High-risk of preterm birth and low birth weight after oocyte donation IVF: analysis of 133,785 live births

Accepted Manuscript Title: High-risk of preterm birth and low birth weight after oocyte donation IVF: analysis of 133,785 live births Author: Mohan Shashikant Kamath, Belavendra Antonisamy, Mariano Mascarenhas, Sesh Kamal Sunkara PII: DOI: Reference:

S1472-6483(17)30266-3 http://dx.doi.org/doi: 10.1016/j.rbmo.2017.06.013 RBMO 1769

To appear in:

Reproductive BioMedicine Online

Received date: Revised date: Accepted date:

9-1-2017 2-6-2017 2-6-2017

Please cite this article as: Mohan Shashikant Kamath, Belavendra Antonisamy, Mariano Mascarenhas, Sesh Kamal Sunkara, High-risk of preterm birth and low birth weight after oocyte donation IVF: analysis of 133,785 live births, Reproductive BioMedicine Online (2017), http://dx.doi.org/doi: 10.1016/j.rbmo.2017.06.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Short title: Preterm birth and low birth weight after donor oocyte IVF High-risk of preterm birth and low birth weight after oocyte donation IVF: analysis of 133,785 live births Mohan Shashikant Kamath,a,* Belavendra Antonisamy,a Mariano Mascarenhas,b Sesh Kamal Sunkarac

a

Reproductive Medicine Unit, Christian Medical College Hospital, Vellore, India, 632004 Leeds Centre for Reproductive Medicine, Seacroft Hospital, Leeds Teaching Hospital NHS trust, Leeds, UK c Queen’s Hospital, Barking Havering Redbridge University Hospitals NHS Trust, Essex, UK b

Comment [S1]: Author: please provide full postal addresses for all authors.

*Corresponding author: Dr Mohan S Kamath, Reproductive Medicine Unit, Christian Medical College Hospital, Vellore, India, 632004. Tel: +91-416-2283301; E-mail address: [email protected]

Author biography Mohan S Kamath obtained his medical training (MBBCh) in 2000, MS in 2003 from the Department of Obstetrics and Gynaecology, Pune University, India and Diplomate of National Board (Obgyn) in 2004. He further specialized in Reproductive Medicine from Christian Medical College, Vellore, India in 2008 .He was awarded the Commonwealth fellowship (Reproductive Medicine) from University of Aberdeen, UK, in 2012. He is presently a peer reviewer for Cochrane Gynaecology and Fertility group.

Key message Our retrospective analysis of a large dataset comparing perinatal outcomes after oocyte donation and autologous IVF found increased risk of preterm birth and low birth weight after oocyte donation cycles.

1

Page 1 of 26

Abstract

A higher risk of pregnancy complications occurs after assisted reproductive techniques compared with spontaneously conceived pregnancies. This is attributed to the underlying infertility and assisted reproduction technique procedures involved during treatment. It is a matter of interest whether use of donor oocytes affects perinatal outcomes compared with pregnancies after autologous IVF. Anonymized data were obtained from the Human Fertilization and Embryology Authority. The analysis included 5929 oocyte donation and 127,856 autologous IVF live births. Data from all women who underwent donor oocyte recipient or autologous IVF cycles, both followed with fresh embryo transfer, were analysed to compare perinatal outcomes of preterm birth (PTB) and low birthweight (LBW) after singleton and multiple live births. The risk of adverse perinatal outcomes after oocyte donation was increased: adjusted OR (aOR) 1.56, 99.5% CI 1.34 to 1.80 for PTB and aOR 1.43, 99.5% CI 1.24 to 1.66 for LBW were significantly higher after oocyte donation compared with autologous IVF singletons. The adjusted odds PTB (aOR 1.21, 99.5% CI 1.02 to 1.43) was significantly higher after oocyte donation compared with autologous IVF multiple births. Analysis of this large dataset suggests significantly higher risk of PTB and LBW after ooctye donation compared with autologous IVF pregnancies.

KEYWORDS: oocyte donation, autologous IVF, live birth, preterm birth, low birth weight

Key message

2

Page 2 of 26

Our retrospective analysis of a large dataset comparing perinatal outcomes after oocyte donation and autologous IVF found increased risk of preterm birth and low birth weight after oocyte donation cycles.

