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Neonatal and maternal outcomes comparing women undergoing two in vitro fertilization (IVF) singleton pregnancies and women undergoing one IVF twin pregnancy
Neonatal and maternal outcomes comparing women undergoing two in vitro fertilization (IVF) singleton pregnancies and women undergoing one IVF twin pregnancy €llen, Ph.D.,b Ann Thurin-Kjellberg, M.D., Ph.D.,a Antonina Sazonova, M.D.,a Karin Ka Ulla-Britt Wennerholm, M.D., Ph.D.,c and Christina Bergh, M.D., Ph.D.a a
Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Reproductive Medicine, Sahlgrenska University Hospital, Gothenburg; b Department of Reproduction Epidemiology, Tornblad Institute, Institution of Clinical Sciences, Lund University, Lund; and c Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Sahlgrenska University Hospital East, Gothenburg, Sweden
Objective: To compare outcomes for women undergoing two in vitro fertilization (IVF) pregnancies with singletons and women undergoing one IVF twin pregnancy. The concept of single-embryo transfer in IVF has reduced the risks of both maternal and neonatal complications, but there is still a discussion of whether or not twins are a desired outcome of IVF. Design: Registry study. Setting: Not applicable. Patient(s): All reported twins after IVF with double-embryo transfer (n ¼ 1,982) and their mothers (n ¼ 991) and all mothers (n ¼ 921) who gave birth to two IVF singletons (n ¼ 1,842). Intervention(s): None. Main Outcome Measure(s): Maternal and neonatal outcomes including severe neonatal morbidity. Result(s): Preterm birth, very preterm birth, low birth weight, very low birth weight, and small for gestational age were dramatically increased for IVF twins compared with two IVF singletons with the same mother, with adjusted odds ratios from 4 to 16. Significantly higher rates of respiratory complications, sepsis, and jaundice were detected among the IVF twins. Significantly higher rates of preeclampsia, preterm premature rupture of the membranes, and cesarean section were observed for IVF twin pregnancies. Conclusion(s): The neonatal and maternal outcomes were dramatically better for women undergoing two IVF singleton pregnancies compared with one IVF twin pregnancy after double-embryo transfer. These results support Use your smartphone single-embryo transfer to minimize the risks associated with twin pregnancies. (Fertil SterilÒ to scan this QR code 2013;99:731–7. Ó2013 by American Society for Reproductive Medicine.) and connect to the Key Words: IVF/ICSI, maternal outcome, neonatal outcome, singletons, twins Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/sazonovaa-neonatal-maternal-outcome-twins-ivf/
Received June 20, 2012; revised November 9, 2012; accepted November 12, 2012; published online December 7, 2012. A.S. has nothing to disclose. K.K. has nothing to disclose. A.T.-K. reports payment for lectures from Merck Serono, Ferring, and MSD and grants/grants pending from Merck Serono. U.-B.W. has nothing to disclose. C.B. has nothing to disclose. Supported by grants from the University of Gothenburg/Sahlgrenska University Hospital (LUA/ALF 70940) and the Hjalmar Svensson Foundation. K.K. supported by the Evy and Gunnar Sandberg Foundation and the Birgit and H akan Ohlsson Foundation. Reprint requests: Antonina Sazonova, M.D., Institute of Clinical Sciences, Department of Obstetrics and Gynaecology, Reproductive Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden (E-mail: [email protected]). Fertility and Sterility® Vol. 99, No. 3, March 1, 2013 0015-0282/$36.00 Copyright ©2013 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.11.023 VOL. 99 NO. 3 / MARCH 1, 2013
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t is well known that multiple births, including twins, after in vitro fertilization (IVF) are an adverse outcome that increases the risks of maternal and neonatal complications. Large registry studies have shown that the risks of preterm birth (PTB) and low birth weight (LBW) are increased in IVF children compared with children after spontaneous conception, and that most of this increased risk is attributable to the 731
ORIGINAL ARTICLE: ASSISTED REPRODUCTION high rate of multiple births among IVF children (1–6). The higher rate of severe child morbidity observed in IVF children is strongly associated with preterm birth and low birth weight (7–10). Cerebral palsy occurred in 0.37% of IVF singletons and in 0.74% of IVF twins in the Swedish study (7). The introduction of single-embryo transfer (SET) has substantially reduced these risks (2, 11–15). Neonatal and maternal outcome after SET and doubleembryo transfer (DET) also has been reported. In a large registry study from Sweden (16), including almost 8,000 children after SET and 6,000 children after DET, the obstetrical and neonatal outcomes were reported. The multiple birth rates in the SET and DET groups were 1.2% and 21.2%, respectively. The DET children were at 2–3 times higher risk of being born preterm and with low/very low birth weight compared with the SET children. Both randomized controlled trials (13) and meta-analyses (15, 17) have reported on the outcomes for the children after SET versus DET. The latest study found risk ratios of 0.37 for preterm birth and 0.25 for low birth weight in favor of SET (17). The concept of SET for IVF has reduced the risks for both maternal and neonatal complications simply by lowering the number of multiple births. Although the supporting data are overwhelming, there is still an ongoing debate whether twins are a desired outcome of IVF. It has been claimed that the risk associated with IVF twins were dramatically exaggerated and that parents should be reassured regarding twins (18). Based on theoretic calculations and particularly for parents who want more than one child, twin deliveries have been regarded as a favorable outcome that should be encouraged. There are fears of lowering pregnancy and delivery rates with the SET concept, especially in countries with private health care and/or insurance systems, including the USA. Before 2002, only 1% of transfers in the USA were elective SET (eSET). However, according to new guidelines from Society for Assisted Reproductive Technology/American Society for Reproductive Medicine, an obvious trend during recent years is observed with more use of eSET among patients <35 years old. The rates of eSET in the USA have risen steadily 1%–2% each year since 2002, and in 2009 eSET among patients <35 years old constituted 10% of all embryo transfers. Women <35 years old contribute, however, to only <50% of all ART cycles. In women >35 years old the eSET rate is most probably lower. Therefore, a more realistic estimate of the frequency of eSET in the USA may be 5% (19, 20). Assuming that most parents want two children, we analyzed the neonatal and maternal outcomes for women undergoing two IVF singleton pregnancies and compared the results with those of women undergoing one IVF twin pregnancy.
