Volume 165 Issue 7

Research Hypertension in pregnancy: maternal and fetal outcomes according to laboratory and clinical features Mark A Brown and Megan L Buddle MJA 1996; 165: 360-365 Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Sexual health Abstract Objectives: To determine the predictive value of clinical and laboratory parameters for maternal and fetal complications in pregnant women with hypertension. Design: Prospective data collection. Setting: Two primary referral hospitals in the southern suburbs of Sydney between March 1987 and July 1994. Subjects: 1183 pregnant women with hypertension managed conjointly by a physician and obstetrician. Intervention: Uniform management protocol, plus antihypertensive medications if systolic blood pressure was persistently ≥ 160 mmHg and/or diastolic blood pressure ≥ 90 mmHg. Main outcome measures: Maternal and fetal complications, as defined by the Australasian Society for the Study of Hypertension in Pregnancy Consensus Statement. Results: Of 825 women with pre-eclampsia (502 mild; 323 severe), univariate analysis showed that hyperuricaemia, proteinuria and severe hypertension were significantly associated with a higher rate of maternal and fetal complications. In multivariate analyses without confounders, only primiparity, low serum albumin levels and absence of diabetes were significantly associated with severe pre-eclampsia. Severe pre-eclampsia, high haemoglobin levels and low platelet count were associated with higher rates of small-for-gestational-age babies, but only low serum albumin levels were associated with increased perinatal mortality rates. Low birthweight was associated with severe hypertension and severe pre-eclampsia. Conclusions: Simple clinical and laboratory parameters are useful predictors for maternal and fetal outcomes in pregnancies complicated by hypertension. Introduction Hypertensive disorders in pregnancy are common and their incidence appears to be increasing.1 These disorders comprise hypertension de novo in pregnancy (variably called pre-eclampsia, gestational or transient hypertension), and chronic forms of hypertension (essential and secondary hypertension), and have multiple modes of clinical presentations. With the current emphasis on outpatient management of pregnant women with non-proteinuric hypertension,2 clinicians require readily available clinical and laboratory parameters as indicators of the likely outcome of pregnancies complicated by hypertension. Such information is often difficult to obtain because of the selective nature of cases and complications reported by high-risk tertiary-care obstetric units, and is confounded by the varying treatments given to pregnant women before referral.3,4 Our study examined prospectively the maternal and fetal outcomes in women with hypertension in pregnancy, and the associated clinical and laboratory features. In particular, we sought to determine whether complications were greater if the woman had hyperuricaemia, severe hypertension and/or proteinuria, was nulliparous, or presented with hypertension early in the pregnancy. We also sought to determine which clinical and laboratory features were associated with severe pre-eclampsia. Methods The study group consisted of all pregnant women with hypertension who were referred by their obstetrician to one physician (M A B) at primary referral hospitals (St George or Hurstville community hospitals) in Sydney between March 1987 and July 1994. Indications for referral were: Hypertension failing to settle after overnight rest in hospital, or repeated measurement in a day-only unit; The presence of proteinuria or other abnormal urinalysis, abnormal biochemistry (serum electrolytes and creatinine levels, liver function tests) or thrombocytopenia; Recurrent admissions for hypertension; or A suspected secondary cause for hypertension. The definitions, classifications and complications of hypertension in pregnancy used in our study were those of the Australasian Society for the Study of Hypertension in Pregnancy (ASSHP) (Boxes 1 and 2).5 The maternal biochemical and haematological data used in our analysis were those recorded immediately before delivery. Complications were those having occurred by the time of discharge from hospital or by the postpartum check-up (after three months). Each patient's management was overseen by one physician (M A B) in conjunction with the patient's obstetrician. A standardised management protocol was followed by all staff during the course of this study (Box 3). Statistical analysis All data were stored in a database program (iBANK) and analysed using Minitab statistical package6 and BMDP statistical software.7For initial bivariate analyses, the frequency of adverse events within groups was tested by χ2 analysis and, where significant, by 2 x 2 contingency tables. Biochemical and haematological indices and birthweights were compared using Student's t tests, and significance assessed using Hochberg's method for interpreting multiple comparisons. The maternal-outcome variable was severity of pre-eclampsia. Logistic regression analysis was used to analyse the following variables as predictors of severe pre-eclampsia: parity; gestation at presentation; age; plasma uric acid level; serum albumin, haemoglobin and haematocrit levels; and diabetes. Proteinuria, platelet count and serum creatinine levels were not analysed because abnormalities of these form part of the diagnosis of severe pre-eclampsia. Fetal-outcome variables were birthweight, small-for-gestational-age (SGA) and perinatal mortality (PNM). Each of the following variables was analysed as a predictor of poor fetal outcome: maternal complications, age, parity, diabetes, gestation at presentation and laboratory data. Multiple regression analysis was used for birthweight and logistic regression analysis for SGA and PNM. For regressions, backward elimination was used until all remaining predictors were statistically significant (P < 0.05). Results Clinical details From March 1987 to July 1994, 1183 pregnant women with hypertension fulfilled the criteria for referral to a physician (M A B) and were entered into the study, representing 6.7% of all confinements at the two hospitals. During this period, 2121 women were documented in hospital records as having hypertension in pregnancy, representing 12% of all confinements. There were 825 women (70%) with pre-eclampsia (mild, 502; severe, 323), 82 (7%) with superimposed pre-eclampsia, 223 (19%) with essential hypertension, and 53 (4%) with secondary hypertension (predominantly renal disease). Oral antihypertensive medications were given to 563 women (48%), additional parenteral antihypertensives were required by 281 (24%), and 339 (29%) received no antihypertensive medications. Thirteen women (1%) received "prophylactic" low-dose aspirin. Five women (0.4%) required dialysis during or after pregnancy and four women (0.3%) had convulsions. Seventy-three women (6%) had pre-existing or gestational diabetes mellitus. Of the 1242 babies born to the women in the study, there were 15 perinatal deaths (12 per 1000 hypertensive pregnancies). There was one maternal death (0.08%) in a 29-year-old woman