LONDON, SATURDAY 10 NOVEMBER 1990
1840-1990
Tubal pregnancy Rising incidence, earlier diagnosis, more conservative treatment Ectopic pregnancy has become more common in Western countries during the past 20 years. National figures for England are not available,' but in Scotland between 1970 and 1985 the incidence rose by half to six in 1000 pregnancies, and in parts of Scotland the incidence has doubled or trebled. I In the United States over the same period there was a fourfold increase to 20 in 1000 live births.5 In Finland, where the rate of ectopic pregnancy is among the highest in the world, a study of different age groups showed the incidence steadily increasing from the cohort of women born in the late 1930s to those born in 1954-8. The results suggest that the "baby boom" cohort born in 1945-54 has been mainly responsible for the current epidemic.6 Risk factors for ectopic pregnancy include a history of infertility, pelvic inflammatory disease or pelvic operations (particularly tubal surgery), and the current use of an intrauterine device."8 There is a link between smoking and ectopic pregnancy,9 but a previous legal termination of pregnancy increases the risk only slightly if at all.78 10 Sexually transmitted disease is an important factor: antibodies to Chlamydia trachomatis have been found in 76-78% of women with ectopic pregnancy compared with 13-38% of healthy pregnant women," 12 and IgG antibody to the gonococcus has been found in 32% of cases compared with 4% of controls." The diagnosis of ectopic pregnancy may be difficult. Rapid sensitive tests (using monoclonal antibodies) for human chorionic gonadotrophin in urine or serum can confirm or exclude pregnancy in women with lower abdominal pain, and by using these tests hospitals can save resources.'3 When the result of a urinary test for human chorionic gonadotrophin is positive and ectopic pregnancy is suspected a quantitative assay of the serum concentration of human chorionic gonadotrophin may be helpful. In normal pregnancy a gestation sac may be seen in the uterus on transabdominal ultrasonography when the serum concentration of human chorionic gonadotrophin is above 3000 IU/l (second international standard'4) and sometimes at much lower concentrations of human chorionic gonadotrophin. '5 If no sac is seen an ectopic pregnancy is likely and should be confirmed by laparoscopy. In normal pregnancy transvaginal ultrasonography can detect a fetal heartbeat 17 days after the missed period and will detect an intrauterine sac at serum concentrations of human chorionic gonadotrophin of 1000 IU/l. 617 Because of inconsistencies in the calibration of assays for human chorionic gonadotrophin'4 and variations in the ability of ultrasonographers each department should define its own BMJ VOLUME 301
10
NOVEMBER
1990
"discriminatory zone" for human chorionic gonadotrophin.'8 Most patients with suspected ectopic pregnancy have a serum concentration of human chorionic gonadotrophin below 3000 IU/1. In these patients the rate of rise of human chorionic gonadotrophin should be checked.'4 The normal rise is not linear, but a doubling time of around two days indicates a normal pregnancy.'9 In the early asymptomatic stages of ectopic pregnancy the rate of rise may be normal, but it slows down on repeated checking.2" Plasma progesterone concentrations are lower in ectopic pregnancy than in normal pregnancy,2' and rapid measurement of concentrations of both progesterone and human chorionic gonadotrophin may improve the accuracy of diagnosis.222 Transabdominal ultrasonography cannot reliably diagnose ectopic pregnancy,24 and transvaginal ultrasonography is the technique of choice when the condition is suspected.'62526 Transvaginal ultrasonography can identify diagnostic signs of ectopic pregnancy such as a "tubal ring," a non-specific adnexal mass, or particulate fluid in the peritoneal cavity.' 