MATERIALS AND METHODS Data were collected from all IVF clinics in Sweden for IVF treatments (both publicly and privately funded) during the years 2002–2006. All reported twins after IVF with DET (n ¼ 991 twin pairs; n ¼ 1,982 children) and their mothers (n ¼ 991) and all mothers (n ¼ 921) who gave birth to two IVF singletons (n ¼ 1,842) in Sweden during this time period 732
were included. Data collected from the IVF clinics included personal identification number of the women, IVF/intracytoplasmic sperm injection (ICSI), fresh/cryopreserved, ejaculated/epididymal/testicular sperm, number of oocytes retrieved, cleavage-stage/blastocyst transfer, date of embryo transfer, number of embryos transferred, number of cryopreserved embryos, number of gestational sacs and date at first ultrasound, date of delivery, and number of children born. Data from the IVF clinics were cross-linked with the Swedish Medical Birth Registry (21), and obstetrical outcomes were retrieved. Data on severe neonatal morbidity were collected from the Medical Birth Registry and from the National Patient Registry. The International Classification of Diseases (ICD) 10 codes were used. Outcome measures were: preterm (<37 w), very preterm (VPTB; <32 w), and extreme preterm (<28 w) birth, LBW (<2,500 g), and very low birth weight (VLBW; <1,500 g). Other outcome measures were small for gestational age (SGA; more than two standard deviations below the Swedish growth standard, <22%) (22), perinatal mortality (stillbirths after 28 completed gestational weeks and neonatal deaths the first 7 days), and Apgar score (Apgar score <7 at 5 minutes). Maternal outcomes included preeclampsia (O.14, O.15), gestational diabetes (O.24.4), placenta previa (O.44), placental abruption (O.45), and preterm premature rupture of the membranes (PPROM; O.42). The rate of cesarean section was also assessed. Neonatal severe morbidity included intraventricular hemorrhage grade R3 (P.52.2), periventricular leucomalacia (P.91.2), septicemia (P.36.9), necrotizing enterocolitis (P.77.9), retinopathy of prematurity (H.35.1), bronchopulmonary dysplasia (P.27.1), jaundice (P.59.0–9), respiratory diagnoses (include infants treated with continuous positive airway pressure or mechanical ventilation), relatively severe malformations (ICD-10 code beginning with a Q, excluding infants with one or more of the following conditions: preauricular appendix, undescended testicle, tongue tie, hip [sub] luxation or unstable hip, patent ductus arteriosus in a preterm infant, single umbilical artery, and nevus) (23), meconium aspiration (P.24.0), convulsions (P.90.9), and hypoxic-ischemic encephalopathy Rgrade 3 (P.91.6C). In addition, a composite outcome was created including the most severe neonatal diagnosis (intraventricular hemorrhage Rgrade 3, periventricular leucomalacia, necrotizing enterocolitis, retinopathy of prematurity Rstage 3, bronchopulmonary dysplasia, hypoxic-ischemic encephalopathy Rgrade 3, and infant mortality, including stillbirth after 28 completed gestational weeks or death during the first year). Gestational age was determined according to the day of embryo transfer and the number of days in culture. This was regarded to be appropriate because all statistical comparisons in the present report were performed within the IVF cohort, and the day of embryo transfer was assumed to give a more precise dating of gestation than a second-trimester sonography. For the interpretation of this study it is of important to note that in Sweden IVF is both publicly and privately funded. Publicly funded IVF is offered to childless couples after investigation, which is performed after at least 1 year of infertility and if no other treatment is considered to be suitable. Certain age limits exist, usually 40 years for women. Exact rules differ VOL. 99 NO. 3 / MARCH 1, 2013
Fertility and Sterility® somewhat between different regions. Up to three subsidized cycles with fresh embryos are offered in most regions. After achieving one live birth, no more publicly funded cycles are offered. Ethical approval was obtained from the Ethics Committee of the University of Gothenburg.
Statistical Methods Descriptive data are given as numbers and percentages. Selected maternal and neonatal outcomes in IVF twin pregnancies after DET versus two IVF singleton pregnancies were calculated per woman and/or per infant when appropriate. The outcomes of the children were calculated per child in both groups. Maternal outcomes for the twin group were calculated per twin mother. For the singleton group, maternal outcomes were calculated for mothers having the relevant complication in at least one of the two pregnancies. This rate was used for comparison. In addition, mothers having the relevant complication in both of her pregnancies are presented. The maternal and neonatal outcome measurements were analyzed with univariate and multiple logistic regression analyses, using generalized estimating equation technology to obtain robust variance estimation. If not otherwise stated, adjustments were made for year of birth (continuous variable), maternal age at delivery (continuous), nulliparity (yes/no), maternal smoking at the first antenatal visit (semicontinuous variable: 1 ¼ none; 2 ¼ smoking <10 cigarettes per day; 3 ¼ smoking R10 cigarettes per day), and maternal body mass index (BMI, kg/m2) at the first antenatal visit (continuous variable). In cases of missing information on smoking or maternal BMI, imputations were made so that the missing values were replaced by the overall mean among records with valid information: 24.6 for BMI, and 1.03 for the semicontinuous smoking scale. For the other background characteristics, there was no loss of information. All statistical analyses were done with the use of Gauss (Aptech Systems).
RESULTS Maternal characteristics (for singleton mothers the data from the first pregnancy) are described in Table 1. Mothers of IVF twins were older (46.2% >35 years) than mothers of IVF singletons (29.4% >35 years). The mothers of IVF twins were multiparous in 35.4% of cases compared with only 6.5% of mothers of IVF singletons. Smoking, BMI, and infertility duration were similar distributed in both groups. Tables 2–4 demonstrate the neonatal and maternal outcomes in IVF twin pregnancies compared with two IVF singleton pregnancies based per woman and per infant. In total, 991 women with 1,982 twins (991 pairs of twins) after DET (frozen and fresh) were compared with 1,842 IVF singletons after SET (frozen and fresh) born to the 921 women who had two singleton pregnancies.
Neonatal Outcomes Neonatal outcomes are presented in Tables 2 and 4. When comparing neonatal outcome in IVF twins with IVF singletons, significantly higher rates of PTB (<37 w, adjusted odds ratio VOL. 99 NO. 3 / MARCH 1, 2013
TABLE 1 Maternal characteristics by study group, n (%). Twins (DET) Total 991 Maternal age, y 20–24 9 (0.9) 25–29 124 (12.5) 30–34 400 (40.4) 35–38 322 (32.5) 39–40 99 (10.0) 41–42 32 (3.2) R43 5 (0.5) Maternal parity 1 650 (65.6) 2 285 (28.8) 3 40 (4.0) R4 16 (1.6) Maternal smoking Unknown 105 (10.6) No 861 (97.2) 1–9/d 21 (2.4) R10/d 4 (0.5) Maternal BMI, kg/m2 Unknown 165 (16.6) <20 63 (7.6) 10–24.9 427 (51.7) 25–29.9 252 (30.5) R30 84 (10.6) Years of involuntary childlessness Unknown 290 (29.3) %2 179 (25.5) 3–4 296 (42.2) 5–19 226 (32.2)
Singleton 3 2 921 16 (1.7) 182 (19.8) 453 (49.2) 231 (25.1) 30 (3.3) 8 (0.9) 1 (0.1) 861 (93.5) 46 (5.0) 12 (1.3) 2 (0.2) 83 (9.0) 816 (97.4) 18 (2.1) 4 (0.5) 136 (14.8) 73 (9.3) 435 (55.4) 202 (25.7) 75 (9.6) 206 (22.4) 230 (32.2) 339 (47.4) 146 (20.4)
Note: Singleton 2: mothers who gave birth to two IVF singletons. Percentages based on records with obtainable information. DET ¼ double-embryo transfer; BMI ¼ body mass index. Sazonova. Twins and singletons after IVF. Fertil Steril 2013.
[AOR] 12.67, 95% CI 9.62–16.68), VPTB (<32w, AOR 7.43, 95% CI 4.25–12.99), LBW (<2,500 g, AOR 16.6, 95% CI 12.28– 22.42), VLBW (<1,500 g, AOR 4.72, 95% CI 2.83–7.88), and SGA (AOR 7.62, 95% CI 5.14–11.29) were found for IVF twins (Table 4). There were no significant differences in incidences of perinatal mortality or Apgar score <7 at 5 minutes. All neonatal adverse outcomes occurred more often in the first compared with the second singleton pregnancy (e.g., <1,500 g: 1.8% vs. 0.8%, respectively; <2,500 g: 6.4% vs. 2.8%; SGA: 3.1% vs. 1.5%; complete data not shown).