who presented at 29 weeks' gestation with severe pre-eclampsia and who delivered immediately and died unexpectedly the next day. Despite autopsy, the cause of death was not established. Predictors of outcomes in women with pre-eclampsia Univariate analysis Hyperuricaemia was significantly associated with higher rates of all maternal complications and SGA babies and babies with lower average birthweights than normal plasma uric acid levels (Box 4). Severe hypertension was significantly associated with higher maternal complication rates and earlier gestation at delivery than mild hypertension (Box 4). This group of women had babies of a lower average birthweight, a higher proportion of SGA babies and a higher perinatal mortality rate. Proteinuria was significantly associated with similar maternal and fetal complication rates as severe hypertension, and the proportion of SGA babies was similar to non-proteinuric hypertension (Box 4). Parity did not affect maternal complication rates, except for a higher prevalence of severe hypertension and liver disease in nulliparae (Box 5). Early gestation at presentation with hypertension (at or before 32 weeks' gestation) was significantly associated with a higher prevalence of proteinuria than later presentation (Box 5). Multivariate analysis Severe pre-eclampsia was associated with low serum albumin (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.90-0.97; P = 0.0001), primiparity (OR, 0.51; 95% CI, 0.33-0.79; P = 0.002) and the absence of diabetes (OR, 0.21; 95% CI, 0.05-0.93; P = 0.04). SGA was associated with severe pre-eclampsia (OR, 2.5; 95% CI, 1.6-3.9; P = 0.0001), high maternal haemoglobin levels (OR, 3.7; 95% CI, 1.1-12.8; P = 0.04) and low platelet counts (OR, 1.4; 95% CI, 1.1-1.8; P = 0.02). Birthweight was positively associated with gestation at presentation (regression coefficient [β], 41; standard error [SE], 5; P < 0.0001) and serum albumin levels (β, 28; SE, 5; P < 0.0001) and inversely associated with severe hypertension (β, 2193; SE, 69; P < 0.005) and severe pre-eclampsia (β, 2311; SE, 60; P < 0.0001). Perinatal mortality was associated only with low serum albumin levels (OR, 0.88; 95% CI, 0.82-0.95; P < 0.0003), but there were too few perinatal deaths to support a useful formal analysis. Outcomes in women with all forms of hypertension in pregnancy Box 6 shows the maternal and fetal outcomes in women with the different forms of hypertension in pregnancy. Maternal and fetal outcomes were better for women with essential hypertension than for the other groups. Twenty-seven per cent (or 10% if proteinuria was included in the diagnosis) of women with essential hypertension developed superimposed pre-eclampsia. Women with superimposed pre-eclampsia delivered their babies earlier, had babies with lower average birthweights, significantly more SGA babies and significantly higher rates of all maternal complications than women with essential hypertension alone. Women with secondary (predominantly renal) hypertension had similar maternal and fetal outcomes to women with superimposed pre-eclampsia (data available from author). Discussion In our prospective study, there was uniform management of all women with hypertensive disorders in pregnancy. As the database excluded very mild cases of hypertension in pregnancy, an inherent bias exists, but our study provides a general estimate of fetal and maternal outcomes for women with hypertension managed in primary referral hospitals. During the study period, 12% of all confinements were complicated by hypertension, which is either similar to or higher than previous reports.8-11 Hjertberg et al. noted a 5% incidence of hypertension in pregnancy, of whom 83% had hypertension de novo in pregnancy.12 In our study, 70% of women had pre-eclampsia (hypertension de novo in pregnancy), 19% had essential hypertension alone, 7% had superimposed pre-eclampsia, and 4% had a renal or other secondary cause. These results are similar to those from a smaller study in a tertiary referral unit.13 When analysed separately, hyperuricaemia, proteinuria and severe hypertension were associated with higher rates of all maternal and fetal complications, while parity was associated with severe hypertension and liver disease. Presentation before 32 weeks' gestation impacted negatively on fetal outcome. We have reported previously on the adverse impact of proteinuria on maternal and fetal outcomes.14 Hyperuricaemia is an established marker of severe pre-eclampsia, correlating histologically with the severity of renal lesions,15 and clinically with adverse fetal outcomes.16 We found that hyperuricaemia, when considered alone, was associated with higher maternal complication rates and fetal growth retardation, but, with multivariate analysis, was not a significant predictor of adverse maternal or fetal outcomes. Hyperuricaemia remains a useful marker of pre-eclampsia, but women with normal serum uric acid levels and pre-eclampsia may still develop complications. Severe hypertension was confirmed by multivariate analysis to be associated with low birthweight babies, and, in univariate analysis, with a higher incidence of all fetal complications and a higher incidence of SGA babies. Therefore, the more severe the hypertension, the more the likelihood of fetal as well as maternal complications. Pre-eclampsia has long been considered a disorder of primigravidae.17 However, it is clear that pre-eclampsia does occur in second or subsequent pregnancies (particularly following a change of partner); in our study, approximately two-fifths of the women with pre-eclampsia were parous women. Parous women had a lower incidence of severe hypertension and liver disease when compared with nulliparae, but there were no other differences in outcomes between these groups. Therefore, equal risk to the fetus should be assumed in both groups of women once hypertension has developed in the second half of pregnancy. The gestation at presentation in pre-eclampsia influences fetal outcome because of the likelihood of early delivery, but we are unaware of any prospective studies that relate gestation at presentation to maternal complication rates. Apart from proteinuria, maternal complication rates for women presenting before 33 weeks' gestation in our study were similar to those who presented later. Two retrospective studies have reported a higher incidence of maternal complications in women with pre-eclampsia of early onset.18,19 Our patients presenting early with pre-eclampsia had milder disease than that reported by Sibai et al.20 As expected, the earlier the gestation with pre-eclampsia the lower the birthweight (because gestation did not proceed as far as those presenting later), but the likelihood of having an SGA baby was not increased. Although maternal diabetes was associated with a lower risk of severe pre-eclampsia, only 6% of our study population had diabetes. Therefore, it should not be assumed that diabetes protects pregnant women against severe pre-eclampsia. The consistent relationship between low serum albumin levels and adverse maternal and fetal outcomes was independent of proteinuria and implies that hepatic albumin synthesis is altered