DOI 10.1515/jpm-2014-0036 J. Perinat. Med. 2014; 42(4): 431–433
Academy’s paper Joachim W. Dudenhausen*
Primary prevention of preterm birth *Corresponding author: Joachim W. Dudenhausen, Weill Cornell Medical College, Sidra Medical and Research Center, Qatar Foundation, POB 26999, Doha, State of Qatar, E-mail: [email protected]
The prevalence of preterm birth has increased, despite efforts to treat pregnant women with symptoms of preterm labor (PTL). In the United States, the preterm delivery (PTD) rate increased from 10.6% in 1990 to 11.7% in 2011, in Germany from 7.1% in 2007 to 9.0% in 2008, and in Portugal from 6.8% in 2004 to 9.0% in 2008. Numerous medical and surgical procedures have been used to treat or prevent spontaneous PTL. There is a need to revisit strategies to reduce the rate of preterm birth.
Definition of prevention The term “prevention” means “general measures to avoid bad conditions.” The objective of this communication is to present a framework for the prevention of spontaneous PTL leading to PTD. The conventional approach in epidemiology is to divide prevention into primary, secondary and tertiary levels, and these concepts could be applied to the prevention of PTL. In this case, primary prevention would consist of interventions directed to all women, which are implemented before or during pregnancy, to reduce risks [8]. Secondary prevention measures are directed toward reducing the risk in women with already assessed risk factors (i.e., tocolysis in patients with spontaneous PTL). Tertiary prevention refers to the measures deployed to improve neonatal outcome after a PTD has occurred (i.e., the administration of surfactant to mitigate respiratory distress syndrome).
Prevention of PTL and PTD Treatments to reduce the risk of PTL and PTD, such as tocolytic treatment, antenatal corticosteroids and surgical treatment (cerclage or cervical occlusion), are considered to be secondary or tertiary prevention measures. For primary prevention strategies against PTL and PTD, there is a need to acknowledge and evaluate the risk factors involved. Such primary prevention may uncover
benefits that are beyond secondary and tertiary measures. Moreover, through education and public policy, such benefits may depend on sound scientific evidence and may require decades of research effort. Spontaneous PTD is not a single entity, but a collection of conditions (phenotypes) caused by multiple pathologic processes [13]. Hence, it is unrealistic to assume that a single measure would be universally effective to prevent this condition. Improved understanding of the mechanisms of the disease responsible for each particular phenotype and continued efforts to develop early biomarkers and interventions would be required to accomplish this goal. At this point, some general ideas can be proposed in discussing primary prevention measures employed to reduce spontaneous PTB.
Iatrogenic risk factors Reducing the rate of induction of labor and elective cesarean delivery (without labor) is one approach that can be employed to decrease the rate of PTD [12]. However, some PTDs would be required for maternal or fetal indications (e.g., in cases of intrauterine growth restriction or preeclampsia). Multiple gestations after assisted reproductive technology (ART) procedures can increase the risk for PTL and PTD. This risk remains elevated when conception occurs with ART, even in singleton gestations. Thus far, recommendations aimed at reducing the number of multiple gestations after ART (one embryo transfer) have achieved success in some countries in Europe [2, 7]. Preconceptional primary prevention includes the education of women and health care providers about the evidence, which states that repeated uterine instrumentation (repeated abortion and uterine curettage) is associated with an increased rate of subsequent PTL and PTD [16].
Environmental risk factors A low body mass index and obesity, defined as a body mass index higher than 30, are both associated with PTL and PTD. Smoking cessation can also reduce the rate of spontaneous PTL and PTD [3, 6, 20, 22].
