Impact of Conception Method on Twin Pregnancy Course and Outcome.

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The aim of the study was to investigate the course and outcomes of twin pregnancies conceived by different methods of assisted repro- duction (ART) compared to those conceived spon- taneously.

The study involved patients with twin pregnancies who delivered at the Ob/Gyn Clinic of the Clinical Center of Serbia over a period of three years. Patients were differentiated accord- ing to method of conception and type of ART. Age, parity, etiology of infertility, pregnancy com- plications, time of membrane rupture and type of delivery was recorded for each patient. Gestation- al week at delivery, presentation, birth weight, Apgar score, chorionicity and accompanying dis- orders were separately recorded for each twin. The data were analyzed statistically.

A total of 431 patients were included in the study. Although more twins were conceived by ART, the difference was not statistically signifi- cant (p = 0.092). The most common ART proce- dure was IVF/ICSI (p = 0.001). ART procedures, particularly IVF/ICSI, were significantly correlated with more advanced maternal age, fewer pre- vious pregnancies and delivery by cesarean sec- tions, usually planned (p = 0.001). Preterm mem- brane rupture was more common after ICSI, but preterm delivery and pregnancy complications were infrequent, irrespective of the method of conception (p = 0.001). ART twins were mostly di- chorionic (p = 0.036). Monochorionic twins were conceived either spontaneously or with ICSI. Con- ception by ART was not correlated with twins ʼ outcome (weight, Apgar score, disorders).

ART procedures do not have a nega- tive impact on twin pregnancy course and out- come. Twin pregnancies conceived spontaneously or by ART have similar outcomes. Zusammenfassung ! Zielsetzung: Die vorliegende Studie untersucht den Verlauf und die Ergebnisse von Zwillings- schwangerschaften bei nach verschiedenen Me- thoden der assistierten Reproduktion (ART) kon- zipierten Zwillingen verglichen mit spontan kon- zipierten Zwillingen. Methoden: Patientinnen mit Zwillingsschwan- gerschaften, die in der Frauenklinik des Klini- kums von Serbien innerhalb eines Zeitraums von 3 Jahren entbunden hatten, wurden in die Studie aufgenommen. Die Patientinnen wurden je nach Konzeptionsmodus und ART-Methode in ver- schiedene Gruppen eingeteilt. Alter, vorangehen- de Schwangerschaften, Gründe der Unfruchtbar- keit, Schwangerschaftskomplikationen, Zeitpunkt des Blasensprungs und Entbindungsmodus jeder Patientin wurden vermerkt. Gestationswoche bei der Geburt, Kindslage, Geburtsgewicht, Apgar- Werte, Chorionizität sowie Komorbiditäten wur- den für jedes Neugeborene separat vermerkt. Die gewonnenen Daten wurden einer statistischen Analyse unterzogen. Ergebnisse: Insgesamt 431 Patientinnen nahmen an der Studie teil. Obwohl die Gruppe von ART- konzipierten Zwillingen größer war, war dieser Unterschied statistisch nicht signifikant (p = 0,092). Die am häufigsten verwendete Me- thode zur assistierten Reproduktion war IVF/ICSI (p = 0,001). ART-Verfahren, insbesondere IVF/ICSI, korrelierten signifikant mit höherem mütterli- chem Alter, geringerer Anzahl vorangegangener Schwangerschaften und geplanter Sectio-Entbin- dung (p = 0,001). Vorzeitiger Blasensprung war häufiger nach ICSI, aber vorzeitige Entbindung sowie Schwangerschaftskomplikationen waren in allen Gruppen selten (p = 0,001). ART-kon- zipierte Zwillinge waren meist dichorial (p = 0,036). Monochoriale Zwillinge entwickelten sich entweder nach Spontankonzeption oder ICSI. Es gab keine Korrelation zwischen assistierter Re- Impact of Conception Method on Twin Pregnancy Course and Outcome Auswirkungen der Konzeptionsmethode auf Verlauf und Ergebnis von Zwillingsschwangerschaften Authors S. Andrijasevic 1, J. Dotlic 2, S. Aksam 1, J. Micic 2, M. Terzic 2 Affiliations 1 Clinic of Obstetrics and Gynecology, Clinical Center of Serbia, Belgrade, Serbia 2 Clinic of Obstetrics and Gynecology, Clinical Center of Serbia, Medical Faculty, University of Belgrade, Belgrade, Serbia Key words l" assisted reproductive technology (ART) l " pregnancy l" spontaneous conception l" pregnancy outcome l" twins Schlüsselwörter l" assistierte Reproduktion l" Schwangerschaft l" Spontankonzeption l" Ausgang der Schwangerschaft l " Zwillinge received 24. 4. 2014 revised 1. 9. 2014 accepted 12. 9. 2014

