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Perspectives in the prevention of premature birth
European Journal of Obstetrics & Gynecology and Reproductive Biology 117S (2004) S2–S5 www.elsevier.com/locate/ejogrb
Perspectives in the prevention of premature birth Pierre-Yves Ancel* Epidemiological Research Unit on Perinatal and Women’s Health, INSERM U149-IFR69, 16 Avenue Paul Vaillant-Couturier, 94807 Villejuif Cedex, France
Abstract Obstetric and neonatal interventions have improved the survival of preterm infants, but there has not been an equivalent reduction in longterm neurological disability. Thus, some effort must be invested in finding ways of preventing preterm birth. Numerous programmes have been promoted to address the matter of how the frequency of preterm birth could be prevented. Most interventions intended to prevent preterm labour do not have the desired effect, except for antibiotic treatment in cases of asymptomatic bacteriuria or bacterial vaginosis and progesterone administered prophylactically in high-risk women. Tocolytic drugs appear to delay delivery long enough for successful administration of corticosteroids in women in preterm labour, but without decreasing the risk of preterm birth. Some authors promote public health approaches that address all risk factors and affect the entire population of pregnant women, given that prevention programmes directed only at high-risk women have had little effect in preventing preterm births. However, the lack of progress in reducing the frequency of preterm births is also due to our limited understanding of the aetiology of preterm delivery. Although there is growing evidence that infection and neuroendocrine processes are involved, progress has remained slow. Recently, the hypothesis of a genetic predisposition to preterm delivery has been set up. Additional research exploring the pathophysiology of preterm labour is obviously needed, which will hopefully lead to the development of new therapeutic approaches. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Preterm birth; Prevention; Review
1. Preventive strategies and their results The prevalence of premature birth remains high in many countries, including the United States (11%) [1], Canada (7%) [2] and France (7%) [3]. Furthermore, the frequency of premature birth in these countries has increased by 10–20% in the last few years [2,3]. This is worrying, because 60% of neonatal deaths and almost half of all cases of cerebral palsy occur in children born before term [1,4]. Obstetric and neonatal practices have changed. Improvements in screening for fetal distress and the use of new treatments, such as antenatal corticosteroid therapy and surfactant treatment, have increased survival and reduced neonatal morbidity [5]. This progress has led to increasingly early induction of preterm deliveries. The proportion of caesarean sections performed before the onset of labour has doubled for very premature infants and has increased by a factor of 1.4 for * Fax: +33 145595089. E-mail address: [email protected].
moderately premature infants over the last 10 years [6]. Although some studies have shown benefits in terms of lower mortality rates, the data required to evaluate these extraction policies correctly are not available [6]. In particular, the potential benefits in terms of neurological prognosis are less clear [4,7]. For this reason, the prevention of premature birth remains a high priority. Various types of intervention have been suggested [8– 10]. Some are designed to prevent premature labour. These methods are based on the identification of women at risk. These women are then offered a prevention programme with nutritional supplements, more intense prenatal monitoring and/or social support and limitation of behaviour that might pose a risk during pregnancy. These programmes have no effect on the frequency of premature birth [8–10]. In contrast, two types of drug treatment have proved to be effective. Antibiotic treatment in cases of asymptomatic bacteriuria (OR = 0.56; CI: 0.43–0.73) or bacterial vaginosis (OR = 0.37; CI: 0.23–0.60) reduces the frequency of preterm birth in women at risk [11]. According to studies in North
0301-2115/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2004.07.007
P.Y. Ancel / European Journal of Obstetrics & Gynecology and Reproductive Biology 117S (2004) S2–S5
