Article Neonatal and obstetric outcome of pregnancies conceived by ICSI or IVF

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1 RBMOnline - Vol 11. No Reproductive BioMedicine Online; on web 27 July 2005 Article Neonatal and obstetric outcome of pregnancies conceived by ICSI or IVF Ariel Hourvitz is currently employed in the IVF unit at Sheba Medical Center, Tel-Hashomer, Israel. Born in 1960, he obtained his MD degree in 1985 as a graduate of the Sackler Faculty of Medicine in Tel-Aviv. He received his qualification in Obstetrics and Gynaecology in 1998 and then spent 2 years as a research fellow in Dr Eli Adashi s laboratory, in Salt Lake City, Utah, USA. In 2002 he obtained a Master s degree in Health Administration (MHA) cum laude from the Faculty of Management, Tel-Aviv University. Current basic research interests include ovarian physiology and molecular characterization of ovulation. Dr Ariel Hourvitz Ariel Hourvitz 1, Shai Pri-paz, Jeoshuah Dor, Daniel S Seidman IVF Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat-Gan, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 1 Correspondence: Department of Obstetrics and Gynecology, The Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel. Tel: ; Fax: ; arieliris@bezeqint.net Abstract Intracytoplasmic sperm injection (ICSI) is currently widely used despite concern regarding pregnancy complications and outcome, specifically congenital malformations. The aim of this study was to compare the obstetric and neonatal outcome of pregnancies conceived by IVF and ICSI. Long-term follow-up was achieved through questionnaires sent to women who conceived after IVF/ICSI treatment. Information was obtained regarding 219 pregnancies (322 children) conceived after ICSI and 145 pregnancies (201 children) conceived after IVF. There were no significant differences between the ICSI and regular IVF pregnancies in regard to the couple s characteristics and the obstetric complications. The mean ± SD birth weight of the singletons conceived after ICSI was similar to that of singletons conceived after IVF: 3001 ± 703 versus 3059 ± 643 g respectively. In both groups there was a high incidence of multiple pregnancies, Caesarean sections, prematurity and low birth weights. The incidence of congenital malformations following IVF or ICSI pregnancies was similar, 6.3 and 7.7% respectively, but was increased compared with the general Israeli population. In summary, concern remains regarding the incidence of congenital malformations after IVF and the long-term outcome of ICSI pregnancies. However, the present results are reassuring with regard to the obstetric and neonatal outcome of pregnancies conceived by ICSI compared with those achieved by IVF. Keywords: congenital malformations, ICSI, IVF, long-term follow-up, neonatal outcome Introduction Infertility afflicts approximately 10% of couples of reproductive age (Novak et al., 1996). The development of new assisted reproductive technologies in the last two decades and the growing awareness of new modes of treatment have increased the number of pregnancies conceived following assisted reproduction (Osmanagaoglu et al., 2004; Elizur et al., 2005). Intracytoplasmic sperm injection (ICSI) was introduced only a decade ago, but was rapidly adapted to clinical practice worldwide, thereby raising concerns regarding its safety (Oehninger and Gosden, 2002). Currently, about 2% of all births in Israel are achieved through assisted reproductive technologies. To date, only a limited number of studies comparing pregnancy complications, malformation rate and outcome of IVF and ICSI have been reported (Speroff et al., 1999; Bonduelle et al., 2002; Koivurova et al., 2002; Ludwig and Katalinic, 2002). Many of these studies did not demonstrate an increase in the rate of complications in the ICSI pregnancies (Sutcliffe et al., 2001, 2003). However, one comparative study (Mansour, 1998) showed that ICSI twin pregnancies last 1 week longer than the IVF twin pregnancies, and result in a significantly higher mean birth weight. Another study (Lanzendorf et al., 1988) found low birth weight to be less common after ICSI than with IVF. Data published in recent reports on the malformation rate among children born after ICSI is conflicting (Craft et al., 469