Introduction Over the years, the average age of a woman at first childbirth has increased owing to the trend of delayed childbearing (Lutz et al., 2003; Matthews and Hamilton, 2009). This deferred attempt at starting a family along with age-related fertility decline has resulted in a higher proportion of women aged over 40 years seeking assisted reproductive technique treatment (Ishihara et al., 2015). Live birth rates for women aged over 40 years after autologous IVF, however, remains, low varying from 5–15% overall, and approaching almost zero at age 45 years or over (van Disseldorp et al., 2007; Mansour et al., 2014; European IVF-Monitoring Consortium et al., 2016). Oocyte donation has been offered as a more successful alternative compared with autologous IVF for women of advanced reproductive age (Sauer et al., 1996). Oocyte donation cycles result in higher success rates, with reported delivery rates of up to 47% (Ishihara et al., 2015).

3

Page 3 of 26

Pregnancy and live birth rates are comparable for recipients across all age groups (European IVF-Monitoring Consortium et al., 2016). Over the years, the number of oocyte donation treatment cycles worldwide has steadily increased (Dyer et al., 2016). In Europe, about 30,000 oocyte donation cycles out of the reported 600,000 IVF and intracytoplasmic spem injection (IVF–ICSI) cycles were carried out in 2011 (European IVF-Monitoring Consortium et al., 2016). In the USA, the number of reported oocyte donation cycles increased from 10,801 in 2000 to 18,306 in 2010 (Kawwass et al., 2013). Singleton pregnancies after IVF–ICSI have been associated with adverse obstetric and perinatal outcomes compared with spontaneous conceptions (Helmerhorst et al., 2004; Jackson et al., 2004; Pandey et al., 2012). One of the reasons for adverse perinatal outcomes afrer IVF is underlying infertility, which is an independent risk factor (Basso and Baird, 2003). Hormonal changes caused by ovarian stimulation and IVF processes may also negatively affect obstetric and neonatal outcomes after IVF (Pinborg et al., 2013). Earlier studies have indicated higher obstetric complications and poorer perinatal outcomes in pregnancies after oocyte donation compared with spontaneous conceptions (SöderströmAnttila et al., 1998; Henne et al., 2007; Malchau et al., 2013; Elenis et al., 2015). The poorer perinatal outcomes have been linked to higher prevalence of pre-eclampsia in oocyte donation pregnancies compared with spontaneous conceptions (Klatsky et al., 2010; Malchau et al., 2013; Elenis et al., 2015) . Although the available studies have consistently indicated adverse perinatal outcomes after oocyte donation compared with with spontaneous conceptions, the evidence is conflicting when comparing perinatal outcomes after oocyte donation pregnancies versus autologous IVF pregnancies. Krieg et al., (2008) compared oocyte donation and autologous IVF pregnancies and found similar obstetric and neonatal complications. Another controlled study reported a

4

Page 4 of 26

higher risk of pregnancy-induced hypertension in oocyte donation pregnancies but found no overall effect on perinatal outcomes when compared with pregnancies after autologous IVF (Stoop et al., 2012). Conversely, Gibbons et al., (2011) found significantly lower mean birth weight and length of gestation in oocyte donation pregnancies compared with autologous IVF (Gibbons et al., 2011). Recent studies have also reported higher perinatal risks after oocyte donation compared with autologous IVF–ICSI (Dude et al., 2016; Nejdet et al., 2016). In view of the existing uncertainty about the effect of oocyte donation on perinatal outcomes, we conducted a study based on the analysis of a large national database of 100,092 singleton and 33,693 multiple live births. The aim of this study was to compare the perinatal outcomes of PTB and LBW in singleton and multiple pregnancies after fresh oocyte donation versus autologous fresh IVF cycles. Materials and methods Anonymized data from assisted reproduction technique cycles carried out in the UK between 1991 and 2011 were obtained from the Human Fertilization and Embryology Authority, which maintains records of all assisted reproduction technique cycles submitted prospectively by all centres in the UK (www.hfea.gov.uk/5874.html, HFEA authority). We included only fresh oocyte donation and autologous IVF cycles that resulted in a live birth. The treatment cycles that were not included in the analysis are shown in Figure 1, along with reasons for exclusion. As HFEA anonymized data are freely accessible on their website, ethics approval was not required for the present study. Information was obtained for recipient age groups and age groups of women having autologous IVF (18–34, 35–37, 38–39, 40–42, 43–44, 45 years and over), type of infertility (female primary or secondary infertility), cause of infertility (tubal disease, ovulatory disorder, male factor, unexplained, endometriosis), previous live births, day of embryo 5