26 These allow the condition to be diagnosed from a single ultrasonogram in up to four fifths of women, and if those in whom there is doubt have ultrasonography again within three days a positive predictive value of 98% and a negative predictive value of 100% have been reported.'8 The traditional treatment of ectopic pregnancy is removing the affected fallopian tube. Oophorectomy should be avoided if possible. Salpingectomy is still necessary in many cases, either because of haemorrhage or because the tube is large, but an early diagnosis may allow less radical treatment. If the tube is unruptured and haemoperitoneum or pelvic adhesions are absent, laparoscopic treatment may be carried out.27 The maximum tubal diameter for this approach is usually 3 cm, but with experience larger pregnancies may be treated. Methods that have been used include aspiration of the pregnancy, milking the tube, or resection of the affected segment,27 but the preferred technique is linear salpingostomy, which may be carried out by cautery26 or laser.29 In some cases surgery may not be necessary. Expectant treatment has been used when the tubal diameter was less than 2 cm, and there is said to be a high chance of spontaneous resolution when the serum concentration of human chorionic gonadotrophin at diagnosis is less than 1000 IU/1. Nevertheless, an operation may be required, and chronic ectopic pregnancy may lead to the formation of dense adhesions.3" Methotrexate has been given to women with unruptured ectopic pregnancies less than 3 cm in diameter; in two small 1057
reported series resolution took an average of 14-30 days, and about 5-20% of patients still required laparotomy. 3 What is the prognosis after an ectopic pregnancy? Among 55 American women treated by salpingectomy or salpingostomy and followed up for three to 41 months 30 became pregnant again: 24 pregnancies were intrauterine and six were repeat ectopics.32 In a four to eight year follow up of 110 Finnish women (42 treated by conservative surgery and 68 by salpingectomy) 71 went on to have normal deliveries, 22 had recurrent ectopic pregnancies, and 16 were infertile.33 The outlook was better in patients aged under 30, those using an intrauterine device at the time of their ectopic pregnancy, and those who had conservative surgery. Among women treated in Israel by conservative microsurgery 14 (56%) of 25 women with two tubes achieved an intrauterine pregnancy and three (12%) had a repeat ectopic pregnancy: for 26 women with one tube the figures were 12 (46%) and 10 (39%) respectively.34 These authors concluded that despite the high risk of another ectopic pregnancy conservative surgery is justified because the rates of intrauterine pregnancy are higher than those achieved by in vitro fertilisation. As most of the women who became pregnant did so during the first year after operation the authors recommended that patients try to conceive again without delay. JAMES OWEN DRIFE Professor of Obstetrics and Gynaecology, University of Leeds, Clarendon Wing, Leeds LS2 9NS
9 Handlcr A, Davis F, Ferre C, Yeko F. 'I'he relationship of' smokinig and cctopic pregnancy. Am] l'ublic I'alth 1989;79:1239-42. 10 Holt VL, D)aling JR, Voigt LF, ci al. Induced abortioni anid the risk of subscqucnt ectopic pregnancy. Am 7 Public H'ealih 1989;79:1234-8. 11 Robertson JN, Hogston P, Ward ME. Gonococcal and chlamydial antibodies in ectopic arid
intrauierine pregnancy. Br] Obstil Gvnzaccol 1988;95:711-6. 12 Kihlstrom E, I.indgren R, Rvden G. Antibodies to Chlamydia trachomatis in womeni with infertility, pelvic inflammatory disease and ectopic pregnancy. Eur7 Obstet Gyinecol Reprod Riol 1990;35: 199-204. 13 Baber RJ, Bonifacio M, Saunders DIM. The impact of an instaint pregitancyr test kit on the operations of a major hospital casualty department. AustAZf7 )bstet fGYnaecol 1988;28:134-6. 14 Leach RE, Ory SJ. Modern management of cctopic pregnancy. 7 ReprodAled 1989;34:324-38. 15 Cacciatore B, Ylostalo P, Stenman UH, Widholm 0. Suspccted ectopic pregnancy: ultrasotund findings and hCG levels assessed by an immunofluorometric assay. Br 7 Obsict Gvplaecol 1988;95:497-502. 16 Stiller RJ, de Regt RH, Blair E. Transvaginal ultrasonography in patients at risk for ectopic pregnancy. AmJ7 Obstet Gvnecol 1989;161:930-3. 17 Bateman BG, Ntinley WC, Kolp LA, Kitchin JD, Felder R. Vaginal sonography findings and hCG dynamics of early intrauterine and tubal pregnaticies. f)bstet Gvnecol 1990;75:421-7. 18 Timor-Tritsch IE, Yeh MIJ, Peisner DB, Lesser KB, Slavik TA. The use of transvaginal ultrasonography in the diagnosis of ectopic pregnancy. Am] Obstet Gvnecol 1989;161:157-61. 19 Linblom B, Hahlin M, Sjoblom P. Serial human chorionic gottadotrophin determinations by fluoroimmunoassay for differentiation betweeti intrautcrinic and ectopic gestation. Am,7 Obsttci
GYsnecol 1989;161:397-400.