in severe pre-eclampsia. The association between high maternal haemoglobin levels and SGA babies presumably reflects a reduced plasma volume and haemoconcentration, which is associated with poor fetal growth.21 In conclusion, for women with pre-eclampsia, the traditional clinical markers of proteinuria, parity and severe hypertension remain useful clinical indices of maternal risk, while severe pre-eclampsia, severe hypertension, elevated haemoglobin and low serum albumin levels portend increased fetal risk. Acknowledgements We wish to thank the obstetricians of St George and Hurstville community hospitals, Professor J A Whitworth, Ms Jodie Wilkinson and Dr M Jones (Intstat Australia Pty Ltd). References Crawford JS. Epidemic pre-eclampsia. Lancet 1987; 1: 329-330. Tuffnell DJ, Lilford RJ, Buchan PC, et al. Randomised controlled trial of day care for hypertension in pregnancy. Lancet 1992; 339: 224-227. Horvath JS, Korda A, Child A, et al. Hypertension in pregnancy. A study of 142 women presenting before 32 weeks' gestation. Med J Aust 1985; 143: 19-21. Clarke M, Mason ES, Macvicar J, Clayton DG. Evaluating perinatal mortality rates: effects of referral and case mix. BMJ 1993; 306: 824-827. Australasian Society for the Study of Hypertension in Pregnancy. Consensus Statement on Management of Hypertension in Pregnancy: Executive Summary. Med J Aust 1993; 158: 700-702. Minitab [computer program], version 9.1. Pennsylvania State College: Minitab Inc, 1993. BMDP [computer program]. Berkeley, Calif: University of California, 1990. Martikainen AM, Heinonen KM, Saarikoski SV. The effect of hypertension in pregnancy on fetal and neonatal condition. Int J Gynaecol Obstet 1989; 30: 213-220. Andrews WW, Cox SM, Sherman ML, Leveno KJ. Maternal and perinatal effects of hypertension at term. J Reprod Med 1992; 37: 73-76. Safflas AF, Oldson DR, Franks AL, et al. Epidemiology of pre-eclampsia and eclampsia in the United States, 1979-1986. Am J Obstet Gynecol 1990; 163: 460-465. Pietrantoni M, O'Brien WF. The current impact of the hypertensive disorders of pregnancy. Clin Exp Hypertens 1994; 16: 479-492. Hjertberg R, Bellrage P, Hanson U. Conservative treatment of mild and moderate hypertension in pregnancy. Acta Obstet Gynecol Scand 1992; 71: 439-446. Horvath JS, Phippard A, Henderson-Smart D, et al. High risk hypertensive pregnancies: maternal and foetal outcome. Clin Exp Hypertens Pregnancy 1983; B2: 21-28. Brown MA, Buddle ML. The importance of non proteinuric hypertension in pregnancy. Hypertens Pregnancy 1995; 14: 57-65. Pollak VE, Nettles JB. The kidney in toxemia of pregnancy: a clinical and pathologic study based on renal biopsies. Medicine (Baltimore) 1960; 39: 469-526. Redman CWG, Beilin LJ, Bonnar J, Wilkinson PH. Plasma urate measurements in predicting fetal death in hypertensive pregnancy. Lancet 1976; 2: 1370-1373. Chesley LC. Diagnosis of pre-eclampsia. Obstet Gynecol 1985; 65: 423-425. Sibai BM, Taslimi M, Abdella TN, et al. Maternal and perinatal outcome of conservative management of severe pre-eclampsia in midtrimester. Am J Obstet Gynecol 1985; 152: 32-37. Railton A, Allen DG. Management and outcome of pregnancy complicated by severe pre-eclampsia of early onset. S Afr Med J 1987; 72: 608-610. Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant management of severe pre-eclampsia at 28 to 32 weeks' gestation: a randomized controlled trial. Am J Obstet Gynecol 1994; 171: 818-822. Brown MA, Zammit VC, Mitar DM. Extracellular fluid volumes in pregnancy-induced hypertension. J Hypertens 1992; 10: 821-829. (Received 9 Oct 1995, accepted 13 May 1996) Authors' details Departments of Medicine, Renal Medicine and Obstetrics, St George and Hurstville community hospitals, University of NSW. Mark A Brown, MB BS, FRACP, MD, Associate Professor of Medicine; Megan L Buddle, SRN, Hypertension Unit Registered Nurse. No reprints will be available. Correspondence: Associate Professor M A Brown, Department of Renal Medicine, St George Hospital, Kogarah, NSW 2217. E-mail: "nest::brown"ATdodo.ssahs.unsw.edu.au 1: ASSHP classifications and definitions of hypertension in pregnancy Hypertension: A sitting systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP (phase IV Korotkoff sound) ≥ 90 mmHg, or a rise in systolic BP of ≥ 25 mmHg and/or diastolic BP ≥ 15 mmHg from first-trimester BP (two readings taken six hours apart). Proteinuria: ≥ 300 mg/day (24-hour urine collection) or persistently (over two or more days) ≥ 2+ protein (1 g/L) on urinalysis (dipstick testing). As urinalysis was performed daily, non-proteinuric hypertension that progressed to proteinuric hypertension was always detected. Hyperuricaemia: Plasma uric acid level > 0.35 mmol/L. Pre-eclampsia: The development of hypertension after 20 weeks' gestation in a woman with no known history of hypertension or renal disease and whose blood pressure (BP) was normal in the first half of the pregnancy and returned to normal after delivery: (i) mild pre-eclampsia: hypertension only; (ii) severe pre-eclampsia: hypertension and evidence of maternal organ dysfunction (see Maternal complications, Box 2). Essential hypertension: Hypertension in the first half of pregnancy (often occurring before pregnancy) without a demonstrable secondary cause, or the appearance of hypertension in the second half of pregnancy in a woman whose BP failed to return to normal within three months after delivery. Superimposed pre-eclampsia: The development of proteinuria and/or hyperuricaemia in the second half of pregnancy in a woman with essential hypertension. Secondary hypertension: To exclude a secondary cause of hypertension, all women had serum potassium levels measured and had urinalysis, microscopy and a clinical examination; urinary catecholamines and renal ultrasound were performed in selected cases. Within this group, superimposed pre-eclampsia was not diagnosed as a separate entity as it was too difficult to ascertain whether changes (e.g., increasing proteinuria) reflected superimposed pre-eclampsia or progression of the underlying (usually renal) disease. ASSHP = Australasian Society for the Study of Hypertension in Pregnancy.5 Back to text 2: ASSHP complications of hypertension in pregnancyMaternal complications:(i)Severe hypertension: Blood pressure (BP) ≥ 170 mmHg systolic and/or ≥ 110 mmHg diastolic;(ii)Proteinuria (Box 1);(iii)Haematological abnormalities: haemolysis (haemoglobin < 110g/L, with reticulocytosis, fragments) or thrombocytopenia (< 150 x 109/L platelets);(iv)Renal impairment: serum creatinine level ≥ 0.10 mmol/L;(v)Liver disease: elevated serum aspartate aminotransferase level > 40 IU/L, with or without severe epigastric pain;(vi)Neurological disturbances: visual scotoma; severe headaches with hyperreflexia; hyperreflexia with sustained clonus (> 3 beats). Fetal complications:(i)Small-for-gestational-age (SGA): birthweight below the 10th centile for gestation, corrected for sex;(ii)Perinatal mortality (PNM): stillbirths and neonatal deaths per 1000 hypertensive pregnancies. ASSHP = Australasian Society for the Study of Hypertension in Pregnancy.5Back to text 3: Management protocol during pregnancy Maternal complications: Blood pressure (BP) measurements six times per day; Fetal cardiotocograph recordings on alternate days (or more often if clinically indicated); Daily urinalysis; Biochemistry and haematological testing at least twice weekly; Bedrest if there is evidence of intrauterine fetal growth retardation, or maternal neurological features or severe hypertension. Antihypertensive therapy: Oral antihypertensive therapy (single agent or combinations) of oxprenolol, hydralazine, methyldopa, prazosin or nifedipine was instituted if the systolic BP was persistently > 160 mmHg or diastolic BP persistently > 90 mmHg after overnight bedrest in hospital. Parenteral antihypertensive therapy (sublingual nifedipine or intravenous hydralazine) was given for severe hypertension (Box 2). Convulsion prophylaxis (intravenous phenytoin followed by oral phenytoin) was used for women with neurological disturbances (Box 2). Indications for delivery. Delivery (by induction) was scheduled after 38 weeks' gestation if the BP remained stable and the cervix was favourable. Indications for delivery before 38 weeks' gestation were:5 Fetal compromise: premorbid (cardiotocographic) tracing of fetal heart rate or failure of fetal growth (assessed by doppler ultrasound). Inability to control maternal BP; Persistent neurological disturbances (see Box 2); Progressively rising liver enzyme or serum creatinine levels, or worsening thrombocytopenia. Women whose pregnancies could not be prolonged beyond 30 weeks' (and occasionally 32 weeks') gestation were sometimes transferred before delivery to a tertiary referral unit with neonatal intensive care facilities. Outcomes of this group were included in our analysis. Back to textFor box 4 click here 5: Maternal and fetal outcomes in women with pre-eclampsia (mild and severe) according to parity and gestation at presentation (see text for definitions). Data are percentages or means (standard deviation). Gestation at presentationNulliparae ParousP ≤ 32 wks> 32 wks Pn508317129696Age (years)27 (5)30 (5) < 0.0001*29 (5)28 (5)0.30Nulliparae (%)10000.0001*57630.20Gestation at presentation (weeks)36 (4)35 (6)0.00927 (7)37 (2)< 0.0001*Gestation at delivery (weeks)38 (3)38 (2) 0.8935 (4)38 (2)< 0.0001*Hyperuricaemia (%)61540.0456590.53Maternal complicationsSevere hypertension24%15%0.001*29%19%0.008Thrombocytopenia11%8%0.1011%10%0.75Proteinuria21%16%0.0931%17%0.003*Renal insufficiency8%5%0.089%7%0.27Liver disease12%6%0.005*15%9%0.04Neurological13%10%0.4116%11%0.09Laboratory dataPlasma creatinine (mmol/L).07 (.04).07 (.02).18.08 (.08)0.07 (.02) 0.51Plasma uric acid (mmol/L).40 (.20).37 (.04) .01.38 (.09)0.39 (0.17)0.66Plasma albumin (g/L)33 (5)34 (5) .3431 (8)34 (4)0.002*Haemoglobin (g/L)119 (23)122 (16) .03117 (37)121 (15)0.20Haematocrit (%)35.1 (5.5)35.9 (5.6) .1033.7 (8.7)35.7 (4.7)0.02Platelets (x 109/L)223 (82)232 (82) .11206 (95)230 (79)0.009*Fetal complicationsSGA (%)17210.1724180.10PNM (per 1000)1730.06544< 0.0001*Birthweight (g)2984 (701)2985 (694) 0.982312 (960)3105 (561)< 0.0001* * Statistically significant . SGA = small-for-gestational-age. PNM = perinatal mortality. Back to text 6: Maternal and fetal outcomes in women with different forms of hypertension in pregnancy (ASSHP classifications). Data are percentages or means (standard deviation). Pre-eclampsiaEssential hypertension Superimposed pre-eclampsiaP*n82523382Age (years)28 (5)30 (530 (5)> 0.0001†Nulliparae (%)6237560.290.002†Gestation at presentation (weeks)35 (5)26 (10)28 (10) < 0.0001†0.17Gestation at delivery (weeks)38 (3)38 (2)36 (1)0.0007†< 0.0001†Hyperuricaemia (%)581683< 0.0001†0.0001†Maternal complicationsSevere hypertension21%13%38%0.0005†< 0.0001†Thrombocytopenia10%1%16%0.11< 0.0001†Proteinuria19%035%0.0005†< 0.0001†Renal insufficiency7%09%0.62< 0.0001†Liver disease10%1%11%0.79< 0.0001†Neurological12%3%20%0.06< 0.0001†Laboratory dataPlasma creatinine (mmol/L)0.07 (0.04)0.06 (0.02)0.07 (0.02)0.78< 0.0001†Plasma uric acid (mmol/L)0.39 (0.16)0.32 (0.25)0.46 (0.35)0.090.002†Plasma albumin (g/L)33 (5)35 (6)33 (5)0.810.04Haemoglobin (g/L)120 (20)119 (14) 117 (17)0.140.52Haematocrit (%)35.4 (5.5)35.1 (4.0) 34.7 (5.4)0.290.64Platelets (x 109/L)226 (82)256 (68) 235 (78)0.360.03Fetal complicationsSGA (%)199280.20< 0.0001†PNM (per 1000)129120.930.80Birthweight (g)2984 (701)3260 (652) 2795 (935)0.080.0001†* Significance of difference between outcomes for women with pre-eclampsia and superimposed pre-eclampsia (and for women with essential hypertension and superimposed pre-eclampsia). †Statistically significant. SGA = small-for-gestational-age. PNM = perinatal mortality. ASSHP = Australasian Society for the Study of Hypertension in Pregnancy.5 Back to text

Mark A Brown · Megan L Buddle

Prevalence of hepatitis G virus in Queensland blood donors Len D Moaven, Catherine A Hyland, Ian F Young, D Scott Bowden, Rhonda McCaw, Leigh Mison and Stephen A Locarnini MJA 1996; 165: 369 Subsequently cited in Moaven L. Should we be screening blood donors for hepatitis G virus? The case for screening. MJA 1998; 169: 373-374 and Wong et al. Should we be screening blood donors for hepatitis G virus? The case against screening. MJA 1998; 169: 375-377 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Blood donors - Serological and biochemical testing - Reverse transcription PCR testing - Results - Discussion - Box - References - Authors' details - - ©MJA1996 Abstract Objective: To determine the prevalence of hepatitis G virus (HGV) carriage in Queensland blood donors. Design: Cross-sectional survey with retrospective longitudinal study of HGV-positive donors. Setting: Brisbane Red Cross Blood Bank, 1995. Subjects: 100 consecutive blood donors attending the Blood Bank on two days in October 1995 and 20 blood donors with a raised plasma alanine aminotransferase (ALT) level on their last donation. Outcome measures: Presence of HGV RNA by reverse transcription polymerase chain reaction (RT-PCR) in currently donated blood and in blood samples archived for up to 34 months. RT-PCR used two different reverse transcription methods and three different specific sets of primers and probes. Results: Five of the 120 blood donors were positive for HGV RNA by all RT-PCR methods (four of the 100 with normal ALT levels [4%] and one of the 20 with raised ALT levels [5%]). Retrospective testing of archived samples showed that four of these five had been persistently HGV RNA-positive for at least two years, while the fifth had been HGV RNA-negative on two donations before becoming HGV RNA-positive. No risk factors were identified for this donor. Conclusions: A relatively large number of Queensland blood donors (4%) are persistently HGV RNA-positive. MJA 1996; 165: 369-371 Introduction S ince the introduction of improved diagnostic assays for hepatitis C virus 1 and increased screening of blood donors, 2 the incidence of post-transfusion hepatitis has been reduced to low levels. However, there are still cases of post-transfusion hepatitis where an aetiological agent is not identified. 