America, about 15% of women have bacterial vaginosis [12]. In France, the frequency is lower [13]. Thus, the benefits of antibiotic treatment in decreasing the frequency of premature birth are likely to vary from population to population. Progesterone intake is associated with a 50% decrease in the risk of premature birth, but has no effect on the neonatal prognosis [14,15]. A recent literature review suggests that cervical cerclage reduces the risk of birth before 34 weeks of amenorrhoea [16]. Another preventive approach is based on the identification of the first signs of labour. This can be achieved by educating the women to detect these signs themselves and/or by home monitoring of uterine activity. Earlier diagnosis is required for this approach, and appropriate treatment should make it possible to decrease the rates of premature birth. In American trials, the rate of premature birth was found to be lower in monitored women (OR = 0.9; CI: 0.8–1.0) [17]. Although these results are encouraging, this approach has only a modest effect on the frequency of premature birth and is expensive. Furthermore, it is difficult to extrapolate any results obtained to other countries, as a French trial found that monitored women had a higher rate of premature birth than other women (OR = 1.7; CI: 0.8–3.6) [17]. A third approach is based on the treatment after the beginning of labour or after membrane rupture. Antibiotic treatment has not proved beneficial in case of premature labour [11], whereas it has been found to prolong the pregnancy and to decrease the risk of chorioamnionitis (OR = 0.6; CI: 0.4–0.8), neonatal sepsis (OR = 0.5, CI: 0.3–0.9) and cerebral abnormalities (OR = 0.8; CI: 0.7–1.0) in cases of membrane rupture [11,18]. Trials with tocolytic drugs have shown that beta mimetics, calcium-channel blockers, oxytocin antagonists and non-steroidal anti-inflammatory drugs can prolong the pregnancy by 24–48 h, or possibly by up to 7 days [19], but without decreasing the risk of premature birth or improving the infant’s health. Although modest, this prolongation of the pregnancy makes it possible to initiate corticosteroid treatment or to transfer the mother to a level III maternity unit. Studies on bed rest have been inconclusive [1].
2. Perspectives in the prevention of premature birth Some authors have proposed that the relative failure of preventive programmes may be due to the tendency for them to be too highly targeted [2]. These programmes are often designed to reduce preterm birth rate in women at high risk whereas (1) 60% of premature babies are born to women at low risk; (2) a history of adverse pregnancy outcomes has a major effect on the risk of premature birth, but is difficult to target; and (3) many factors may interact in a complex manner [8]. Thus, even if it is effective, a highly targeted intervention can have no more than a modest effect on premature birth. For this reason, other strategies based on reducing exposure to risk factors known to concern all
S3
pregnant women have been proposed [2]. Vast domains must be covered for such strategies which involve, for instance, implementation of a social and educational policy, organisation of information campaigns aimed at young adolescents, prevention of risk behaviour, screening for and management of psychological problems, and identification and management of women at high medical risk. Very few published papers have suggested such approaches. In France, two prevention programmes, one in Paris and the other in Haguenau, based on the identification of women at risk, intensification of prenatal monitoring and implementation of measures,were designed to reduce physical load during pregnancy which led to a decrease in the frequency of premature births in the 1970s and 1980s [20,21]. At the same time, a national programme was designed to reduce prenatal mortality and the frequency of handicap. The principal aims of this programme were to improve the equipment in maternity units, medical training, the monitoring of deliveries and the management of births, and to introduce the idea of risk. These measures applied at both local and national levels, helped to reduce the premature birth rate, although it is not known which of these measures was responsible for the effect. Thus, programmes combining specific measures with a global policy are possible, but their success depends on the social and health policies of each country and the specific demographic, social and health characteristics of each population. Other authors consider our understanding of the physiopathological mechanisms, and their links with identified risk factors to be too fragmented for prevention measures to be effective. The perspectives for reducing the rate of premature birth therefore, lie in research. Recent progress in this area has helped us to understand how prostaglandins, oxytocin and certain enzyme complexes, metalloproteases in particular, initiate labour, maintain uterine contractions and degrade the fetal membrane [22]. The events triggering these processes remain unknown. Situations of maternal and/or fetal stress have been identified as possible triggering events. Such situations are likely to stimulate the synthesis of prostaglandins and oxytocin by activating the hypothalamic-pituitary and adrenal axis of the fetus, and via the effects of placental corticotropin-releasing hormone (CRH) and the production of steroids [22]. We still do not understand these mechanisms. Although the link between stress and premature birth remains a subject of debate [23], recent studies have demonstrated an effect of psychosocial factors [24]. Furthermore, working conditions that are demanded both physically and mentally are associated with premature birth [25]. Urogenital infections are another area of research. Studies have shown that they are associated with premature labour and preterm premature rupture of membranes [11,26]. In terms of physiopathology, cytokines have been shown to be involved in the synthesis of prostaglandins and in the activation of metalloproteases [22]. Again, the mechanisms involved are not known. In this context, studies have suggested that periodontal conditions may be involved in premature birth
