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Assisted reproductive technology pregnancies were associated with an increased risk of specific negative outcomes
ARTICLE IN PRESS REPRODUCTIVE ENDOCRINOLOGY & INFERTILIT Y
Assisted reproductive technology pregnancies were associated with an increased risk of specific negative outcomes Shevell T, Malone FD,Vidaver J, PorterTF, Luthy DA, Comstock CH, Hankins GD, Eddleman K, Dolan S, Dugoff L, Craigo S, Timor IE, Carr SR, Wolfe HM, Bianchi DW, D’Alton ME. Assisted reproductive technology and pregnancy outcome. Obstet.Gynecol. 2005; 106: 1039^ 45.
OBJECTIVE To assess the associations between assisted reproductive technology (ART) and the outcomes of singleton pregnancies in comparison to spontaneous pregnancies.
DESIGN A prospective multi-centre study using the database from The First and Second Trimester Evaluation of Risk trial (FASTER).
SETTING Participating health care centres in the United States.
SUBJECTS A total of 36,062 women with singleton pregnancies who were enrolled in the FASTER trial at between 10 and 13 weeks gestation. Women were categorized into 3 groups; women who did not undergo ART (n=34,286), women who underwent ovulation induction (n=1222) and women who underwent in vitro fertilization (IVF) (n=554).
INTERVENTION The medical histories of the women were recorded at the start of the study, and follow-up after delivery was through in-person or phone interviews or through the review of medical records.Ten percent of normal subjects, and all women with an abnormal ¢rst or second trimester screening, or any adverse pediatric outcomes had maternal and pediatric medical records reviewed by a perinatologist and a pediatric geneticist. Pregnancy outcomes, including pre-eclampsia, placental abruption, placenta previa, fetal loss and cesarean section were evaluated for all the women and adjusted odds ratios (OR) were calculated. OR were adjusted for maternal age, maternal race, marital status, years of education, prior preterm delivery, prior pregnancy with anomaly, body
110
Evidence-based Obstetrics and Gynecology (2006) 8,110 ^111 doi:10.1016/j.ebobgyn.2006.07.002
mass index, smoking history and bleeding during the current pregnancy.
MAIN OUTCOME MEASURES Pre-eclampsia, placental abruption, placenta previa, spontaneous fetal loss, cesarean section, chromosomal or structural abnormalities.
MAIN RESULTS Women in the ovulation induction group had an OR of 2.4 (95% CI 1.3 ^ 4.2) for placental abruption and an OR of 2.1 (95% CI 1.3 ^ 3.6) for fetal loss after 24 weeks. In the IVF group the OR for pre-eclampsia was 2.7 (95% CI 1.7 ^ 4.4). Placental abruption and placenta previa were also associated with IVF, OR 2.4 (95% CI 1.1 ^ 5.2) and 6 (95% CI 3.4 ^ 10.7), respectively. Women in the IVF group were 2.3 times more likely to undergo cesarean delivery (95% CI 1.8 ^ 2.9). There was no increased risk of chromosomal or structural abnormalities in the ART groups.
CONCLUSION Women who underwent ART had an increased risk of experiencing pre-eclampsia, placental abruption, placenta previa, cesarean delivery and fetal loss when compared to women who conceived spontaneously.
Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
8 6 8
1361-259X/$ - see front matter r 2006 Elsevier Ltd. All rights reserved.
