Preterm Birth and Small Size for Gestational Age in Singleton, In Vitro Fertilization Births Using Donor Oocytes

Preterm Birth and Small Size for Gestational Age in Singleton, In Vitro Fertilization Births... Abstract We used 2006–2015 US National Assisted Reproductive Technology Surveillance System data to compare preterm birth and fetal growth for liveborn singletons (24–42 weeks’ gestation) following in vitro fertilization with donor versus autologous oocytes. Using binary and multinomial logistic regression, we computed adjusted odds ratios and 95% confidence intervals for associations between use of donor oocytes and preterm delivery, being small for gestational age (SGA), and being large for gestational age (LGA), stratified by fresh and thawed embryo status and accounting for maternal characteristics and year of birth. There were 204,855 singleton births from fresh embryo transfers and 106,077 from thawed embryo transfers. Among fresh embryo transfers, donor oocyte births had higher odds of being preterm (adjusted odd ratio (aOR) = 1.32, 95% confidence interval (CI): 1.27, 1.38) or LGA (aOR = 1.27, 95% CI: 1.21, 1.33) but lower odds of being SGA (aOR = 0.81, 95% CI: 0.77, 0.85). Among thawed embryo transfers, donor oocyte births had higher odds of being preterm (aOR = 1.57, 95% CI: 1.48, 1.65) or SGA (aOR = 1.22, 95% CI: 1.14, 1.31) but lower odds of being LGA (aOR = 0.87, 95% CI: 0.82, 0.92). Use of donor oocytes was associated with increased odds of preterm delivery irrespective of embryo status; odds of being SGA were increased for donor versus autologous oocyte births among thawed embryo transfers only. assisted reproduction, donor egg, in vitro fertilization, perinatal outcomes, preterm, small for gestational age In the United States, use of donor oocytes for in vitro fertilization (IVF) procedures has increased over time largely due to delayed childbearing and the concomitant decline in the number and quality of eggs with advancing female age (1). In 2014, donor oocyte cycles accounted for over 9% of all assisted reproductive technology cycles and resulted in over 8,500 live births (2). The literature on the association between donor oocyte cycles and adverse perinatal outcomes is equivocal; results from some but not all studies suggest higher rates of obstetrical complications such as first-trimester vaginal bleeding (3, 4), hypertensive disorders of pregnancy (5–12), induction of labor (13), cesarean delivery (5, 8, 10, 12, 13), and postpartum hemorrhage (5, 10) for IVF conceptions from donor oocytes compared with autologous oocytes. Likewise, use of donor oocytes has been variably associated with increased risk for low birth weight (5, 6, 10, 12, 14–16) and preterm delivery (5, 6, 8, 10, 12, 14–16) when compared with births from IVF using autologous oocytes, even when restricted to singletons. Although there is some evidence of higher proportions of births from donor versus autologous oocytes being small for gestational age (SGA, <10th percentile of birth weight for gestational age), the associations tend to be smaller in magnitude and lack statistical significance (5, 6, 10, 12, 17). Studies of the potential associations between use of donor oocytes and infant outcomes may be complicated by the frequent use of frozen-thawed embryos in donor cycles. In 2014, 58% of donor cycles used frozen-thawed embryos compared with 38% of autologous cycles (2). Infants born following thawed autologous embryo transfer have been found to have higher average birth weights and lower odds of preterm and SGA birth compared with