20 Shepherd RW, Patton PE, Novv MJ, Burrv- KA. Serial jI-H(UC measurcmeiits in the early detection of ectopic pregnancy. Obstet Gvnecol 1990;75:417-20. 21 Sauer MV, Anderson RE, Vermesh MN1, Stone BA, Paulson RJ. Spotttaneously resorbing ectopic pregnancy: preservation of human choriottic gonadotrophin bioactivity despite declining steroid hormone levels. Am] Obstet Gvnecol 1989;161:1673-6. 22 Riss PA, Radiv\totevic K, Bieglmayer C. Serum progesterone and human chorionic gonadotrtphin in tvery early pregnancy: implications for clinical management. Eur.7 Obstut Gvntectl Reprod Bitl 1989;32:71-7. 23 Stovall TG, Ling FW, Cope BJ, Buster JE. Preventing ruiptured ectopic pregtnanucy with a sitigle serum progesterone. Am]7 Obstet Gvnecol 1989;160:1425-31. 24 Stabile I, Campbell S, Grudzinskas JG. Can ultrasound reliably diagnose ectopic pregnancy? Br]f Obstet Gvnaecol 1988;95:1247-52. 25 De Crespigny LC. Demonstration of ectopic pregnancy by transvaginal ultrasound. Br] Obste Gvnaecol 1988;95:1253-6. 26 Fleischer AC, Pcnnell RG, McKee MS, ct al. Ectopic pregnancy: featurcs at transvaginal sonography. Radiology 1990;174:375-8. 27 Meyer WR, Decherney AH. Laparoscopic treatment of ectopic pregnancy. Baillieres CliotfObstet
Gynaecol 1989;3:583-94. 28 Silva PD. A laparoscopic approach can be applied to most cases of ectopic pregnancy. Obstet
1 Newton J. Ectopic pregnancy. BAIJ 1988;297:633-5. 2 Cole S, Clarke JA. Ectopic pregnancy. BMJ 1988;297:1046. 3 Flett GMM, Urquhart DR, Fraser C, Terry PB, Fleming JC. Ectopic pregnancy in Aberdeen 195085. Brj Obstet Gynaecol 1988;95:740-6. 4 Kok KP, Miahmood TA, Lees DAR. A study of the incidence, the trend and the management of patients with ectopic pregnancies in the Scottish highlands (1976-1987). Health Bull (Edinb) 1989;47:295-303. 5 Anonymous. Ectopic pregnancy-United States, 1987. MM.It7'R 1990;39:401-4. 6 Makinen JI. Increase of ectopic pregnancy in Finland-combination of time and cohort effects. Obstet fynecol 1989;73:21-4. 7 Makinen JI, Erkkola RU, Laippala PJ. Causes of the increase in the incidence of ectopic pregnancy. A4m J Obsiet Gynecol 1989;160:642-6. 8 Marchbanks PA, Anegers JF, Coulam CB, Strathy JH, Kurland LT. Risk factors for ectopic pregnancy: a population-based studv. JAM. A1988;259:1823-7.
29
30 31 32 33
Gynecol 1988;72:944-7. Keckstein J, Hepp S, Schneider V, Sasse V, Steiner R. The contact Nd: YAG laser: a niew technique for conservation of the fallopian tube in unruptured ectopic pregnancy. Br ] Obstet Gvnaecol 1990;97:352-6. Vermesh M. Conservative management of ectopic gestation. Fertil Steril 1989;51:559-67. Zakut H, Sadan 0, Katz A, Dreval D, Bernstein D. Management of tubal pregnancy with methotrexate. Br] Obstet Gynaecol 1989;%:725-8. Mitchell DE, NMcSwain HF, Pcterson HB. Fertility after ectopic pregnancy. Am ] Obstet Gynecol 1989;161:576-80. Makinen JI, Salmi TA, Nikkanen VPJ, Koskinen EYJ. Encouraging rates of fertility after ectopic pregnancy. Int Fertil 1989;34:46-5 1.
34) Oelsner G, Morad J, Carp H, Mashiach S, Serr DM. Reproductive performance following conservative microsurgical management of tubal pregnancy. Br]7 Obstet Gvnaecol 1987;94:107883.