3 While searching for novel agents that may be associated with post-transfusion hepatitis, two independent groups recently discovered an RNA virus that causes acute and chronic infection in man. 4,5 The two isolates, designated hepatitis G virus (HGV) and GB virus C, respectively, belong to the same species, 6 and findings for one seem applicable to the other. Currently, the only reliable method for determining the prevalence of infection with these viruses is specific reverse transcription polymerase chain reaction (RT-PCR) assay to detect viral RNA. A serological assay to detect carriers of HGV is unlikely to be available in the immediate future, and much of the epidemiology of HGV will rely on RT-PCR-based assays. From the available RT-PCR data, it appears that HGV is transmitted parenterally, with increased prevalence in injecting drug users and patients who have received multiple transfusions. 4,7,8 HGV has a high prevalence in developed countries, with about 1.5% of volunteer blood donors from the United States and Europe being positive for HGV RNA. 4,8 It is not known whether these positive donors are transiently infected or chronic carriers of HGV. We examined the prevalence of HGV in Queensland blood donors. As most donors had plasma stored from previous donations, we were also able to collect unique longitudinal data. Methods Blood donors Consecutive blood donors at the Brisbane Red Cross Blood Bank over two days in October 1995 were asked to participate. The first 100 to sign a consent form agreeing to be tested for HGV were studied (compliance was 100%). These donors all had normal plasma alanine aminotransferase (ALT) levels. Blood was also collected over a three-month period from 20 donors with a raised ALT level on their most recent donation. Six of the 20 had raised ALT levels on two or more previous donations. All donors had signed the donor declaration form indicating they did not fall into an "at risk" group. All testing was performed with the approval of the Queensland Red Cross Blood Transfusion Service Ethics Committee. Serological and biochemical testing All donors were tested for antibodies to hepatitis C virus (HCV), HIV 1, HIV 2 and human T-cell lymphotropic virus (HTLV) and for hepatitis B surface antigen (HBsAg) (Abbott Diagnostics, Chicago, Illinois, USA). They were also screened with a syphilis antibody assay, Sysmic RPR (Diagast, Lille, France). Plasma ALT levels were measured by a microtitre tray assay. 9 Samples positive for HGV RNA were also tested for hepatitis B core specific antibody (Abbott Diagnostics). Reverse transcription PCR testing For RT-PCR testing, the recommendations of Kwok and Higuchi 10 were followed to prevent sample contamination. Blood samples were collected in acid-citrate-dextrose and plasma was stored at 2 70 o C within two hours of collection. RNA was subsequently extracted from these plasma samples with a guanidine thiocyanate and phenol-chloroform extraction procedure. 11 RT-PCR was performed with random hexamers and two sets of PCR primers from the 5 9 untranslated region and the region encoding the non-structural protein 5a of the HGV genome. These primers are part of an HGV primer and capture probe set commercially available from Boehringer Mannheim (Germany). In addition, RT-PCR was performed with primers from the region encoding the protein 5b, as described previously. 12 If a plasma sample was positive for HGV RNA, a separate aliquot of plasma was retrieved from frozen storage and RNA was extracted and tested with all three primer sets. Samples positive for HGV RNA were also tested for HCV RNA (Amplicor, Roche Diagnostic Systems, Branchberg, New Jersey, USA). Donors positive for HGV RNA were tested retrospectively by recovering archived frozen plasma samples from previous donations. These samples had been frozen within two hours of collection and stored at 2 30 o C. As controls, archived plasma samples were also recovered from donors negative for HGV RNA. Archived samples were coded and tested blind. In addition, four of the five donors found to be positive for HGV RNA returned subsequently to donate blood and were retested for HGV RNA. These retrospective and prospective samples were tested with the NS5b primers alone. Results Five of the 120 blood donors were HGV-positive by RT-PCR with all three of the primer sets. These positive donors comprised four of the 100 with normal ALT levels (4%; 95% confidence interval [CI], 1%-10%) and one of the 20 with raised ALT levels (5%; 95% CI, 0.1%-25%). This donor had not had raised ALT levels previously. The remaining 115 donors were negative by all three primer sets. Repeat PCR testing of a separate aliquot of each HGV-positive sample revealed complete concordance of results. The five HGV-positive donors were negative for hepatitis B core-specific antibody and HCV RNA. All donors were negative for antibodies to HCV, HIV 1, HIV 2 and HTLV, for HBsAg and for syphilis RPR antibody. Plasma samples from 22 previous donations given by the five HGV-positive donors were also tested for HGV RNA (see Box). Four donors were HGV-positive for all previous donations ( n = 18), made up to 22-34 months previously. The fifth, a 38-year-old man, was HGV-positive from August 1994, but two previous donations (May 1994 and November 1993) were HGV-negative. His ALT level was normal on each occasion and no risk factor or illness could be identified for this donor despite specific questioning about the period May 1994 to August 1994. Potential risk factors were noted for three of the other HGV carriers (see Box). All HGV-positive donors were well. Four returned for further testing, including the donor who appeared to acquire HGV infection in 1994; they remained HGV-positive on all occasions (up to six months after initial tests). The control archived plasma samples were tested blindly and found to be HGV-negative. Discussion This is the first study to describe the prevalence of HGV in an Australian blood donor population and to provide longitudinal data on a cohort of HGV-infected donors. Five of 120 blood donors (4.2%) were HGV-positive, a higher prevalence than seen in other developed countries. 4,8 All five appeared to be chronic carriers of HGV (assuming infection does not resolve after HGV carriage for longer than a year). It has yet to be determined why this infection is so prevalent in a group normally assumed to be at low risk for exposure to blood-borne viruses. Mother-to-baby (and early horizontal) transmission may account for the pattern of distribution (analogously to HBV in developing countries). 