S4
P.Y. Ancel / European Journal of Obstetrics & Gynecology and Reproductive Biology 117S (2004) S2–S5
[27], but these studies were subjected to methodological problems and further studies are required. Another hypothesis put forward is that of placental haemorrhage. Although minimal, placental bleeding induces the production of thrombin, which may activate the enzyme systems involved in the degradation of membranes and the uterine contractions [28]. Finally, uterine overdistension, which occurs in multiple pregnancies and is a known risk factor for premature birth, may increase the synthesis of prostaglandins, oxytocin and the enzymes responsible for membrane degradation. To elucidate the links between these mechanisms and the risk of premature birth, several authors have raised the question of genetic factors. Several possible candidate genes have been suspected. Mutations in genes encoding cytokines may increase susceptibility to infection and inflammation, but few studies have found a link with premature birth [29]. It has also been suggested that genetic factors are involved in certain placental vasculopathies. Hyperhomocysteinaemia is an abnormality combining a deficiency of folate and Vitamin B12 and a mutation in a gene encoding methylene tetrahydrofolate reductase. This condition increases the risk of coronary disease, thromboembolism and pre-eclampsia [30]. However, its effects on the risk of premature birth are unknown. In keeping with hypotheses concerning the effects of stress, abnormalities should also be sought in genes encoding maternal, placental or fetal CRH. Finally, dysfunction of genes encoding cytochromes which are involved in detoxification, has been suggested. Such dysfunction may increase the effects of exposure to tobacco or to certain types of professional exposure [30]. The recent increase in rates of premature birth is attributable partly to the increased incidence of multiple pregnancies [3]. Currently, 15–20% of premature births are due to twin pregnancies, and 1% due to triplet pregnancies [31]. Treatments for infertility have played a major part in the increased frequency of multiple pregnancies. Such treatments are responsible for 30–60% of twin pregnancies (10–20% following in vitro fertilisation (IVF) and 20–40% following the use of ovulation inducers alone) [31]. Thus, if we aim to prevent premature births by reducing the number of multiple pregnancies, the control of infertility treatments is a factor that could be manipulated to achieve this effect. During IVF, transfer of fewer embryos decrease the risk of multiple pregnancy. Unfortunately, it also decreases the success rate, from 30%, when three embryos are transferred to only 10%, after transfer of a single embryo [31]. Rather than systematically reducing the number of embryos transferred, one intermediate solution involves adapting the number of embryos transferred to the characteristics of each woman concerned (e.g., her age), the cause of infertility and the fertilisation rate [32]. The same rules should apply to the prescription of ovulation inducers outside IVF programmes. In the medium term, other research strategies should be developed to reduce the frequency of multiple pregnancies. It is essential to improve our understanding of the effects of ovulation inducers, because the data on these
drugs are both scarce and unreliable. We also need to improve the efficacy of these treatments to make it possible to reduce the risk of multiple pregnancies without affecting the success rate. These avenues of research are important, but certain obstacles may be difficult to overcome. Indeed, in many countries, the number of embryos transferred remains high, knowledge about implantation of a single embryo remains limited and the number of couples treated is increasing. The most recent data show an increase in the frequency of premature birth, which must be taken seriously because of its potentially serious consequences for the child. Although considerable progress has been made in the care of premature infants, it is still not possible to resolve all the problems, particularly as these strategies do not always improve the long-term neurological prognosis. Advances in the area of preventing premature birth have been modest. One of the difficulties encountered is the diversity of the aetiological mechanisms involved in premature birth. Several areas in which progress might be possible have been identified: infection, hormonal factors and the control of multiple pregnancies. However, our understanding of physiopathology and of certain practices is still insufficient, to enable us to develop more effective preventive strategies. Our hopes therefore, centre on improving this knowledge and on the adaptation of preventive methods to suit the various mechanisms involved.