2 ; Lundin et al., 1996; Morton et al., 1997; Mansour, 1998; Ludwig and Katalinic, 2002). Studies comparing children born after IVF with natural conception showed that the rates of congenital malformations and developmental problems were not higher among IVF children (Palermo et al., 1992; Tarlatzis, 1996; Tarlatzis and Bili, 1998; Speroff et al., 1999). However, several reports indicated a possible increase in the prevalence of congenital malformations after IVF, such as neural tube defects, oesophageal atresia (Baschat et al., 1996) and cardiac malformations (Aboulghar et al., 1995). Studies comparing the risk of congenital malformations found ICSI to be at least as safe as IVF (Craft et al., 1995; Lundin et al., 1996; Morton et al., 1997; Mansour, 1998). Other studies (Aboulghar et al., 1996; Wisanto et al., 1996; Aytoz et al., 1998; Bonduelle et al., 1998, 1999; Speroff et al., 1999; Bonduelle et al., 2002; Ludwig and Katalinic, 2002, 2003) made no comparisons, but found rates of congenital malformations to be within acceptable range. The range of the major malformation rate was found to be 1 3.4%, comparable to the generally accepted range of 2 3% in the general population (Craft et al., 1995). Minor malformations occurred in % of newborns. Major malformations were most common in limbs, nervous system, cleft lip and palate, cardiovascular system, internal urogenital system and musculoskeletal system (Bonduelle et al., 1998). Several authors reported an increased risk for major malformations among children born after ICSI compared with children that were spontaneously conceived. However, it was suggested that this increased risk might be due to the parental factors that caused infertility and led to the need for ICSI in the first place. The purpose of the present study was to undertake a longterm follow-up, in order to compare the neonatal and obstetric outcome of pregnancies achieved in the unit through IVF and ICSI in an attempt to determine the safety of the frequently used ICSI procedure. Materials and methods Data were obtained retrospectively on 219 deliveries after the transfer of ICSI embryos between January 1995 and December 1997 that resulted in 322 children. The data were compared with a control group that included 145 deliveries after embryo replacement following standard IVF treatment that resulted in the birth of 201 children. The long-term follow-up information was obtained by sending questionnaires and a pre-paid envelope to each couple, 1 3 years after delivery. The questionnaires included questions regarding parental characteristics (age, birth place, origin, education, diseases, smoking), treatment (ICSI or IVF), pregnancy complications (diabetes, hypertension, placenta praevia, placental abruption, vaginal bleeding, poly/ oligohydramnios, infectious diseases, premature rupture of membranes, hospitalization), pregnancy outcome (duration, weight, Apgar scores, multiple fetuses, method of delivery), neonatal problems and congenital malformations. Statistical analysis was performed using the chi-squared and Student s t-test. Two-tailed significance was assumed at P < Results There were no statistically significant differences in maternal and paternal characteristics between the two groups, including birth place, education and risk factors like advanced parental age, parental diseases, smoking and family history (Table 1). The mean ± SD maternal age was 31.8 ± 5.0 and 30.6 ± 4.8 years in the IVF group and ICSI group respectively. There were no statistically significant differences in the rate of pregnancy complications (Table 2). There were also no major differences regarding pregnancy outcomes. Both groups had a high percentage of multiple gestations, 38.8% twins and 4.1% triplets in the ICSI group and 34.5% twins and 2.1% triplets in the IVF group. The mean ± SD gestational age was 37.6 ± 3.3 and 38.0 ± 3.1 weeks in the ICSI and IVF groups respectively. In both groups there was a high incidence of Caesarean sections, 45.9% of the women who conceived by ICSI embryo transfer and 44.4% of those who conceived by IVF. The mean birth weight of the IVF infants (2612 ± 744 g) was significantly higher than that of the newborns conceived through ICSI (2491 ± 774 g; P = 0.003) (Table 3). This seemed at least in part to be attributed to the slightly longer pregnancy in the IVF group and to the higher rate of singleton pregnancies, since there was no statistically significant difference in the birth weights for the singleton, twin and triplet pregnancies when compared between the two study groups. The most common neonatal problem among ICSI and IVF neonates was jaundice, but there was no statistically significant difference between the two groups (Table 4). The incidence of other complications, such as sepsis, necrotizing enterocolitis (NEC) and intraventricular haemorrhage (IVH) was similar. In the ICSI group, three children (of twin pregnancies) died during the 1st month due to infection. In the IVF group, one child of a twin pregnancy died after suffering from IVH, NEC and renal failure. There were no statistically significant differences between the ICSI and IVF groups in the duration of hospitalization. Major congenital malformations were defined as conditions requiring surgical correction or causing functional impairment. The remaining malformations were considered minor. Following these definitions, there were no major malformations in the IVF group compared with two major malformations in the ICSI group, which accounts for 0.7% of the responders (Table 5). One case involved an infant that was diagnosed during pregnancy (by amniocentesis) as having trisomy 18. He was born to a 41- year-old mother and a 41-year-old father who was diagnosed as a cystic fibrosis carrier and suffered from congenital absence of vas deferens. The newborn was delivered vaginally with a birth weight of 2300 g, and was diagnosed as suffering from ventricular septal defect (VSD), unilateral inguinal hernia, umbilical hernia, club feet, a hand deformity and trisomy 18. He died after less than 4 months. The second infant was a female born to a 40-year-old mother