Page 5 of 26

transfer (Statistical analysis Characteristics of the two groups were described using percentages for categorical variables and means or medians for continuous variables. Live birth, singleton live birth, multiple birth, PTB, early PTB, LBW, and very LBW rates were calculated for both groups. Adjusted logistic regression was carried out for all four perinatal outcomes for pre-decided confounding variables: age of women undergoing autologous IVF and recipient age, year of treatment, cause of infertility, previous live birth, number of embryos transferred, day of embryo transfer and vanishing twin. We conducted a subgroup analysis for perinatal outcomes in women aged less than 40 years after oocyte donation and autologous IVF and adjusted the outcomes for same potential confounders mentioned earlier. Within the oocyte donation group, we explored the influence of donor age by adjusted logistic regression. Analysis of one cycle per woman could not be performed owing to anonymised nature of the dataset; as individual woman could have contributed for more than one cycle. For this limitation, we used wider 99.5% confidence intervals instead of the more common 95% confidence intervals. P < 0.05 was considered as statistically significant. STATA, version13.1 (Stata corp, College Station, Tx, USA) was used for statistical analysis 6

Page 6 of 26

Results A total of 397,449 cycles were excluded from 1,004,487 assisted reproduction technique cycles during the data-selection process (Figure 1). The number of IVF–ICSI cycles available for analysis were 607,038, which included 22,207 oocyte donation and 584 831 autologous IVF cycles. A total of 6113 live births took place after oocyte donation cycles and 131,461 live births took place after autologous IVF. Among the oocyte donation live births, perinatal outcome data were not available for 184, hence a total of 4248 singleton live births and 1681 multiple live births were available for analysis. For autologous IVF cycles, a total of 95,844 singleton live births and 32,012 multiple live births were available for analysis after excluding 3605 births with missing data for perinatal outcomes. Characteristics of the cohorts are shown in Table 1. Most (55.7%) donor oocyte recipients were women aged over 40 years compared with 14.2% among women undergoing autologous IVF. Although the main cause of infertility was ovulatory dysfunction (52.2%), among women undergoing oocyte donation IVF, male factor cause (51.5%) was most common in women undergoing autologous IVF. Most oocyte donation (93.2%) cycles and autologous IVF (91.2%) cycles had cleavage stage transfer (<5 day). The mean number of embryos transferred was 2.07 (SD 0.72) in oocyte donation and 1.81 (SD 0.90) in autologous IVF (Table 1). The incidence of vanishing twin in oocyte donation was 5.7% (241/4248) and 4.9% (4663/95844) in autologous IVF singletons. Live birth outcomes after oocyte donor recipient and autologous IVF The overall live birth rates were 27.5% (99.5% CI 26.7 to 28.4%) per initiated cycle after oocyte donation compared with 22.5% (99.5% CI 22.3 to 22.6%) per initiated cycle after

7

Page 7 of 26

autologous IVF. The multiple birth rates were 28.4% (99.5% CI 26.7 to 30.0%) for oocyte donation and 25.0 (99.5% CI 24.6 to 25.3%) for autologous IVF. Perinatal outcomes after oocyte donor recipient and autologous IVF A total of 100,092 singleton live births with information on gestational age at delivery and birth weight were analysed for perinatal outcomes. The incidence of PTB was 14.8% after oocyte donation and 9.4% after autologous IVF. The incidence of early PTB was 3.1% and 1.8% after oocyte donation and autologous IVF, respectively. The incidence of LBW after oocyte donation was 13.8% and 9.5% after autologous IVF. The incidence of very LBW was 2.6% and 1.9% after oocyte donation and autologous IVF, respectively. The unadjusted odds of PTB (OR 1.68, 99.5% CI 1.48 to 1.91), early PTB (OR 1.77, 99.5% CI 1.37 to 2.29), LBW (OR 1.53, 99.5% CI 1.35 to 1.74) and very LBW (OR 1.42, 99.5% CI 1.07 to 1.87) were significantly higher after oocyte donation compared with autologous IVF. There was a higher risk of the adverse perinatal outcomes after adjusting for potential confounding factors; PTB (adjusted odds ratio [aOR] 1.56, 99.5% CI 1.34 to 1.80), early PTB (aOR 1.40, 99.5% CI 1.04 to 1.90) and LBW (aOR 1.43, 99.5% CI 1.24 to 1.66) were significantly higher after fresh oocyte donation compared with fresh autologous IVF. The aOR for very LBW was 1.08, 99.5% CI 0.79 to 1.49 (Table 2). A total of 33,693 multiple births with information on gestational length and birth weight were available for analysis. The incidence of PTB was 54.8 % (921/1 681) after oocyte donation and 51.4% (16 452/32 012) after autologous IVF. The incidence of early PTB was 10.5% (177/1 681) and 9.8 % (3 147/32 012) after oocyte donation and autologous IVF, respectively. The incidence of LBW after oocyte donation was 53.7 % (903/1 681) and 55.1% (17 654/32 012) after autologous IVF. The incidence of very LBW was 11.1% (186/1 681) and 9.8% (3 152/32 012) after oocyte donation and autologous IVF, respectively. No