DOI http://dx.doi.org/ 10.1055/s-0034-1383148 Geburtsh Frauenheilk 2014; 74: 933–939 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0016‑5751 Correspondence Dr. Jelena Dotlic Clinic of Obstetrics and Gynecology Clinical Center of Serbia, Medical Faculty, University of Belgrade Dr Koste Todorovica 26 Belgrade Serbia [email protected] 933 Andrijasevic S et al. Impact of Conception … Geburtsh Frauenheilk 2014; 74: 933 –939 Original Article

! In the last decade, the number of multiple pregnancies occurring worldwide has increased. The main contributors to this rise in- clude increasing maternal age and the use of ovulation stimula- tion in assisted reproductive technologies (ART). There is an on- going debate about the risk of twin pregnancies after assisted re- production. Dual embryo transfer has been the standard for many years [1]. It is estimated that pregnancies resulting from ART procedures account for 0.2–3.9 % of births in Europe [2]. Atti- tudes toward multiple pregnancies and pregnancy complications differ between infertile and fertile women. Patients who are treated for infertility with ART usually have a greater desire for twins in order to increase the success rate of ART [3]. Risks asso- ciated with multiple pregnancies are more acceptable to infertile women, and only a quarter of infertile patients agree to the trans- fer of only one embryo [1]. Careful monitoring and management of twin pregnancies is the basis of modern perinatology because multiple pregnancies carry an increased risk of perinatal morbid- ity and mortality compared with singleton pregnancies [2]. This risk is the result of complications such as premature birth, fetal growth restriction, preeclampsia, etc. [4, 5]. ART twins have con- siderably higher risks compared to ART singletons with regard to most short and long-term outcomes [6, 7]. Thus, high twin birth rates and adverse outcomes in twins are still a major concern in ART [1]. However, previous studies have shown that twins con- ceived by ART have similar physical and neurological develop- ment to those of twins conceived naturally. Moreover, the inci- dence of pregnancy complications in multiple pregnancies was found to be comparable, irrespective of the method of conception [2, 8]. The aim of this study was to investigate the course and outcomes of twin pregnancies conceived by assisted reproduction (ART) compared to twin pregnancies conceived spontaneously.

! Recruitment of study population The study involved patients with twin pregnancies who deliv- ered at the Clinic of Gynecology and Obstetrics, Clinical Center of Serbia between January 1, 2011 and December 31, 2013. Pa- tients were divided into two groups according to the method of conception (spontaneous or ART). Assessment of clinical data Age, parity, illnesses in pregnancy and type/nature of the illness (hypertension [HTA], diabetes mellitus [DM], placental abruption or placenta praevia, other diseases and simultaneous associated comorbidities), etiology of infertility (male, tubal, ovarian insuffi- ciency, endometriosis, immunological, unknown and combined), time of membrane rupture (spontaneous premature preterm rupture of membranes [PPROM] or rupture in hospital after the start of contractions) and type of delivery (vaginal or cesarean) were recorded for each patient. Type of ART (only in vitro fertil- ization [IVF], IVF/ICSI [intracytoplasmic sperm injection] or IUI [intrauterine insemination]) was also noted for each patient. Weeks of gestation at delivery, presentation, gender, weight, Ap- gar score, chorionicity and morbidity (intrauterine growth re- striction [IUGR], malformations, asphyxiation, comorbidities and other disorders) were recorded for each twin. Pregnancy out- come was considered excellent if both twins had Apgar scores above eight (Apgar I + Apgar II > 16), intermediate if Apgar I + Ap- gar II was between 10 and 16, while the outcome was considered bad if Apgar I + Apgar II was < 10. The data were compared between the groups of patients with and without ART as well as between the types of ART. Every pa- tient gave informed consent for all procedures upon admission to the Clinic. The study was approved by the Clinic Board. Statistical analysis Statistical analysis was done using descriptive and analytical sta- tistics (percentages, χ 2 test, Kruskal-Wallis test and correlations) using the SPSS program, version 15. Binary logistic regression was done to test for a possible relationship between assessed characteristics of mothers and twins and conception by ART. Fi- nally, Receiver Operator Curve (ROC) analysis was performed for parameters that correlated significantly with ART use for concep- tion.