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432 Dudenhausen, Preterm birth prevention
Social and genetic risk factors There are laws in place to protect pregnant women, including the following: leave of 14 weeks before the delivery, exemption from night shifts, protection from workplace hazards, access to free antenatal care, timeoff for antenatal visits, legal prohibition of standing position of pregnant women in work, and universal health care coverage for women and children [17–19]. While some progress has been made in the identification of causative genes and variants associated with preterm bith, the true genetic pathology has yet to be fully identified. Studies suggested preliminary associations between maternal polymorphisms in leucyl/cystinyl aminopeptidase (LNPEP) and the risk of PTL [10]. Maternal oxytocin receptor (OXTR) missense single nucleotide polymorphisms rs4686302 and rs237902 have gestational age-dependent effects on PTD. Significant differences between ethnic groups were also observed for IL-6 and IL-6R in maternal and fetal samples, or in TNF-alpha/TNF receptor genes [24]. Genetic factors interact with environmental exposures, and in some instances, the latter result in epigenetic changes. Research is required to discover the contribution of genetic and environmental mechanisms for the design of preventive strategies. There is currently a gap between large-scale informatic approaches combining genomic information and environmental exposure. Thus, gaining a better understanding of the interactions between fetal and maternal genomes is urgently needed [5]. In addition, the importance of genetic predisposition for preterm delivery is shown in the prematurity recurrence rate of 17% of cases with the same father; however, the risk is lower in cases of different fathers. Socioeconomic factors play a role because data suggest an association between income and educational
level with the likelihood of PTD [11]. Moreover, some of these risk factors operate through the induction of stress, anxiety, and low resilience [15].
Medical risk factors Around two-thirds of PTDs are spontaneous with PTL and/or preterm prelabor rupture of membranes. In these cases, intrauterine infection or decidual hemorrhage can be a cause of the clinical condition long before the symptoms occur. Extrauterine or ascending infection is also associated with higher risk of PTL and PTD; hence, early diagnosis of bacterial vaginosis and treatment are crucial [14, 21]. Moreover, prepregnancy treatment of periodontal diseases is associated with a decreased risk of PTL and PTD. However, the association between the risk of PTL and periodontal diseases is evidence-based [4], and the basis of the association has yet to be determined. Does reduce treatment of periodontal disease during pregnancy the rate of PTD? This question isn’t answered finally [1, 9, 23]. Maternal anemia before and during pregnancy and iron deficiency, mainly in the first or second trimester, are associated with a higher risk of PTL and PTD.
Consequences Efforts to lessen risk for PTL or PTD have mainly focused on secondary or tertiary prevention. However, the incidence of PTL and PTD continues to rise. Thus, advances in primary care, policies, and strategies based on primary prevention techniques are needed to reduce the incidence of PTL and PTD.
References [1] American College of Obstetricians and Gynecologists: Oral Health Care during Pregnancy and through Lifespan. Committee Opinion 569, August 2013. [2] Andersen AN, Goossens V, Ferraretti AP, Bhattacharya S, Felberbaum R, de Mouzon J, Nygren KG. European IVFMonitoring Consortium, European Society of Human Reproduction and Embryology: assisted reproductive technology in Europe, 2004: results generated from European registers by ESHRE. Hum Reprod. 2008; 23:756–71. [3] Basso O, Olsen J, Christensen K. Low birthweight and prematurity in relation to paternal factors: a study of recurrence. Int J Epidemiol. 1999;28:695–700.
[4] Bergmann RL, Dudenhausen JW. Prädiktion und Prävention der Frühgeburt. Gynäkologe. 2003;36:391–402. [5] Bezold KY, Karjalainen MK, Hallman M, teramo K, Muglia LJ. The genomics of preterm birth: from animal models to human studies. Genome Med. 2013;5:34. [6] Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and impolications. Lancet. 2012;379:2162–72. [7] Felberbaum RE. Multiole pregnancies after assisted reproduction–international comparison. Reprod Biomed Online. 2007;15:53–60.
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Dudenhausen, Preterm birth prevention 433 [8] Iams JD, Romero R, Culhane JF, Goldenberg RL. Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth. Lancet. 2008;371:164–75. [9] Jeffcoat M, Parry S, Sammel M, Clothier B, Catlin A, Macones G. Periodontal infection and preterm birth: successful periodontal therapy reduces the risk of preterm birth. BJOG. 2011;118:250–6. [10] Kim J, Stirling KJ, Cooper ME, Ascoli M, Momany AM, McDonald EL, et al. Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study. BMC Med Genet. 2013;14:77. [11] Kramer MS, Goulet I, Lyndon J, Séguin L, McNamara H, Dassa C, et al. Socioeconomic disparities in preterm birth: causal pathways and mechanisms. Paediatr Perinat Epidemiol. 2001;15:104–23. [12] Kramer MS, McLean FH, Eason EL, Usher RH. Maternal nutrition and spontaneous preterm birth. Am J Epidemiol. 1992;136: 574–83. [13] Lamont RF. Can antibiotics prevent preterm birth–the pro and con debate. BJOG. 2005;112:67–73. [14] Menon R. Spontaneous preterm birth, a clinical dilemma: etiologic, pathophysiologic and genetic heterogeneities and racial disparity. Acta Obstet Gynecol. 2008;87:590–600. [15] Misra DP, O’Campo P, Strobino D. Testing a sociomedical model for preterm delivery. Paediatr Perinat Epidemiol. 2001;15:110–22. [16] Moreau C, Kaminski M, Auell PY. Previous induced abortions and the risk of very preterm delivery: results of the EPIPAGE study. BJOG. 2005;112:430–7.