8

Page 8 of 26

significant difference in risk of PTB (OR 1.15, 99.5% CI 1.00 to 1.32), early PTB (OR 1.08, 99.5% CI 0.86 to 1.36), LBW (OR 0.94, 99.5% CI 0.82 to 1.09) and very LBW (OR 1.14, 99.5% CI 0.91 to 1.43) was found for oocyte donation and autologous IVF. The adjustment was carried out for all the potential confounders described in the ‘Materials and methods’ section, except vanishing twin. The adjusted odds for PTB were significantly higher for oocyte donation compared with autologous IVF (aOR 1.21, 99.5% CI 1.02 to 1.43). No significant difference was found in risk of early PTB (aOR 1.09, 99.5% CI 0.82 to 1.44), LBW (aOR 0.99, 99.5% CI 0.84 tp1.18) and very LBW (aOR 1.15, 99.5% CI 0.88 to 1.52) for oocyte donation and autologous IVF after adjustment for confounders. Perinatal outcomes after oocyte donor recipient and autologous IVF in women aged younger than 40 years

In singleton births among women aged younger than 40 years, the incidence of PTB was 15.1% after oocyte donation and 9.4% after autologous IVF. The incidence of early PTB was 3.2% and 1.8% after oocyte donation and autologous IVF, respectively. The incidence of LBW after oocyte donation was 15.0% and 9.4% after autologous IVF. The incidence of very LBW was 2.7% and 1.8% after oocyte donation and autologous IVF, respectively. The unadjusted odds of PTB (OR 1.72, 99.5% CI 1.43 to 2.07), early PTB (OR 1.84, 99.5% CI 1.26 to 2.69), LBW (OR 1.69, 99.5% CI 1.41 to 2.04) and very LBW (OR 1.47, 99.5% CI 0.97 to 2.22) were significantly higher after oocyte donation compared with autologous IVF. There was a higher risk of the adverse perinatal outcomes after adjusting for potential confounding factors; PTB (aOR 1.60, 99.5% CI 1.32 to 1.94), early PTB (aOR 1.51, 99.5% CI 1.02 to 2.25) and LBW (aOR 1.58, 99.5% CI 1.30 to 1.92) were significantly higher after fresh oocyte donation compared with fresh autologous IVF. The aOR for very LBW was 1.18, 99.5% CI 0.77 to 1.82 (Table 3).

9

Page 9 of 26

Influence of donor age on perinatal outcomes The influence of donor ages categorized as 20 years or younger, 21–25 years, 26–30 years and 31–35 years on the risk of PTB and LBW in recipient was analysed. The donor age group 21–25 years was considered as the reference. No significant difference was observed in risk of PTB or LBW between donor age group 21–25 years compared with other donor age groups (≤20, 26–30 and 31–35years) in singletons (Table 4). Discussion The results of the study demonstrate significantly higher risk of PTB and LBW after oocyte donation compared with autologous IVF. In women aged younger than 40 years, risk of PTB and LBW was significantly higher in oocyte donation compared with autologous IVF. Influence of donor age on the above mentioned perinatal risks was not observed. The strength of the present study was analysis of large data set collected from various centres. The study design has an additional strength in that perinatal outcomes after oocyte donation and autologous IVF were compared, helping explore oocyte donation as an independent risk factor since the underlying infertility and IVF process were common confounders. Although an earlier study has shown no difference in perinatal outcomes after fresh versus cryopreserved transfers in oocyte donation cycles, other studies have shown differences in perinatal outcomes after cryopreserved versus fresh embryo transfers, hence we excluded cryopreserved embryo transfer cycles (Maheshwari et al., 2012; Evans et al., 2014; Galliano et al., 2015). The limitation of the study is lack of information on other confounding factors, such as smoking, BMI, related oocyte donor and recipient, ethnicity and co-existing medical conditions during pregnancy, which could influence the perinatal outcomes. Analysis of one cycle per woman could not be carried out owing to anonymized nature of the dataset. For this