! Characteristics of investigated women Parameters of pregnant women and their pregnancies for the overall group and according to type of conception (spontaneous, ART) are presented in l " Table 1. The same parameters differenti- ated according to ART type are shown in l" Table 2. The study included 431 patients with twin pregnancies. The mean age of the women was 32.99 ± 6.46 years (minimum = 17 years; maximum = 43 years). The majority of women were pri- miparous. The most frequent cause of infertility was male. Delivery time and mode Delivery mostly occurred in the 36th gestational week (mini- mum = 25; maximum = 40; mean ± SD = 35.42 ± 2.80). Only 18 patients delivered before the 30th gestational week. 33.2 % of women gave birth after the 38th gestational week. Although more women had cesarean sections, the incidence of planned and urgent operative deliveries was similar. Pregnancy complications and treatment Hypertensive disorders were the most common, but the majority of mothers had no pregnancy-related disease. Only a few women (n = 30) had pre-existing medical conditions, mostly diabetes. However, more than half of the patients received a combined therapy for pregnancy support, and almost 90 % of women re- ceived some kind of medication during pregnancy. produktion und Entwicklung der Zwillinge (Geburtsgewicht, Ap- gar-Werte, Morbidität). Schlussfolgerungen: ART-Verfahren haben keine negative Aus- wirkung auf Verlauf und Ergebnis von Zwillingsschwangerschaf- ten. Die Ergebnisse für Zwillingsschwangerschaften nach Spon- tankonzeption bzw. ART sind gleichwertig. 934 Andrijasevic S et al. Impact of Conception … Geburtsh Frauenheilk 2014; 74: 933 –939 GebFra Science Preterm membrane rupture was relatively rare and amniotic flu- id was usually normal. Cerclage and maturation of fetal lungs were usually not done. Characteristics of assessed twins Parameters of twins for the whole group and differentiated ac- cording to method of conception (spontaneous, ART) are shown in l " Table 3. Parameters of twins differentiated according to type of ART are given in l" Table 4. The majority of both first and second twins were in head presen- tation. The first twins were mostly male and the second twins were often female, but overall, there was a similar number of twins of both sexes. There were considerably more dichorionic twins irrespective of the method of conception. Twinsʼ condition and outcome The majority of twins were in good condition. Only a few twins had illnesses or other complications during pregnancy. There were four stillbirths (one naturally conceived and three con- ceived by IVF/ICSI). Mean birth weight of the first twins was 2331.53 ± 591.29 g (minimum = 460; maximum = 3840 g) and of the second twins was 2257.27 ± 604.44 g (minimum = 300; max- imum = 3500 g). Average Apgar score of the first twins was 7.11 ± 2.06 while for the second twins it was 7.04 ± 2.06. In most cases, both twins (over 50 %) had a good Apgar score (above eight). Thus, the major- ity of twins had excellent pregnancy outcomes, regardless of the conception method. Poor pregnancy outcomes were recorded more frequently for naturally conceived twins. Conception method The rate of twins conceived by ART was slightly higher (n = 233; 54.1 %). The most common type of ART used was IVF/ICSI (n = 164; 38.1 %), while IUI was rare (n = 10; 2.3 %). Correlations between parameters and conception method Both the use of ART and the type of method used were signifi- cantly positively correlated with maternal age and delivery type. Women who required more sophisticated ART methods were older ( ρ = 0.319; p < 0.001) and were delivered by cesarean sec- tion, usually planned ( ρ = 0.523; p < 0.001). However, as ex- pected, there was a significant negative correlation with parity (ρ = −0.364; p < 0.001), since women