those conceived following a fresh embryo transfer (18–21); however, none of these studies compared infant outcomes for births from donor and autologous oocytes stratified by embryo status (fresh versus frozen-thawed embryo transfer). The aim of this study was to examine patterns of preterm birth and being SGA for singleton births resulting from donor oocyte IVF versus autologous oocyte IVF and to explore the role of embryo status as a potential effect measure modifier. We hypothesized that donor oocyte infants would have higher rates of preterm birth and growth restriction than autologous oocyte infants but that the associations would be attenuated for frozen-thawed cycles, given prior report of improved perinatal outcomes following frozen-thawed transfer. METHODS Study cohort The data used for this study were derived from the Center for Disease Control and Prevention’s National Assisted Reproductive Technology Surveillance System (NASS), which collects information on nearly all (98%) assisted reproductive technology (ART) cycles performed in US fertility clinics, as mandated by the Fertility Clinic Success Rates and Certification Act (22). Since 1995, NASS has collected data on patient demographic factors, obstetrical and medical history, ART treatment procedures, and resultant pregnancies and births. Each year, a random sample of fertility clinics that submitted data to NASS is selected for data validation, in which trained abstractors visit the clinics and compare data reported to NASS with medical records. Discrepancy rates were <5.6% for all fields evaluated in 2015 (23). We included all IVF cycles performed between 2006 and 2015 that resulted in a singleton gestation (1 fetal heart observed on ultrasound prior to 7 weeks’ gestation) and a liveborn singleton infant (n = 333,113). We excluded cycles using donated embryos (n = 2,837), cryopreserved eggs (n = 2,833, only reported for fresh embryo transfers from 2013 onward), or a gestational carrier (n = 8,215). Infants with gestational ages <24 weeks and >42 weeks (n = 7,798) and those with implausible birth weight and gestational age combinations (n = 498) (24) were also excluded. The study was approved by the institutional review board of the Centers for Disease Control and Prevention. Assessment of exposure Information on type of oocytes and embryos was ascertained from clinic-reported data on oocyte source and embryo state (autologous oocyte with a fresh embryo transfer, donor oocyte with a fresh embryo transfer, autologous oocyte with thawed embryo transfer, donor oocyte with thawed embryo transfer). Assessment of outcomes For fresh embryo transfers with information on date of oocyte retrieval, gestational week was calculated as: (date of delivery − date of oocyte retrieval + 14 days)/7. When date of oocyte retrieval was missing, gestational week was calculated as (date of delivery − date of embryo transfer + 17 days)/7 and assumed that the average time in embryo culture was 3 days during the study period. Information on infant birth weight was collected by clinics and was based on clinician or patient report. Using gestational age and birth weight information, we classified births as preterm (<37 weeks of gestation), SGA (<10th percentile of birth weight for gestational age), appropriate for gestational age (AGA; 10th–90th percentile of birth weight for gestational age), or large for gestational age (LGA; >90th percentile of birth weight for gestational age). In addition, we further categorized SGA, AGA, and LGA births according to preterm and term (37–42 