10

Page 10 of 26

limitation, we used wider 99.5% confidence intervals instead of the more common 95% confidence intervals. Studies comparing IVF pregnancies with spontaneous conceptions found significantly higher adverse perinatal outcomes after oocyte donation compared with spontaneous pregnancies after adjusting for important confounders (Malchau et al., 2013; Marino et al., 2014). A Swedish study that included pregnancies after oocyte donation found a higher incidence of hypertensive disorders in the recipient pregnancies compared with spontaneous conceptions even though the oocyte recipients were relatively younger and healthier. The incidence of hypertensive disorders was not significantly different when oocyte donation recipient pregnancies were compared with autologous IVF pregnancies (Elenis et al., 2015). A recent systematic review, which included 86,515 pregnancies from 19 studies, found increased risk of preeclampsia after oocyte donation compared with natural conceptions and other assisted reproduction technique methods (Masoudian et al., 2016). Overall, the comparison of adverse perinatal outcomes after oocyte donation with spontaneous conceptions showed a higher risk after oocyte donation as assisted reproduction techniques themselves are considered a risk factor (Malchau et al., 2013; Pinborg et al., 2013; Elenis et al., 2015). In a retrospective cohort analysis study, which included 71 oocyte recipients and 108 women who underwent autologous IVF, the investigators found no significant difference in PTB in oocyte donation (aOR 0.97, 95% CI 0.43 to 2.20) compared with autologous IVF, which is contrary to our finding (Krieg et al., 2008). In this study, both singleton and multiple births were analysed together, whereas, in the present study, they were analysed separately, and this could be a possible reason for conflicting results. A study analysing data from Society for Assisted Reproductive Technology (SART) reported lower mean birth weights of 3 236 ± 652 g versus 3 265 ± 611 g and lower mean gestational ages 37.4 ± 2.4 weeks versus 37.7 ± 2.2 weeks for oocyte donation compared with autologous IVF singleton pregnancies 11

Page 11 of 26

(Gibbons et al., 2011). In another cohort study from SART data set, a total of fresh 8 852 oocyte donation and 55,126 fresh autologous IVF singletons were analysed. The risks of PTB (aOR 1.28, 95% CI 1.12-1.46) and LBW (aOR 1.21, 95%CI 1.02 -1.44) were significantly higher in oocyte donation compared with autologous IVF singletons (Dude et al., 2016). A recent systematic review, which included 35 studies, found higher risk of PTB (aOR 1.75, 95% CI 1.39 to 2.20) and LBW (aOR 1.53, 95% CI 1.16 to 2.01) in singletons after oocyte donation versus autologous IVF–ICSI, which is in agreement with results of previous metaanalysis (Adams et al., 2015; Storgaard et al., 2016). The investigators suggested single embryo transfer policy in oocyte donation cycles to avoid additional risk of multiple pregnancies.

Age is an important confounding factor for adverse perinatal outcomes. In the present study, subgroup analysis of women aged younger than 40 years was carried out to make the oocyte donation and autologous IVF groups more comparable. The subsequent analysis revealed significantly higher risk of PTB and LBW in oocyte donation compared with autologous IVF, which further validates our finding. A previous study (Gibbons et al., 2011) found no influence of donor age on perinatal outcomes, which is in agreement with our findings. The study included only two donor age groups (<35 years and 35–37 years), whereas the present study categorized donors into age groups 20 years and younger, 21–25 years, 26–30 years, 31–35 years. Current practices in most centres recommend donors aged less than 35 years for optimal outcomes. In our study, a non-significant trend towards higher risk of PTB and LBW was observed when donor age was 20 years or younger compared with 21–25 years. These data need cautious interpretation

12

Page 12 of 26

owing to low numbers in this subgroup. Further investigation into the effect of oocyte donation from very young donors on perinatal outcomes is needed. Our study found significantly higher odds of having PTB and LBW after oocyte donation compared with autologous IVF, and risks of adverse perinatal outcomes remained significant in women younger than 40 years. This evidence is useful for clinicians in order to counsel women and couples undergoing oocyte donation IVF treatment. The information is important in the management of such pregnancies.

13

Page 13 of 26

Acknowledgement We thank the Human Fertilisation and Embryology Authority for providing access to and validating the data. SKS conceived the hypothesis. SKS directed the data analysis by MSK and BA. MSK and MM drafted the manuscript. MSK, SKS, MM and BA appraised the manuscript.

