Obstetrical and perinatal complications of twin pregnancies: is there a link with the type of infertility treatment?

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1 AOGS ORIGINAL RESEARCH ARTICLE Obstetrical and perinatal complications of twin pregnancies: is there a link with the type of infertility treatment? SOPHIE DELTOMBE-BODART 1, PHILIPPE DERUELLE 1,2, ELODIE DRUMEZ 3, SOPHIE CORDIEZ 1, SOPHIE CATTEAU-JONARD 4 & CHARLES GARABEDIAN 1,2 1 Department of Obstetrics, GemJDF Project, CHU Lille, Lille, 2 EA 4489 Perinatal Health and Environment, University of Lille, Lille, 3 Department of Biostatistics, EA 2694 Public Health: Epidemiology and Healthcare Quality, CHU Lille, Lille, and 4 Department of Reproductive Medicine, CHU Lille, Lille, France Key words Assisted reproductive technology, infertility treatment, intracytoplasmic sperm injection, intrauterine insemination, in vitro fertilization, ovulation induction, twin pregnancy Correspondence Charles Garabedian, Department of Obstetrics, Jeanne de Flandre Hospital, Lille University Hospital, Lille 59000, France. charles.garabedian@chru-lille.fr Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Please cite this article as: Deltombe-Bodart S, Deruelle P, Drumez E, Cordiez S, Catteau- Jonard S, Garabedian C. Obstetrical and perinatal complications of twin pregnancies: is there a link with the type of infertility treatment? Acta Obstet Gynecol Scand 2017; 96: Received: 11 November 2016 Accepted: 19 March 2017 DOI: /aogs Abstract Introduction. The aim of this study was to compare the maternal and perinatal data from spontaneous twin pregnancies with twin pregnancies conceived via assisted reproductive technology, and to evaluate the outcomes depending on the type of treatment. Material and methods. A historical cohort of all twin live births between 1997 and 2014 was used to create two groups: spontaneous pregnancies and pregnancies after infertility treatment (ovulation induction, intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection). The population characteristics and pregnancy, childbirth, and neonatal complications were compared, and the data were adjusted for age, parity, chorionicity, and the mother s body mass index to assess only the impact of the infertility treatments. Results. In total, 1580 twin pregnancies were included, with 575 requiring assisted conception. We did not observe any differences between the assisted conception pregnancies and the spontaneous twin pregnancies with regard to the obstetric and childbirth complications and neonatal outcomes. In addition, there were no statistically significant differences between the types of infertility treatment. Conclusion. After adjusting for the maternal parameters and chorionicity, the twin pregnancies conceived via assisted reproductive technology were not at an increased risk of obstetric and neonatal complications. Moreover, the type of treatment did not alter the obstetric and neonatal complications. Therefore, the higher complication rate was related to the patient s medical specifics, rather than to the infertility treatment. Abbreviations: ART, assisted reproductive technology; BMI, body mass index; ICSI, intracytoplasmic sperm injection; IT, infertility treatment; IUI, intrauterine insemination; IVF, in vitro fertilization; OI, ovulation induction; OR, odds ratio; SP, spontaneous pregnancy. Introduction The rate of twin births has been steadily increasing in France. In 2008, the rate of twin births was 15.6/1000, which corresponded to an 80% increase over a period of 35 years (1). This has been explained by the increasing maternal age and development of infertility treatments (2). Generally, in the literature, we observed that twin pregnancies were at an Key Message After adjustment for maternal parameters and chorionicity, twin pregnancies conceived by assisted reproductive technology were not at increased risk of obstetric and neonatal complications. 844 ª 2017 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