weeks) delivery. Assessment of patient and treatment characteristics The patient and treatment characteristics included in the study were reported by clinics as part of routine ART surveillance. They included female patient age at cycle start, age of oocyte source at retrieval, race/ethnicity, prepregnancy body mass index, parity, previous preterm birth, reason for ART, number of prior ART cycles, number of oocytes retrieved, oocyte donor age at retrieval, embryo stage at transfer, number of embryos transferred, number of embryos cryopreserved, use of assisted hatching, use of intracytoplasmic sperm injection, and use of donor sperm. Statistical analyses We examined the distribution of patient and treatment characteristics for singleton births from donor and autologous oocytes, stratified by use of a fresh or thawed embryo transfer. χ2 tests were used to test for differences in distributions of characteristics for births from donor versus autologous oocytes. We calculated the 10th, 50th, and 90th percentiles of birth weight for gestational age for singleton births according to oocyte source (autologous or donor) and embryo status (fresh or thawed) for all births and stratified by male and female sex. Cubic splines were used to smooth gestational age–specific birth weight values. Finally, we used binary and multinomial logistic regression models to compute unadjusted and adjusted odds ratios and 95% confidence intervals for associations between use of donor oocytes and preterm delivery (binary) and fetal growth categorized as a 3-level (SGA, AGA, and LGA) or 6-level (SGA preterm, SGA term, AGA preterm, AGA term, LGA preterm, and LGA term) outcome. The birth weight–gestational age thresholds (SGA, AGA, and LGA) accounted for infant sex. The interaction of use of donor oocytes and embryo status (fresh or thawed) was included in the models, and stratified results are reported. Covariates for the adjusted model were selected a priori and included female patient age, infertility diagnosis (tubal factor, history of endometriosis, uterine factor, ovulatory disorder, diminished ovarian reserve, male factor infertility, and unexplained infertility), parity, number of prior ART cycles, and year of cycle start. To account for variation in use of donor oocytes among clinics, we used a hybrid fixed-effects approach with cluster mean values for proportion of donor cycles included as a fixed effect and clinic included as a random effect (25). This approach accounts for clinic-level variation in the outcome and the exposure and adjusts the other covariates for clinic-level differences related to use of donor oocytes (25). Because women using donor oocytes tend to be older and because advanced maternal age is associated with increased risk for adverse perinatal outcomes, we conducted a sensitivity analysis limiting the study population to births to women <40 years of age. Also, because we were unable to include body mass index in the models due to a high proportion of missing values (>40%), we included an additional sensitivity analysis restricted to records with information on body mass index. Analyses were conducted using SAS, version 9.4 (SAS Institute, Inc., Cary, North Carolina). P values of <0.05 were considered statistically significant. RESULTS After exclusions, the final sample included 310,932 singleton births at 24–42 weeks’ gestation that resulted from IVF cycles initiated between 2006 and 2015. Of those, 57.5% (n = 178,654) were conceived using fresh embryos with autologous oocytes, 8.4% (n = 26,201) used fresh embryos with donor oocytes, 29.1% (n = 90,494) used thawed embryos with autologous oocytes, and 5.0% (n = 15,583) used thawed embryos with donor oocytes. Regardless of embryo status, women who used donor oocytes tended to be older, had a history of 2 or more prior ART cycles, and were more frequently diagnosed with diminished ovarian reserve than women using autologous oocytes. (Table 1) Among births from fresh embryo transfers, the proportion of births following the transfer of 2 or more embryos was lower for those using donor versus autologous oocytes (8.0% versus 23.3%, respectively); similarly, the proportion of births where assisted hatching was used was lower for donor oocyte births (18.6% versus 34.3%, respectively). Table 1. Characteristics of Embryo Transfers Resulting in Singleton Births at 24–42 Weeks Gestation, United States, 2006–2015 Characteristic Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) No. % No. % No. % No. % Patient age, years  <30 688 2.6 28,931 16.2a 339 2.2 11,713 12.9a  30–34 2,237 8.5 70,161 39.3 1,112 7.1 35,419 39.1  35–39 5,405 20.6 62,291 34.9 2,672 17.2 33,168 36.7  ≥40 17,871 68.2 17,271 9.7 11,460 73.5 10,194 11.3 Age of oocyte source at retrieval, yearsb  <30 17,192 82.3 28,931 16.2a 7,300 82.2 14,474 21.9a  30–34 3,213 15.4 70,161 39.3 1,270 14.3 27,992 42.4  35–39 412 2.0 62,291 34.9 238 2.7 19,694 29.8  ≥40 66 0.3 17,271 9.7 77 0.9 3,906 5.9  Missing 5,318 0 6,698 24,428 Race/ethnicity  Non-Hispanic white 12,684 74.9 85,923 74.8a 6,968 72.3 41,387 71.7a  Non-Hispanic black 885 5.2 6,172 5.4 558 5.8 3,102 5.4  Hispanic 1,284 7.6 9,548 8.3 620 6.4 4,424 7.7  Asian/Pacific Islander 2,055 12.1 12,973 11.3 1,476 15.3 8,690 15.1  Other 23 0.1 226 0.2 21 0.2 117 0.2  Missing 9,270 63,812 5,940 32,774 Parityc  0 18,584 71.5 127,614 71.7a 8,063 52.0 50,247 55.8a  1 5,270 20.3 38,530 21.7 5,677 36.6 31,327 34.8  ≥2 2,138 8.2 11,843 6.7 1,773 11.4 8,489 9.4 No. of previous preterm deliveriesc  0 25,105 97.0 172,108 97.1 14,177 91.6 82,837 92.3a  1 697 2.7 4,611 2.6 1,204 7.8 6,389 7.1  ≥2 81 0.3 530 0.3 99 0.6 492 0.6 Body mass indexd  <18.5 450 2.7 3,671 2.9a 309 3.0 2,215 3.3a  18.5–24.9 9,907 58.9 72,655 57.4 6,009 58.2 39,842 59.7  25.0–29.9 4,029 24.0 29,424 23.2 2,390 23.1 14,916 22.4  ≥30.0 2,424 14.4 20,941 16.5 1,624 15.7 9,752 14.6  Missing 9,391 51,963 5,251 23,769 Reason for ART  Tubal factor 1,705 6.5 27,482 15.4 1,009 6.5 12,782 14.1a  History of endometriosis 1,561 6.0 20,051 11.2a 880 5.7 9,147 10.1a  Uterine factor 1,098 4.2 6,805 3.8a 774 5.0 4,369 4.8  Ovulatory disorder 1,096 4.2 29,973 16.8a 675 4.3 19,017 21.0a  Diminished ovarian reserve 20,208 77.1 27,668 15.5a 12,280 78.8 12,216 13.5a  Male infertility 4,796 18.3 71,906 40.3a 2,633 16.9 34,848 38.5a  Unexplained infertility 914 3.5 27,528 15.4a 538 3.5 12,530 13.9a  Other reason 4,578 17.5 20,951 11.7a 2,973 19.1 15,598 17.2a No. of prior ART cycles  0 11,256 43.0 113,656 63.7a 1,790 11.5 5,041 5.6a  1 4,597 17.6 31,488 17.6 4,147 26.6 43,052 47.7  ≥2 10,340 39.5 33,430 18.7 9,635 61.9 42,230 46.8 No. of oocytes retrievede  <5 339 1.3 12,636 7.1a  5–9 2,413 9.2 47,227 26.4  10–20 12,239 46.7 90,120 50.4  >20 11,210 42.8 28,671 16.1 Embryo stage, dayse  2–3 6,958 26.6 81,324 45.5a  5–6 18,700 71.4 93,719 52.5  Other 543 2.1 3,611 2.0 No. of embryos transferred  1 7,666 29.3 38,502 21.6a 6,613 42.4 41,182 45.5a  2 16,451 62.8 98,570 55.2 7,166 46.0 39,590 43.8  >2 2,084 8.0 41,582 23.3 1,804 11.6 9,722 10.7 No. of embryos cryopreserved  0 6,312 24.1 88,492 49.5a 14,941 95.9 87,310 96.5a  1–2 5,189 19.8 35,275 19.7 426 2.7 1,937 2.1  >2 14,700 56.1 54,887 