3 Table 1. Parental risk factors in women treated by intracytoplasmic sperm injection (ICSI) or conventional IVF. Numbers are calculated per newborn and not per pregnancy, i.e. a risk factor in a twin pregnancy was calculated twice. Non-genetic factors IVF ICSI Genetic factors IVF ICSI (n = 96) (n = 135) (n = 96) (n = 135) Cigarettes per day Maternal age 35 years Cigarettes per day < Paternal age 50 years 0 3 Medications Chromosomal 8 5 Insulin 2 6 Diseases Antibiotics Total Eltroxin 6 8 Hypertension 1 0 Aspirin/clexane Diabetes 0 0 Congenital malformations Hypothyroidism 7 10 Infection Hyperthyroidism 3 0 CMV 0 1 Other 6 a 10 b UTI 9 4 HSV 1 0 a Asthma, factor V, thalassaemia intermedia, cervical intraepithelial neoplasia-3 (CIN-3). b Systemic lupus erythematosis, migraine, epilepsy, polycystic kidney, Crohn s disease, cholelithiasis, Dubin Johnson. CMV = cytomegalovirus; UTI = urinary tract infection; HSV = herpes simplex virus. Table 2. Pregnancy complications following conception by intracytoplasmic sperm injection (ICSI) or conventional IVF. IVF ICSI % of No. % of No. responders responders Gestational diabetes Fetal growth delay Oligohydramnios Polyhydramnios Placenta previa Placental abruption Hypertension/pre-eclampsia Infection disease PROM Week of PROM (mean ± SD) 35.0 ± ± 4.1 Threatened abortion (bleeding) Hospitalization (other) PROM = premature rupture of membranes. 471

4 Table 3. Mean birth weights for singletons and multiple births following conception by intracytoplasmic sperm injection (ICSI) or conventional IVF, and mean percentages of babies in low, very low and extremely low birth weight categories. Pregnancy No. Mean ± ELBW < VLBW < LBW < SD (g) 1000 g 1500 g 2500 g ICSI Singleton ± IVF ± ICSI Twin ± IVF ± ICSI Triplet ± IVF ± ICSI Total ± 774 a IVF ± 744 a ELBW = extremely low birth weight; VLBW = very low birth weight; LBW = low birth weight. a Significantly different (P = 0.003). Table 4. Neonatal complications following conception by intracytoplasmic sperm injection (ICSI) or conventional IVF. IVF ICSI Triplet Twin Single Total Triplet Twin Single Total Questionnaires Jaundice Sepsis Respiratory complications Meningitis IVH NEC Neonatal fever Other Total IVH = intraventricular haemorrhage, NEC = necrotizing enterocolitis. 472

5 Table 5. Congenital malformations in the population of Israel and in the present study population. Congenital Code by Rates per 1000 live births Malformations included in this category malformations ICD-10-CM IVF ICSI In Israel and that appeared in the present study populations 1995 Total Nervous system Eye a 0 a 0.22 Orofacial 744, Cardiovascular ASD, VSD, PDA, single artery in umbilical cord Respiratory system Gastro-intestinal Pyloric stenosis, malrotation Genito-urinary Cryptorchidism, dilated kidney pelvis Musculo-skeletal Torticollis b, club feet, different problems of toes or fingers Chromosomal anomalies Trisomy 18, Trisomy 21 a Puncture of lacrimal sac was not included (1 in ICSI and 2 in IVF). b Assuming it is congenital torticolis and not due to birth trauma. ICD-10-CM = International Classification of Diseases, 10th revision, clinical modification; ICSI = intracytoplasmic sperm injection; ASD = atrial septal defect; VSD = ventricular septal defect; PDA = patent ductus arteriosus. and a 44-year-old father with no other known risk factors. She was born by Caesarean section at week 37 of gestation. She was diagnosed as suffering from Down s syndrome, VSD and atrial septal defect (ASD). Minor malformations (including inguinal hernia and pyloric stenosis) were found in 45 of the ICSI children (15.1% of the responders) and in 28 of the IVF children (14.7% of the responders). Eight of the ICSI children and four of the IVF children had more than one minor malformation. Discussion The rate of congenital malformations following ICSI was not increased in the current study population compared with the rate after regular IVF. This finding is in agreement with recent reports on the follow-up of children born after ICSI. Thus, currently published data do not demonstrate a higher rate of malformations in ICSI children (Bonduelle et al., 1998, 2002; Van Steirteghem et al., 2002; Schieve et al., 2004a,b). Commenting on the paper by Bonduelle et