Neonatal Morbidity Significantly higher rates of respiratory complications (AOR 4.92, 95% CI 3.68–6.58), sepsis (AOR 2.31, 95% CI 1.29–4.13), and jaundice (AOR 5.03, 95% CI 3.77–6.70) were detected among the IVF twins. Higher rates of unadjusted composite serious morbidity were found for IVF twins (crude OR 1.84, 95% CI 1.06–3.17), but after adjustment for maternal confounders (age, parity, BMI, smoking, years of infertility) the difference was no longer significant (AOR 1.34, 95% CI 0.70–2.57; Table 4). There were no significant differences in incidences of mortality during the first year or relatively severe malformations between the two groups. 733
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
TABLE 2 Neonatal outcomes in IVF twin pregnancies (after DET) versus two IVF singleton pregnancies—outcome per infant, n (%).
Total infants <37 wk <32 wk <2,500 g <1,500 g Small for gestational age Peri/neonatal mortality Apgar <75 Severe neonatal morbidity Relatively severe malformations Respiratory disorders Meconium aspiration Bronchopulmonary dysplasia Intraventricular hemorrhage (Rgrade 3) Convulsions Periventricular leukomalacia Hypoxic-ischemic encephalopathy (Rgrade 3) Retinopathy of prematurity Retinopathy of prematurity (Rstage 3) Sepsis Necrotizing enterocolitis Jaundice Stillbirth and infant mortality <1 y Composite serious morbidityb
Twins
Singletons
Siblingsa
1,982 925 (46.7) 148 (7.5) 769 (38.8) 106 (5.3) 246 (12.4) 23 (1.2) 59 (3.0)
1,842 133 (7.2) 23 (1.2) 85 (4.6) 24 (1.3) 43 (2.3) 18 (1.0) 30 (1.6)
17 (0.9) 2 (0.1) 9 (0.5) 2 (0.1) 5 (0.3) 1 (0.1) 0 (0.0)
97 (4.9) 322 (16.2) 1 (0.1) 12 (0.6) 4 (0.2) 4 (0.2) 4 (0.2) 1 (0.1) 13 (0.7) 5 (0.3) 45 (2.3) 3 (0.2) 381 (19.2) 27 (1.4) 45 (2.3)
70 (3.8) 83 (4.5) 4 (0.2) 5 (0.3) 1 (0.1) 6 (0.3) 0 (0.0) 1 (0.1) 2 (0.1) 0 (0.0) 20 (1.1) 0 (0.0) 90 (4.9) 18 (1.0) 23 (1.2)
Note: Abbreviations as in Table 1. a Complications occurring in both singletons. b Composite serious morbidity: bronchopulmonary dysplasia, intraventricular hemorrhage (Rgrade 3), periventricular leukomalacia, hypoxic-ischemic encephalopathy (Rgrade 3), retinopathy of prematurity (Rstage 3), necrotizing enterocolitis, stillbirth, and infant mortality <1 year. Sazonova. Twins and singletons after IVF. Fertil Steril 2013.
Maternal Outcomes Maternal outcomes are described in Tables 3 and 4. Significantly higher rates of preeclampsia (AOR 2.64, 95% CI 1.81–3.86) and PPROM (AOR 8.43, 95% CI 4.86–14.63) were observed for the IVF twin pregnancies. The rate of cesarean section was also significantly higher for IVF twin pregnancies (AOR 4.19, 95% CI 3.32–5.29). In a few mothers of singletons the maternal complications occurred in both pregnancies (Table 3). Placenta previa was observed less frequently (AOR 0.37, 95% CI 0.17–0.81) in IVF twin pregnancies than in IVF two-singleton pregnancies.
TABLE 3 Maternal outcomes in IVF twin pregnancies (after DET) versus two IVF singleton pregnancies—outcome per woman, n (%). Twins DET Singleton 3 2a Singleton 3 2b Total, women 991 Preeclampsia 135 (13.6) Gestational diabetes 13 (1.3) Placenta previa 9 (0.9) Placental abruption 14 (1.4) PPROM 119 (12.0) Cesarean section 571 (60.7)
921 59 (6.4) 15 (1.6) 27 (2.9) 12 (1.3) 23 (2.5) 252 (27.4)
9 (1.0) 3 (0.3) 2 (0.2) 0 (0.0) 1 (0.1) 116 (12.6)
Note: PPROM ¼ preterm premature rupture of the membranes; other abbreviations as in Table 1. a Complications occurring with at least one of the two pregnancies. b Complications occurring with both pregnancies. Sazonova. Twins and singletons after IVF. Fertil Steril 2013.
734
Many maternal adverse outcomes occurred more often in the first singleton pregnancy than in the second (e.g., preeclampsia: 5.1% vs. 2.3%; complete data not shown).
DISCUSSION The main finding of this study was that adverse outcomes (PTB, VPTB, LBW, VLBW, and SGA) were dramatically increased for IVF twins compared with two IVF singletons with the same mother, with AORs from 4 to 16. These risk estimates are presented per child, i.e., each twin has these increased risks compared with a singleton child. Most importantly, the above-mentioned increased rates of adverse perinatal outcomes in IVF twins were mirrored in significantly higher rates of child morbidity. Significantly higher rates of respiratory complications, sepsis, and jaundice were found among twins. For other more severe diagnoses, we created a composite outcome, because each of the individual diagnoses occur relatively infrequently. Regarding the composite outcome, the number of children in each group having at least one of the included complications was described. We used this more conservative approach despite our awareness that having two or more severe diagnoses is a much more serious condition for the child than having only one diagnosis. The rate of the composite outcome, representing the most severe child morbidity, was almost doubled and significantly higher for IVF twins in the crude analysis but significance disappeared after adjustment for confounders. Even in a large registry study such as this one, severe child morbidity is VOL. 99 NO. 3 / MARCH 1, 2013
Fertility and Sterility®
TABLE 4 Neonatal and maternal outcomes (crude and adjusted odds ratios [ORs]) in IVF twin pregnancies after DET versus two IVF singleton pregnancies. Outcome Neonatal outcomes <37 wk <32 wk <2,500 g <1,500 g Small for gestational age Perinatal mortality Apgar <75 Severe neonatal morbidity Relatively severe malformations Respiratory complications Sepsis Jaundice Peri/neonatal mortality <1 y Composite serious morbiditye Maternal outcomes Preeclampsia Gestational diabetes Placenta previa Placental abruption PPROM Cesarean section
Crude OR (95% CI)
Adjusted ORa (95% CI)
11.24 (8.94–14.15) 6.38 (3.86–10.55) 13.10 (10.09–17.02) 4.28 (2.60–7.06) 5.93 (4.13–8.51) 1.19 (0.62–2.27) 1.30 (0.95–1.79)
12.67 (9.62–16.68) 7.43 (4.25–12.99) 16.60 (12.28–22.42) 4.72 (2.83–7.88)b 7.62 (5.14–11.29) 0.91 (0.43–1.92)b 1.52 (0.83–2.80)
1.30 (0.95–1.79) 4.11 (3.13–5.40) 2.12 (1.21–3.72) 4.63 (3.55–6.05) 1.40 (0.75–2.62) 1.84 (1.06–3.17)
1.14 (0.81–1.62) 4.92 (3.68–6.58) 2.31 (1.29–4.13) 5.03 (3.77–6.70) 0.98 (0.46–2.09) 1.34 (0.70–2.57)
2.30 (1.67–3.17) 0.80 (0.38–1.70) 0.30 (0.14–0.65) 1.09 (0.50–2.36) 5.33 (3.38–8.41) 4.01 (3.30–4.86)
2.64 (1.81–3.86) NA 0.37c (0.17–0.81) 1.30d (0.58–2.89) 8.43 (4.86–14.63) 4.19 (3.32–5.29)
Note: NA ¼ not available (not calculated owing to few events); other abbreviations as in Tables 1 and 3. a Adjustment was performed for age, BMI, parity, smoking, and years of infertility if not otherwise stated. b Adjusted for parity and age. c Adjusted for parity and age. d Adjusted for parity. e Composite serious morbidity: bronchopulmonary dysplasia, intraventricular hemorrhage (Rgrade 3), periventricular leukomalacia, hypoxic-ischemic encephalopathy (Rgrade 3), retinopathy of prematurity (Rstage 3), necrotizing enterocolitis, stillbirth, and infant mortality <1 year. Sazonova. Twins and singletons after IVF. Fertil Steril 2013.