30.7 216 1.4 1,247 1.4 Assisted hatching  Yes 4,864 18.6 61,350 34.3a 8,934 57.3 47,114 52.1a  No 21,337 81.4 117,304 65.7 6,649 42.7 43,380 47.9 ICSIc,e  Yes 19,882 75.9 132,603 74.3a  No 6,309 24.1 45,896 25.7 Donor sperme  Yesf 2,582 9.9 7,494 4.2  No 23,606 90.1 171,104 95.8 Characteristic Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) No. % No. % No. % No. % Patient age, years  <30 688 2.6 28,931 16.2a 339 2.2 11,713 12.9a  30–34 2,237 8.5 70,161 39.3 1,112 7.1 35,419 39.1  35–39 5,405 20.6 62,291 34.9 2,672 17.2 33,168 36.7  ≥40 17,871 68.2 17,271 9.7 11,460 73.5 10,194 11.3 Age of oocyte source at retrieval, yearsb  <30 17,192 82.3 28,931 16.2a 7,300 82.2 14,474 21.9a  30–34 3,213 15.4 70,161 39.3 1,270 14.3 27,992 42.4  35–39 412 2.0 62,291 34.9 238 2.7 19,694 29.8  ≥40 66 0.3 17,271 9.7 77 0.9 3,906 5.9  Missing 5,318 0 6,698 24,428 Race/ethnicity  Non-Hispanic white 12,684 74.9 85,923 74.8a 6,968 72.3 41,387 71.7a  Non-Hispanic black 885 5.2 6,172 5.4 558 5.8 3,102 5.4  Hispanic 1,284 7.6 9,548 8.3 620 6.4 4,424 7.7  Asian/Pacific Islander 2,055 12.1 12,973 11.3 1,476 15.3 8,690 15.1  Other 23 0.1 226 0.2 21 0.2 117 0.2  Missing 9,270 63,812 5,940 32,774 Parityc  0 18,584 71.5 127,614 71.7a 8,063 52.0 50,247 55.8a  1 5,270 20.3 38,530 21.7 5,677 36.6 31,327 34.8  ≥2 2,138 8.2 11,843 6.7 1,773 11.4 8,489 9.4 No. of previous preterm deliveriesc  0 25,105 97.0 172,108 97.1 14,177 91.6 82,837 92.3a  1 697 2.7 4,611 2.6 1,204 7.8 6,389 7.1  ≥2 81 0.3 530 0.3 99 0.6 492 0.6 Body mass indexd  <18.5 450 2.7 3,671 2.9a 309 3.0 2,215 3.3a  18.5–24.9 9,907 58.9 72,655 57.4 6,009 58.2 39,842 59.7  25.0–29.9 4,029 24.0 29,424 23.2 2,390 23.1 14,916 22.4  ≥30.0 2,424 14.4 20,941 16.5 1,624 15.7 9,752 14.6  Missing 9,391 51,963 5,251 23,769 Reason for ART  Tubal factor 1,705 6.5 27,482 15.4 1,009 6.5 12,782 14.1a  History of endometriosis 1,561 6.0 20,051 11.2a 880 5.7 9,147 10.1a  Uterine factor 1,098 4.2 6,805 3.8a 774 5.0 4,369 4.8  Ovulatory disorder 1,096 4.2 29,973 16.8a 675 4.3 19,017 21.0a  Diminished ovarian reserve 20,208 77.1 27,668 15.5a 12,280 78.8 12,216 13.5a  Male infertility 4,796 18.3 71,906 40.3a 2,633 16.9 34,848 38.5a  Unexplained infertility 914 3.5 27,528 15.4a 538 3.5 12,530 13.9a  Other reason 4,578 17.5 20,951 11.7a 2,973 19.1 15,598 17.2a No. of prior ART cycles  0 11,256 43.0 113,656 63.7a 1,790 11.5 5,041 5.6a  1 4,597 17.6 31,488 17.6 4,147 26.6 43,052 47.7  ≥2 10,340 39.5 33,430 18.7 9,635 61.9 42,230 46.8 No. of oocytes retrievede  <5 339 1.3 12,636 7.1a  5–9 2,413 9.2 47,227 26.4  10–20 12,239 46.7 90,120 50.4  >20 11,210 42.8 28,671 16.1 Embryo stage, dayse  2–3 6,958 26.6 81,324 45.5a  5–6 18,700 71.4 93,719 52.5  Other 543 2.1 3,611 2.0 No. of embryos transferred  1 7,666 29.3 38,502 21.6a 6,613 42.4 41,182 45.5a  2 16,451 62.8 98,570 55.2 7,166 46.0 39,590 43.8  >2 2,084 8.0 41,582 23.3 1,804 11.6 9,722 10.7 No. of embryos cryopreserved  0 6,312 24.1 88,492 49.5a 14,941 95.9 87,310 96.5a  1–2 5,189 19.8 35,275 19.7 426 2.7 1,937 2.1  >2 14,700 56.1 54,887 30.7 216 1.4 1,247 1.4 Assisted hatching  Yes 4,864 18.6 61,350 34.3a 8,934 57.3 47,114 52.1a  No 21,337 81.4 117,304 65.7 6,649 42.7 43,380 47.9 ICSIc,e  Yes 19,882 75.9 132,603 74.3a  No 6,309 24.1 45,896 25.7 Donor sperme  Yesf 2,582 9.9 7,494 4.2  No 23,606 90.1 171,104 95.8 Abbreviations: ART, assisted reproductive technology; ICSI, intracytoplasmic sperm injection. aP < 0.01 for comparison of donor versus autologous oocyte births (χ2 test). b For autologous cycles, age at oocyte retrieval is patient’s age at the time oocytes were