2 S. Deltombe-Bodart et al. Twin pregnancy after assisted conception increased risk for fetal and infant mortality, premature birth, low birthweight, and cerebral palsy (3). In France, children were born via assisted reproductive technology (ART) in 2010, which represented about 1 pregnancy in 40, and a twin birth rate of 14.5% (1). For singletons, after infertility treatment, the pregnancy outcome was less favorable than after a spontaneous conception, no matter which infertility treatment was used (4). McDonald et al. found increased risks of perinatal mortality [odds ratio (OR) 2.40, 95% CI ], premature delivery (before 33 weeks of gestation) (OR 2.99, 95% CI ), premature delivery (before 37 weeks of gestation) (OR 1.93, 95% CI ), low birthweight (<1500 g) (OR 3.78, 95% CI ), and small-for-gestational-age (OR 1.59, 95% CI ) for singleton pregnancies after ART (5). With regard to twin pregnancies, several studies have compared pregnancies after ART with spontaneous pregnancies. They reported that the risk of preterm delivery (before weeks of gestation) seemed higher (6 10) and the mean birthweight was lower in the infertility treatment group (11 13). However, we did not find significant differences in the rates of pregnancy-induced hypertension and gestational diabetes, or in neonatal condition (14). There were conflicting results on the mode of delivery. For example, Geisler et al. found that the cesarean rate was higher in the infertility treatment group (OR 2.35, 95% CI ) (15). Nassar et al. found similar results (76% vs. 58%, p = 0.026) (6), whereas Caserta et al. and Vasario et al. did not report any difference between the two groups (14,16). A few studies have compared the outcomes for different types of ART with spontaneous twin pregnancies, and their discordant results (17,18). For instance, Davies et al. showed that the infertility treatment modality had an impact on the risk of complications at birth (17). However, Marino et al. did not find any significant difference between the groups (18). Overall, our primary endpoint was to compare the maternal and perinatal data of spontaneous twin pregnancies with infertility treatment twin pregnancies, first in a global manner, and then depending on the type of treatment. Material and methods This was a historical single-center cohort study including all twin births between 1997 and 2014 from spontaneous and infertility treatment pregnancies. Our center is a reference center for diseases in twin pregnancies. Before we began this research, the study was approved by the ethics committee for research in gynecology and obstetrics ( CEROG OBS). We excluded twin pregnancies following egg donation (n = 17) because these pregnancies presented a specific risk with increased vascular complications, such as preeclampsia and immunologically-mediated high blood pressure (19 22). Any cases of intrauterine fetal death (n = 14), twin-to-twin transfusion syndrome (n = 74), and polymalformation syndrome (n = 15) were also excluded. The gestational age was calculated from the date of puncture for pregnancies resulting from in vitro fertilization (IVF) or an intracytoplasmic sperm injection (ICSI), 2 days after ovulation induction (OI) for pregnancies resulting from OI and intrauterine insemination (IUI), and the date of the first day of the last menstrual period and ultrasound measurement of the cranio caudal length between and weeks of gestation for the spontaneous pregnancies. The chorionicity was determined during the first-trimester ultrasound by the number of placentas, lambda sign, T-sign, and the thickness of the membrane. The pregnancy monitoring was performed as recommended by the National College of French Gynecologists and Obstetricians, with monthly ultrasound scans for dichorionic diamniotic pregnancies, and fortnightly ultrasound scans for monochorionic diamniotic pregnancies (23). The population data included the maternal age, parity, chorionicity, spontaneous conception or fertility treatment (OI, IUI, IVF, and ICSI), and obstetric complications, including pregnancy-induced hypertension (blood pressure above 140/90 mmhg), preeclampsia (hypertension and proteinuria of 0.3 g/24 h), gestational diabetes, premature rupture of membranes, cholestasis of pregnancy, and placenta previa. We studied the