rare. Such complications increase the risk of neonatal intensive care admission and may also have long-term health consequences for the children. Similar results have been reported in other studies where a considerably poorer outcome for IVF/ ICSI twins than in singletons has been found (24, 25). It is obvious that more complications, both maternal and neonatal, occurred more often in the first than in the second pregnancy in the singleton group. This might be expected, because primiparity has been found to be an independent predictor of adverse neonatal outcome (26, 27). One could therefore assume that the second delivery of the mothers of singletons would carry lower risks, and our data support this. It was also evident that the twin pregnancies carried a significantly higher risk of several maternal complications, although maternal complications were more difficult to compare statistically in a study of this kind. For the group of singleton mothers we chose to include complications occurring in at least one of the two pregnancies for comparison. When using this kind of calculation, the rate of preeclampsia was doubled in the group of twin mothers, but it should be borne in mind that nine women in the singleton group had preeclampsia in both pregnancies. PPROM and cesarean section also occurred more often in the mothers with a twin pregnancy, although a large part of the mothers with singleton pregnancies had cesarean sections in both pregnancies. Placenta previa was observed less frequently in the group of mothers with IVF twin pregnancy than in the group of mothers with two IVF singleton pregnancies. Although this might be unexpected, when calculated per pregnancy no significant difference was observed (9/991 [0.9%] vs. 29/1,844 VOL. 99 NO. 3 / MARCH 1, 2013
[1.6%]; P¼ .20). The incidence of placenta previa in the general population is 0.28%–1.5%. Risk factors for placenta previa include previous cesarean section, increased maternal age and parity, smoking, and infertility treatment (28). Rates of placenta previa are significantly increased in IVF singleton and twin pregnancies (3–6-fold) compared with spontaneous conceptions, but the rates are reported to be similar in IVF twin and singleton pregnancies (29). In spontaneous pregnancies, placenta previa occurs in a slightly increased rate in twin pregnancies compared with singleton pregnancies (30). Repeated cesarean sections in women with singleton IVF pregnancies may explain the higher rate of placenta previa in the present study. It was not possible to account for all potential confounders, such as previous cesarean section, medical history of previous complications, and family history. This information was not available, which was a weakness of our study. It is obvious from randomized controlled trials that DET gives higher delivery rates than eSET when comparing only fresh cycles (15). However, when adding transfer of a single frozen-thawed embryo to the eSET group not achieving live birth in the fresh cycle, no significant difference in live birth rates was found between eSET and DET (11). Large observational data, particularly from northern Europe, have indicated similar delivery results for SET and DET. In Sweden, data from the National Quality IVF Registry show that delivery rates have remained unchanged at 27% per cycle since introduction of eSET almost 10 years ago, whereas multiple birth rates have decreased from 25% to 5%. The SET rate has increased to >70% (31). 735
ORIGINAL ARTICLE: ASSISTED REPRODUCTION The financial consequences for both parents and society, when comparing an IVF program with a high twin rate to one with a low twin rate, was not one of the main issues in this study, but a comment is in order. Financial consequences for the patients and differences in reimbursement systems are important aspects of IVF in different countries. In the Scandinavian randomized SET study (11), a costeffectiveness analysis was performed comparing the SET and the DET strategies (13). All costs, both direct and indirect, for mothers and children were calculated, including a followup at 6 months after the birth. Because of the much higher costs, especially for pediatric care for the large number of twins in the DET group, the cost calculated per live-born child up to the age of 6 months did not differ greatly (34,395 US$ in the DET group and 37,398 US$ in the SET group). Even if the costs per child was some higher with the SET strategy compared to DET, the additional costs ought to be regarded limited in view of the considerably better outcome for the children in the SET group. The rate of severe neonatal complications among the children was twice as high in the DET group versus the SET group (13, 32), some giving severe neurologic sequelae. The costs for these many times lifetime-lasting conditions were not included in the analysis above and are difficult to calculate, but they have been estimated to be considerable (33, 34). In the present cohort, national 2002–2006 data from Sweden, it was not possible to estimate how many cycles were needed to achieve two singleton live births or one twin birth, because the registry where the data were obtained includes only delivery after IVF, not failed cycles. However, since 2007 Sweden has a national quality registry for IVF that includes all cycles, successful as well as failed (31). From that registry the delivery rate after SET (eSET and non-eSET combined) for women of all ages was 28% for fresh cycles and 22% for frozen-thawed SET cycles in 2010. The SET rates were 73% and 87%, respectively. To estimate the number of cycles, SET or DET, that would be needed to achieve two children, we have used data from the Swedish National Quality IVF Registry (31) and from randomized controlled trials (11). With an SET strategy we have estimated the following:
trials (11) when extending those results to all treated women. Of these deliveries, 20% are twins (31). This gives 0.29 singletons and 0.07 twins, which corresponds to 0.29 þ 0.14 ¼ 0.43 children. 2. In DET cycles a mean of 1.1 embryos are frozen (32). With 75% survival, that would give 0.83 transfers 22% deliveries ¼ 0.18 children (all singletons because only one embryo is available for transfer). In total: 0.43 þ 0.18 ¼ 0.61 children per DET. To achieve two children: 2/0.61 ¼ 3.3 DET, which means 3.3 fresh DET þ 3.3 0.83 frozen ¼ 3.3 fresh DET þ 2.7 frozen SET. In summary, 3.3 fresh cycles are needed with both SET and DET strategies. When DET is applied in the fresh cycle, one-half the number of frozen transfers is needed to achieve the same number of children compared with SET. In conclusion, the maternal and neonatal outcomes were dramatically better for women who had two IVF singleton pregnancies than for those with one IVF twin pregnancy. Our results demonstrate that the use of SET lowers the risk associated with twin pregnancies without any substantial increase in the number of cycles needed to achieve children. This is vital information to the couples undergoing IVF and the clinicians working in assisted reproduction techniques. Acknowledgments: The authors are greatful to the Swedish IVF clinics for providing data and Professor Orvar Finnstr€ om for evaluation of neonatal morbidity.
REFERENCES 1.
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1. One fresh SET transfer results in 0.26% children. We have decreased the delivery rate from 28%, which is the actual figure from the quality registry, because that figure includes only 73% of all cycles and better-prognosis patients. We assume it would be lower if SET was applied to all women. 2. In the quality registry, the mean number of frozen embryos per SET cycle is 2.1. With 75% survival, that would give 1.6 transfers 22% (32) deliveries ¼ 0.35% children. In total: 0.26 þ 0.35 ¼ 0.61 children per SET. To achieve two children: 2/0.61 ¼ 3.3 SET, which means 3.3 fresh SET þ 3.3 1.6 frozen SET cycles ¼ 3.3 fresh SET þ 5.3 frozen SET.