ARTICLE IN PRESS Commentary In vitro fertilization (IVF) has played a crucial role in the treatment of infertility since 1978, and currently serves as the basis of various assisted reproductive techniques. It has become a widespread realistic alternative for infertile couples. Nonetheless, these advances have also led to numerous concerns regarding the safety of these techniques.The major concerns about the obstetric risk of pregnancy after IVF are related to a higher rate of multiplicity, previous infertility, primiparas aged over 35 and the technique itself. Recent nationwide register studies have indicated higher rates of bleeding in early pregnancy, preterm delivery, low infant birthweight, shorter gestation, cesarean section, placenta previa, placental abruption, bleeding in association with vaginal delivery and pregnancy-induced hypertension after IVF.1 However, matched controls have yielded controversial results. The signif|cant increases in the prevalence of preeclampsia, placental abruption, and placenta previa mentioned in the current study are all related to abnormalities of the location and the function of the placenta. There is increasing evidence that genetic factors in infertile couples and also environmental factors (hormones and culture media) can exert adverse effects on the epigenetic processes controlling implantation, placentation, organ formation and fetal growth, all of which could explain this observation. Concern has recently been expressed about the unfavorable obstetrical and neonatal outcome of singletons after assisted reproduction. Nevertheless, for patients in whom elective singleembryo transfer is applied, the prognosis is good: not only is there a higher chance of conception, but also the singleton baby does not have an unfavourable outcome when compared with singleton pregnancies conceived spontaneously. Interestingly, the perinatal outcome of the infertile population treated with non-IVF-assisted reproduction (controlled ovarian stimulation, with or without artif|cial insemination) is signif|cantly poorer compared with naturally conceived matched controls.2 Some reports have concluded that there is an increased risk of congenital malformation, though this association has not been observed consistently. A recent overview of systematic reviews of IVF singletons examined separately and after controlled for maternal age, showed a 30 ^35% higher rate of birth defects.3
Patients undergoing IVF should be advised of the moderately increased risk of an adverse perinatal outcome. Obstetricians should not only manage these pregnancies as high risk but also should avoid the iatrogenic harm caused by elective preterm labour induction or cesarean section. All these data, including the prospective, large-scale, well-designed and analyzed, powerful study of Shevell et al. conf|rm the theory that it is mainly the infertile population and only to a lesser extent, the method and technique applied to treat their infertility that generates the less than optimal obstetric and neonatal outcome. Despite this dilemma, the literature is coherent in that treatment-related multiple pregnancy poses the greatest threat to the safety of IVF. Multicentre studies are needed in the future to collect data to shed light on the particular cause of infertility and the obstetric and neonatal outcome in these subgroups, compared both with each other and with naturally conceived controls. The correct interpretation of the data, despite the additional degree of risk, is that the overall chance of having a healthy child through ART is extremely high. Ja¤nos Za¤dori, MD, Ph.D Center For Assisted Reproduction, Kaali Institute, University of Szeged, Szeged, Hungary
Literature cited 1. Kallen B, Finnstrom O, Nygren KG, Otterblad Olausson P, Wennerholm UB. In vitro fertilisation in Sweden: obstetric characteristics, maternal morbidity and mortality. BJOG. 2005; 112: 1529^35. 2. Ombelet W, Martens G, De Sutter P,Gerris J, Bosmans E, Ruyssinck G, Defoort P, Molenberghs G, Gyselaers W. Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study. Hum Reprod. 2006; 21: 1025 ^32. 3. Bower C, Hansen M. Assisted reproductive technologies and birth outcomes: overview of recent systematic reviews. Reprod Fertil Dev. 2005; 17: 329^33.
Evidence-based Obstetrics and Gynecology (2006) 8,110 ^111
111
Assisted reproductive technology pregnancies were associated with an increased risk of specific negative outcomes Shevell T, Malone FD,Vidaver J, PorterTF, Luthy DA, Comstock CH, Hankins GD, Eddleman K, Dolan S, Dugoff L, Craigo S, Timor IE, Carr SR, Wolfe HM, Bianchi DW, D’Alton ME. Assisted reproductive technology and pregnancy outcome. Obstet.Gynecol. 2005; 106: 1039^ 45.
OBJECTIVE To assess the associations between assisted reproductive technology (ART) and the outcomes of singleton pregnancies in comparison to spontaneous pregnancies.
DESIGN A prospective multi-centre study using the database from The First and Second Trimester Evaluation of Risk trial (FASTER).
SETTING Participating health care centres in the United States.
SUBJECTS A total of 36,062 women with singleton pregnancies who were enrolled in the FASTER trial at between 10 and 13 weeks gestation. Women were categorized into 3 groups; women who did not undergo ART (n=34,286), women who underwent ovulation induction (n=1222) and women who underwent in vitro fertilization (IVF) (n=554).
INTERVENTION The medical histories of the women were recorded at the start of the study, and follow-up after delivery was through in-person or phone interviews or through the review of medical records.Ten percent of normal subjects, and all women with an abnormal ¢rst or second trimester screening, or any adverse pediatric outcomes had maternal and pediatric medical records reviewed by a perinatologist and a pediatric geneticist. Pregnancy outcomes, including pre-eclampsia, placental abruption, placenta previa, fetal loss and cesarean section were evaluated for all the women and adjusted odds ratios (OR) were calculated. OR were adjusted for maternal age, maternal race, marital status, years of education, prior preterm delivery, prior pregnancy with anomaly, body
110
Evidence-based Obstetrics and Gynecology (2006) 8,110 ^111 doi:10.1016/j.ebobgyn.2006.07.002
mass index, smoking history and bleeding during the current pregnancy.
MAIN OUTCOME MEASURES Pre-eclampsia, placental abruption, placenta previa, spontaneous fetal loss, cesarean section, chromosomal or structural abnormalities.