suffering from infertility usually conceived using ART. Conception by ART was associated with dichorionicity ( ρ = −0.100; p = 0.036). There were no other significant correlations between ART use or type and the other evaluated characteristics of mothers and twins (infertility cause, comorbidities of mothers and twins, treatment, cerclage, preg- nancy outcome, fetal lung maturation, fetal gender, etc.). Table 1 Parameters of pregnant women and their pregnancies for the overall group and according to type of conception (spontaneous, ART). Parameters Whole group ART No Yes Number % Number % Number % Parity 1 335 77.7 120 27.84 215 49.88 2 68 15.8 51 11.83 17 3.94 3 15 3.5 14 3.25 1 0.23 more 13 3.1 13 3.02 0 0.00 Cause of infertility male 67 28.7 0 0.00 67 28.76 tubal 53 22.7 0 0.00 53 22.75 immunologic 4 1.7 0 0.00 4 1.72 ovarian insufficiency 5 2.1 0 0.00 5 2.15 endometriosis 25 10.7 0 0.00 25 10.73 combined 36 15.5 0 0.00 36 15.45 unknown 43 18.5 0 0.00 43 18.45 PPROM no 327 75.9 157 36.43 170 39.44 yes 104 24.1 41 9.51 63 14.62 Amniotic fluid clear 399 92.6 187 43.39 212 49.19 not clear 32 7.4 11 2.55 21 4.87 Delivery type vaginal 175 40.6 146 33.87 29 6.73 planned CS 149 34.6 30 6.96 119 27.61 urgent CS 107 24.8 22 5.10 85 19.72 Maternal comorbidities none 243 56.4 110 25.52 133 30.86 hypertension 58 13.5 31 7.19 27 6.26 diabetes 21 4.9 5 1.16 16 3.71 placental 8 1.9 4 0.93 4 0.93 other 64 14.8 31 7.19 33 7.66 multiple 37 8.6 17 3.94 20 4.64 Supportive therapy no 45 10.4 22 5.10 23 5.34 progesterone 6 1.4 1 0.23 5 1.16 antibiotics 25 5.8 12 2.78 13 3.02 combined 284 65.9 127 29.47 157 36.43 other 71 16.5 36 8.35 35 8.12 Cerclage no 379 87.9 172 39.91 207 48.03 yes 52 12.1 26 6.03 26 6.03 ART: assisted reproductive technology; PPROM: premature preterm rupture of membranes; CS: cesarean section 935 Andrijasevic S et al. Impact of Conception … Geburtsh Frauenheilk 2014; 74: 933 –939 Original Article Differences in parameters with regard to conception method Regarding the use of ART, there were significant differences in patient age (KW χ2 = 55.909; p < 0.001) and parity (KW χ2 = 64.600; p < 0.001) as well as delivery type (KW χ2 = 136.658; p < 0.001). When we assessed the type of ART procedure, signifi- cant differences were found for PPROM (KW χ 2 = 6.721; p = 0.035) and patient age (KWχ2 = 10.485; p = 0.005). Patients who had ICSI were older and PPROM was more common. Dichorionic twins were mostly conceived by ART and had better survival rates (KWχ 2 = 4.370; p = 0.037). Monochorionic twins were conceived either spontaneously or using ICSI. There were no other signifi- cant differences between patients who conceived using ART or spontaneously or between ART types with regard to characteris- tics of mothers and twins and overall outcome of pregnancy. Relationship model and ROC analysis A significant logistic regression equation for the relationship be- tween assessed characteristics of mothers and twins and concep- tion using ART was obtained ( χ 2 = 224.820; p = 0.001; total classi- fication = 84.9 %). Based on the equation it was found that ad- vanced maternal age, the presence of comorbidities and lower parity were the most important predictors for ART conception. Additionally, twins conceived by ART were more likely to have PPROM and be delivered by cesarean section. According to results of the ROC analysis, maternal age correctly explained the use of ART for the conception of twins in 70.8 % of cases, parity in 33.7 %, chorionicity in 48.7 %, and predicted that ART twins would be delivered by cesarean section in 80.6 % of cases (l " Fig. 1). When an age of 32.5 years was taken as the cut- off value, the sensitivity of ART use for conception of twins was 68.2 %, the specificity was 63.1 %, the positive predictive value was 53.2 % and the negative predictive value was 71.6 %.