5.
With the DET strategy we have estimated the following:
10.
1. One fresh DET transfer results in 0.36% deliveries. This figure is not known exactly but is assumed to be around 0.36% according to results from randomized controlled 736
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Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Reproductive Medicine, Sahlgrenska University Hospital, Gothenburg; b Department of Reproduction Epidemiology, Tornblad Institute, Institution of Clinical Sciences, Lund University, Lund; and c Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Sahlgrenska University Hospital East, Gothenburg, Sweden
Objective: To compare outcomes for women undergoing two in vitro fertilization (IVF) pregnancies with singletons and women undergoing one IVF twin pregnancy. The concept of single-embryo transfer in IVF has reduced the risks of both maternal and neonatal complications, but there is still a discussion of whether or not twins are a desired outcome of IVF. Design: Registry study. Setting: Not applicable. Patient(s): All reported twins after IVF with double-embryo transfer (n ¼ 1,982) and their mothers (n ¼ 991) and all mothers (n ¼ 921) who gave birth to two IVF singletons (n ¼ 1,842). Intervention(s): None. Main Outcome Measure(s): Maternal and neonatal outcomes including severe neonatal morbidity. Result(s): Preterm birth, very preterm birth, low birth weight, very low birth weight, and small for gestational age were dramatically increased for IVF twins compared with two IVF singletons with the same mother, with adjusted odds ratios from 4 to 16. Significantly higher rates of respiratory complications, sepsis, and jaundice were detected among the IVF twins. Significantly higher rates of preeclampsia, preterm premature rupture of the membranes, and cesarean section were observed for IVF twin pregnancies. Conclusion(s): The neonatal and maternal outcomes were dramatically better for women undergoing two IVF singleton pregnancies compared with one IVF twin pregnancy after double-embryo transfer. These results support Use your smartphone single-embryo transfer to minimize the risks associated with twin pregnancies. (Fertil SterilÒ to scan this QR code 2013;99:731–7. Ó2013 by American Society for Reproductive Medicine.) and connect to the Key Words: IVF/ICSI, maternal outcome, neonatal outcome, singletons, twins Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/sazonovaa-neonatal-maternal-outcome-twins-ivf/
Received June 20, 2012; revised November 9, 2012; accepted November 12, 2012; published online December 7, 2012. A.S. has nothing to disclose. K.K. has nothing to disclose. A.T.-K. reports payment for lectures from Merck Serono, Ferring, and MSD and grants/grants pending from Merck Serono. U.-B.W. has nothing to disclose. C.B. has nothing to disclose. Supported by grants from the University of Gothenburg/Sahlgrenska University Hospital (LUA/ALF 70940) and the Hjalmar Svensson Foundation. K.K. supported by the Evy and Gunnar Sandberg Foundation and the Birgit and H akan Ohlsson Foundation. Reprint requests: Antonina Sazonova, M.D., Institute of Clinical Sciences, Department of Obstetrics and Gynaecology, Reproductive Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden (E-mail: [email protected]). Fertility and Sterility® Vol. 99, No. 3, March 1, 2013 0015-0282/$36.00 Copyright ©2013 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.11.023 VOL. 99 NO. 3 / MARCH 1, 2013
discussion forum for this article now.*
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I
t is well known that multiple births, including twins, after in vitro fertilization (IVF) are an adverse outcome that increases the risks of maternal and neonatal complications. Large registry studies have shown that the risks of preterm birth (PTB) and low birth weight (LBW) are increased in IVF children compared with children after spontaneous conception, and that most of this increased risk is attributable to the 731
ORIGINAL ARTICLE: ASSISTED REPRODUCTION high rate of multiple births among IVF children (1–6). The higher rate of severe child morbidity observed in IVF children is strongly associated with preterm birth and low birth weight (7–10). Cerebral palsy occurred in 0.37% of IVF singletons and in 0.74% of IVF twins in the Swedish study (7). The introduction of single-embryo transfer (SET) has substantially reduced these risks (2, 11–15). Neonatal and maternal outcome after SET and doubleembryo transfer (DET) also has been reported. In a large registry study from Sweden (16), including almost 8,000 children after SET and 6,000 children after DET, the obstetrical and neonatal outcomes were reported. The multiple birth rates in the SET and DET groups were 1.2% and 21.2%, respectively. The DET children were at 2–3 times higher risk of being born preterm and with low/very low birth weight compared with the SET children. Both randomized controlled trials (13) and meta-analyses (15, 17) have reported on the outcomes for the children after SET versus DET. The latest study found risk ratios of 0.37 for preterm birth and 0.25 for low birth weight in favor of SET (17). The concept of SET for IVF has reduced the risks for both maternal and neonatal complications simply by lowering the number of multiple births. Although the supporting data are overwhelming, there is still an ongoing debate whether twins are a desired outcome of IVF. It has been claimed that the risk associated with IVF twins were dramatically exaggerated and that parents should be reassured regarding twins (18). Based on theoretic calculations and particularly for parents who want more than one child, twin deliveries have been regarded as a favorable outcome that should be encouraged. There are fears of lowering pregnancy and delivery rates with the SET concept, especially in countries with private health care and/or insurance systems, including the USA. Before 2002, only 1% of transfers in the USA were elective SET (eSET). However, according to new guidelines from Society for Assisted Reproductive Technology/American Society for Reproductive Medicine, an obvious trend during recent years is observed with more use of eSET among patients <35 years old. The rates of eSET in the USA have risen steadily 1%–2% each year since 2002, and in 2009 eSET among patients <35 years old constituted 10% of all embryo transfers. Women <35 years old contribute, however, to only <50% of all ART cycles. In women >35 years old the eSET rate is most probably lower. Therefore, a more realistic estimate of the frequency of eSET in the USA may be 5% (19, 20). Assuming that most parents want two children, we analyzed the neonatal and maternal outcomes for women undergoing two IVF singleton pregnancies and compared the results with those of women undergoing one IVF twin pregnancy.