14

Page 14 of 26

References Adams DH, Clark RA, Davies MJ, Lacey S de. A meta-analysis of neonatal health outcomes from oocyte donation. J Dev Orig Health Dis 2015;1–16. Basso O, Baird DD. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod Oxf Engl 2003;18:2478– 2484. Disseldorp J van, Eijkemans MJC, Klinkert ER, Velde ER te, Fauser BC, Broekmans FJM. Cumulative live birth rates following IVF in 41- to 43-year-old women presenting with favourable ovarian reserve characteristics. Reprod Biomed Online 2007;14:455– 463. Dude AM, Yeh JS, Muasher SJ. Donor oocytes are associated with preterm birth when compared to fresh autologous in vitro fertilization cycles in singleton pregnancies. Fertil Steril 2016;106:660–665. Dyer S, Chambers GM, Mouzon J de, Nygren KG, Zegers-Hochschild F, Mansour R, Ishihara O, Banker M, Adamson GD. International Committee for Monitoring Assisted Reproductive Technologies world report: Assisted Reproductive Technology 2008, 2009 and 2010. Hum Reprod Oxf Engl 2016;31:1588–1609. Elenis E, Svanberg AS, Lampic C, Skalkidou A, Åkerud H, Sydsjö G. Adverse obstetric outcomes in pregnancies resulting from oocyte donation: a retrospective cohort case study in Sweden. BMC Pregnancy Childbirth 2015;15:247. European IVF-Monitoring Consortium (EIM), European Society of Human Reproduction and Embryology (ESHRE), Kupka MS, D’Hooghe T, Ferraretti AP, Mouzon J de, Erb K, Castilla JA, Calhaz-Jorge C, De Geyter C, Goossens V. Assisted reproductive

15

Page 15 of 26

technology in Europe, 2011: results generated from European registers by ESHRE. Hum Reprod Oxf Engl 2016;31:233–248. Evans J, Hannan NJ, Edgell TA, Vollenhoven BJ, Lutjen PJ, Osianlis T, Salamonsen LA, Rombauts LJF. Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence. Hum Reprod Update 2014;20:808–821. Galliano D, Garrido N, Serra-Serra V, Pellicer A. Difference in birth weight of consecutive sibling singletons is not found in oocyte donation when comparing fresh versus frozen embryo replacements. Fertil Steril 2015;104:1411-1418-3. Gibbons WE, Cedars M, Ness RB, Society for Assisted Reproductive Technologies Writing Group. Toward understanding obstetrical outcome in advanced assisted reproduction: varying sperm, oocyte, and uterine source and diagnosis. Fertil Steril 2011;95:1645– 1649.e1. Helmerhorst FM, Perquin DAM, Donker D, Keirse MJNC. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328:261. Henne MB, Zhang M, Paroski S, Kelshikar B, Westphal LM. Comparison of obstetric outcomes in recipients of donor oocytes vs. women of advanced maternal age with autologous oocytes. J Reprod Med 2007;52:585–590. Ishihara O, Adamson GD, Dyer S, Mouzon J de, Nygren KG, Sullivan EA, ZegersHochschild F, Mansour R. International committee for monitoring assisted reproductive technologies: world report on assisted reproductive technologies, 2007. Fertil Steril 2015;103:402–413.e11. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004;103:551–563.

16

Page 16 of 26

Kawwass JF, Monsour M, Crawford S, Kissin DM, Session DR, Kulkarni AD, Jamieson DJ, National ART Surveillance System (NASS) Group. Trends and outcomes for donor oocyte cycles in the United States, 2000-2010. JAMA 2013;310:2426–2434. Klatsky PC, Delaney SS, Caughey AB, Tran ND, Schattman GL, Rosenwaks Z. The role of embryonic origin in preeclampsia: a comparison of autologous in vitro fertilization and ovum donor pregnancies. Obstet Gynecol 2010;116:1387–1392. Krieg SA, Henne MB, Westphal LM. Obstetric outcomes in donor oocyte pregnancies compared with advanced maternal age in in vitro fertilization pregnancies. Fertil Steril 2008;90:65–70. Lutz W, O’Neill BC, Scherbov S. Demographics. Europe’s population at a turning point. Science 2003;299:1991–1992. Maheshwari A, Pandey S, Shetty A, Hamilton M, Bhattacharya S. Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril 2012;98:368-377-9. Malchau SS, Loft A, Larsen EC, Aaris Henningsen A-K, Rasmussen S, Andersen AN, Pinborg A. Perinatal outcomes in 375 children born after oocyte donation: a Danish national cohort study. Fertil Steril 2013;99:1637–1643. Mansour R, Ishihara O, Adamson GD, Dyer S, Mouzon J de, Nygren KG, Sullivan E, ZegersHochschild F. International Committee for Monitoring Assisted Reproductive Technologies world report: Assisted Reproductive Technology 2006. Hum Reprod 2014;29:1536–1551. Marino JL, Moore VM, Willson KJ, Rumbold A, Whitrow MJ, Giles LC, Davies MJ. Perinatal Outcomes by Mode of Assisted Conception and Sub-Fertility in an Australian Data Linkage Cohort. In Lambalk CB, editor. PLoS ONE 2014;9:e80398.