Hepatitis B virus "escape" mutants A rare event which causes vaccination failure The protection given by vaccination has considerably reduced the morbidity and mortality from acute viral diseases. For many years vaccination was an empirical procedure, and dead or live attenuated whole organisms were used with little knowledge of the responses required to provide protection. Modern refinements have been introduced after scientific study of the immunological basis of effective prophylaxis. Thus in some cases live attenuated vaccines have superseded dead preparations and the specific antigens that induce immunodominant responses have been mapped. Safe preparations are now being made using molecular biological techniques to produce recombinant proteins or synthetic peptides known to induce protective responses. Protection against persistent or latent viral infections is more complicated than that against acute infections, particularly if infection occurs perinatally, when early intervention is essential. Nevertheless the protection given by vaccination against such infections is now being assessed. In the early 1980s trials of vaccines against hepatitis B virus were begun using hepatitis B surface antigen (HBsAg) derived from plasma of asymptomatic chronic carriers. Trials among people at high risk showed that these preparations were safe and effective in preventing transmission to susceptible people in the 95% of vaccinees who develop adequate 1058
antibody titres to HBsAg. These preparations, and the newer recombinant HBsAg vaccines, are now recommended for all high risk groups in the developed world. In some parts of the developing world, however, up to one fifth of the apparently healthy population are chronic carriers of the virus. Progression to cirrhosis or hepatocellular carcinoma occurs in 25-30% of these people. Mothers who are chronic carriers may transmit the virus to their offspring in the perinatal period, and these babies then become chronic carriers themselves. Transmission rates of up to 90% have been recorded in China and Japan, but the rate is much lower in African countries. This sequence of events is preventable by passive immunisation of the baby within 12 hours of birth with simultaneous administration of vaccine-so called active-passive immunisation. The passively administered hepatitis B immunoglobulin does not interfere with the active immune response to vaccine if given at a different site. This strategy, which has been encouragingly successful so far, aims at preventing the maternal virus reaching the infant liver and thereby preventing replication and chronic infection. In recent trials of hepatitis B virus in a high risk area in southern Italy Carman et al reported that 44 of the 1590 vaccinees showed evidence of viral replication (HBsAg), although all had developed protective titres of antibody. I The BMJ VOLUME 301
10 NOVEMBER 1990
1840-1990
Tubal pregnancy Rising incidence, earlier diagnosis, more conservative treatment Ectopic pregnancy has become more common in Western countries during the past 20 years. National figures for England are not available,' but in Scotland between 1970 and 1985 the incidence rose by half to six in 1000 pregnancies, and in parts of Scotland the incidence has doubled or trebled. I In the United States over the same period there was a fourfold increase to 20 in 1000 live births.5 In Finland, where the rate of ectopic pregnancy is among the highest in the world, a study of different age groups showed the incidence steadily increasing from the cohort of women born in the late 1930s to those born in 1954-8. The results suggest that the "baby boom" cohort born in 1945-54 has been mainly responsible for the current epidemic.6 Risk factors for ectopic pregnancy include a history of infertility, pelvic inflammatory disease or pelvic operations (particularly tubal surgery), and the current use of an intrauterine device."8 There is a link between smoking and ectopic pregnancy,9 but a previous legal termination of pregnancy increases the risk only slightly if at all.78 10 Sexually transmitted disease is an important factor: antibodies to Chlamydia trachomatis have been found in 76-78% of women with ectopic pregnancy compared with 13-38% of healthy pregnant women," 12 and IgG antibody to the gonococcus has been found in 32% of cases compared with 4% of controls." The diagnosis of ectopic pregnancy may be difficult. Rapid sensitive tests (using monoclonal antibodies) for human chorionic gonadotrophin in urine or serum can confirm or exclude pregnancy in women with lower abdominal pain, and by using these tests hospitals