[17] Newman RB, Goldenberg RL, Moawad AH, Iams JD, Meis PJ, Das A, et al. Occupational fatigue and preterm premature rupture of membranes. Am J Obstet Gynecol. 2001;184: 438–46. [18] Papiernik E, Kaminski M. Multifactorial study of the risk of prematurity at 32 weeks of gestation. J Perinat Med. 1974;2:30–42. [19] Papiernik E, Bouyer J, Dreyfus J, Collin D, Winisdorffer G, Guegen S, et al. Prevention of preterm births: a perinatal study in Haguenau, France. Pediat. 1985;76:154–8. [20] Peacock JL, Bland JM, Anderson R. Preterm delivery: effect of socioeconomic factors, psychological stress, smoking, alcohol, and caffeine. BMJ. 1995;311:531–5. [21] Saling E. Problems in prevention of preterm birth–regrettable contradictions. J Perint Med. 2011;39:223–5. [22] Sebire NJ, Jolly M, Harris J, Regan I, Robinson S. Is maternal underweight really a risk factor for adverse pregnancy outcome? A population based study in London. Br J Obstet Gynecol. 2001;108:61–6. [23] Vergnes JN, Sixou M. Preterm low birth weight and paternal peridontal status: a meta-analysis. Am J Obstet Gynecol. 2007;196:135e1–7. [24] Wang X, Zuckermann B, Kaufmann G, Wise P, Hill M, Niu T, et al. Molecular epidemiology of preterm delivery: methodology and challenges. Paediatr Perinat Epidemiol. 2001;15:63–77. The author stated that there are no conflicts of interest regarding the publication of this article.
Brought to you by | University of Iowa Libraries Authenticated Download Date | 6/4/15 9:39 AM
Academy’s paper Joachim W. Dudenhausen*
Primary prevention of preterm birth *Corresponding author: Joachim W. Dudenhausen, Weill Cornell Medical College, Sidra Medical and Research Center, Qatar Foundation, POB 26999, Doha, State of Qatar, E-mail: [email protected]
The prevalence of preterm birth has increased, despite efforts to treat pregnant women with symptoms of preterm labor (PTL). In the United States, the preterm delivery (PTD) rate increased from 10.6% in 1990 to 11.7% in 2011, in Germany from 7.1% in 2007 to 9.0% in 2008, and in Portugal from 6.8% in 2004 to 9.0% in 2008. Numerous medical and surgical procedures have been used to treat or prevent spontaneous PTL. There is a need to revisit strategies to reduce the rate of preterm birth.
Definition of prevention The term “prevention” means “general measures to avoid bad conditions.” The objective of this communication is to present a framework for the prevention of spontaneous PTL leading to PTD. The conventional approach in epidemiology is to divide prevention into primary, secondary and tertiary levels, and these concepts could be applied to the prevention of PTL. In this case, primary prevention would consist of interventions directed to all women, which are implemented before or during pregnancy, to reduce risks [8]. Secondary prevention measures are directed toward reducing the risk in women with already assessed risk factors (i.e., tocolysis in patients with spontaneous PTL). Tertiary prevention refers to the measures deployed to improve neonatal outcome after a PTD has occurred (i.e., the administration of surfactant to mitigate respiratory distress syndrome).
Prevention of PTL and PTD Treatments to reduce the risk of PTL and PTD, such as tocolytic treatment, antenatal corticosteroids and surgical treatment (cerclage or cervical occlusion), are considered to be secondary or tertiary prevention measures. For primary prevention strategies against PTL and PTD, there is a need to acknowledge and evaluate the risk factors involved. Such primary prevention may uncover
benefits that are beyond secondary and tertiary measures. Moreover, through education and public policy, such benefits may depend on sound scientific evidence and may require decades of research effort. Spontaneous PTD is not a single entity, but a collection of conditions (phenotypes) caused by multiple pathologic processes [13]. Hence, it is unrealistic to assume that a single measure would be universally effective to prevent this condition. Improved understanding of the mechanisms of the disease responsible for each particular phenotype and continued efforts to develop early biomarkers and interventions would be required to accomplish this goal. At this point, some general ideas can be proposed in discussing primary prevention measures employed to reduce spontaneous PTB.
