- Email: [email protected]
Effective Tocolysis—Our Quest for the Holy Grail
, , , , ,
G U E S T
The Society of Obstetricians and Gynaecologists of Canada COUNCIL MEMBERS 1995-1996 PRESIDENT Dr. Garry Krepart - Winnipeg
EDITORIAL
, , , , ,
Effective Tocolysis-Our Quest for the Holy Grail
PAST PRESIDENT: Dr. Rodolphe Maheux - Quebec PRESIDENT ELECT: Dr. Nan Schuurmans - Edmonton EXECUTIVE VICE-PRESIDENT: Dr. Andre B. Lalonde - Ottawa ASSOClATE EXECUTIVE VICE-PRESIDENT: Dr Robert Klnch - Ottawa TREASURER : Dr. Antonin Rochette - Loretteville VICE PRESIDENTS: Dr. Robert Reid - KIngston Dr. Thomas Baskett - Halifax REGIONAL CHAIRS & DEPUTY CHAIRS WESTERN REGION Dr. Don Davis - Mediclne Hat Dr. Jan Christilaw - White Rock CENTRAL REGION Dr. Chui Kin Yuen - Winnipeg Dr. Thirza Smith - Saskatoon ONTARIO REGION Dr. Donna Fedorkow - Hamilton Dr. Catherine Claire Kane - Ottawa QUEBEC REGION Dr. Cajetan Gauth,er - Levis Dr. Vyta Senikas - Montreal ATLANTIC REGION Dr. Davld A . Knickle - Charlottetown Dr. Garth Christie - Fredericton PUBLIC REPRESENTATIVE Ms. Janet MacMilian - Halifax JUNIOR FELLOW REPRESENTATIVE Dr. Georges Sylvestre - Montreal ASSOCIATE MD REPRESENTATIVE Dr. T. Riley - Oakville ASSOCIATE NURSING REPRESENTATIVE Ms. Mane-Josee Trepanier - Ottawa NATIONAL OFFICE EXECUTIVE VICE-PRESIDENT Dr. Andre B. Lalonde DIRECTOR OF COMMUNICATIONS Martine Joly
774 Echo Drive Ottawa,Ontario K1S 5N8 tel : (613) 730-4192 or 1-800-561-2416 fax: (613) 730-4314
Ouring the first half of this century, physicians practising obstetrics were preoccupied primarily with the health and welfare of the mother, and understandably so. Matemal mortality and morbidity were, by today's standards, alarmingly high, and although the same could be said for the fetus and neonate, there was a general acceptance of the priority attached to the wellbeing of pregnant women as opposed to that of their offspring. It was not until after World War II that remarkable reductions in matemal mortality began to occur. Hannah, MD, FRCSC, The advent of antibiotics, blood transfusions, safer W.J. Professor Emeritus, University of anaesthesia, more widespread availability of pre- Toronto natal care, and the development ofbetter training programmes for physicians and nurses in obstetric care, brought a much more congenial environment for women undertaking pregnancy, and from the early 1960s, the level of safety for pregnant women has changed only marginally. This improvement in the mother's lot was almost immediately followed by a concerted effort to effect a comparable reduction in perinatal mortality and morbidity. Numerous examples co me to mind where this has been achieved: the virtual resolution of the problem of erythroblastosis due to Rhesus incompatibility; the development of the concept of neon at al intensive care, which has contributed so much to the increased survival rate of preterm, low birthweight infants; the beneficial effects of antenatal glucocorticoids given to the mother in preterm labour in reducing perinatal mortality due to neonatal respiratory distress syndrome; the introduction of surfactant to accomplish the same objective; antenatal diagnosis for detection of genetic and structural abnormalities-all highlight some of the important advances in the care we now provide that have resulted in dramatic improvements in perinatal welfare. Most of these developments have originated with research at the basic science level and its subsequent application in the clinical setting. With the very best of intentions, but with much more limited success, we have made enormous efforts to achieve reductions in perinatal mortality and morbidity associated with antepartum and intrapartum hypoxia by me ans of a variety of fetal surveillance techniques. The introduction of continuous electronic fetal heart rate monitoring (EFM) in the 1960s held out the promise
JOURNAL SOGC
1059
NOVEMBER 1995
, , , of earlier recognition of intra-uterine hypoxia, leading to earlier intervention in the hope that this would have a profound effect in reducing mortality and neurologie morbidity in the neonate. Unfortunately, and for a variety of reasons, our expectations have not been realized. The majority of weil designed trials demonstrate that the use of continuous EFM is not associated with any improvement in mortality or morbidity, but is associated with higher intervention rates. Before the earlier promise of this technology can ever be realized, it is clear that we must double our efforts to improve the precis ion of our interpretation of the information it currently provides. The struggle to reduce neurologic morbidity from intra-uterine hypoxia and acidosis must continue unabated. One of the most important areas of clinical obstetrics in which we have met with a conspicuous lack of success is, of course, the resolution of the problem of preterm labour. Although our neonatology colleagues have made contributions of enormous importance in improving the survival rates of preterm, low birthweight infants in the past two decades, it is a sobering reality that, for our part, we have made litde or no progress in reducing the rate of preterm birth during this same time period. This very important problem is more than ours alone to solve. We have known for a long time that the