MAIN RESULTS Women in the ovulation induction group had an OR of 2.4 (95% CI 1.3 ^ 4.2) for placental abruption and an OR of 2.1 (95% CI 1.3 ^ 3.6) for fetal loss after 24 weeks. In the IVF group the OR for pre-eclampsia was 2.7 (95% CI 1.7 ^ 4.4). Placental abruption and placenta previa were also associated with IVF, OR 2.4 (95% CI 1.1 ^ 5.2) and 6 (95% CI 3.4 ^ 10.7), respectively. Women in the IVF group were 2.3 times more likely to undergo cesarean delivery (95% CI 1.8 ^ 2.9). There was no increased risk of chromosomal or structural abnormalities in the ART groups.
CONCLUSION Women who underwent ART had an increased risk of experiencing pre-eclampsia, placental abruption, placenta previa, cesarean delivery and fetal loss when compared to women who conceived spontaneously.
Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
8 6 8
1361-259X/$ - see front matter r 2006 Elsevier Ltd. All rights reserved.
ARTICLE IN PRESS Commentary In vitro fertilization (IVF) has played a crucial role in the treatment of infertility since 1978, and currently serves as the basis of various assisted reproductive techniques. It has become a widespread realistic alternative for infertile couples. Nonetheless, these advances have also led to numerous concerns regarding the safety of these techniques.The major concerns about the obstetric risk of pregnancy after IVF are related to a higher rate of multiplicity, previous infertility, primiparas aged over 35 and the technique itself. Recent nationwide register studies have indicated higher rates of bleeding in early pregnancy, preterm delivery, low infant birthweight, shorter gestation, cesarean section, placenta previa, placental abruption, bleeding in association with vaginal delivery and pregnancy-induced hypertension after IVF.1 However, matched controls have yielded controversial results. The signif|cant increases in the prevalence of preeclampsia, placental abruption, and placenta previa mentioned in the current study are all related to abnormalities of the location and the function of the placenta. There is increasing evidence that genetic factors in infertile couples and also environmental factors (hormones and culture media) can exert adverse effects on the epigenetic processes controlling implantation, placentation, organ formation and fetal growth, all of which could explain this observation. Concern has recently been expressed about the unfavorable obstetrical and neonatal outcome of singletons after assisted reproduction. Nevertheless, for patients in whom elective singleembryo transfer is applied, the prognosis is good: not only is there a higher chance of conception, but also the singleton baby does not have an unfavourable outcome when compared with singleton pregnancies conceived spontaneously. Interestingly, the perinatal outcome of the infertile population treated with non-IVF-assisted reproduction (controlled ovarian stimulation, with or without artif|cial insemination) is signif|cantly poorer compared with naturally conceived matched controls.2 Some reports have concluded that there is an increased risk of congenital malformation, though this association has not been observed consistently. A recent overview of systematic reviews of IVF singletons examined separately and after controlled for maternal age, showed a 30 ^35% higher rate of birth defects.3
Patients undergoing IVF should be advised of the moderately increased risk of an adverse perinatal outcome. Obstetricians should not only manage these pregnancies as high risk but also should avoid the iatrogenic harm caused by elective preterm labour induction or cesarean section. All these data, including the prospective, large-scale, well-designed and analyzed, powerful study of Shevell et al. conf|rm the theory that it is mainly the infertile population and only to a lesser extent, the method and technique applied to treat their infertility that generates the less than optimal obstetric and neonatal outcome. Despite this dilemma, the literature is coherent in that treatment-related multiple pregnancy poses the greatest threat to the safety of IVF. Multicentre studies are needed in the future to collect data to shed light on the particular cause of infertility and the obstetric and neonatal outcome in these subgroups, compared both with each other and with naturally conceived controls. The correct interpretation of the data, despite the additional degree of risk, is that the overall chance of having a healthy child through ART is extremely high. Ja¤nos Za¤dori, MD, Ph.D Center For Assisted Reproduction, Kaali Institute, University of Szeged, Szeged, Hungary
Literature cited 1. Kallen B, Finnstrom O, Nygren KG, Otterblad Olausson P, Wennerholm UB. In vitro fertilisation in Sweden: obstetric characteristics, maternal morbidity and mortality. BJOG. 2005; 112: 1529^35. 2. Ombelet W, Martens G, De Sutter P,Gerris J, Bosmans E, Ruyssinck G, Defoort P, Molenberghs G, Gyselaers W. Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study. Hum Reprod. 2006; 21: 1025 ^32. 3. Bower C, Hansen M. Assisted reproductive technologies and birth outcomes: overview of recent systematic reviews. Reprod Fertil Dev. 2005; 17: 329^33.
Evidence-based Obstetrics and Gynecology (2006) 8,110 ^111
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