Iatrogenic risk factors Reducing the rate of induction of labor and elective cesarean delivery (without labor) is one approach that can be employed to decrease the rate of PTD [12]. However, some PTDs would be required for maternal or fetal indications (e.g., in cases of intrauterine growth restriction or preeclampsia). Multiple gestations after assisted reproductive technology (ART) procedures can increase the risk for PTL and PTD. This risk remains elevated when conception occurs with ART, even in singleton gestations. Thus far, recommendations aimed at reducing the number of multiple gestations after ART (one embryo transfer) have achieved success in some countries in Europe [2, 7]. Preconceptional primary prevention includes the education of women and health care providers about the evidence, which states that repeated uterine instrumentation (repeated abortion and uterine curettage) is associated with an increased rate of subsequent PTL and PTD [16].
Environmental risk factors A low body mass index and obesity, defined as a body mass index higher than 30, are both associated with PTL and PTD. Smoking cessation can also reduce the rate of spontaneous PTL and PTD [3, 6, 20, 22].
Brought to you by | University of Iowa Libraries Authenticated Download Date | 6/4/15 9:39 AM
432 Dudenhausen, Preterm birth prevention
Social and genetic risk factors There are laws in place to protect pregnant women, including the following: leave of 14 weeks before the delivery, exemption from night shifts, protection from workplace hazards, access to free antenatal care, timeoff for antenatal visits, legal prohibition of standing position of pregnant women in work, and universal health care coverage for women and children [17–19]. While some progress has been made in the identification of causative genes and variants associated with preterm bith, the true genetic pathology has yet to be fully identified. Studies suggested preliminary associations between maternal polymorphisms in leucyl/cystinyl aminopeptidase (LNPEP) and the risk of PTL [10]. Maternal oxytocin receptor (OXTR) missense single nucleotide polymorphisms rs4686302 and rs237902 have gestational age-dependent effects on PTD. Significant differences between ethnic groups were also observed for IL-6 and IL-6R in maternal and fetal samples, or in TNF-alpha/TNF receptor genes [24]. Genetic factors interact with environmental exposures, and in some instances, the latter result in epigenetic changes. Research is required to discover the contribution of genetic and environmental mechanisms for the design of preventive strategies. There is currently a gap between large-scale informatic approaches combining genomic information and environmental exposure. Thus, gaining a better understanding of the interactions between fetal and maternal genomes is urgently needed [5]. In addition, the importance of genetic predisposition for preterm delivery is shown in the prematurity recurrence rate of 17% of cases with the same father; however, the risk is lower in cases of different fathers. Socioeconomic factors play a role because data suggest an association between income and educational
level with the likelihood of PTD [11]. Moreover, some of these risk factors operate through the induction of stress, anxiety, and low resilience [15].
Medical risk factors Around two-thirds of PTDs are spontaneous with PTL and/or preterm prelabor rupture of membranes. In these cases, intrauterine infection or decidual hemorrhage can be a cause of the clinical condition long before the symptoms occur. Extrauterine or ascending infection is also associated with higher risk of PTL and PTD; hence, early diagnosis of bacterial vaginosis and treatment are crucial [14, 21]. Moreover, prepregnancy treatment of periodontal diseases is associated with a decreased risk of PTL and PTD. However, the association between the risk of PTL and periodontal diseases is evidence-based [4], and the basis of the association has yet to be determined. Does reduce treatment of periodontal disease during pregnancy the rate of PTD? This question isn’t answered finally [1, 9, 23]. Maternal anemia before and during pregnancy and iron deficiency, mainly in the first or second trimester, are associated with a higher risk of PTL and PTD.
Consequences Efforts to lessen risk for PTL or PTD have mainly focused on secondary or tertiary prevention. However, the incidence of PTL and PTD continues to rise. Thus, advances in primary care, policies, and strategies based on primary prevention techniques are needed to reduce the incidence of PTL and PTD.