preterm birth rate is highest in those members of our society who are the most disadvantaged socially, economically, nutritionally, and educationally. Further, we have also known that prematurity and low birthweight are the most important causes of perinatal mortality and morbidity. It is apparent therefore, or at least it should be, that the rate of preterm birth serves as a marker of the socio-economic quality oflife in our society, and the challenge this represents is one that is faced by our nation as a whole. As we enter aperiod of economic retrenchment where reduction of the deficit, and debt, must assurne high priority, one can be forgiven for being somewhat pessimistic about the likelihood of seriously addressing this problem at a societallevel, at least for the foreseeable future. As a consequence, we are under a very great obligation to do everything we can at the pharmacologic and clinicallevel to resolve wh at most would agree is the most important perinatal problem we face. For the past three decades we have attempted, by one means or another, to find a way to inhibit or elimi-
JOURNAL SOGC
nate unwanted uterine activity when it poses a threat of allowing an otherwise normal fetus to be born prematurely and face the associated hazards. Wehave used narcotics in the hope of damping down uterine contractility. As a result of Csapo's "progesterone block" theory to explain the origin of labour, the use of large doses of parenteral progesterone was in a vogue far aperiod of time. The work of Fuchs in demonstrating the tocolytic effects of intravenous alcohol followed the clinical observation that women in labour could, for at least a time, slow down their labour by the generous ingestion of wine, spirits or beer. For many women, the treatment proved unacceptable because of the sometimes nasty side effects. An apparently major advance made its appearance in the early 1970s when the betamimetic agents were recognized as having tocolytic properties, and they came into widespread use from that time. The term "major advance" is used because it was evident from both laboratory and clinical observations that this group of agents had the capacity to inhibit uterine contractility, often dramatically; the ward "apparently" is used, however, because it soon became clear that the tocolytic effect did not pers ist, and we now know that this is due to the down regulation of myometrial cell receptors. Nevertheless, the use of these agents was associated with an average delay in birth of 24 to 48 hours, wh ich allowed for the administration of antenatal steroids with their proven benefit to the neonate. The maternal side effects of this group of agents, however, are by no means inconsequential and the combination of their relatively short duration of action and the side effects have limited their clinical usefulness. More recendy, magnesium sulphate (MgS04) and indomethacin have come into clinieal use as tocolytics, and the survey carried out by the Planning Group for the recent Consensus Conference on Tocolytics, whose report may be read elsewhere in this Journal, indicates that betamimetics, MgS0 4, and indomethacin are the favoured medications in the centres represented by the Conference participants, despite litde or no evidence of their effectiveness. Newer agents such as nifedipine, sulindac, glyceryl trinitrate, and atosiban are in preliminary stages of clinical application ar are undergoing clinical trials. Ir is axiomatic that when a clinical problem has a wide variety of treatments available to it, it is almost
1060
NOVEMBER 1995
, , , always the case that none of these treatments is entirely satisfactory, and this certainly seems to hold true with the current group of tocolytic drugs. The fundamental problem with each one of these agents seems to be a combination of short duration of action and/or distressing side effects. Furthermore, there is disagreemenr among the clinicians of this country, and others, as to the relative superiority of one drug over the others. Ir is crucially important that, of the agents currently in use, properly designed clinical trials be undertaken to compare them with one another and/or with placebo, so that we will come to a general agreement on the most effective treatment. Looking to the future, perhaps nowhere in obstetric science has there been such a demonstrable need for the active collaboration of basic and clinical research as in the search for the ideal tocolytic agent (if indeed there is one). As the Consensus Conference Report advises us, the complexities of unravelling the mysteries of labour at any gestational age are formidable, but the search must continue for the chemical which satisfies the requirement for effective tocolysis on the one hand, with a minimum of side effects on the other. lts usefulness must then be confirmed by the same kind of rigorously designed clinical trials referred to above, clearly demonstrating its superiority over current agents. When this all happens, obstetric science will have made a gigantic stride in confronting the spectre of unwanted preterm labour which has haunted us for so long, and we can then perhaps look forward to the achievement of something we have only dreamed of-the irreducible minimum in perinatal mortality and morbidity.