Acknowledgements We owe sincere thanks to Ge´ rard Bre´ art for helpful advice during the preparation of this review.
References [1] Goldenberg RL. The management of preterm labour. Obstet Gynecol 2002;100:1020–37. [2] Heaman MI, Sprague AE, Stewart PJ. Reducing the preterm birth rate: a population health strategy. J Obstet Gynecol Neonatal Nurs 2001;30:20–9. [3] Blondel B, Norton J, du Mazaubrun C. Bre´ art G pour la coordination nationale des enqueˆ tes nationales pe´ rinatales. Evolution des principaux indicateurs de sante´ pe´ rinatale en France me´ tropolitaine entre 1995 et 1998. Re´ sultats des enqueˆ tes nationales pe´ rinatales. J Gynecol Obstet Biol Reprod 2001;30:552–64. [4] Hagberg B, Hagberg G, Beckung E, Uvebrant P. Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991–94. Acta Paediatr 2001;90:271–7. [5] Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. BJOG 1990;97:11–25. [6] Lumley J. Method of delivery for preterm infant. BJOG 2003;110(Suppl 20):88–92. [7] Topp M, Uldall P, Langhoff-Roos J. Trend in cerebral palsy birth prevalence in eastern Denmark: birth-year period 1979–86. Paediatr Perinat Epidemiol 1997;11:451–60.
P.Y. Ancel / European Journal of Obstetrics & Gynecology and Reproductive Biology 117S (2004) S2–S5 [8] Alexander G, Weiss J, Hulsey TC, Papiernik E. Preterm birth prevention: an evaluation of programs in the United States. Birth 1991;18:160–9. [9] Goldenberg RL, Rouse DJ. Prevention of premature birth. N Engl J Med 1998;339:313–20. [10] Blondel B. Social and medical support during pregnancy: an overview of the randomized controlled trials. Prenat Neonat Med 1998;3:141–4. [11] Romero R, Gomez R, Chaiworapongsa T, Conoscenti G, Kim JC, Kim YM, et al. The role of infection in preterm labour and delivery. Paediatr Perinat Epidemiol 2001;15(Suppl 2):41–56. [12] Hillier SL, Nugent RP, Eschenbach DA, Krohn MA, Gibbs RS, Martin DH, Klebanoff MA, et al. Vaginal Infections and Prematurity Study Group. N Engl J Med 1995;333:1737–42. [13] Goffinet F, Maillard F, Mihoubi N, Kayem G, Papiernik E, Cabrol D, et al. Bacterial vaginosis: prevalence and predictive value for premature delivery and neonatal infection in women with preterm labour and intact membranes. Eur J Obstet Gynecol Reprod Biol 2003;108:146– 51. [14] Keirse MJ. Progestogen administration in pregnancy may prevent preterm delivery. BJOG 1990;97:149–54. [15] da Fonseca EB, Bittar RE, Carvalho MHB. Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419–24. [16] Bachmann LM, Coomarasamy A, Honest H, Khan KS. Elective cervical cerclage for prevention of preterm birth: a systematic review. Acta Obstet Gynecol Scand 2003;82:398–404. [17] Blondel B. Organisation de la surveillance pre´ natale pour les femmes a` bas ou haut risque. Bilan des e´ tudes d’e´valuation. In: Collet M, Treisser A, editors. Journe´ es Nationales de la Socie´ te´ Franc¸aise de Me´ decine Pe´ rinatale. Paris: Arnette; 1999. [18] Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev 2003;2:CD001058. [19] Carbonne B, Tsatsaris V. Menace d’accouchement pre´ mature´ : quels tocolytiques utiliser? J Gynecol Obstet Biol Reprod Paris 2002;31(suppl 7):5S96–5S104.
