimester showed massive abdominal fetal ascites and at post-mortem, laryngeal atresia was identified in two cases, and severe laryngeal stenosis in the third. All were associated with pulmonary hyperplasia. No additional abnormalities were found in other systems. Overdistended lung tissue and ascites are resultant from aberrant laryngeal growth; laryngeal anomalies are a cause of isolated fetal ascites. The association of ascites and voluminous lungs should arouse suspicion of laryngeal atresia and should be an indication for careful pathological study of the fetal larynx.     

Fetal alcohol syndrome

The most notable features of fetal alcohol syndrome involve the face and eyes, and include microcephaly, short palpebral fissures, an underdeveloped philtrum and a thin upper lip. Evidence of intrauterine or postnatal growth retardation, mental retardation or other neurologic abnormalities, and at least two of the typical facial features are necessary to make the diagnosis. Newborns with the syndrome may be irritable, with hypotonia, severe tremors and withdrawal symptoms. Mild mental retardation, the most common and serious deficit, and a variety of other anomalies may accompany fetal alcohol syndrome. Sensory deficits include optic nerve hypoplasia, poor visual acuity, hearing loss, and receptive and expressive language delays. Atrial and ventricular septal defects, as well as renal hypoplasia, bladder diverticula and other genitourinary tract abnormalities, may occur. Complete abstinence during pregnancy is recommended, since alcohol consumption in each trimester has been associated with abnormalities, and the lowest innocuous dose of alcohol is not known.     

Acute leukemia during reproductive life: its course, complications and sequelae for fertility

Acute leukemia is less common during the reproductive years than in children or in post-menopausal women. Effective chemotherapy exists for adult lymphocytic leukemia, and the median survival is 18 to 20 months. Acute myelogenous leukemia still has a less favorable prognosis, with a medial survival of 12 months despite effective chemotherapeutic agents. The occurrence of acute leukemia in pregnancy does not change the overall prognosis, which depends primarily on the cytopathologic types. If leukemia occurs during the first trimester, therapeutic abortion is advised since the rate of spontaneous abortion after chemotherapy is high in the first trimester and fetal malformations are common. Acute leukemia can be treated in the second and third trimesters with little effect on the pregnancy or fetus. In patients cured of acute leukemia, the potential for subsequent pregnancies exists with little likelihood of increases in fetal malformations.     

The scientific venture of Battista Grassi and the discovery of Anopheles in malaria

Harlequin ichthyosis (HI) is a severe congenital ichthyosis in which newborn infants are covered with a thick plate of stratum corneum. We examined skin specimens from a variety of regions of the body including the scalp, face, tongue, trunk, upper and lower extremities, digits, palms, and soles of three fetuses affected with HI that were diagnosed prenatally. In all the skin regions, characteristic morphological abnormalities (absent or abnormal lamellar granules and intercellular lamellae, lipid inclusions in the cornified cells) were expressed in the late second trimester of the fetal period. The cornified cells in hair canals showed morphological abnormalities of HI more strongly than the interfollicular epidermis. Immunoblot study of epidermal extracts revealed that profilaggrin was much more prominent than filaggrin in all the hairy skin regions where the hair canals were extensively keratinized, but filaggrin was prominent in the palm. These observations support the idea that, in the hairy skin, HI phenotype expression is associated with keratinization and abnormal filaggrin metabolism in hair. In addition, the prenatal diagnosis or prenatal exclusion of HI is thought to be possible from whichever site of the fetal body the skin biopsy is taken in the late second trimester of the fetal period.