route of delivery, incidence of postpartum hemorrhage (defined as >500 ml blood loss), and the presence of perineal tearing. On the neonatal level, we identified the following parameters: gestational age at birth, small for-gestationalage as defined by an estimated fetal weight below the third percentile, low birthweight (<1500 g), birthweight <2500 g, Apgar score <7 at 5 min, admission to the neonatal intensive care unit, neonatal respiratory distress, neonatal sepsis, and neonatal death. The type of infertility treatment was determined during the first prenatal consultation, and noted in the obstetric record. Statistical analyses The data were collected using CLINSIGHT software (version , 2011). First, we compared the maternal and perinatal data between the spontaneous twin pregnancies (reference, SP group) and twin pregnancies after infertility treatment (any technique pooled together, IT group). Second, we compared the maternal and perinatal data ª 2017 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

3 Twin pregnancy after assisted conception S. Deltombe-Bodart et al. between the SP group and each technique in the IT group (OI, IUI, IVF, and ICSI). The quantitative variables were described in terms of the frequency and percentage, and as the mean standard deviation. The normality of the quantitative variables was checked graphically and tested using the Shapiro Wilks test. The maternal characteristics were compared between the groups using the chi-squared test for the categorical variables and the Student s t test for the quantitative variables. The pregnancy, childbirth, and neonatal complications were compared between the groups by logistic regression models to adjust for any potential confounders selected a priori [age, gender, chorionicity, and mother s body mass index (BMI)]. The delivery term (analyzed as a continuous variable) was compared between the groups using an analysis of covariance adjusted for the potential confounders. Considering the low number of placenta previa complications in both groups (SP and IT), no statistical comparison was made. Additionally, we did not perform statistical comparisons between the SP group and each technique in the IT group for the following complications: cholestasis of pregnancy, umbilical cord ph < 7.10 at birth, and neonatal death. This was due to the small number of complications for each technique in the IT group. The bilateral tests were conducted with a level of significance of 5%, except for the comparisons according to the type of assisted conception treatment, in which a Bonferroni correction was applied. The statistical analyses were performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA). Results In total, 1580 pregnant women (only one birth per woman) were included in this research, of which 594 (37.6%) received infertility treatments (Figure 1). Nineteen of them were excluded; 17 underwent egg donations and two had incomplete records. Of these 575 remaining women, 152 (26.4%) underwent OI, 63 (11%) underwent IUI, 192 (33.4%) underwent IVF, and 168 (29.2%) underwent ICSI. Table 1 shows the characteristics of these patients according to the mode of conception. The IT group population was older when compared with the SP group, with mean ages of and years, respectively (p < 0.001). The proportion of primiparous patients was higher in the IT group when compared with the SP group (67.2% vs. 38.1%, respectively, p < 0.001), and there were more dichorionic diamniotic pregnancies in the IT group than the SP Inclusion of 1580 twin pregnancies between 1997 and 2014 Pregnancies after IT n = 594 (37%) Spontaneous pregnancies n = 986 (63%) 19 exlusions Egg donation (n = 17) Missing data (n = 2) Pregnancies after IT n = 575 OI n = 152(26.4%) IUI n = 63(11%) IVF n = 192(33.4%) IVF/ICSI n = 168(29.2%) Figure 1. Study population. SP, spontaneous pregnancy; IT, infertility treatments; OI, ovulation induction; IUI, intrauterine insemination; IVF, in vitro fertilization; ICSI, intracytoplamic sperm injection. [Color figure can be viewed at wileyonlinelibrary.com]. 846 ª 2017 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