S5
[20] Bouyer J, Dreyfus J, Lazar P, Collin D, Winisdoerffer G, Papiernik E, et al. Pre´vention de la pre´ maturite´ : enqueˆ te pe´ rinatale de Hagueneau 1971–1985. Rev Epidemiol Sante Publique 1988;36:83–8. [21] Bre´ art G, Goujard J, Blondel B, Maillard F, Chavigny C, Sureau C, et al. A comparison of two policies of ante-natal supervision for the prevention of prematurity. Int J Epidemiol 1981;10:241–4. [22] Norwitz ER, Robinson JN, Challis JRG. The control of labour. N Engl J Med 1999;341:660–6. [23] Hoffman S, Hatch MC. Stress, social support and pregnancy outcome: a reassessment based on recent research. Paediatr Perinat Epidemiol 1996;10:380–405. [24] Dole N, Savitz DA, Hertz-Picciotto I, Siega-Riz AM, McMahon MJ, Buekens P, et al. Maternal stress and preterm birth. Am J Epidemiol 2003;157:14–24. [25] Mozurkewich EL, Luke B, Avni M, Wolf FM. Working conditions and adverse pregnancy outcome: a meta-analysis. Obstet Gynecol 2000;95:623–35. [26] Gomez R, Romero R, Edwin SS, David C. Pathogenesis of preterm labour and preterm premature rupture of membranes associated with intraamniotic infection. Infect Dis Clin North Am 1997;11:135–76. [27] Jeffcoat MK, Geurs NC, Reddy MS, Cliver SP, Goldenberg RL, Hauth JC, et al. Periodontal infection and preterm birth-results of a prospective study. J Am Dent Assoc 2001;132:875–80. [28] Lockwood CJ. Predicting premature delivery—no easy task. N Engl J Med 2002;346:282–4. [29] Dizon-Townson DS. Preterm labour and delivery: a genetic predisposition. Paediatr Perinat Epidemiol 2001;15(Suppl 2):57–62. [30] Wang X, Zuckerman B, Kaufman G, Wise P, Hill M, Niu T, et al. Molecular epidemiology of preterm delivery: methodology and challenges. Paediatr Perinat Epidemiol 2001;15(Suppl 2):63–77. [31] Blondel B, Kaminski M. Trends in the occurrence, determinants, and consequences of multiple births. Seminars in Perinatology 2002;26:239–49. [32] Belaisch-Allart J. Peut-on vraiment pre´venir les grossesses multiples hors FIV? In: Pons JC, Charlemaine C, Papiernik E, editors. Les grossesses multiples. Paris: Me´ decine-Sciences Flammarion; 2000. p. 271–7.