! Based on our results it can be stated that the use of ART for con- ception does not have a significant negative influence on twin pregnancy outcomes. Maternal age, comorbidities and parity all influence the decision to use ART for conception. We have shown that uncomplicated twin pregnancies with successful delivery at term are possible, although currently the majority of twins con- ceived by ART are delivered by cesarean section. The literature on the outcome of twin pregnancies, including meta-analyses, has been contradictory [9]. While some studies Table 2 Parameters of pregnant women and their pregnancies differentiated according to type of ART. Parameters ART type IVF IVF/ICSI IUI Number % Number % Number % Parity 1 55 23.61 150 64.38 10 4.29 2 4 1.72 13 5.58 0 0.00 3 0 0.00 1 0.43 0 0.00 more 0 0.00 0 0.00 0 0.00 Cause of infertility male 14 6.01 50 21.46 3 1.29 tubal 22 9.44 27 11.59 4 1.72 immunologic 0 0.00 4 1.72 0 0.00 ovarian insufficiency 0 0.00 4 1.72 1 0.43 endometriosis 5 2.15 19 8.15 1 0.43 combined 7 3.00 29 12.45 0 0.00 unknown 11 4.72 31 13.30 1 0.43 PPROM no 41 17.60 125 53.65 4 1.72 yes 18 7.73 39 16.74 6 2.58 Amniotic fluid clear 53 22.75 151 64.81 8 3.43 not clear 6 2.58 13 5.58 2 0.86 Delivery type vaginal 7 3.00 20 8.58 2 0.86 planned CS 29 12.45 86 36.91 4 1.72 urgent CS 23 9.87 58 24.89 4 1.72 Maternal comorbidities none 32 13.73 94 40.34 7 3.00 hypertension 9 3.86 16 6.87 2 0.86 diabetes 3 1.29 13 5.58 0 0.00 placental 0 0.00 3 1.29 1 0.43 other 12 5.15 21 9.01 0 0.00 multiple 3 1.29 17 7.30 0 0.00 Supportive therapy no 7 3.00 14 6.01 2 0.86 progesterone 2 0.86 3 1.29 0 0.00 antibiotics 7 3.00 6 2.58 0 0.00 combined 37 15.88 113 48.50 7 3.00 other 6 2.58 28 12.02 1 0.43 Cerclage no 55 23.61 143 61.37 9 3.86 yes 4 1.72 21 9.01 1 0.43 ART: assisted reproductive technology; IVF: in vitro fertilization; ICSI: intracytoplasmic sperm injection; IUI: intrauterine insemination; PP ROM: premature preterm rupture of membranes; CS: cesarean section 936 Andrijasevic S et al. Impact of Conception … Geburtsh Frauenheilk 2014; 74: 933 –939 GebFra Science Table 3 Parameters of twins for the whole group and according to type of conception (spontaneous, ART). Parameters Whole group ART No Yes Number % Number % Number % I twin presentation head 268 62.2 122 28.31 146 33.87 pelvis 142 32.9 66 15.31 76 17.63 other 21 4.9 10 2.32 11 2.55 II twin presentation head 222 51.5 97 22.51 125 29.00 pelvis 107 24.8 52 12.06 55 12.76 other 102 23.7 49 11.37 53 12.30 I twin gender male 226 52.4 105 24.36 121 28.07 female 205 47.6 93 21.58 112 25.99 II twin gender male 203 47.1 95 22.04 108 25.06 female 228 52.9 103 23.90 125 29.00 Twins comorbidities none 360 83.5 163 37.82 197 45.71 malformations 16 3.7 9 2.09 7 1.62 IUGR 3 0.7 2 0.46 1 0.23 asphyxiation 13 3.0 6 1.39 7 1.62 multiple 11 2.6 4 0.93 7 1.62 other 28 6.5 14 3.25 14 3.25 Maturation no 345 80.0 157 36.43 188 43.62 yes 86 20.0 41 9.51 45 10.44 Chorionicity dichorionic 404 93.7 190 44.08 214 49.65 monochorionic 27 6.3 8 1.86 19 4.41 Outcome excellent 208 25.1 99 22.97 109 25.29 intermediate 157 19.0 64 14.85 93 21.58 bad 66 8.0 35 8.12 31 7.19 IUGR: intrauterine growth restriction; ART: assisted reproductive technology Table 4 Frequency of assessed parameters of twins concerning ART type. Parameters ART type IVF IVF/ICSI IUI Number % Number % Number % I twin presentation head 39 16.74 102 43.78 5 2.15 pelvis 17 7.30 54 23.18 5 2.15 other 3 1.29 8 3.43 0 0.00 II twin presentation head 37 15.88 82 35.19 6 2.58 pelvis 14 6.01 38 16.31 3 1.29 other 8 3.43 44 18.88 1 0.43 I twin sex male 32 13.73 84 36.05 5 2.15 female 27 11.59 80 34.33 5 2.15 II twin sex male 31 13.30 71 30.47 6 2.58 female 28 12.02 93 39.91 4 1.72 Twins comorbidities none 49 21.03 140 60.09 8 3.43 malformations 0 0.00 6 2.58 1 0.43 IUGR 0 0.00 1 0.43 0 0.00 asphyxiation 4 1.72 2 0.86 1 0.43 multiple 3 1.29 4 1.72 0 0.00 other 3 1.29 11 4.72 0 0.00 Maturation no 46 19.74 135 57.94 7 3.00 yes 13 5.58 29 12.45 3 1.29 Chorionicity dichorionic 59 25.32 145 62.23 10 4.29 monochorionic 0 0.00 19 8.15 0 0.00 Outcome excellent 24 10.30 80 34.33 5 2.15 intermediate 28 12.02 63 27.04 2 0.86 bad 7 3.00 21 9.01 3 1.29 IUGR: intrauterine growth restriction; IVF: in vitro fertilization; ICSI: intracytoplasmic sperm injection; IUI: intrauterine insemination 937 Andrijasevic