can save resources.'3 When the result of a urinary test for human chorionic gonadotrophin is positive and ectopic pregnancy is suspected a quantitative assay of the serum concentration of human chorionic gonadotrophin may be helpful. In normal pregnancy a gestation sac may be seen in the uterus on transabdominal ultrasonography when the serum concentration of human chorionic gonadotrophin is above 3000 IU/l (second international standard'4) and sometimes at much lower concentrations of human chorionic gonadotrophin. '5 If no sac is seen an ectopic pregnancy is likely and should be confirmed by laparoscopy. In normal pregnancy transvaginal ultrasonography can detect a fetal heartbeat 17 days after the missed period and will detect an intrauterine sac at serum concentrations of human chorionic gonadotrophin of 1000 IU/l. 617 Because of inconsistencies in the calibration of assays for human chorionic gonadotrophin'4 and variations in the ability of ultrasonographers each department should define its own BMJ VOLUME 301
10
NOVEMBER
1990
"discriminatory zone" for human chorionic gonadotrophin.'8 Most patients with suspected ectopic pregnancy have a serum concentration of human chorionic gonadotrophin below 3000 IU/1. In these patients the rate of rise of human chorionic gonadotrophin should be checked.'4 The normal rise is not linear, but a doubling time of around two days indicates a normal pregnancy.'9 In the early asymptomatic stages of ectopic pregnancy the rate of rise may be normal, but it slows down on repeated checking.2" Plasma progesterone concentrations are lower in ectopic pregnancy than in normal pregnancy,2' and rapid measurement of concentrations of both progesterone and human chorionic gonadotrophin may improve the accuracy of diagnosis.222 Transabdominal ultrasonography cannot reliably diagnose ectopic pregnancy,24 and transvaginal ultrasonography is the technique of choice when the condition is suspected.'62526 Transvaginal ultrasonography can identify diagnostic signs of ectopic pregnancy such as a "tubal ring," a non-specific adnexal mass, or particulate fluid in the peritoneal cavity.' 26 These allow the condition to be diagnosed from a single ultrasonogram in up to four fifths of women, and if those in whom there is doubt have ultrasonography again within three days a positive predictive value of 98% and a negative predictive value of 100% have been reported.'8 The traditional treatment of ectopic pregnancy is removing the affected fallopian tube. Oophorectomy should be avoided if possible. Salpingectomy is still necessary in many cases, either because of haemorrhage or because the tube is large, but an early diagnosis may allow less radical treatment. If the tube is unruptured and haemoperitoneum or pelvic adhesions are absent, laparoscopic treatment may be carried out.27 The maximum tubal diameter for this approach is usually 3 cm, but with experience larger pregnancies may be treated. Methods that have been used include aspiration of the pregnancy, milking the tube, or resection of the affected segment,27 but the preferred technique is linear salpingostomy, which may be carried out by cautery26 or laser.29 In some cases surgery may not be necessary. Expectant treatment has been used when the tubal diameter was less than 2 cm, and there is said to be a high chance of spontaneous resolution when the serum concentration of human chorionic gonadotrophin at diagnosis is less than 1000 IU/1. Nevertheless, an operation may be required, and chronic ectopic pregnancy may lead to the formation of dense adhesions.3" Methotrexate has been given to women with unruptured ectopic pregnancies less than 3 cm in diameter; in two small 1057
reported series resolution took an average of 14-30 days, and about 5-20% of patients still required laparotomy. 3 What is the prognosis after an ectopic pregnancy? Among 55 American women treated by salpingectomy or salpingostomy and followed up for three to 41 months 30 became pregnant again: 24 pregnancies were intrauterine and six were repeat ectopics.32 In a four to eight year follow up of 110 Finnish women (42 treated by conservative surgery and 68 by salpingectomy) 71 went on to have normal deliveries, 22 had recurrent ectopic pregnancies, and 16 were infertile.33 The outlook was better in patients aged under 30, those using an intrauterine device at the time of their ectopic pregnancy, and those who had conservative surgery. Among women treated in Israel by conservative microsurgery 14 (56%) of 25 women with two tubes achieved an intrauterine pregnancy and three (12%) had a repeat ectopic pregnancy: for 26 women with one tube the figures were 12 (46%) and 10 (39%) respectively.34 These authors concluded that despite the high risk of another ectopic pregnancy conservative surgery is justified because the rates of intrauterine pregnancy are higher than those achieved by in vitro fertilisation. As most of the women who became pregnant did so during the first year after operation the authors recommended that patients try to conceive again without delay. JAMES OWEN DRIFE Professor of Obstetrics and Gynaecology, University of Leeds, Clarendon Wing, Leeds LS2 9NS