17

Page 17 of 26

Masoudian P, Nasr A, Nanassy J de, Fung-Kee-Fung K, Bainbridge SA, El Demellawy D. Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis. Am J Obstet Gynecol 2016;214:328–339. Matthews TJ, Hamilton BE. Delayed childbearing: more women are having their first child later in life. NCHS Data Brief 2009;1–8. Nejdet S, Bergh C, Källén K, Wennerholm U-B, Thurin-Kjellberg A. High risks of maternal and perinatal complications in singletons born after oocyte donation. Acta Obstet Gynecol Scand 2016;95:879–886. Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update 2012;18:485–503. Pinborg A, Wennerholm UB, Romundstad LB, Loft A, Aittomaki K, Söderström-Anttila V, Nygren KG, Hazekamp J, Bergh C. Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis. Hum Reprod Update 2013;19:87–104. Sauer MV, Paulson RJ, Lobo RA. Oocyte donation to women of advanced reproductive age: pregnancy results and obstetrical outcomes in patients 45 years and older. Hum Reprod Oxf Engl 1996;11:2540–2543. Söderström-Anttila V, Tiitinen A, Foudila T, Hovatta O. Obstetric and perinatal outcome after oocyte donation: comparison with in-vitro fertilization pregnancies. Hum Reprod Oxf Engl 1998;13:483–490. Stoop D, Baumgarten M, Haentjens P, Polyzos NP, De Vos M, Verheyen G, Camus M, Devroey P. Obstetric outcome in donor oocyte pregnancies: a matched-pair analysis. Reprod Biol Endocrinol RBE 2012;10:42.

18

Page 18 of 26

Storgaard M, Loft A, Bergh C, Wennerholm U, Söderström-Anttila V, Romundstad L, Aittomaki K, Oldereid N, Forman J, Pinborg A. Obstetric and neonatal complications in pregnancies conceived after oocyte donation - a systematic review and metaanalysis. BJOG Int J Obstet Gynaecol [Internet] 2016;Available from: http://doi.wiley.com/10.1111/1471-0528.14257.

Declaration The authors report no financial or commercial conflicts of interest.

19

Page 19 of 26

Figure 1: Data selection process for analysis of live births and perinatal outcomes with oocyte donor recipient and autologous IVF.

Total number of cycles recorded in the HFEA database from 1991-2011: n = 1 004 487

n=1004487

Cycles excluded with reasons: n = 397 449           

DI cycles (n= 215 107) Cryopreserved cycles (n= 143 599) Donated embryos (n= 1828) Surrogacy (n= 838) PGD cycles (n= 2209) Unstimulated autologous (n= 6553) Use of cryopreserved eggs (n= 138) Fresh eggs cryopreserved (n= 1717) Treatment other than main reasons for cryopreserving embryos (n=10 345) IVF + GIFT, IVF+SUZI, SUZI, ZIFT ( n= 203) Cycles with no fresh embryo transfer and embryos were cryopreserved (n= 14 912)

Total number of fresh IVF cycles: n=607 038

Donor recipient (n=22 207)

Autologous (n=584 831)

Live births (n=6113)

Live births (n=131 461)

Missing birth weight & gestational age excluded

Missing birth weight & gestational age excluded 



Live births that had missing information on either gestational age and/or birth weight (n=184)

Live births that had missing information on gestational age and/or birth weight (n=3605)

Singleton (n=95844) + multiple live births (n=32012)

Singleton (n=4248) + multiple live births (n=1681)

Number of cycles that resulted in live births (n=133785)

20

Page 20 of 26

21

Page 21 of 26

Table 1. Baseline characteristics for oocyte donor recipient and autologous IVF cycles. Characteristic

Donor recipient, n (%) (n = 22207)

Autologous, n (%)

18–34 years

4299 (19.4)

279019 (47.7)

35–37 years

2990 (13.5)

141415 (24.2)

38–39 years

2555 (11.5)

81295 (13.9)

40–42 years

4344 (19.6)

64476 (11.0)

43–44 years

3090 (13.9)

14518 (2.5)

≥45 years

4929 (22.2)

4108 (0.7)

10352 (46.6)

260795 (44.6)

Tubal disease

2712 (12.2)

152023 (26.0)

Ovulatory disorder

11597 (52.2)

67297 (11.5)

Male factor

7929 (35.7)

300997 (51.5)

Unexplained

3593 (16.2)

186863 (32.0)

Endometriosis

868 (3.9)

42949 (7.3)

0

8215 (37.0)

309973 (53.0)

1

4301 (19.4)

130995 (22.4)

2

3424 (15.4)

68991 (11.8)

3

2266 (10.2)

34853 (6.0)

4+

4001 (18.0)

40019 (6.8)

1991–1995

2409 (10.8)

79646 (13.6)

1996–2000

5832 (26.3)

128478 (22.0)

2001–2005

6761 (30.4)

140246 (24.0)