S et al. Impact of Conception … Geburtsh Frauenheilk 2014; 74: 933 –939 Original Article suggest that twins conceived by ART have a higher risk of preg- nancy complications, premature birth, low birth weight, and mortality at birth, other studies argue that there is no evidence of a higher incidence of adverse outcomes [10]. Several previous investigations have shown that obstetrical out- comes in ART pregnancies are worse than in the general popula- tion, which can be mainly explained by the higher multiple birth rates after ART, which account for the most severe obstetric out- comes [9]. Some researchers, after controlling for maternal age and nulliparity, have provided evidence that twin pregnancies conceived using ART and ovulation induction have an increased risk of gestational diabetes mellitus. The most common complica- tions of pregnancies after ART are bleeding in the first trimester and disproportionate growth of twins [11]. In addition, IVF-con- ceived pregnancies have been associated with a higher incidence of preterm births and prematurity-related respiratory complica- tions with longer stays in the neonatal intensive care unit [12, 13]. Conversely, our study found no significant differences with re- gard to pregnancy complications between groups with and with- out ART. Other researchers have also claimed that, although some antenatal complications are more common in ART twins than in spontaneously conceived twins, the overall prevalence of compli- cations is low and thus their impact on the morbidity and mortal- ity of an individual pregnancy is limited. Pregnancy complica- tions do not contribute to higher rates of premature rupture of membranes or the frequency of IUGR in ART twin pregnancies [12, 13]. In our population, although delivery mostly occurred during the 36th gestational week, PPROM was also not common. However, PPROM was more common if ICSI was used for concep- tion. Moreover, some data show that the rate of preterm births is similar to that of spontaneously conceived twins and that very preterm deliveries even occurred more frequently with sponta- neously conceived twin pregnancies [14, 15]. It is possible that women with an IVF pregnancy were more compliant with ther- apy and more likely to take early work leave, both of which could have a positive effect on preventing preterm labor. Hence, in healthy women younger than 45 years of age, twin pregnancies after ART do not require additional antenatal care compared with spontaneously conceived twins [16 –18]. The increased risk of congenital malformations associated with ART was not significant in different studies after adjusting for confounding parental factors [19]. We also found that there were no significant malformations in twins as a result of ART proce- dures. Our results suggest that twin pregnancies conceived by ART have similar outcomes for both mother and child to outcomes after spontaneously conceived pregnancies, which is consistent with findings in the majority of other studies [19]. We found no differ- ence in birth weight of the first and second twin between groups with and without ART, which is in agreement with other studies [10]. Our findings showed no significant difference in mortality or general condition at birth between twins conceived using ART methods or spontaneously. The majority of twins were in good condition, complications were rare, and the twins usually had an Apgar score ≥ 8. There were no significant correlations be- tween ART and the evaluated characteristics of twins. The risk profiles for ART twins and two consecutive ART single- tons can be assumed to be very similar. Moreover, the overall consensus, with few exceptions, is that ART twins have neonatal outcomes that are similar to those of infants conceived spontane- ously. Some literature reviews reported that ART twins had even better outcomes than spontaneously conceived twins. This might be due to mothers with spontaneously conceived twins having fewer regular check-ups compared to mothers with ART-con- ceived twins. Studies reported that uncomplicated twin pregnan- cies with successful delivery at term are possible [20]. This was also confirmed by our study. Therefore, it can be stated that twin pregnancies represent an entirely reasonable option for IVF pa- tients [21]. It remains unclear whether the