Perspectives in the prevention of premature birth Pierre-Yves Ancel* Epidemiological Research Unit on Perinatal and Women’s Health, INSERM U149-IFR69, 16 Avenue Paul Vaillant-Couturier, 94807 Villejuif Cedex, France
Abstract Obstetric and neonatal interventions have improved the survival of preterm infants, but there has not been an equivalent reduction in longterm neurological disability. Thus, some effort must be invested in finding ways of preventing preterm birth. Numerous programmes have been promoted to address the matter of how the frequency of preterm birth could be prevented. Most interventions intended to prevent preterm labour do not have the desired effect, except for antibiotic treatment in cases of asymptomatic bacteriuria or bacterial vaginosis and progesterone administered prophylactically in high-risk women. Tocolytic drugs appear to delay delivery long enough for successful administration of corticosteroids in women in preterm labour, but without decreasing the risk of preterm birth. Some authors promote public health approaches that address all risk factors and affect the entire population of pregnant women, given that prevention programmes directed only at high-risk women have had little effect in preventing preterm births. However, the lack of progress in reducing the frequency of preterm births is also due to our limited understanding of the aetiology of preterm delivery. Although there is growing evidence that infection and neuroendocrine processes are involved, progress has remained slow. Recently, the hypothesis of a genetic predisposition to preterm delivery has been set up. Additional research exploring the pathophysiology of preterm labour is obviously needed, which will hopefully lead to the development of new therapeutic approaches. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Preterm birth; Prevention; Review
1. Preventive strategies and their results The prevalence of premature birth remains high in many countries, including the United States (11%) [1], Canada (7%) [2] and France (7%) [3]. Furthermore, the frequency of premature birth in these countries has increased by 10–20% in the last few years [2,3]. This is worrying, because 60% of neonatal deaths and almost half of all cases of cerebral palsy occur in children born before term [1,4]. Obstetric and neonatal practices have changed. Improvements in screening for fetal distress and the use of new treatments, such as antenatal corticosteroid therapy and surfactant treatment, have increased survival and reduced neonatal morbidity [5]. This progress has led to increasingly early induction of preterm deliveries. The proportion of caesarean sections performed before the onset of labour has doubled for very premature infants and has increased by a factor of 1.4 for * Fax: +33 145595089. E-mail address: [email protected].
moderately premature infants over the last 10 years [6]. Although some studies have shown benefits in terms of lower mortality rates, the data required to evaluate these extraction policies correctly are not available [6]. In particular, the potential benefits in terms of neurological prognosis are less clear [4,7]. For this reason, the prevention of premature birth remains a high priority. Various types of intervention have been suggested [8– 10]. Some are designed to prevent premature labour. These methods are based on the identification of women at risk. These women are then offered a prevention programme with nutritional supplements, more intense prenatal monitoring and/or social support and limitation of behaviour that might pose a risk during pregnancy. These programmes have no effect on the frequency of premature birth [8–10]. In contrast, two types of drug treatment have proved to be effective. Antibiotic treatment in cases of asymptomatic bacteriuria (OR = 0.56; CI: 0.43–0.73) or bacterial vaginosis (OR = 0.37; CI: 0.23–0.60) reduces the frequency of preterm birth in women at risk [11]. According to studies in North
0301-2115/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2004.07.007
P.Y. Ancel / European Journal of Obstetrics & Gynecology and Reproductive Biology 117S (2004) S2–S5
America, about 15% of women have bacterial vaginosis [12]. In France, the frequency is lower [13]. Thus, the benefits of antibiotic treatment in decreasing the frequency of premature birth are likely to vary from population to population. Progesterone intake is associated with a 50% decrease in the risk of premature birth, but has no effect on the neonatal prognosis [14,15]. A recent literature review suggests that cervical cerclage reduces the risk of birth before 34 weeks of amenorrhoea [16]. Another preventive approach is based on the identification of the first signs of labour. This can be achieved by educating the women to detect these signs themselves and/or by home monitoring of uterine activity. Earlier diagnosis is required for this approach, and appropriate treatment should make it possible to decrease the rates of premature birth. In American trials, the rate of premature birth was found to be lower in monitored women (OR = 0.9; CI: 0.8–1.0) [17]. Although these results are encouraging, this approach has only a modest effect on the frequency of premature birth and is expensive. Furthermore, it is difficult to extrapolate any results obtained to other countries, as a French trial found that monitored women had a higher rate of premature birth than other women (OR = 1.7; CI: 0.8–3.6) [17]. A third approach is based on the treatment after the beginning of labour or after membrane rupture. Antibiotic treatment has not proved beneficial in case of premature labour [11], whereas it has been found to prolong the pregnancy and to decrease the risk of chorioamnionitis (OR = 0.6; CI: 0.4–0.8), neonatal sepsis (OR = 0.5, CI: 0.3–0.9) and cerebral abnormalities (OR = 0.8; CI: 0.7–1.0) in cases of membrane rupture [11,18]. Trials with tocolytic drugs have shown that beta mimetics, calcium-channel blockers, oxytocin antagonists and non-steroidal anti-inflammatory drugs can prolong the pregnancy by 24–48 h, or possibly by up to 7 days [19], but without decreasing the risk of premature birth or improving the infant’s health. Although modest, this prolongation of the pregnancy makes it possible to initiate corticosteroid treatment or to transfer the mother to a level III maternity unit. Studies on bed rest have been inconclusive [1].