4 S. Deltombe-Bodart et al. Twin pregnancy after assisted conception Table 1. Population characteristics. According to the ART technique SP (n = 986) IT (n = 575) p OI (n = 152) IUI (n = 63) IVF (n = 192) ICSI (n = 168) Maternal age (years) Mean age < * * < (48.9) 196 (34.1) 85 (55.9) 27 (42.9) 42 (21.9) 42 (25.0) (32.8) 264 (45.9) 51 (33.6) 26 (41.3) 92 (47.9) 95 (56.6) (15.3) 96 (16.7) 15 (9.9) 7 (11.1) 46 (24.0) 28 (16.7) >40 30 (3.0) 19 (3.3) 1 (0.7) 3 (4.8) 12 (6.3) 3 (1.8) Primiparous 376 (38.1) 384 (66.8) < (61.2)* 44 (69.8)* 130 (67.7)* 117 (69.6)* Dichorial/diamniotic 715 (72.6) 556 (96.9) < (96.0)* 63 (100)* 184 (95.8)* 164 (97.6)* Smoking 192 (19.5) 44 (7.7) < (6.6)* 6 (9.5) 17 (9.0)* 11 (6.6)* BMI (kg/m 2 ) Mean BMI * < (89.3) 507 (91.2) 128 (88.3) 54 (88.3) 179 (94.7) 149 (90.8) (8.9) 47 (8.4) 16 (11.0) 7 (11.7) 10 (5.3) 14 (8.6) >40 17 (1.8) 2 (0.4) 1 (0.7) (0.6) ART, assisted reproductive technology; BMI, body mass index; ICSI, intracytoplasmic sperm injection; IT, infertility treatment; IUI, intrauterine insemination; IVF, in vitro fertilization; OI, ovulation induction; SP, spontaneous pregnancy. Results are expressed in n (%) or mean standard deviation. p-values were unadjusted. *p 0.05 for comparison with the reference group (spontaneous pregnancies) after Bonferroni correction. group [574 (96.8%) vs. 715 (72.6%), respectively, p < 0.001]. The use of tobacco was less common in the IT group than in the SP group [45 (7.6%) vs. 192 (19.5%), respectively, p < 0.001]. The BMI was significantly different between the two groups, with a mean BMI of kg/m 2 for the IT group and kg/m 2 for the SP group (p = ). Table 2 summarizes the obstetric complications according to the groups. We noted no significant difference between the IT and SP groups, or between the types of treatment in the IT group and the SP group. With regard to the obstetric outcomes, no difference was found between the IT and SP groups in the delivery term or the occurrence of postpartum hemorrhage (Table 3). The mean delivery term in both groups was weeks of gestation. In the delivery route, no difference was noted between the IT and SP groups in the rate of cesarean sections. In addition, no differences were found in the delivery route between the types of treatment in the IT group and the SP group. Table 4 presents the neonatal outcomes. There were no significant differences between the IT and SP groups in the occurrences of small-for-gestational-age, birthweights <1500 g and <2500 g, an Apgar score <7 at 5 min, an umbilical cord ph < 7.10, neonatal complications, or neonatal death. In addition, no differences were found in the comparisons between the different treatment types in the IT group and the SP group. Discussion The data from the current literature are sparse and discordant with regard to the comparisons of the obstetric and neonatal complications of twin pregnancies according to conception and the fertility treatment used. Our study was based on a large number of women, and after adjustment for maternal factors and chorionicity, we found no differences in the obstetric and neonatal complications between infertility treatment twin pregnancies and spontaneous twin pregnancies. There were no differences between the different types of fertility treatment that we evaluated (OI, IUI, IVF, and ICSI). The worst outcomes of twin pregnancies with secondary infertility treatments could be linked to the medical history of the infertile patient and the infertility treatment used. Indeed, Caserta et al. found more patients with thrombophilia, hypothyroidism, and endometriosis in the ART group consisting of patients with hormonal imbalances and placentation disorders (14). K allen et al. found better outcomes in ICSI pregnancies than in IVF pregnancies because, in most cases, the ICSI treatment was due to male factor infertility (24). Some infertility treatments (hormonal stimulation, manipulation of oocytes and sperm during IVF, embryo manipulation with some freezing of the embryos, and late fertilization of the oocytes) might be responsible for alterations in the embryo and utero placental interactions, causing pregnancy complications (25). Therefore, it seemed important to assess the specific outcomes of twin pregnancies according to the infertility treatments used. Overall, the characteristics of our population were consistent with those of the literature. The patients in the IT group were older and more commonly primiparous when compared with the SP group, increasing the risk of ª 2017 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