retrieved. For donor cycles, age at oocyte retrieval is donor’s age at the time oocytes were retrieved. c Data for categories does not sum to total due to missing data (≤1%). d Body mass index was calculated as weight (kg)/height (m)2. e Data not reported consistently for frozen embryo cycles. f Includes donor sperm and mixed (donor and partner) sperm. Table 1. Characteristics of Embryo Transfers Resulting in Singleton Births at 24–42 Weeks Gestation, United States, 2006–2015 Characteristic Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) No. % No. % No. % No. % Patient age, years  <30 688 2.6 28,931 16.2a 339 2.2 11,713 12.9a  30–34 2,237 8.5 70,161 39.3 1,112 7.1 35,419 39.1  35–39 5,405 20.6 62,291 34.9 2,672 17.2 33,168 36.7  ≥40 17,871 68.2 17,271 9.7 11,460 73.5 10,194 11.3 Age of oocyte source at retrieval, yearsb  <30 17,192 82.3 28,931 16.2a 7,300 82.2 14,474 21.9a  30–34 3,213 15.4 70,161 39.3 1,270 14.3 27,992 42.4  35–39 412 2.0 62,291 34.9 238 2.7 19,694 29.8  ≥40 66 0.3 17,271 9.7 77 0.9 3,906 5.9  Missing 5,318 0 6,698 24,428 Race/ethnicity  Non-Hispanic white 12,684 74.9 85,923 74.8a 6,968 72.3 41,387 71.7a  Non-Hispanic black 885 5.2 6,172 5.4 558 5.8 3,102 5.4  Hispanic 1,284 7.6 9,548 8.3 620 6.4 4,424 7.7  Asian/Pacific Islander 2,055 12.1 12,973 11.3 1,476 15.3 8,690 15.1  Other 23 0.1 226 0.2 21 0.2 117 0.2  Missing 9,270 63,812 5,940 32,774 Parityc  0 18,584 71.5 127,614 71.7a 8,063 52.0 50,247 55.8a  1 5,270 20.3 38,530 21.7 5,677 36.6 31,327 34.8  ≥2 2,138 8.2 11,843 6.7 1,773 11.4 8,489 9.4 No. of previous preterm deliveriesc  0 25,105 97.0 172,108 97.1 14,177 91.6 82,837 92.3a  1 697 2.7 4,611 2.6 1,204 7.8 6,389 7.1  ≥2 81 0.3 530 0.3 99 0.6 492 0.6 Body mass indexd  <18.5 450 2.7 3,671 2.9a 309 3.0 2,215 3.3a  18.5–24.9 9,907 58.9 72,655 57.4 6,009 58.2 39,842 59.7  25.0–29.9 4,029 24.0 29,424 23.2 2,390 23.1 14,916 22.4  ≥30.0 2,424 14.4 20,941 16.5 1,624 15.7 9,752 14.6  Missing 9,391 51,963 5,251 23,769 Reason for ART  Tubal factor 1,705 6.5 27,482 15.4 1,009 6.5 12,782 14.1a  History of endometriosis 1,561 6.0 20,051 11.2a 880 5.7 9,147 10.1a  Uterine factor 1,098 4.2 6,805 3.8a 774 5.0 4,369 4.8  Ovulatory disorder 1,096 4.2 29,973 16.8a 675 4.3 19,017 21.0a  Diminished ovarian reserve 20,208 77.1 27,668 15.5a 12,280 78.8 12,216 13.5a  Male infertility 4,796 18.3 71,906 40.3a 2,633 16.9 34,848 38.5a  Unexplained infertility 914 3.5 27,528 15.4a 538 3.5 12,530 13.9a  Other reason 4,578 17.5 20,951 11.7a 2,973 19.1 15,598 17.2a No. of prior ART cycles  0 11,256 43.0 113,656 63.7a 1,790 11.5 5,041 5.6a  1 4,597 17.6 31,488 17.6 4,147 26.6 43,052 47.7  ≥2 10,340 39.5 33,430 18.7 9,635 61.9 42,230 46.8 No. of oocytes retrievede  <5 339 1.3 12,636 7.1a  5–9 2,413 9.2 47,227 26.4  10–20 12,239 46.7 90,120 50.4  >20 11,210 42.8 28,671 16.1 Embryo stage, dayse  2–3 6,958 26.6 81,324 45.5a  5–6 18,700 71.4 93,719 52.5  Other 543 2.1 3,611 2.0 No. of embryos transferred  1 7,666 29.3 38,502 21.6a 6,613 42.4 41,182 45.5a  2 16,451 62.8 98,570 55.2 7,166 46.0 39,590 43.8  >2 2,084 8.0 41,582 23.3 1,804 11.6 9,722 10.7 No. of embryos cryopreserved  0 6,312 24.1 88,492 49.5a 14,941 95.9 87,310 96.5a  1–2 5,189 19.8 35,275 19.7 426 2.7 1,937 2.1  >2 14,700 56.1 54,887 30.7 216 1.4 1,247 1.4 Assisted hatching  Yes 4,864 18.6 61,350 34.3a 8,934 57.3 47,114 52.1a  No 21,337 81.4 117,304 65.7 6,649 42.7 43,380 47.9 ICSIc,e  Yes 19,882 75.9 132,603 74.3a  No 6,309 24.1 45,896 25.7 Donor sperme  Yesf 2,582 9.9 7,494 4.2  No 23,606 90.1 171,104 95.8 Characteristic Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) No. % No. % No. % No. % Patient