12 One donor had grown up in a developing country and another had potential risk factors (e.g., tattooing). Even so, one of the donors appeared to acquire HGV infection recently, without evident risk factors. This suggests that there are multiple modes of transmission. We found that only one of the HGV-positive donors had a raised ALT level, and on only one occasion. Although HGV infection is associated with an early and mild rise in results of liver function tests in some recipients of HGV-infected blood, 4 this is not unusual in acute viral infections. There is currently little evidence that HGV commonly causes chronic liver disease, but this does not preclude association with another disease. Indeed, we would argue that it is unlikely that a positive-strand RNA virus could cause chronic infection and not be associated with a disease syndrome. It is worth noting that with such a high prevalence of HGV in the general population the demonstration of a disease association will have to be particularly rigorous. The strategy we developed for HGV testing is time consuming and expensive, but, without a reliable serological or alternative virological marker, nucleic acid amplification by PCR remains the method of choice. An alternative to our PCR strategy could be use of a single reliable primer set, with automation of RNA extraction and RT-PCR. Blood donations may have to be tested for HGV RNA when suitable assays become available for mass screening, especially if evidence emerges that it causes significant disease. A National Health and Medical Research Council working party on novel viral hepatides has been set up in collaboration with the Red Cross Blood Transfusion Service to determine the significance of HGV in blood donations. In the meantime, it is important that recipients of donated blood continue to be advised of the potential complications of heterologous blood transfusion and, specifically, that they may acquire HGV infection. 2 However, currently the clinical significance of HGV infection is unclear and further clinical and epidemiological studies are needed on this new and emerging virus. References Aach RD, Stevens CE, Hollinger B, et al. Hepatitis C virus infection in post-transfusion hepatitis: an analysis with first and second generation assays. N Engl J Med 1991; 325: 1325-1329. Sloand EM, Pitt E, Klein HG. Safety of the blood supply. JAMA 1995; 274: 1368-1373. Alter HJ. Transfusion transmitted hepatitis C and non-A, non-B, non-C. Vox Sang 1994; 67: 19-24. Linnen J, Wages J, Zhen-Yong ZK, et al. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent. Science 1996; 271: 505-508. Simons JN, Leary TP, Dawson JG, et al. Isolation of novel virus-like sequences associated with human hepatitis. Nat Med 1995; 1: 564-569. Zuckerman AJ. Alphabet of hepatitis viruses [editorial]. Lancet 1996; 347: 558-559. Bowden DS, Moaven LD, Locarnini SA. New hepatitis viruses: are there enough letters in the alphabet? Med J Aust 1996; 164: 87-89. Dawson GJ, Schlauder GG, Coleman P, et al. Prevalence and clinical significance of GBV-C [abstract]. Proceedings of the Ninth Triennial International Symposium on Viral Hepatitis and Liver Disease; 1996 April 21-25; Rome (Italy). Rome: CpA (Viale delle Medaglie d'Oro, 342100136), 33: 116. Hyland CA, Douglas R, Mazzocchi R, Young IF. Surrogate testing for non-A, non-B hepatitis in Queensland, Australia, an ALT microtitre tray method for screening blood donors. Pathology 1988; 20: 271-274. Kwok S, Higuchi R. Avoiding false positives with PCR. Nature 1989; 339: 237-238. Chemczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate phenol-chloroform extraction. Anal Biochem 1987; 167: 156-159. Moaven LD, Tennakoon PS, Bowden DS, Locarnini SA. Mother-to-baby transmission of hepatitis G virus. Med J Aust 1996; 165: 84-85. (Received 15 May, accepted 9 Aug 1996) Authors details Victorian Infectious Diseases Reference Laboratory, Fairfield Hospital, Melbourne, VIC. Len D Moaven, FRCPA, Senior Registrar in Virology; D Scott Bowden, PhD, Senior Scientist (Molecular Virology); Rhonda McCaw, BSc, Scientist (Molecular Virology); Stephen A Locarnini, PhD, MRC(Path), Director. Red Cross Blood Transfusion Service, Brisbane, QLD. Catherine A Hyland, PhD, Scientist-in-Charge (Viral Serology); Ian F Young, FRCPA, Director; Leigh Mison, BSc, Scientist. Reprints: Dr S A Locarnini, Victorian Infectious Diseases Reference Laboratory, Fairfield Hospital, PO Box 65, Fairfield, VIC 3078. E-mail: stephenL AT hna.ffh.vic.gov.au <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Len D Moaven · Catherine A Hyland · Ian F Young · Rhonda McCaw · Leigh Mison · Stephen A Locarnini

Congenital syphilis: still a reality in 1996 Michael D Humphrey and David L Bradford MJA 1996; 165: 382 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Introduction - What is the true incidence of congenital syphilis in Australia? - Diagnosis - Risk factors for congenital syphilis - Measures to control syphilis - Problems in targeting those at risk - Action plan - Acknowledgements - References - Authors' details - - ©MJA1996 Despite the widespread use of penicillin for more than 50 years, syphilis continues to be a problematic health issue in many parts of the world. In Australia, congenital syphilis is again a significant cause of stillbirth, preterm labour and neonatal disease in some areas (including central and northern Australia). Control mechanisms based on screening, reliable treatment protocols, contact-tracing and adequate follow-up appear to be less effective than they were in the past. It is difficult to discuss such a socially stigmatising disease when it is clear that some community groups are at high risk, and may be offended by and feel disempowered in the face of well-meaning medical debate. If congenital syphilis is to be eradicated, new approaches are required. These include public-awareness campaigns to stress the need for antenatal care in affected communities; involving the community in efforts to prevent syphilis; providing culturally appropriate services; improving notification and surveillance systems; improving the management of pregnant women who present to maternity units without prior booking; and improving the management of syphilis in pregnancy. There is a need to raise awareness that antenatal care is important not only for the mother's health but also for the wellbeing of the baby. (MJA 1996; 165: 382-385) Introduction I n the last decade, much of the world has experienced a marked increase in the incidence of syphilis, with rates in reproductive-age adults the highest since the 1940s. 1 In Australia, notifications of syphilis between 1991 and 1994 varied from 12.2 to 16.0 per 100 000 population. 2 There was wide geographical variance, with reported rates greater than 100 per 100 000 in much of northern Australia; however, all States and Territories were involved (Box 1). The incidence was much higher in females than in males in the 10 to 24 years age group, and rates in Aboriginal people varied from 114 to 913 per 100 000 in different regions. 2 Elsewhere in the world, incidences similar to those in Australia are being reported, with particular emphasis on the high incidence of new and repeated infections in marginalised groups. 1,3-9 In regions where the prevalence of syphilis is high, congenital syphilis is a major preventable cause of perinatal death. 