5 Twin pregnancy after assisted conception S. Deltombe-Bodart et al. Table 2. Complications of pregnancy. According to the ART technique IUI IVF ICSI SP (n = 986) IT (n = 575) OI (n = 152) (n = 63) (n = 192) (n = 168) n % n % Adjusted OR (95% CI) n % n % n % n % Gestational hypertension ( ) Preeclampsia ( ) Gestational diabetes ( ) Premature delivery threat ( ) Premature rupture of ( ) membranes (PROM) Cholestasis of pregnancy ( ) Placenta previa NA ART, assisted reproductive technology; ICSI, intracytoplasmic sperm injection; IT, infertility treatment; IUI, intrauterine insemination; IVF, in vitro fertilization; OI, ovulation induction; OR, odds ratio; SP, spontaneous pregnancy. p-values were adjusted for age, parity, chorionicity and mother s body mass index. For all ART technique comparisons with reference group (spontaneous pregnancies), no significant differences were found (p > 0.05 after Bonferroni correction). Adjusted odds ratios were calculated using spontaneous pregnancies as reference group. Table 3. Delivery complications. According to the ART technique SP (n = 986) IT (n = 575) Adjusted OR (95% CI) OI (n = 152) IUI (n = 63) IVF (n = 192) ICSI (n = 168) Delivery term (weeks of gestation) Delivery route Postpartum hemorrhage Mean term * ( 0.39 to 0.30) <28 50 (5.1) 25 (4.4) 12 (8.1) 2 (3.2) 9 (4.7) 2 (1.2) (9.1) 49 (8.6) 16 (10.7) 7 (11.1) 11 (5.8) 15 (8.9) (47.6) 285 (49.9) 68 (45.6) 23 (36.5) 102 (53.4) 92 (54.8) > (38.3) 212 (37.1) 53 (35.6) 31 (49.2) 69 (36.1) 59 (35.1) Cesarean 421 (43.0) 235 (41.1) 0.93 ( ) 60 (40.0) 30 (47.6) 86 (45.0) 59 (35.1) section Elective 199 (47.3) 104 (44.3) 0.87 ( ) 27 (45.0) 13 (43.3) 37 (43.0) 27 (45.8) cesarean section Emergency 225 (53.7) 132 (56.2) 1.12 ( ) 33 (55.0) 17 (56.7) 49 (57.0) 33 (55.9) cesarean section Sup 500 ml 371 (37.9) 231 (40.6) 0.98 ( ) 53 (36.1) 29 (46.0) 83 (43.5) 66 (39.3) Sup 1000 ml 118 (12.1) 65 (11.4) 0.90 ( ) 12 (8.2) 4 (6.4) 27 (14.1) 22 (13.1) ART, assisted reproductive technology; ICSI, intracytoplasmic sperm injection; IT, infertility treatment; IUI, intrauterine insemination; IVF, in vitro fertilization; OI, ovulation induction; OR, odds ratio; SP, spontaneous pregnancy; Sup, superior to. Results expressed as n (%) or as mean standard deviation. p-values were adjusted for age, parity, chorionicity and mother s body mass index. For all ART technique comparisons with reference group (spontaneous pregnancies), no significant differences were found (p > 0.05 after Bonferroni correction). Adjusted odds ratios were calculated using spontaneous pregnancies as reference group. *For delivery term, the adjusted mean difference was reported. perinatal and obstetric complications. Different authors have found increased occurrences of gestational hypertension, gestational diabetes, premature delivery, cesarean section, and intrauterine fetal death in older patients (26 28). Therefore, we chose to adjust our results based on these parameters to investigate the sheer impact of the infertility treatments. Our results confirmed those of Caserta et al. and Yang et al., who did not find any 848 ª 2017 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