increased risk of adverse obstetric outcomes after ART is a direct effect of the procedure and the technology or whether it reflects some other factor related to the underlying infertility of the couple. If the problem lies in the ART technology itself, more adverse outcomes would be docu- mented for ART twins, but this has not been the case so far. Some data, including our findings, show that the increased risk for ad- verse pregnancy outcomes does not depend on the type of ART procedure. These results suggest that perhaps underlying factors associated with the mother ʼs infertility exert more negative ef- fects on children than the ART procedure itself [12, 22]. The literature shows that mothers of twins conceived using ART are usually significantly older [23]. This was also the case in our study. However, this observation may indicate a potential bias with regard to maternal age and the number of embryos trans- ferred, since older women are more likely to desire twin preg- nancies. Moreover, almost all mothers in different studies were under the age of 40, and therefore overall study populations are young. This is also due to the fact that there is usually an age limit for performing ART procedures [19]. In some populations, the rate of cesarean sections was slightly, but not significantly, higher in ART pregnancies. In the majority of studies, the most common indication for cesarean section is the presentation of the first twin [13]. In our population, the in- cidence of cesarean sections was also higher compared to vaginal deliveries, but there was no difference with regard to the method of ART used. In our study cohort, most twins were in head pre- sentation, irrespective of the delivery method. In spontaneously conceived pregnancies, cesarean sections were often done be- 1 – Specificity Sensitivity 1.0 0.8 0.6 0.4 0.2 0 0 0.2 0.4 0.6 0.8 1.0 Parity Delivery Age Chorionicity

line Fig. 1 ROC analysis of maternal age, parity, chorionicity and type of de- livery for the prediction of ART conception of twins. 938 Andrijasevic S et al. Impact of Conception … Geburtsh Frauenheilk 2014; 74: 933 –939 GebFra Science cause of a previous operative delivery, whereas ART pregnancies were usually the first pregnancy. The majority of our patients were also primiparas. Although most women did not have any pregnancy-related morbidities, almost 90 % received some kind of medication during pregnancy. The increased incidence of ce- sarean sections and the multiple medications may be due to the patientʼs and/or physician ʼs concerns regarding pregnancy out- come rather than obstetric indications [15, 23]. Finally, it should be noted that this study has some limitations. We did not assess fetal losses in the first trimester. In this inves- tigation we focused on pregnancies that lasted more than 30 ges- tational weeks. Pregnancies terminated before that period are not currently sufficiently numerous to be analyzed. Further re- search in this area might be possible in a few years. Our study cre- ated an equation showing the relationship between assessed ma- ternal and twin characteristics and the use of ART procedures for conception.

! Maternal age, illnesses and parity can influence the decision whether to use ART for conception. Older women suffering from infertility need more sophisticated ART methods to conceive and generally take multiple medications during pregnancy. Our re- sults suggest that twin pregnancies conceived by ART methods have similar outcomes for both mother and child to those of spontaneously conceived pregnancies. The use of ART for concep- tion does not have a significant negative influence on twin preg- nancy outcomes. If IVF/ICSI is used, PPROM is more frequent, and cesarean section is usually the method of delivery for these pa- tients. However, preterm delivery is infrequent irrespective of the conception method. The majority of twins had favorable pregnancy outcomes and good Apgar scores, and complications were rare. Our findings suggest that the transfer of two embryos is safe. Uncomplicated twin pregnancies with successful delivery at term are possible, and ART twins do not require additional an- tenatal care compared to spontaneously conceived twins. Conflict of Interest ! Authors declare no conflict of interest.

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