al. (2004), Ludwig (2004) stressed some of the problems associated with largescale trials in human subjects. Bonduelle et al. (2004) studied 300 children conceived after ICSI and 265 born after spontaneous conception. Drop-out rates were high and refusal of participation also reached levels ranging between 10 and 45% after ICSI. Differences also emerged in the means of recruitment, with significant differences emerging in the respective ages of ICSI and control parents. Ludwig (2004) therefore did not compliment these investigations in their attempts at a multicentric and multinational analyses of longterm follow-up and the enormous investment needed for these studies. The incidence of congenital malformations following IVF or ICSI pregnancies in the present study population was increased when compared with the general Israeli population. In order to compare the results for IVF or ICSI pregnancies with the rate in the general population of Israel, this study used the data published by the Central Bureau of Statistics regarding selected congenital malformations detected at birth and for which it is compulsory to report to the Ministry of Health (Israel National IVF Register, ). Only those conditions that were classified by the International Classification of Diseases, 10th revision, clinical modification (ICD-10-CM) were used. This comparison suggested that in the present study the malformation (major and minor) incidence among ICSI and IVF patients, was three times higher than that in the general population. This is consistent with the findings of Kurinczuk et al. (Rizk et al., 1991), who used a strict classification of malformations and concluded that the major malformation rate was 7.38% in comparison with 3.78% in the control group. It must be remembered that the incidence of major and minor congenital malformations is difficult to compare within different study populations. Furthermore, the present study is confounded by several factors. First, the size of the study population is limited. Second, the Bureau of Statistics collects data only about malformations detected at birth, while the present study obtained information from questionnaires up to 3 years after birth. Third, it is not clear how accurate and complete is the report given by different medical centres in Israel. Fourth, and maybe most important, is the great difference in the percentage of multifetal pregnancies between the two populations. It was previously noted (Verlaenen et al., 1995) that an apparently significant increase in the malformation rate after ICSI did not remain significant when compared with the general population and with IVF children after stratification to singletons and twins (Rizk et al., 1991; Van Steirteghem et al., 2002). In addition, it is impossible to rule out a possible selection bias in this study that may have led to an underestimation of the true incidence of congenital malformations following ICSI treatment. A selective lower report rate among parents of children with malformations is also possible. However, comparison of the present study with 473

6 474 previous studies shows that the incidence rates are within the expected range, although data in the various studies may have been obtained using different methods (Verlaenen et al., 1995). The incidence of multifetal pregnancies in the ICSI group was very high, and as a result there was a correspondingly high rate of Caesarean sections, prematurity and low birth weights. This was also found for IVF pregnancies in this study in comparison with IVF pregnancies in other studies. This is in agreement with a study from Finland (Koivurova et al., 2002) and a recent systematic review of previous reports (Helmerhorst et al., 2004). The high incidence of multifetal pregnancies can probably be attributed to the relatively liberal approach in Israel at the time of the present study in regard to the number of embryos transferred. Recent studies regarding perinatal outcome among singleton infants conceived through assisted reproduction found an increased risk for adverse perinatal outcome (Schieve et al., 2004). This has led to revised clinical guidelines and a realization that high success rates can be achieved with elective transfer of one or two embryos (Thurin et al., 2004). However, the incidence of multifetal pregnancies remains high, as many couples in Israel still consider a twin pregnancy as a very desirable outcome. It is concluded that no significant differences were found between pregnancies conceived after either ICSI or IVF, except for the lower birth weights of ICSI children. Thus, infertile couples can be reassured that the ICSI procedure seems at present to be safe, although more long-term follow-up data are needed. It is also clear that an effort should be made to further restrict the number of embryos transferred. 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