1,8,10,11 In 1994 and 1995, 232 new or repeated infections were notified in women from Cairns and the surrounding region involving Cape York and the Torres Strait (D Brookes, Public Health Nurse, Tropical Public Health Unit, Northern Zone, Queensland Health Department, Cairns, personal communication). Twenty-seven of the 3058 women who gave birth at Cairns Base Hospital during this period had active syphilis complicating their pregnancy (Tropical Public Health Unit, Northern Zone, Queensland Health Department, Cairns [unpublished data]), and eight of the region's 91 perinatal deaths were judged to be due to congenital syphilis in association with inadequate antenatal care (Cairns Base Hospital Perinatal Mortality Committee [unpublished data]). The main features of untreated congenital syphilis during pregnancy are stillbirth (which may be preceded by non-immune hydrops fetalis), preterm labour and intrauterine growth restriction; in the newborn the main features are hepatosplenomegaly, prolonged jaundice, thrombocytopenia, failure to thrive and radiologically visible metaphyseal changes. To prevent congenital syphilis, institutional, administrative and cultural barriers to the successful management of the problem must be overcome. The true incidence of syphilis must be determined, diagnostic procedures improved, the risk factors more readily recognised and control measures re-examined. What is the true incidence of congenital syphilis in Australia? The accurate diagnosis of syphilis depends on the microbiological demonstration of Treponema pallidum . Serological tests provide indirect evidence of infection, and, without clinical assessment, are crude indicators of whether infection is likely to be recent or long-standing. Nevertheless, in many jurisdictions in Australia case reporting of syphilis is dependent on laboratory notification of positive syphilis serology. Thus, notification of syphilis is based on an arbitrary decision as to whether an infection is likely to be recent, as determined by the rapid plasma reagin (RPR) or Venereal Disease Research Laboratories (VDRL) titre. For example, in Queensland the case definition for notification is based on an RPR/VDRL titre of 1 : 8 or more, in association with positive specific treponemal serology. 12 Cases so notified are likely to be in individuals who have a recently acquired infection, and non-notification of lower titres may mean that there is a degree of under-reporting, particularly in the latent phase of the disease. No agreed definition of the criteria for reporting congenital syphilis exists in Australia, and only 13 cases have been reported nationally in the last five years, including two in women over 65 years of age (J Irvine, Surveillance Officer, Communicable Diseases Network of Australia and New Zealand -- National Notifiable Diseases Surveillance System, Canberra, personal communication). Thus, the true incidence of this problem nationwide is unknown. Diagnosis Definitive diagnosis is by trepo nemal-specific tests ( Treponema pallidum haemagglutination antibody [TPHA], fluorescent treponemal antibody [FTA]) when screening non-treponemal serological tests (RPR or VDRL) are positive, as pregnancy, HIV infection and other conditions (such as systemic lupus erythematosus, rheumatoid arthritis, infectious mononucleosis, and many other diseases associated with autoimmune complexes) can be associated with false positive screening reactions, or with difficulties in interpreting results. 13 Care must be taken to ensure that lack of familiarity with the codes used to express the results of syphilis serology does not lead to failure to recognise the disease and, consequently, failure to follow-up. 5 It is necessary to carefully follow-up all babies born to women who have positive serological tests for syphilis, as more than 50% of liveborn affected infants are asymptomatic. Failure to conduct such follow-up may lead to significant long term physical and/or mental handicap. Risk factors for congenital syphilis These risk factors include: Lack of adequate antenatal care; 8 Failure to repeat a serological test for syphilis in the third trimester when it tested negative at first booking; 8 Past history of sexually transmitted disease (STD); 8 Multiple sexual partners; 8 Substance abuse; 8 and Being in a displaced or marginalised population group (indigenous peoples, and people marginalised by chemical dependency, poverty, prostitution). 9 Vertical transmission usually takes place after four months' gestation, so that early antenatal screening and appropriate treatment should prevent most cases. It is clear that, if screening is not performed, the diagnosis is unlikely to be made in a timely fashion. Therefore, major efforts must be made in the future to alter the way we deliver antenatal care so that it is accessible and appropriate to those at high risk. Measures to control syphilis Guidelines for syphilis control, formulated almost 60 years ago in the United States, 14 included the principal elements of public education (including community participation), case-finding, prompt clinical treatment, contact-tracing and routine serological screening (including antenatal screening) of high-risk groups. The implementation of this program in the United States proved to be effective. However, in 1986 the incidence of early syphilis in the United States increased, 15 with a predictable increase in congenital syphilis accompanying this new epidemic. 16 By 1990, at the peak of the epidemic, African Americans accounted for more than 80% of reported cases of early syphilis. 17 A dramatic increase in the availability of "crack" cocaine (accompanied by an increase in the practice of exchanging sex for money and drugs), increasing poverty, disenfranchisement of minorities and urban decay were some of the reasons for this disproportionate incidence of syphilis in black communities in the United States. 17 The efficacy of control programs for sexually transmitted disease, and especially contact-tracing activities, employed to control this outbreak of syphilis in the United States was seriously questioned. 18 In Australia, we have sought to control syphilis by broadly following the same United States guidelines. In the major cities, where syphilis rates today are minimal, this has served us well. However, throughout northern Australia, as well as in northern Victoria, central Australia and northwest New South Wales, the prevalence of syphilis has remained high, despite our best efforts. Allan Brandt (Professor of the History of Medicine and Science, Harvard University), in No Magic Bullet , argues that a biomedical approach (e.g., case-finding, contact-tracing and treatment protocols) is too restrictive, and that social conditions and other variables need to be addressed. 