age, years  <30 688 2.6 28,931 16.2a 339 2.2 11,713 12.9a  30–34 2,237 8.5 70,161 39.3 1,112 7.1 35,419 39.1  35–39 5,405 20.6 62,291 34.9 2,672 17.2 33,168 36.7  ≥40 17,871 68.2 17,271 9.7 11,460 73.5 10,194 11.3 Age of oocyte source at retrieval, yearsb  <30 17,192 82.3 28,931 16.2a 7,300 82.2 14,474 21.9a  30–34 3,213 15.4 70,161 39.3 1,270 14.3 27,992 42.4  35–39 412 2.0 62,291 34.9 238 2.7 19,694 29.8  ≥40 66 0.3 17,271 9.7 77 0.9 3,906 5.9  Missing 5,318 0 6,698 24,428 Race/ethnicity  Non-Hispanic white 12,684 74.9 85,923 74.8a 6,968 72.3 41,387 71.7a  Non-Hispanic black 885 5.2 6,172 5.4 558 5.8 3,102 5.4  Hispanic 1,284 7.6 9,548 8.3 620 6.4 4,424 7.7  Asian/Pacific Islander 2,055 12.1 12,973 11.3 1,476 15.3 8,690 15.1  Other 23 0.1 226 0.2 21 0.2 117 0.2  Missing 9,270 63,812 5,940 32,774 Parityc  0 18,584 71.5 127,614 71.7a 8,063 52.0 50,247 55.8a  1 5,270 20.3 38,530 21.7 5,677 36.6 31,327 34.8  ≥2 2,138 8.2 11,843 6.7 1,773 11.4 8,489 9.4 No. of previous preterm deliveriesc  0 25,105 97.0 172,108 97.1 14,177 91.6 82,837 92.3a  1 697 2.7 4,611 2.6 1,204 7.8 6,389 7.1  ≥2 81 0.3 530 0.3 99 0.6 492 0.6 Body mass indexd  <18.5 450 2.7 3,671 2.9a 309 3.0 2,215 3.3a  18.5–24.9 9,907 58.9 72,655 57.4 6,009 58.2 39,842 59.7  25.0–29.9 4,029 24.0 29,424 23.2 2,390 23.1 14,916 22.4  ≥30.0 2,424 14.4 20,941 16.5 1,624 15.7 9,752 14.6  Missing 9,391 51,963 5,251 23,769 Reason for ART  Tubal factor 1,705 6.5 27,482 15.4 1,009 6.5 12,782 14.1a  History of endometriosis 1,561 6.0 20,051 11.2a 880 5.7 9,147 10.1a  Uterine factor 1,098 4.2 6,805 3.8a 774 5.0 4,369 4.8  Ovulatory disorder 1,096 4.2 29,973 16.8a 675 4.3 19,017 21.0a  Diminished ovarian reserve 20,208 77.1 27,668 15.5a 12,280 78.8 12,216 13.5a  Male infertility 4,796 18.3 71,906 40.3a 2,633 16.9 34,848 38.5a  Unexplained infertility 914 3.5 27,528 15.4a 538 3.5 12,530 13.9a  Other reason 4,578 17.5 20,951 11.7a 2,973 19.1 15,598 17.2a No. of prior ART cycles  0 11,256 43.0 113,656 63.7a 1,790 11.5 5,041 5.6a  1 4,597 17.6 31,488 17.6 4,147 26.6 43,052 47.7  ≥2 10,340 39.5 33,430 18.7 9,635 61.9 42,230 46.8 No. of oocytes retrievede  <5 339 1.3 12,636 7.1a  5–9 2,413 9.2 47,227 26.4  10–20 12,239 46.7 90,120 50.4  >20 11,210 42.8 28,671 16.1 Embryo stage, dayse  2–3 6,958 26.6 81,324 45.5a  5–6 18,700 71.4 93,719 52.5  Other 543 2.1 3,611 2.0 No. of embryos transferred  1 7,666 29.3 38,502 21.6a 6,613 42.4 41,182 45.5a  2 16,451 62.8 98,570 55.2 7,166 46.0 39,590 43.8  >2 2,084 8.0 41,582 23.3 1,804 11.6 9,722 10.7 No. of embryos cryopreserved  0 6,312 24.1 88,492 49.5a 14,941 95.9 87,310 96.5a  1–2 5,189 19.8 35,275 19.7 426 2.7 1,937 2.1  >2 14,700 56.1 54,887 30.7 216 1.4 1,247 1.4 Assisted hatching  Yes 4,864 18.6 61,350 34.3a 8,934 57.3 47,114 52.1a  No 21,337 81.4 117,304 65.7 6,649 42.7 43,380 47.9 ICSIc,e  Yes 19,882 75.9 132,603 74.3a  No 6,309 24.1 45,896 25.7 Donor sperme  Yesf 2,582 9.9 7,494 4.2  No 23,606 90.1 171,104 95.8 Abbreviations: ART, assisted reproductive technology; ICSI, intracytoplasmic sperm injection. aP < 0.01 for comparison of donor versus autologous oocyte births (χ2 test). b For autologous cycles, age at oocyte retrieval is patient’s age at the time oocytes were retrieved. For donor cycles, age at oocyte retrieval is donor’s age at the time oocytes were retrieved. c Data for categories does not sum to total due to missing data (≤1%). d Body mass index was calculated as weight (kg)/height (m)2. e Data not reported consistently for frozen embryo cycles. f Includes donor sperm and mixed (donor and