References [1] American College of Obstetricians and Gynecologists: Oral Health Care during Pregnancy and through Lifespan. Committee Opinion 569, August 2013. [2] Andersen AN, Goossens V, Ferraretti AP, Bhattacharya S, Felberbaum R, de Mouzon J, Nygren KG. European IVFMonitoring Consortium, European Society of Human Reproduction and Embryology: assisted reproductive technology in Europe, 2004: results generated from European registers by ESHRE. Hum Reprod. 2008; 23:756–71. [3] Basso O, Olsen J, Christensen K. Low birthweight and prematurity in relation to paternal factors: a study of recurrence. Int J Epidemiol. 1999;28:695–700.
[4] Bergmann RL, Dudenhausen JW. Prädiktion und Prävention der Frühgeburt. Gynäkologe. 2003;36:391–402. [5] Bezold KY, Karjalainen MK, Hallman M, teramo K, Muglia LJ. The genomics of preterm birth: from animal models to human studies. Genome Med. 2013;5:34. [6] Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and impolications. Lancet. 2012;379:2162–72. [7] Felberbaum RE. Multiole pregnancies after assisted reproduction–international comparison. Reprod Biomed Online. 2007;15:53–60.
Brought to you by | University of Iowa Libraries Authenticated Download Date | 6/4/15 9:39 AM
Dudenhausen, Preterm birth prevention 433 [8] Iams JD, Romero R, Culhane JF, Goldenberg RL. Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth. Lancet. 2008;371:164–75. [9] Jeffcoat M, Parry S, Sammel M, Clothier B, Catlin A, Macones G. Periodontal infection and preterm birth: successful periodontal therapy reduces the risk of preterm birth. BJOG. 2011;118:250–6. [10] Kim J, Stirling KJ, Cooper ME, Ascoli M, Momany AM, McDonald EL, et al. Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study. BMC Med Genet. 2013;14:77. [11] Kramer MS, Goulet I, Lyndon J, Séguin L, McNamara H, Dassa C, et al. Socioeconomic disparities in preterm birth: causal pathways and mechanisms. Paediatr Perinat Epidemiol. 2001;15:104–23. [12] Kramer MS, McLean FH, Eason EL, Usher RH. Maternal nutrition and spontaneous preterm birth. Am J Epidemiol. 1992;136: 574–83. [13] Lamont RF. Can antibiotics prevent preterm birth–the pro and con debate. BJOG. 2005;112:67–73. [14] Menon R. Spontaneous preterm birth, a clinical dilemma: etiologic, pathophysiologic and genetic heterogeneities and racial disparity. Acta Obstet Gynecol. 2008;87:590–600. [15] Misra DP, O’Campo P, Strobino D. Testing a sociomedical model for preterm delivery. Paediatr Perinat Epidemiol. 2001;15:110–22. [16] Moreau C, Kaminski M, Auell PY. Previous induced abortions and the risk of very preterm delivery: results of the EPIPAGE study. BJOG. 2005;112:430–7.
[17] Newman RB, Goldenberg RL, Moawad AH, Iams JD, Meis PJ, Das A, et al. Occupational fatigue and preterm premature rupture of membranes. Am J Obstet Gynecol. 2001;184: 438–46. [18] Papiernik E, Kaminski M. Multifactorial study of the risk of prematurity at 32 weeks of gestation. J Perinat Med. 1974;2:30–42. [19] Papiernik E, Bouyer J, Dreyfus J, Collin D, Winisdorffer G, Guegen S, et al. Prevention of preterm births: a perinatal study in Haguenau, France. Pediat. 1985;76:154–8. [20] Peacock JL, Bland JM, Anderson R. Preterm delivery: effect of socioeconomic factors, psychological stress, smoking, alcohol, and caffeine. BMJ. 1995;311:531–5. [21] Saling E. Problems in prevention of preterm birth–regrettable contradictions. J Perint Med. 2011;39:223–5. [22] Sebire NJ, Jolly M, Harris J, Regan I, Robinson S. Is maternal underweight really a risk factor for adverse pregnancy outcome? A population based study in London. Br J Obstet Gynecol. 2001;108:61–6. [23] Vergnes JN, Sixou M. Preterm low birth weight and paternal peridontal status: a meta-analysis. Am J Obstet Gynecol. 2007;196:135e1–7. [24] Wang X, Zuckermann B, Kaufmann G, Wise P, Hill M, Niu T, et al. Molecular epidemiology of preterm delivery: methodology and challenges. Paediatr Perinat Epidemiol. 2001;15:63–77. The author stated that there are no conflicts of interest regarding the publication of this article.
Brought to you by | University of Iowa Libraries Authenticated Download Date | 6/4/15 9:39 AM
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