19 While there will always be a place for contact-tracing the immediate partner(s) of index cases -- particularly of pregnant women with syphilis (as a control measure) -- this is less successful in practice than theory would suggest. Various factors, such as the time involved and the patient's embarrassment and reluctance to contribute to the program, make contact tracing difficult to conduct from the urban consulting room. However, in indigenous communities other factors, such as cultural sensitivity about the discussion of sexual issues outside the family or tribal group, beliefs in what constitutes "men's business" and "women's business" and the dilemma of finding health workers of the same sex and tribal group to conduct the tracing, pose additional difficulties. These factors, together with a relative dearth of male indigenous health workers, a rapid turnover of staff and the low priority placed on public health activities, result in often-insurmountable difficulties in implementing contact-tracing. In any case, many diagnoses of syphilis in adults in northern Australia are likely to represent latent rather than currently infectious disease, so th at even highly successful contact-tracing will have a relatively small impact on public health control of the disease. Problems in targeting those at risk A recent editorial in Sexually Transmitted Diseases notes that in the United States "syphilis is a marker for social marginalization" (i.e., the spread of the disease is disproportionate in poor members of minority groups). The authors state that: . . . Underlying the problem of syphilis in the United States, and central to any plans to eliminate it, are the issues of race, racism, and poverty, and our ability to speak frankly and intelligently about these issues. . . . It is from a legitimate fear of the consequences of the social stigma of syphilis that many community advocates prefer not to talk about racial differences in syphilis rates. . . . This hiding of the key fact about syphilis may be making it difficult for concerned persons to mobilise the kind of support needed for effective prevention programs. 1 We believe a "key fact" in Australia is that Aboriginal and Torres Strait Islander populations are disproportionately affected by syphilis, yet it is difficult to talk openly about this for fear of further marginalising or stigmatising indigenous people. This understandable sensitivity has tended to stifle productive debate about how we can best deal with the issue, and has hampered communication between affected communities and health professionals. The continuing high prevalence of syphilis in indigenous communities in Australia is a major threat to the welfare of unborn and newborn children. It is vital that those at most risk can be targeted for the provision of high quality antenatal care (if necessary, through special outreach programs); for retesting in the third trimester or at birth; 20,21 for the development of appropriate treatment protocols; and for contact-tracing that is realistic and achievable. Action plan It seems clear that we need a new approach if syphilis is to be controlled, and if congenital syphilis is to become (as it should be) a tragedy of the past. While accepting that the persistence of infectious syphilis (and the accompanying sporadic cases of congenital syphilis) in indigenous communities in Australia is a complex issue, we suggest some measures that could be considered in addressing the problem ( Box 2). We must find a way to discuss honestly and openly the continuing high prevalence of syphilis in indigenous communities, which is a major threat to the welfare of unborn and newborn children, so that those at most risk can get the most appropriate care. Acknowledgements We wish to thank Ms D Brookes, RN (Public Health Nurse, Tropical Public Health Unit, Northern Zone, Queensland Health Department, Cairns), Dr W J Smith (Cairns District Health Service) and the staff of the Communicable Diseases Network of Australia and New Zealand -- National Notifiable Diseases Surveillance System, Canberra, for their assistance. References St Louis ME, Farley TA, Aral SO. Untangling the persistence of syphilis in the south [editorial]. Sex Transm Dis 1996; 23: 1-4. Hargreaves J, Longbottom H, Myint H, et al. Annual Report of the National Notifiable Diseases Surveillance System, 1994. Commun Dis Intell 1995; 19: 542-574. Garland SM, Kelly VN. Is antenatal screening for syphilis worth while? Med J Aust 1989; 151: 368-372. How JHY, Bowditch JDP. Syphilis in pregnancy: experience from a rural aboriginal community. Aust N Z J Obstet Gynaecol 1994; 34: 383-389. Gurry DL, Porter PA, Evans DTP. Congenital syphilis: when the medium fails to transmit the message. Med J Aust 1993; 159: 121-124. Humphrey MD. Syphilis -- alive and well as a cause of perinatal death [letter]. Med J Aust 1996; 164: 381-382. Mascola L, Pelosi R, Blount JH, et al. Congenital syphilis. Why is it still occurring? JAMA 1984; 252: 1719-1722. Lim CT, Koh MT, Sivanesaratnam V. Early congenital syphilis -- a continuing problem in Malaysia. Med J Malaysia 1995; 50: 131-135. McFarlin BL, Bottoms SF, Dock BS, Isada NB. Epidemic syphilis: maternal factors associated with congenital infection. Am J Obstet Gynecol 1994; 170: 535-540. Duthie SJ, King PA, Yung GLK, Ma HK. Routine serological screening for syphilis during pregnancy -- disposable anachronism or fundamental necessity? Aust N Z J Obstet Gynaecol 1990; 30: 29-31. Klass PE, Brown ER, Pelton SI. The incidence of perinatal syphilis at the Boston City Hospital: a comparison across four decades. Pediatrics 1994; 94: 24-28. McCall B. Surveillance of sexually transmissible disease in Queensland 1988-1993. Commun Dis Intell 1995; 19: 58-68. Nandwani R, Evans DT. Are you sure it's syphilis? A review of false positive serology. Int J STD AIDS 1995; 6: 241-248. Parran T. Shadow on the land. New York: Reynal and Hitchcock, 1937. CDC. Primary and secondary syphilis -- United States, 1981-1990. MMWR Morb Mortal Wkly Rep 1991; 40: 314-315, 321-323. CDC. Surveillance for geographic and secular trends in congenital syphilis -- United States, 1983-1991. MMWR Morb Mortal Wkly Rep 1993; 42 (Suppl 6): 59-71. Nakashima AK, Rolfs RT, Flock ML, et al. Epidemiology of syphilis in the United States, 1941-1993. Sex Transm Dis 1996; 23: 16-23. Andrus JK, Fleming DW, Harger DR, et al. Partner notification: can it control epidemic syphilis? Ann Intern Med 1990; 112: 539-543. Brandt AM. No magic bullet: a social history of venereal disease in the United States since 1880. Expanded edition. New York: Oxford University Press, 1987: 4. Qolohle DC, Hoosen AA, Moodley J, et al. Serological screening for sexually transmitted infections in pregnancy: is there any value in re-screening for HIV and syphilis at the time of delivery? Genitourin Med 1995; 71: 65-67. Opai-tetteh ET, Hoosen AA, Moodley J. Re-screening for syphilis at the time of delivery in areas of high prevalence. S Afr Med J 1993; 83: 725-726. Metropolitan New York City Area Task Force on Syphilis. Report to the New York State Department of Health 1991: 1-16. Ernst AA, Romolo R, Nick T. Emergency department screening for syphilis in pregnant women without prenatal care. Ann Emerg Med 1993; 22: 781-785. Sanchez PJ, McCracken GH Jr, Wendel GD, et al. Molecular analysis of the fetal IgM response to Treponema pallidum antigens: implications for improved sero diagnosis of congenital syphilis. J Infect Dis 1989; 159: 508-517. Quinn TC. Recent advances in diagnosis of sexually transmitted diseases. Sex Transm Dis 1994; 21 (Suppl): S24. Authors details North Queensland Clinical School, The University of Queensland. Michael D Humphrey, FRACOG, Professor of Obstetrics and Gynaecology; and Director of Obstetrics and Gynaecology, Cairns Base Hospital, QLD. Cairns District Health Service, Cairns, QLD. David L Bradford, FACVen, Director of Sexual Health. No reprints will be available. Correspondence: Professor Michael D Humphrey, Department of Obstetrics and Gynaecology, Cairns Base Hospital, PO Box 902, Cairns, QLD 4870. - - To top of article - ©MJA1996 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Michael D Humphrey · David L Bradford