2. Perspectives in the prevention of premature birth Some authors have proposed that the relative failure of preventive programmes may be due to the tendency for them to be too highly targeted [2]. These programmes are often designed to reduce preterm birth rate in women at high risk whereas (1) 60% of premature babies are born to women at low risk; (2) a history of adverse pregnancy outcomes has a major effect on the risk of premature birth, but is difficult to target; and (3) many factors may interact in a complex manner [8]. Thus, even if it is effective, a highly targeted intervention can have no more than a modest effect on premature birth. For this reason, other strategies based on reducing exposure to risk factors known to concern all
S3
pregnant women have been proposed [2]. Vast domains must be covered for such strategies which involve, for instance, implementation of a social and educational policy, organisation of information campaigns aimed at young adolescents, prevention of risk behaviour, screening for and management of psychological problems, and identification and management of women at high medical risk. Very few published papers have suggested such approaches. In France, two prevention programmes, one in Paris and the other in Haguenau, based on the identification of women at risk, intensification of prenatal monitoring and implementation of measures,were designed to reduce physical load during pregnancy which led to a decrease in the frequency of premature births in the 1970s and 1980s [20,21]. At the same time, a national programme was designed to reduce prenatal mortality and the frequency of handicap. The principal aims of this programme were to improve the equipment in maternity units, medical training, the monitoring of deliveries and the management of births, and to introduce the idea of risk. These measures applied at both local and national levels, helped to reduce the premature birth rate, although it is not known which of these measures was responsible for the effect. Thus, programmes combining specific measures with a global policy are possible, but their success depends on the social and health policies of each country and the specific demographic, social and health characteristics of each population. Other authors consider our understanding of the physiopathological mechanisms, and their links with identified risk factors to be too fragmented for prevention measures to be effective. The perspectives for reducing the rate of premature birth therefore, lie in research. Recent progress in this area has helped us to understand how prostaglandins, oxytocin and certain enzyme complexes, metalloproteases in particular, initiate labour, maintain uterine contractions and degrade the fetal membrane [22]. The events triggering these processes remain unknown. Situations of maternal and/or fetal stress have been identified as possible triggering events. Such situations are likely to stimulate the synthesis of prostaglandins and oxytocin by activating the hypothalamic-pituitary and adrenal axis of the fetus, and via the effects of placental corticotropin-releasing hormone (CRH) and the production of steroids [22]. We still do not understand these mechanisms. Although the link between stress and premature birth remains a subject of debate [23], recent studies have demonstrated an effect of psychosocial factors [24]. Furthermore, working conditions that are demanded both physically and mentally are associated with premature birth [25]. Urogenital infections are another area of research. Studies have shown that they are associated with premature labour and preterm premature rupture of membranes [11,26]. In terms of physiopathology, cytokines have been shown to be involved in the synthesis of prostaglandins and in the activation of metalloproteases [22]. Again, the mechanisms involved are not known. In this context, studies have suggested that periodontal conditions may be involved in premature birth
S4
P.Y. Ancel / European Journal of Obstetrics & Gynecology and Reproductive Biology 117S (2004) S2–S5