6 S. Deltombe-Bodart et al. Twin pregnancy after assisted conception Table 4. Neonatal complications. According to the ART technique SP (n = 986) IT (n = 575) OI (n = 152) IUI (n = 63) IVF (n = 192) ICSI (n = 168) n % n % Adjusted OR (95% CI) n % n % n % n % Small-for-gestational-age ( ) Birthweight < 1500 g ( ) Birthweight < 2500 g ( ) Apgar < 7 at 5 min ( ) Umbilical cord ph < ( ) Neonatal intensive care unit admission ( ) Neonatal respiratory distress ( ) Neonatal sepsis ( ) Neonatal death ( ) ART, assisted reproductive technology; ICSI, intracytoplasmic sperm injection; IT, infertility treatment; IUI, intrauterine insemination; IVF, in vitro fertilization; OI, ovulation induction; OR, odds ratio; SP, spontaneous pregnancy. p-values were adjusted for age, parity, chorionicity and mother s body mass index. For all ART technique comparisons with reference group (spontaneous pregnancies), no significant differences were found (p > 0.05 after Bonferroni correction). Adjusted odds ratios were calculated using spontaneous pregnancies as reference group. differences in the perinatal and obstetric complications between the IT and SP groups after adjusting for maternal age and parity. Before adjusting for these, Caserta et al. found more preterm births (OR 2.08, 95% CI vs. OR 1.33, 95% CI after the adjustment) and more small-for-gestational-age cases (OR 1.49, 95% CI vs. OR 1.08, 95% CI after the adjustment) in the IT group. Hence, the unfavorable outcomes of twin pregnancies after infertility treatments described in the literature could be more related to the woman s medical history and type of twin pregnancy than to the infertility treatment (14,29). The results were similar in our fertility treatment subgroups, regardless of the mode of assisted conception, reinforcing the only study evaluating the effect of adjusting for the infertility treatment. Indeed, Marino et al. isolated several differences, including more low birthweights (<1500 g) in the IUI subgroup (OR 1.96, 95% CI ), a lower average birthweight in the IVF subgroup (with fresh embryos), and less incidence of small-forgestational-age in the ICSI subgroup (with fresh embryos) (OR 0.64, 95% CI ). However, among singletons, Marino et al. found differences between the various treatments for infertility, especially more low birthweights, premature births, and neonatal deaths in the IVF and ICSI subgroups (18). Our study was one of the largest cohorts comparing infertility treatment twin pregnancies with spontaneous twin pregnancies. It was also one of the few studies comparing twin pregnancies according to the infertility treatment, while adjusting for the maternal parameters and chorionicity. All of the twin pregnancies (IT and SP groups) benefited from similar management by the same medical team, with the same department protocols, and we chose to include IVF, ICSI, OI, and IUI pregnancies to be exhaustive. Our study did have some limitations. For example, it was conducted in a single center with the possibility of selection bias. We excluded pregnancies with intrauterine fetal deaths because these outcomes did not originally appear in our database. Moreover, we chose to adjust the results based on the mother s age, chorionicity, parity, and the mother s BMI because these were the potential confounders reported in the literature. We did not adjust the results for smoking during pregnancy because previous authors did not find it to be a confounder, despite the fact that smoking during pregnancy was more common in the SP group. We chose to include diamniotic monochorionic pregnancies in this study. However, several studies in the literature excluded diamniotic monochorionic pregnancies because they are less common after infertility treatments, with a higher risk of complications. We included them to be exhaustive, and adjusted our results based on chorionicity. In addition, our collection period was long, with consequent changes in the ART procedures and obstetric practices over that period of time. Furthermore, we had no way of knowing if the IVF pregnancies included fresh or frozen embryos, because the infertility treatments were not routinely performed in our center. ª 2017 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