2006–2011

7205 (32.4)

236461 (40.4)

7 (5, 10)

10 (7, 14)

5 (3, 7)

5 (2, 8)

(n = 584831)

Age at treatment

Type of infertility Female primary a

Cause of infertility

Number of previous IVF cycles

Year of treatment

Number of oocytes: median (IQR) Number of embryos: median (IQR)

22

Page 22 of 26

Previous live birth (yes)

1333 (6.0)

37690 (6.4)


19751 (93.2)

462513 (91.2)

≥day 5

1440 (6.8)

44,464 (8.8)

2.07 (0.72)

1.81 (0.90)

Day of embryo transfer

Number of embryos transferred (Mean and SD)

a

Causes of infertility are not mutually exclusive

IQR, interquartile range (25th and 75th percentile).

23

Page 23 of 26

Table 2. Risk of preterm birth and low birth weight in singletons after oocyte donation and autologous IVF.

Preterm birth (<37 weeks)

Donor, n (%)

Autologous, n (%)

628/4248 (14.8)

8965/95844 (9.4)

OR (99.5% CI)

aORa (99.5% CI)

1.68 (1.48 to 1.91)

1.56 (1.34 to 1.80)

Early preterm birth (<32 weeks)

132/4248 (3.1)

1707/95844 (1.8)

1.77 (1.37 to 2.29)

1.40 (1.04 to 1.90)

585/4248 (13.8)

9058/95844 (9.5)

1.53 (1.35 to 1.74)

1.43 (1.24 to 1.66)

110/4248 (2.6)

1764/95844 (1.8)

1.42 (1.07 to 1.87)

1.08 (0.79 to 1.49)

Low birth weight (<2500 g)

Very low birth weight (<1500 g)

a

Adjusted for female age category, period of treatment, causes of infertility, previous live birth, number of embryos transferred, stage of embryos transferred, and multiple pregnancy with spontaneous reduction resulting in singleton live birth. aOR, adjusted odds ratio.

24

Page 24 of 26

Table 3: Risk of preterm birth and low birth weight in singletons after oocyte donation and autologous IVF in women younger than 40 years.

Donor, n (%)

Autologous, n (%)

OR (99.5% CI)

aORa (99.5% CI)

Preterm birth (<37 278/1842 (15.1) 8362/89399 (9.4) 1.72 (1.43 to weeks) 2.07)

1.60 (1.32 to 1.94)

1578/89399 (1.8) 1.84 (1.26 to 2.69)

1.51 (1.02 to 2.25)

Low birth weight 277/1842 (15.0) 8444/89399 (9.4) 1.69 (1.41 to 2.04) (<2500 g)

1.58 (1.30 to 1.92)

Very low birth weight (<1500 g)

1.18 (0.77 to 1.82)

Early preterm birth 59/1842 (3.2) (<32 weeks)

49/1842 (2.7)

1631/89399 (1.8) 1.47 (0.97 to 2.22)

a

Adjusted for female age category, period of treatment, causes of infertility, previous live birth, embryos transferred, stage of embryos transfer, and multiple pregnancy with spontaneous reduction resulting in singleton live birth. aOR, adjusted odds ratio.

25

Page 25 of 26

Comment [S2]: Author: please indicate what dashes denote

Table 4. Risk of preterm birth and low birth weight in singletons in relation to oocyte donor age.a Oocyte donor age groups (years)

Preterm birth (<37 weeks) n (%)

OR

Low birth weight (<2500 g)

aORc (99.5% CI)

n (%)

(99.5% CI) ≤20

12/51 (23.5)

1.86 (0.68 to 5.06)

1.96 (0.71–5.41)

12/51 (23.5)

OR

aORb

(99.5% CI)

(99.5% CI)

2.04 (0.75 to 5.59)

2.11 (0.76 to 5.89)

21–25b

63/443 (14.2)

26–30

165/1228 (13.4)

–

–

0.94 (0.60–1.47)

0.98 (0.62–1.54)

58/443 (13.1) 153/1228 (12.5)

– 0.94 (0.59 to 1.50)

– 0.98 (0.61 to 1.57)

31–35

309/2007 (15.4)

1.10 (0.72–1.67)

1.12 (0.73–1.72)

279/2007 (13.9)

1.07 (0.69 to 1.66)

1.08 (0.69 to 1.68)

a

Denominators include singleton live births for which oocyte donor ages were available. Reference group. c Adjusted for female age category, period of treatment, causes of infertility, previous live birth, number of embryos transferred, stage of embryos transferred, and multiple pregnancy with spontaneous reduction resulting in singleton live birth. aOR, adjusted odds ratio. b

26

Page 26 of 26