J SOGe
1995;17:1059-62
JOURNAL SOGC
1062
NOVEMBER 1995
G U E S T
The Society of Obstetricians and Gynaecologists of Canada COUNCIL MEMBERS 1995-1996 PRESIDENT Dr. Garry Krepart - Winnipeg
EDITORIAL
, , , , ,
Effective Tocolysis-Our Quest for the Holy Grail
PAST PRESIDENT: Dr. Rodolphe Maheux - Quebec PRESIDENT ELECT: Dr. Nan Schuurmans - Edmonton EXECUTIVE VICE-PRESIDENT: Dr. Andre B. Lalonde - Ottawa ASSOClATE EXECUTIVE VICE-PRESIDENT: Dr Robert Klnch - Ottawa TREASURER : Dr. Antonin Rochette - Loretteville VICE PRESIDENTS: Dr. Robert Reid - KIngston Dr. Thomas Baskett - Halifax REGIONAL CHAIRS & DEPUTY CHAIRS WESTERN REGION Dr. Don Davis - Mediclne Hat Dr. Jan Christilaw - White Rock CENTRAL REGION Dr. Chui Kin Yuen - Winnipeg Dr. Thirza Smith - Saskatoon ONTARIO REGION Dr. Donna Fedorkow - Hamilton Dr. Catherine Claire Kane - Ottawa QUEBEC REGION Dr. Cajetan Gauth,er - Levis Dr. Vyta Senikas - Montreal ATLANTIC REGION Dr. Davld A . Knickle - Charlottetown Dr. Garth Christie - Fredericton PUBLIC REPRESENTATIVE Ms. Janet MacMilian - Halifax JUNIOR FELLOW REPRESENTATIVE Dr. Georges Sylvestre - Montreal ASSOCIATE MD REPRESENTATIVE Dr. T. Riley - Oakville ASSOCIATE NURSING REPRESENTATIVE Ms. Mane-Josee Trepanier - Ottawa NATIONAL OFFICE EXECUTIVE VICE-PRESIDENT Dr. Andre B. Lalonde DIRECTOR OF COMMUNICATIONS Martine Joly
774 Echo Drive Ottawa,Ontario K1S 5N8 tel : (613) 730-4192 or 1-800-561-2416 fax: (613) 730-4314
Ouring the first half of this century, physicians practising obstetrics were preoccupied primarily with the health and welfare of the mother, and understandably so. Matemal mortality and morbidity were, by today's standards, alarmingly high, and although the same could be said for the fetus and neonate, there was a general acceptance of the priority attached to the wellbeing of pregnant women as opposed to that of their offspring. It was not until after World War II that remarkable reductions in matemal mortality began to occur. Hannah, MD, FRCSC, The advent of antibiotics, blood transfusions, safer W.J. Professor Emeritus, University of anaesthesia, more widespread availability of pre- Toronto natal care, and the development ofbetter training programmes for physicians and nurses in obstetric care, brought a much more congenial environment for women undertaking pregnancy, and from the early 1960s, the level of safety for pregnant women has changed only marginally. This improvement in the mother's lot was almost immediately followed by a concerted effort to effect a comparable reduction in perinatal mortality and morbidity. Numerous examples co me to mind where this has been achieved: the virtual resolution of the problem of erythroblastosis due to Rhesus incompatibility; the development of the concept of neon at al intensive care, which has contributed so much to the increased survival rate of preterm, low birthweight infants; the beneficial effects of antenatal glucocorticoids given to the mother in preterm labour in reducing perinatal mortality due to neonatal respiratory distress syndrome; the introduction of surfactant to accomplish the same objective; antenatal diagnosis for detection of genetic and structural abnormalities-all highlight some of the important advances in the care we now provide that have resulted in dramatic improvements in perinatal welfare. Most of these developments have originated with research at the basic science level and its subsequent application in the clinical setting. With the very best of intentions, but with much more limited success, we have made enormous efforts to achieve reductions in perinatal mortality and morbidity associated with antepartum and intrapartum hypoxia by me ans of a variety of fetal surveillance techniques. The introduction of continuous electronic fetal heart rate monitoring (EFM) in the 1960s held out the promise
JOURNAL SOGC
1059
NOVEMBER 1995
, , , of earlier recognition of intra-uterine hypoxia, leading to earlier intervention in the hope that this would have a profound effect in reducing mortality and neurologie morbidity in the neonate. Unfortunately, and for a variety of reasons, our expectations have not been realized. The majority of weil designed trials demonstrate that the use of continuous EFM is not associated with any improvement in mortality or morbidity, but is associated with higher intervention rates. Before the earlier promise of this technology can ever be realized, it is clear that we must double our efforts to improve the precis ion of our interpretation of the information it currently provides. The struggle to reduce neurologic morbidity from intra-uterine hypoxia and acidosis must continue unabated. One of the most important areas of clinical obstetrics in which we have met with a conspicuous lack of success is, of course, the resolution of the problem of preterm labour. Although our neonatology colleagues have made contributions of enormous importance in improving the survival rates of preterm, low birthweight infants in the past two decades, it is a sobering reality that, for our part, we have made litde or no progress in reducing the rate of preterm birth during this same time period. This very important problem is more than ours alone to solve. We have known for a long time that the preterm birth rate is highest in those members