7 Twin pregnancy after assisted conception S. Deltombe-Bodart et al. Conclusion According to the results of our study, the infertility treatment twin pregnancies, whatever the technique, were not at an increased risk for obstetric and neonatal complications, after adjusting for the maternal parameters and chorionicity. An increased risk for complications was more related to the medical history of the woman undergoing infertility treatment, which is valuable information for a clinician during the counseling process. Funding No specific funding. References 1. Blondel B. Augmentation des naissances gemellaires et consequences sur la sante. J Gynecologie Obstetrique Biol Reprod. 2009;38:S de Mouzon J, Goossens V, Bhattacharya S, Castilla JA, Ferraretti AP, Korsak V, et al. Assisted reproductive technology in Europe, 2006: results generated from European registers by ESHRE. Hum Reprod. 2010;25: Conde-Agudelo A, Belizan JM, Lindmark G. Maternal morbidity and mortality associated with multiple gestations. Obstet Gynecol. 2000;95(6 Pt 1): Helmerhorst FM, Perquin DAM, Donker D, Keirse MJNC. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ. 2004;328: McDonald SD, Murphy K, Beyene J, Ohlsson A. Perinatal outcomes of singleton pregnancies achieved by in vitro fertilization: a systematic review and meta-analysis. J Obstet Gynaecol Can. 2005;27: Nassar AH, Usta IM, Rechdan JB, Harb TS, Adra AM, Abu-Musa AA. Pregnancy outcome in spontaneous twins versus twins who were conceived through in vitro fertilization. Am J Obstet Gynecol. 2003;189: K allen B, Finnstr om O, Lindam A, Nilsson E, Nygren K-G, Olausson PO. Selected neonatal outcomes in dizygotic twins after IVF versus non-ivf pregnancies. BJOG. 2010;117: Verstraelen H, Goetgeluk S, Derom C, Vansteelandt S, Derom R, Goetghebeur E, et al. Preterm birth in twins after subfertility treatment: population based cohort study. BMJ. 2005;331: Adler-Levy Y, Lunenfeld E, Levy A. Obstetric outcome of twin pregnancies conceived by in vitro fertilization and ovulation induction compared with those conceived spontaneously. Eur J Obstet Gynecol Reprod Biol. 2007;133: Bamberg C, Fotopoulou C, Neissner P, Slowinski T, Dudenhausen JW, Proquitte H, et al. Maternal characteristics and twin gestation outcomes over 10 years: impact of conception methods. Fertil Steril. 2012;98: e McDonald SD, Han Z, Mulla S, Ohlsson A, Beyene J, Murphy KE. Preterm birth and low birth weight among in vitro fertilization twins: a systematic review and metaanalyses. Eur J Obstet Gynecol Reprod Biol. 2010;148: McDonald S, Murphy K, Beyene J, Ohlsson A. Perinatal outcomes of in vitro fertilization twins: a systematic review and meta-analyses. Am J Obstet Gynecol. 2005;193: Moini A, Shiva M, Arabipoor A, Hosseini R, Chehrazi M, Sadeghi M. Obstetric and neonatal outcomes of twin pregnancies conceived by assisted reproductive technology compared with twin pregnancies conceived spontaneously: a prospective follow-up study. Eur J Obstet Gynecol Reprod Biol. 2012;165: Caserta D, Bordi G, Stegagno M, Filippini F, Podagrosi M, Roselli D, et al. Maternal and perinatal outcomes in spontaneous versus assisted conception twin pregnancies. Eur J Obstet Gynecol Reprod Biol. 2014;174: Geisler ME, O Mahony A, Meaney S, Waterstone JJ, O Donoghue K. Obstetric and perinatal outcomes of twin pregnancies conceived following IVF/ICSI treatment compared with spontaneously conceived twin pregnancies. Eur J Obstet Gynecol Reprod Biol. 2014;181: Vasario E, Borgarello V, Bossotti C, Libanori E, Biolcati M, Arduino S, et al. IVF twins have similar obstetric and neonatal outcome as spontaneously conceived twins: a prospective follow-up study. Reprod Biomed Online. 2010;21: Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366: Marino JL, Moore VM, Willson KJ, Rumbold A, Whitrow MJ, Giles LC, et al. Perinatal outcomes by mode of assisted conception and sub-fertility in an Australian data linkage cohort. PLoS ONE. 2014;9:e Lutjen P, Trounson A, Leeton J, Findlay J, Wood C, Renou P. The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature. 1984;307: Klein J, Sauer MV. Oocyte donation. Best Pract Res Clin Obstet Gynaecol. 2002;16: Sekhon LH, Gerber RS, Rebarber A, Saltzman DH, Klauser CK, Gupta S, et al. Effect of oocyte donation on pregnancy outcomes in in vitro fertilization twin gestations. Fertil Steril. 2014;101: Levron Y, Dviri M, Segol I, Yerushalmi GM, Hourvitz A, Orvieto R, et al. The immunologic theory of preeclampsia revisited: a lesson from donor oocyte gestations. Am J Obstet Gynecol. 2014;211:e ª 2017 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

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