MATERIALS AND METHODS Data were collected from all IVF clinics in Sweden for IVF treatments (both publicly and privately funded) during the years 2002–2006. All reported twins after IVF with DET (n ¼ 991 twin pairs; n ¼ 1,982 children) and their mothers (n ¼ 991) and all mothers (n ¼ 921) who gave birth to two IVF singletons (n ¼ 1,842) in Sweden during this time period 732
were included. Data collected from the IVF clinics included personal identification number of the women, IVF/intracytoplasmic sperm injection (ICSI), fresh/cryopreserved, ejaculated/epididymal/testicular sperm, number of oocytes retrieved, cleavage-stage/blastocyst transfer, date of embryo transfer, number of embryos transferred, number of cryopreserved embryos, number of gestational sacs and date at first ultrasound, date of delivery, and number of children born. Data from the IVF clinics were cross-linked with the Swedish Medical Birth Registry (21), and obstetrical outcomes were retrieved. Data on severe neonatal morbidity were collected from the Medical Birth Registry and from the National Patient Registry. The International Classification of Diseases (ICD) 10 codes were used. Outcome measures were: preterm (<37 w), very preterm (VPTB; <32 w), and extreme preterm (<28 w) birth, LBW (<2,500 g), and very low birth weight (VLBW; <1,500 g). Other outcome measures were small for gestational age (SGA; more than two standard deviations below the Swedish growth standard, <22%) (22), perinatal mortality (stillbirths after 28 completed gestational weeks and neonatal deaths the first 7 days), and Apgar score (Apgar score <7 at 5 minutes). Maternal outcomes included preeclampsia (O.14, O.15), gestational diabetes (O.24.4), placenta previa (O.44), placental abruption (O.45), and preterm premature rupture of the membranes (PPROM; O.42). The rate of cesarean section was also assessed. Neonatal severe morbidity included intraventricular hemorrhage grade R3 (P.52.2), periventricular leucomalacia (P.91.2), septicemia (P.36.9), necrotizing enterocolitis (P.77.9), retinopathy of prematurity (H.35.1), bronchopulmonary dysplasia (P.27.1), jaundice (P.59.0–9), respiratory diagnoses (include infants treated with continuous positive airway pressure or mechanical ventilation), relatively severe malformations (ICD-10 code beginning with a Q, excluding infants with one or more of the following conditions: preauricular appendix, undescended testicle, tongue tie, hip [sub] luxation or unstable hip, patent ductus arteriosus in a preterm infant, single umbilical artery, and nevus) (23), meconium aspiration (P.24.0), convulsions (P.90.9), and hypoxic-ischemic encephalopathy Rgrade 3 (P.91.6C). In addition, a composite outcome was created including the most severe neonatal diagnosis (intraventricular hemorrhage Rgrade 3, periventricular leucomalacia, necrotizing enterocolitis, retinopathy of prematurity Rstage 3, bronchopulmonary dysplasia, hypoxic-ischemic encephalopathy Rgrade 3, and infant mortality, including stillbirth after 28 completed gestational weeks or death during the first year). Gestational age was determined according to the day of embryo transfer and the number of days in culture. This was regarded to be appropriate because all statistical comparisons in the present report were performed within the IVF cohort, and the day of embryo transfer was assumed to give a more precise dating of gestation than a second-trimester sonography. For the interpretation of this study it is of important to note that in Sweden IVF is both publicly and privately funded. Publicly funded IVF is offered to childless couples after investigation, which is performed after at least 1 year of infertility and if no other treatment is considered to be suitable. Certain age limits exist, usually 40 years for women. Exact rules differ VOL. 99 NO. 3 / MARCH 1, 2013
Fertility and Sterility® somewhat between different regions. Up to three subsidized cycles with fresh embryos are offered in most regions. After achieving one live birth, no more publicly funded cycles are offered. Ethical approval was obtained from the Ethics Committee of the University of Gothenburg.
Statistical Methods Descriptive data are given as numbers and percentages. Selected maternal and neonatal outcomes in IVF twin pregnancies after DET versus two IVF singleton pregnancies were calculated per woman and/or per infant when appropriate. The outcomes of the children were calculated per child in both groups. Maternal outcomes for the twin group were calculated per twin mother. For the singleton group, maternal outcomes were calculated for mothers having the relevant complication in at least one of the two pregnancies. This rate was used for comparison. In addition, mothers having the relevant complication in both of her pregnancies are presented. The maternal and neonatal outcome measurements were analyzed with univariate and multiple logistic regression analyses, using generalized estimating equation technology to obtain robust variance estimation. If not otherwise stated, adjustments were made for year of birth (continuous variable), maternal age at delivery (continuous), nulliparity (yes/no), maternal smoking at the first antenatal visit (semicontinuous variable: 1 ¼ none; 2 ¼ smoking <10 cigarettes per day; 3 ¼ smoking R10 cigarettes per day), and maternal body mass index (BMI, kg/m2) at the first antenatal visit (continuous variable). In cases of missing information on smoking or maternal BMI, imputations were made so that the missing values were replaced by the overall mean among records with valid information: 24.6 for BMI, and 1.03 for the semicontinuous smoking scale. For the other background characteristics, there was no loss of information. All statistical analyses were done with the use of Gauss (Aptech Systems).
RESULTS Maternal characteristics (for singleton mothers the data from the first pregnancy) are described in Table 1. Mothers of IVF twins were older (46.2% >35 years) than mothers of IVF singletons (29.4% >35 years). The mothers of IVF twins were multiparous in 35.4% of cases compared with only 6.5% of mothers of IVF singletons. Smoking, BMI, and infertility duration were similar distributed in both groups. Tables 2–4 demonstrate the neonatal and maternal outcomes in IVF twin pregnancies compared with two IVF singleton pregnancies based per woman and per infant. In total, 991 women with 1,982 twins (991 pairs of twins) after DET (frozen and fresh) were compared with 1,842 IVF singletons after SET (frozen and fresh) born to the 921 women who had two singleton pregnancies.
Neonatal Outcomes Neonatal outcomes are presented in Tables 2 and 4. When comparing neonatal outcome in IVF twins with IVF singletons, significantly higher rates of PTB (<37 w, adjusted odds ratio VOL. 99 NO. 3 / MARCH 1, 2013
TABLE 1 Maternal characteristics by study group, n (%). Twins (DET) Total 991 Maternal age, y 20–24 9 (0.9) 25–29 124 (12.5) 30–34 400 (40.4) 35–38 322 (32.5) 39–40 99 (10.0) 41–42 32 (3.2) R43 5 (0.5) Maternal parity 1 650 (65.6) 2 285 (28.8) 3 40 (4.0) R4 16 (1.6) Maternal smoking Unknown 105 (10.6) No 861 (97.2) 1–9/d 21 (2.4) R10/d 4 (0.5) Maternal BMI, kg/m2 Unknown 165 (16.6) <20 63 (7.6) 10–24.9 427 (51.7) 25–29.9 252 (30.5) R30 84 (10.6) Years of involuntary childlessness Unknown 290 (29.3) %2 179 (25.5) 3–4 296 (42.2) 5–19 226 (32.2)
Singleton 3 2 921 16 (1.7) 182 (19.8) 453 (49.2) 231 (25.1) 30 (3.3) 8 (0.9) 1 (0.1) 861 (93.5) 46 (5.0) 12 (1.3) 2 (0.2) 83 (9.0) 816 (97.4) 18 (2.1) 4 (0.5) 136 (14.8) 73 (9.3) 435 (55.4) 202 (25.7) 75 (9.6) 206 (22.4) 230 (32.2) 339 (47.4) 146 (20.4)
Note: Singleton 2: mothers who gave birth to two IVF singletons. Percentages based on records with obtainable information. DET ¼ double-embryo transfer; BMI ¼ body mass index. Sazonova. Twins and singletons after IVF. Fertil Steril 2013.
[AOR] 12.67, 95% CI 9.62–16.68), VPTB (<32w, AOR 7.43, 95% CI 4.25–12.99), LBW (<2,500 g, AOR 16.6, 95% CI 12.28– 22.42), VLBW (<1,500 g, AOR 4.72, 95% CI 2.83–7.88), and SGA (AOR 7.62, 95% CI 5.14–11.29) were found for IVF twins (Table 4). There were no significant differences in incidences of perinatal mortality or Apgar score <7 at 5 minutes. All neonatal adverse outcomes occurred more often in the first compared with the second singleton pregnancy (e.g., <1,500 g: 1.8% vs. 0.8%, respectively; <2,500 g: 6.4% vs. 2.8%; SGA: 3.1% vs. 1.5%; complete data not shown).