of our society who are the most disadvantaged socially, economically, nutritionally, and educationally. Further, we have also known that prematurity and low birthweight are the most important causes of perinatal mortality and morbidity. It is apparent therefore, or at least it should be, that the rate of preterm birth serves as a marker of the socio-economic quality oflife in our society, and the challenge this represents is one that is faced by our nation as a whole. As we enter aperiod of economic retrenchment where reduction of the deficit, and debt, must assurne high priority, one can be forgiven for being somewhat pessimistic about the likelihood of seriously addressing this problem at a societallevel, at least for the foreseeable future. As a consequence, we are under a very great obligation to do everything we can at the pharmacologic and clinicallevel to resolve wh at most would agree is the most important perinatal problem we face. For the past three decades we have attempted, by one means or another, to find a way to inhibit or elimi-
JOURNAL SOGC
nate unwanted uterine activity when it poses a threat of allowing an otherwise normal fetus to be born prematurely and face the associated hazards. Wehave used narcotics in the hope of damping down uterine contractility. As a result of Csapo's "progesterone block" theory to explain the origin of labour, the use of large doses of parenteral progesterone was in a vogue far aperiod of time. The work of Fuchs in demonstrating the tocolytic effects of intravenous alcohol followed the clinical observation that women in labour could, for at least a time, slow down their labour by the generous ingestion of wine, spirits or beer. For many women, the treatment proved unacceptable because of the sometimes nasty side effects. An apparently major advance made its appearance in the early 1970s when the betamimetic agents were recognized as having tocolytic properties, and they came into widespread use from that time. The term "major advance" is used because it was evident from both laboratory and clinical observations that this group of agents had the capacity to inhibit uterine contractility, often dramatically; the ward "apparently" is used, however, because it soon became clear that the tocolytic effect did not pers ist, and we now know that this is due to the down regulation of myometrial cell receptors. Nevertheless, the use of these agents was associated with an average delay in birth of 24 to 48 hours, wh ich allowed for the administration of antenatal steroids with their proven benefit to the neonate. The maternal side effects of this group of agents, however, are by no means inconsequential and the combination of their relatively short duration of action and the side effects have limited their clinical usefulness. More recendy, magnesium sulphate (MgS04) and indomethacin have come into clinieal use as tocolytics, and the survey carried out by the Planning Group for the recent Consensus Conference on Tocolytics, whose report may be read elsewhere in this Journal, indicates that betamimetics, MgS0 4, and indomethacin are the favoured medications in the centres represented by the Conference participants, despite litde or no evidence of their effectiveness. Newer agents such as nifedipine, sulindac, glyceryl trinitrate, and atosiban are in preliminary stages of clinical application ar are undergoing clinical trials. Ir is axiomatic that when a clinical problem has a wide variety of treatments available to it, it is almost
1060
NOVEMBER 1995
, , , always the case that none of these treatments is entirely satisfactory, and this certainly seems to hold true with the current group of tocolytic drugs. The fundamental problem with each one of these agents seems to be a combination of short duration of action and/or distressing side effects. Furthermore, there is disagreemenr among the clinicians of this country, and others, as to the relative superiority of one drug over the others. Ir is crucially important that, of the agents currently in use, properly designed clinical trials be undertaken to compare them with one another and/or with placebo, so that we will come to a general agreement on the most effective treatment. Looking to the future, perhaps nowhere in obstetric science has there been such a demonstrable need for the active collaboration of basic and clinical research as in the search for the ideal tocolytic agent (if indeed there is one). As the Consensus Conference Report advises us, the complexities of unravelling the mysteries of labour at any gestational age are formidable, but the search must continue for the chemical which satisfies the requirement for effective tocolysis on the one hand, with a minimum of side effects on the other. lts usefulness must then be confirmed by the same kind of rigorously designed clinical trials referred to above, clearly demonstrating its superiority over current agents. When this all happens, obstetric science will have made a gigantic stride in confronting the spectre of unwanted preterm labour which has haunted us for so long, and we can then perhaps look forward to the achievement of something we have only dreamed of-the irreducible minimum in perinatal mortality and morbidity.
J SOGe
1995;17:1059-62
JOURNAL SOGC
1062
NOVEMBER 1995