9 Handlcr A, Davis F, Ferre C, Yeko F. 'I'he relationship of' smokinig and cctopic pregnancy. Am] l'ublic I'alth 1989;79:1239-42. 10 Holt VL, D)aling JR, Voigt LF, ci al. Induced abortioni anid the risk of subscqucnt ectopic pregnancy. Am 7 Public H'ealih 1989;79:1234-8. 11 Robertson JN, Hogston P, Ward ME. Gonococcal and chlamydial antibodies in ectopic arid
intrauierine pregnancy. Br] Obstil Gvnzaccol 1988;95:711-6. 12 Kihlstrom E, I.indgren R, Rvden G. Antibodies to Chlamydia trachomatis in womeni with infertility, pelvic inflammatory disease and ectopic pregnancy. Eur7 Obstet Gyinecol Reprod Riol 1990;35: 199-204. 13 Baber RJ, Bonifacio M, Saunders DIM. The impact of an instaint pregitancyr test kit on the operations of a major hospital casualty department. AustAZf7 )bstet fGYnaecol 1988;28:134-6. 14 Leach RE, Ory SJ. Modern management of cctopic pregnancy. 7 ReprodAled 1989;34:324-38. 15 Cacciatore B, Ylostalo P, Stenman UH, Widholm 0. Suspccted ectopic pregnancy: ultrasotund findings and hCG levels assessed by an immunofluorometric assay. Br 7 Obsict Gvplaecol 1988;95:497-502. 16 Stiller RJ, de Regt RH, Blair E. Transvaginal ultrasonography in patients at risk for ectopic pregnancy. AmJ7 Obstet Gvnecol 1989;161:930-3. 17 Bateman BG, Ntinley WC, Kolp LA, Kitchin JD, Felder R. Vaginal sonography findings and hCG dynamics of early intrauterine and tubal pregnaticies. f)bstet Gvnecol 1990;75:421-7. 18 Timor-Tritsch IE, Yeh MIJ, Peisner DB, Lesser KB, Slavik TA. The use of transvaginal ultrasonography in the diagnosis of ectopic pregnancy. Am] Obstet Gvnecol 1989;161:157-61. 19 Linblom B, Hahlin M, Sjoblom P. Serial human chorionic gottadotrophin determinations by fluoroimmunoassay for differentiation betweeti intrautcrinic and ectopic gestation. Am,7 Obsttci
GYsnecol 1989;161:397-400.
20 Shepherd RW, Patton PE, Novv MJ, Burrv- KA. Serial jI-H(UC measurcmeiits in the early detection of ectopic pregnancy. Obstet Gvnecol 1990;75:417-20. 21 Sauer MV, Anderson RE, Vermesh MN1, Stone BA, Paulson RJ. Spotttaneously resorbing ectopic pregnancy: preservation of human choriottic gonadotrophin bioactivity despite declining steroid hormone levels. Am] Obstet Gvnecol 1989;161:1673-6. 22 Riss PA, Radiv\totevic K, Bieglmayer C. Serum progesterone and human chorionic gonadotrtphin in tvery early pregnancy: implications for clinical management. Eur.7 Obstut Gvntectl Reprod Bitl 1989;32:71-7. 23 Stovall TG, Ling FW, Cope BJ, Buster JE. Preventing ruiptured ectopic pregtnanucy with a sitigle serum progesterone. Am]7 Obstet Gvnecol 1989;160:1425-31. 24 Stabile I, Campbell S, Grudzinskas JG. Can ultrasound reliably diagnose ectopic pregnancy? Br]f Obstet Gvnaecol 1988;95:1247-52. 25 De Crespigny LC. Demonstration of ectopic pregnancy by transvaginal ultrasound. Br] Obste Gvnaecol 1988;95:1253-6. 26 Fleischer AC, Pcnnell RG, McKee MS, ct al. Ectopic pregnancy: featurcs at transvaginal sonography. Radiology 1990;174:375-8. 27 Meyer WR, Decherney AH. Laparoscopic treatment of ectopic pregnancy. Baillieres CliotfObstet
Gynaecol 1989;3:583-94. 28 Silva PD. A laparoscopic approach can be applied to most cases of ectopic pregnancy. Obstet
1 Newton J. Ectopic pregnancy. BAIJ 1988;297:633-5. 2 Cole S, Clarke JA. Ectopic pregnancy. BMJ 1988;297:1046. 3 Flett GMM, Urquhart DR, Fraser C, Terry PB, Fleming JC. Ectopic pregnancy in Aberdeen 195085. Brj Obstet Gynaecol 1988;95:740-6. 4 Kok KP, Miahmood TA, Lees DAR. A study of the incidence, the trend and the management of patients with ectopic pregnancies in the Scottish highlands (1976-1987). Health Bull (Edinb) 1989;47:295-303. 5 Anonymous. Ectopic pregnancy-United States, 1987. MM.It7'R 1990;39:401-4. 6 Makinen JI. Increase of ectopic pregnancy in Finland-combination of time and cohort effects. Obstet fynecol 1989;73:21-4. 7 Makinen JI, Erkkola RU, Laippala PJ. Causes of the increase in the incidence of ectopic pregnancy. A4m J Obsiet Gynecol 1989;160:642-6. 8 Marchbanks PA, Anegers JF, Coulam CB, Strathy JH, Kurland LT. Risk factors for ectopic pregnancy: a population-based studv. JAM. A1988;259:1823-7.