Neonatal Morbidity Significantly higher rates of respiratory complications (AOR 4.92, 95% CI 3.68–6.58), sepsis (AOR 2.31, 95% CI 1.29–4.13), and jaundice (AOR 5.03, 95% CI 3.77–6.70) were detected among the IVF twins. Higher rates of unadjusted composite serious morbidity were found for IVF twins (crude OR 1.84, 95% CI 1.06–3.17), but after adjustment for maternal confounders (age, parity, BMI, smoking, years of infertility) the difference was no longer significant (AOR 1.34, 95% CI 0.70–2.57; Table 4). There were no significant differences in incidences of mortality during the first year or relatively severe malformations between the two groups. 733
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
TABLE 2 Neonatal outcomes in IVF twin pregnancies (after DET) versus two IVF singleton pregnancies—outcome per infant, n (%).
Total infants <37 wk <32 wk <2,500 g <1,500 g Small for gestational age Peri/neonatal mortality Apgar <75 Severe neonatal morbidity Relatively severe malformations Respiratory disorders Meconium aspiration Bronchopulmonary dysplasia Intraventricular hemorrhage (Rgrade 3) Convulsions Periventricular leukomalacia Hypoxic-ischemic encephalopathy (Rgrade 3) Retinopathy of prematurity Retinopathy of prematurity (Rstage 3) Sepsis Necrotizing enterocolitis Jaundice Stillbirth and infant mortality <1 y Composite serious morbidityb
Twins
Singletons
Siblingsa
1,982 925 (46.7) 148 (7.5) 769 (38.8) 106 (5.3) 246 (12.4) 23 (1.2) 59 (3.0)
1,842 133 (7.2) 23 (1.2) 85 (4.6) 24 (1.3) 43 (2.3) 18 (1.0) 30 (1.6)
17 (0.9) 2 (0.1) 9 (0.5) 2 (0.1) 5 (0.3) 1 (0.1) 0 (0.0)
97 (4.9) 322 (16.2) 1 (0.1) 12 (0.6) 4 (0.2) 4 (0.2) 4 (0.2) 1 (0.1) 13 (0.7) 5 (0.3) 45 (2.3) 3 (0.2) 381 (19.2) 27 (1.4) 45 (2.3)
70 (3.8) 83 (4.5) 4 (0.2) 5 (0.3) 1 (0.1) 6 (0.3) 0 (0.0) 1 (0.1) 2 (0.1) 0 (0.0) 20 (1.1) 0 (0.0) 90 (4.9) 18 (1.0) 23 (1.2)
Note: Abbreviations as in Table 1. a Complications occurring in both singletons. b Composite serious morbidity: bronchopulmonary dysplasia, intraventricular hemorrhage (Rgrade 3), periventricular leukomalacia, hypoxic-ischemic encephalopathy (Rgrade 3), retinopathy of prematurity (Rstage 3), necrotizing enterocolitis, stillbirth, and infant mortality <1 year. Sazonova. Twins and singletons after IVF. Fertil Steril 2013.
Maternal Outcomes Maternal outcomes are described in Tables 3 and 4. Significantly higher rates of preeclampsia (AOR 2.64, 95% CI 1.81–3.86) and PPROM (AOR 8.43, 95% CI 4.86–14.63) were observed for the IVF twin pregnancies. The rate of cesarean section was also significantly higher for IVF twin pregnancies (AOR 4.19, 95% CI 3.32–5.29). In a few mothers of singletons the maternal complications occurred in both pregnancies (Table 3). Placenta previa was observed less frequently (AOR 0.37, 95% CI 0.17–0.81) in IVF twin pregnancies than in IVF two-singleton pregnancies.
TABLE 3 Maternal outcomes in IVF twin pregnancies (after DET) versus two IVF singleton pregnancies—outcome per woman, n (%). Twins DET Singleton 3 2a Singleton 3 2b Total, women 991 Preeclampsia 135 (13.6) Gestational diabetes 13 (1.3) Placenta previa 9 (0.9) Placental abruption 14 (1.4) PPROM 119 (12.0) Cesarean section 571 (60.7)
921 59 (6.4) 15 (1.6) 27 (2.9) 12 (1.3) 23 (2.5) 252 (27.4)
9 (1.0) 3 (0.3) 2 (0.2) 0 (0.0) 1 (0.1) 116 (12.6)
Note: PPROM ¼ preterm premature rupture of the membranes; other abbreviations as in Table 1. a Complications occurring with at least one of the two pregnancies. b Complications occurring with both pregnancies. Sazonova. Twins and singletons after IVF. Fertil Steril 2013.
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Many maternal adverse outcomes occurred more often in the first singleton pregnancy than in the second (e.g., preeclampsia: 5.1% vs. 2.3%; complete data not shown).
DISCUSSION The main finding of this study was that adverse outcomes (PTB, VPTB, LBW, VLBW, and SGA) were dramatically increased for IVF twins compared with two IVF singletons with the same mother, with AORs from 4 to 16. These risk estimates are presented per child, i.e., each twin has these increased risks compared with a singleton child. Most importantly, the above-mentioned increased rates of adverse perinatal outcomes in IVF twins were mirrored in significantly higher rates of child morbidity. Significantly higher rates of respiratory complications, sepsis, and jaundice were found among twins. For other more severe diagnoses, we created a composite outcome, because each of the individual diagnoses occur relatively infrequently. Regarding the composite outcome, the number of children in each group having at least one of the included complications was described. We used this more conservative approach despite our awareness that having two or more severe diagnoses is a much more serious condition for the child than having only one diagnosis. The rate of the composite outcome, representing the most severe child morbidity, was almost doubled and significantly higher for IVF twins in the crude analysis but significance disappeared after adjustment for confounders. Even in a large registry study such as this one, severe child morbidity is VOL. 99 NO. 3 / MARCH 1, 2013
Fertility and Sterility®
TABLE 4 Neonatal and maternal outcomes (crude and adjusted odds ratios [ORs]) in IVF twin pregnancies after DET versus two IVF singleton pregnancies. Outcome Neonatal outcomes <37 wk <32 wk <2,500 g <1,500 g Small for gestational age Perinatal mortality Apgar <75 Severe neonatal morbidity Relatively severe malformations Respiratory complications Sepsis Jaundice Peri/neonatal mortality <1 y Composite serious morbiditye Maternal outcomes Preeclampsia Gestational diabetes Placenta previa Placental abruption PPROM Cesarean section
Crude OR (95% CI)
Adjusted ORa (95% CI)
11.24 (8.94–14.15) 6.38 (3.86–10.55) 13.10 (10.09–17.02) 4.28 (2.60–7.06) 5.93 (4.13–8.51) 1.19 (0.62–2.27) 1.30 (0.95–1.79)
12.67 (9.62–16.68) 7.43 (4.25–12.99) 16.60 (12.28–22.42) 4.72 (2.83–7.88)b 7.62 (5.14–11.29) 0.91 (0.43–1.92)b 1.52 (0.83–2.80)
1.30 (0.95–1.79) 4.11 (3.13–5.40) 2.12 (1.21–3.72) 4.63 (3.55–6.05) 1.40 (0.75–2.62) 1.84 (1.06–3.17)
1.14 (0.81–1.62) 4.92 (3.68–6.58) 2.31 (1.29–4.13) 5.03 (3.77–6.70) 0.98 (0.46–2.09) 1.34 (0.70–2.57)
2.30 (1.67–3.17) 0.80 (0.38–1.70) 0.30 (0.14–0.65) 1.09 (0.50–2.36) 5.33 (3.38–8.41) 4.01 (3.30–4.86)
2.64 (1.81–3.86) NA 0.37c (0.17–0.81) 1.30d (0.58–2.89) 8.43 (4.86–14.63) 4.19 (3.32–5.29)
Note: NA ¼ not available (not calculated owing to few events); other abbreviations as in Tables 1 and 3. a Adjustment was performed for age, BMI, parity, smoking, and years of infertility if not otherwise stated. b Adjusted for parity and age. c Adjusted for parity and age. d Adjusted for parity. e Composite serious morbidity: bronchopulmonary dysplasia, intraventricular hemorrhage (Rgrade 3), periventricular leukomalacia, hypoxic-ischemic encephalopathy (Rgrade 3), retinopathy of prematurity (Rstage 3), necrotizing enterocolitis, stillbirth, and infant mortality <1 year. Sazonova. Twins and singletons after IVF. Fertil Steril 2013.