[27], but these studies were subjected to methodological problems and further studies are required. Another hypothesis put forward is that of placental haemorrhage. Although minimal, placental bleeding induces the production of thrombin, which may activate the enzyme systems involved in the degradation of membranes and the uterine contractions [28]. Finally, uterine overdistension, which occurs in multiple pregnancies and is a known risk factor for premature birth, may increase the synthesis of prostaglandins, oxytocin and the enzymes responsible for membrane degradation. To elucidate the links between these mechanisms and the risk of premature birth, several authors have raised the question of genetic factors. Several possible candidate genes have been suspected. Mutations in genes encoding cytokines may increase susceptibility to infection and inflammation, but few studies have found a link with premature birth [29]. It has also been suggested that genetic factors are involved in certain placental vasculopathies. Hyperhomocysteinaemia is an abnormality combining a deficiency of folate and Vitamin B12 and a mutation in a gene encoding methylene tetrahydrofolate reductase. This condition increases the risk of coronary disease, thromboembolism and pre-eclampsia [30]. However, its effects on the risk of premature birth are unknown. In keeping with hypotheses concerning the effects of stress, abnormalities should also be sought in genes encoding maternal, placental or fetal CRH. Finally, dysfunction of genes encoding cytochromes which are involved in detoxification, has been suggested. Such dysfunction may increase the effects of exposure to tobacco or to certain types of professional exposure [30]. The recent increase in rates of premature birth is attributable partly to the increased incidence of multiple pregnancies [3]. Currently, 15–20% of premature births are due to twin pregnancies, and 1% due to triplet pregnancies [31]. Treatments for infertility have played a major part in the increased frequency of multiple pregnancies. Such treatments are responsible for 30–60% of twin pregnancies (10–20% following in vitro fertilisation (IVF) and 20–40% following the use of ovulation inducers alone) [31]. Thus, if we aim to prevent premature births by reducing the number of multiple pregnancies, the control of infertility treatments is a factor that could be manipulated to achieve this effect. During IVF, transfer of fewer embryos decrease the risk of multiple pregnancy. Unfortunately, it also decreases the success rate, from 30%, when three embryos are transferred to only 10%, after transfer of a single embryo [31]. Rather than systematically reducing the number of embryos transferred, one intermediate solution involves adapting the number of embryos transferred to the characteristics of each woman concerned (e.g., her age), the cause of infertility and the fertilisation rate [32]. The same rules should apply to the prescription of ovulation inducers outside IVF programmes. In the medium term, other research strategies should be developed to reduce the frequency of multiple pregnancies. It is essential to improve our understanding of the effects of ovulation inducers, because the data on these
drugs are both scarce and unreliable. We also need to improve the efficacy of these treatments to make it possible to reduce the risk of multiple pregnancies without affecting the success rate. These avenues of research are important, but certain obstacles may be difficult to overcome. Indeed, in many countries, the number of embryos transferred remains high, knowledge about implantation of a single embryo remains limited and the number of couples treated is increasing. The most recent data show an increase in the frequency of premature birth, which must be taken seriously because of its potentially serious consequences for the child. Although considerable progress has been made in the care of premature infants, it is still not possible to resolve all the problems, particularly as these strategies do not always improve the long-term neurological prognosis. Advances in the area of preventing premature birth have been modest. One of the difficulties encountered is the diversity of the aetiological mechanisms involved in premature birth. Several areas in which progress might be possible have been identified: infection, hormonal factors and the control of multiple pregnancies. However, our understanding of physiopathology and of certain practices is still insufficient, to enable us to develop more effective preventive strategies. Our hopes therefore, centre on improving this knowledge and on the adaptation of preventive methods to suit the various mechanisms involved.
Acknowledgements We owe sincere thanks to Ge´ rard Bre´ art for helpful advice during the preparation of this review.
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