29
30 31 32 33
Gynecol 1988;72:944-7. Keckstein J, Hepp S, Schneider V, Sasse V, Steiner R. The contact Nd: YAG laser: a niew technique for conservation of the fallopian tube in unruptured ectopic pregnancy. Br ] Obstet Gvnaecol 1990;97:352-6. Vermesh M. Conservative management of ectopic gestation. Fertil Steril 1989;51:559-67. Zakut H, Sadan 0, Katz A, Dreval D, Bernstein D. Management of tubal pregnancy with methotrexate. Br] Obstet Gynaecol 1989;%:725-8. Mitchell DE, NMcSwain HF, Pcterson HB. Fertility after ectopic pregnancy. Am ] Obstet Gynecol 1989;161:576-80. Makinen JI, Salmi TA, Nikkanen VPJ, Koskinen EYJ. Encouraging rates of fertility after ectopic pregnancy. Int Fertil 1989;34:46-5 1.
34) Oelsner G, Morad J, Carp H, Mashiach S, Serr DM. Reproductive performance following conservative microsurgical management of tubal pregnancy. Br]7 Obstet Gvnaecol 1987;94:107883.
Hepatitis B virus "escape" mutants A rare event which causes vaccination failure The protection given by vaccination has considerably reduced the morbidity and mortality from acute viral diseases. For many years vaccination was an empirical procedure, and dead or live attenuated whole organisms were used with little knowledge of the responses required to provide protection. Modern refinements have been introduced after scientific study of the immunological basis of effective prophylaxis. Thus in some cases live attenuated vaccines have superseded dead preparations and the specific antigens that induce immunodominant responses have been mapped. Safe preparations are now being made using molecular biological techniques to produce recombinant proteins or synthetic peptides known to induce protective responses. Protection against persistent or latent viral infections is more complicated than that against acute infections, particularly if infection occurs perinatally, when early intervention is essential. Nevertheless the protection given by vaccination against such infections is now being assessed. In the early 1980s trials of vaccines against hepatitis B virus were begun using hepatitis B surface antigen (HBsAg) derived from plasma of asymptomatic chronic carriers. Trials among people at high risk showed that these preparations were safe and effective in preventing transmission to susceptible people in the 95% of vaccinees who develop adequate 1058
antibody titres to HBsAg. These preparations, and the newer recombinant HBsAg vaccines, are now recommended for all high risk groups in the developed world. In some parts of the developing world, however, up to one fifth of the apparently healthy population are chronic carriers of the virus. Progression to cirrhosis or hepatocellular carcinoma occurs in 25-30% of these people. Mothers who are chronic carriers may transmit the virus to their offspring in the perinatal period, and these babies then become chronic carriers themselves. Transmission rates of up to 90% have been recorded in China and Japan, but the rate is much lower in African countries. This sequence of events is preventable by passive immunisation of the baby within 12 hours of birth with simultaneous administration of vaccine-so called active-passive immunisation. The passively administered hepatitis B immunoglobulin does not interfere with the active immune response to vaccine if given at a different site. This strategy, which has been encouragingly successful so far, aims at preventing the maternal virus reaching the infant liver and thereby preventing replication and chronic infection. In recent trials of hepatitis B virus in a high risk area in southern Italy Carman et al reported that 44 of the 1590 vaccinees showed evidence of viral replication (HBsAg), although all had developed protective titres of antibody. I The BMJ VOLUME 301
10 NOVEMBER 1990