rare. Such complications increase the risk of neonatal intensive care admission and may also have long-term health consequences for the children. Similar results have been reported in other studies where a considerably poorer outcome for IVF/ ICSI twins than in singletons has been found (24, 25). It is obvious that more complications, both maternal and neonatal, occurred more often in the first than in the second pregnancy in the singleton group. This might be expected, because primiparity has been found to be an independent predictor of adverse neonatal outcome (26, 27). One could therefore assume that the second delivery of the mothers of singletons would carry lower risks, and our data support this. It was also evident that the twin pregnancies carried a significantly higher risk of several maternal complications, although maternal complications were more difficult to compare statistically in a study of this kind. For the group of singleton mothers we chose to include complications occurring in at least one of the two pregnancies for comparison. When using this kind of calculation, the rate of preeclampsia was doubled in the group of twin mothers, but it should be borne in mind that nine women in the singleton group had preeclampsia in both pregnancies. PPROM and cesarean section also occurred more often in the mothers with a twin pregnancy, although a large part of the mothers with singleton pregnancies had cesarean sections in both pregnancies. Placenta previa was observed less frequently in the group of mothers with IVF twin pregnancy than in the group of mothers with two IVF singleton pregnancies. Although this might be unexpected, when calculated per pregnancy no significant difference was observed (9/991 [0.9%] vs. 29/1,844 VOL. 99 NO. 3 / MARCH 1, 2013
[1.6%]; P¼ .20). The incidence of placenta previa in the general population is 0.28%–1.5%. Risk factors for placenta previa include previous cesarean section, increased maternal age and parity, smoking, and infertility treatment (28). Rates of placenta previa are significantly increased in IVF singleton and twin pregnancies (3–6-fold) compared with spontaneous conceptions, but the rates are reported to be similar in IVF twin and singleton pregnancies (29). In spontaneous pregnancies, placenta previa occurs in a slightly increased rate in twin pregnancies compared with singleton pregnancies (30). Repeated cesarean sections in women with singleton IVF pregnancies may explain the higher rate of placenta previa in the present study. It was not possible to account for all potential confounders, such as previous cesarean section, medical history of previous complications, and family history. This information was not available, which was a weakness of our study. It is obvious from randomized controlled trials that DET gives higher delivery rates than eSET when comparing only fresh cycles (15). However, when adding transfer of a single frozen-thawed embryo to the eSET group not achieving live birth in the fresh cycle, no significant difference in live birth rates was found between eSET and DET (11). Large observational data, particularly from northern Europe, have indicated similar delivery results for SET and DET. In Sweden, data from the National Quality IVF Registry show that delivery rates have remained unchanged at 27% per cycle since introduction of eSET almost 10 years ago, whereas multiple birth rates have decreased from 25% to 5%. The SET rate has increased to >70% (31). 735
ORIGINAL ARTICLE: ASSISTED REPRODUCTION The financial consequences for both parents and society, when comparing an IVF program with a high twin rate to one with a low twin rate, was not one of the main issues in this study, but a comment is in order. Financial consequences for the patients and differences in reimbursement systems are important aspects of IVF in different countries. In the Scandinavian randomized SET study (11), a costeffectiveness analysis was performed comparing the SET and the DET strategies (13). All costs, both direct and indirect, for mothers and children were calculated, including a followup at 6 months after the birth. Because of the much higher costs, especially for pediatric care for the large number of twins in the DET group, the cost calculated per live-born child up to the age of 6 months did not differ greatly (34,395 US$ in the DET group and 37,398 US$ in the SET group). Even if the costs per child was some higher with the SET strategy compared to DET, the additional costs ought to be regarded limited in view of the considerably better outcome for the children in the SET group. The rate of severe neonatal complications among the children was twice as high in the DET group versus the SET group (13, 32), some giving severe neurologic sequelae. The costs for these many times lifetime-lasting conditions were not included in the analysis above and are difficult to calculate, but they have been estimated to be considerable (33, 34). In the present cohort, national 2002–2006 data from Sweden, it was not possible to estimate how many cycles were needed to achieve two singleton live births or one twin birth, because the registry where the data were obtained includes only delivery after IVF, not failed cycles. However, since 2007 Sweden has a national quality registry for IVF that includes all cycles, successful as well as failed (31). From that registry the delivery rate after SET (eSET and non-eSET combined) for women of all ages was 28% for fresh cycles and 22% for frozen-thawed SET cycles in 2010. The SET rates were 73% and 87%, respectively. To estimate the number of cycles, SET or DET, that would be needed to achieve two children, we have used data from the Swedish National Quality IVF Registry (31) and from randomized controlled trials (11). With an SET strategy we have estimated the following:
trials (11) when extending those results to all treated women. Of these deliveries, 20% are twins (31). This gives 0.29 singletons and 0.07 twins, which corresponds to 0.29 þ 0.14 ¼ 0.43 children. 2. In DET cycles a mean of 1.1 embryos are frozen (32). With 75% survival, that would give 0.83 transfers 22% deliveries ¼ 0.18 children (all singletons because only one embryo is available for transfer). In total: 0.43 þ 0.18 ¼ 0.61 children per DET. To achieve two children: 2/0.61 ¼ 3.3 DET, which means 3.3 fresh DET þ 3.3 0.83 frozen ¼ 3.3 fresh DET þ 2.7 frozen SET. In summary, 3.3 fresh cycles are needed with both SET and DET strategies. When DET is applied in the fresh cycle, one-half the number of frozen transfers is needed to achieve the same number of children compared with SET. In conclusion, the maternal and neonatal outcomes were dramatically better for women who had two IVF singleton pregnancies than for those with one IVF twin pregnancy. Our results demonstrate that the use of SET lowers the risk associated with twin pregnancies without any substantial increase in the number of cycles needed to achieve children. This is vital information to the couples undergoing IVF and the clinicians working in assisted reproduction techniques. Acknowledgments: The authors are greatful to the Swedish IVF clinics for providing data and Professor Orvar Finnstr€ om for evaluation of neonatal morbidity.
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1. One fresh SET transfer results in 0.26% children. We have decreased the delivery rate from 28%, which is the actual figure from the quality registry, because that figure includes only 73% of all cycles and better-prognosis patients. We assume it would be lower if SET was applied to all women. 2. In the quality registry, the mean number of frozen embryos per SET cycle is 2.1. With 75% survival, that would give 1.6 transfers 22% (32) deliveries ¼ 0.35% children. In total: 0.26 þ 0.35 ¼ 0.61 children per SET. To achieve two children: 2/0.61 ¼ 3.3 SET, which means 3.3 fresh SET þ 3.3 1.6 frozen SET cycles ¼ 3.3 fresh SET þ 5.3 frozen SET.
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