partner) sperm. Figure 1 depicts the 10th, 50th and 90th percentiles of birth weight according to gestational age after smoothing for all singleton IVF births from autologous and donor oocyte embryos, stratified by embryo status. Among fresh embryo transfers, the 10th-percentile values between 25 and 41 weeks were higher for donor oocyte births compared with those using autologous oocytes (Figure 1A), although differences were minimal (<5%) at gestational ages beyond 32 weeks. Likewise, gestational age–specific birth weights at the 90th percentile were slightly higher for donor oocyte births than autologous oocyte births from 25 weeks onward. In contrast, among thawed embryo transfers, the 10th-percentile values for donor oocyte births were lower than autologous oocyte births for nearly every gestational age, and the 90th-percentile values were lower after 27 weeks’ gestation (Figure 1B). Similar trends were observed using sex-specific growth curves. (Web Figures 1 and 2, available at https://academic.oup.com/aje). Figure 1. View largeDownload slide Smoothed 10th, 50th, and 90th percentiles of birth weight for singleton births by oocyte source for fresh embryo transfers (A) and thawed embryo transfers (B), United States, 2006–2015. Figure 1. View largeDownload slide Smoothed 10th, 50th, and 90th percentiles of birth weight for singleton births by oocyte source for fresh embryo transfers (A) and thawed embryo transfers (B), United States, 2006–2015. P values for the interaction of the use of donor oocytes and embryo status were <0.0001 for all models with the exception of preterm birth in the sensitivity analysis restricted to women <40 years of age. Among fresh embryo transfers, use of a donor oocyte was associated with increased odds of preterm birth (adjusted odd ratio (aOR) = 1.32, 95% confidence interval (CI): 1.27, 1.38). (Table 2) Donor oocyte births also had decreased odds of being SGA compared with autologous oocyte births (aOR = 0.81, 95% CI: 0.77, 0.85) but increased odds of being LGA (aOR = 1.30, 95% CI: 1.23, 1.37). When fetal growth was further classified according to preterm and term birth, use of donor oocytes was associated with reduced odds of SGA term birth (aOR = 0.83, 95% CI: 0.79, 0.88) but not SGA preterm birth (aOR = 1.01, 95% CI: 0.89, 1.15). In addition, odds of being AGA and preterm, LGA and preterm, or LGA and term were all higher for donor versus autologous oocyte births. Table 2. Association Between Use of Donor Oocytes and Adverse Perinatal Outcomes According to Embryo Status Among Singleton Births at 24–42 Weeks’ Gestation, United States, 2006–2015 Birth Outcome Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Unadjusted Adjusteda Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) Unadjusted Adjusteda No. % No. % OR 95% CI OR 95% CI No. % No. % OR 95% CI OR 95% CI Pretermb 3,947 15.1 20,338 11.4 1.40 1.35, 1.46 1.32 1.27, 1.38 3,068 19.7 11,919 13.2 1.65 1.58, 1.73 1.57 1.48, 1.65 SGAc 2,737 10.5 21,660 12.1 0.85 0.81, 0.88 0.81 0.77, 0.85 1,271 8.2 5,674 6.3 1.27 1.19, 1.36 1.22 1.14, 1.31 LGAc 2,446 9.3 13,461 7.5 1.27 1.21, 1.33 1.30 1.23, 1.37 1,873 12.0 12,938 14.3 0.86 0.81, 0.90 0.87 0.82, 0.92 SGA, pretermd 408 1.6 2,585 1.5 1.10 0.99, 1.23 1.01 0.89, 1.15 229 1.5 694 0.8 2.04 1.75, 2.37 1.89 1.60, 2.24 SGA, termd 2,329 8.9 19,075 10.7 0.86 0.82, 0.90 0.83 0.79, 0.88 1,042 6.7 4,980 5.5 1.29 1.20, 1.38 1.26 1.16, 1.36 AGA, pretermd 3,197 12.2 16,138 9.0 1.44 1.39, 1.51 1.39 1.32, 1.46 2,523 16.2 9,629 10.6 1.70 1.62, 1.78 1.61 1.52, 1.71 LGA, pretermd 342 1.3 1,615 0.9 1.54 1.36, 1.73 1.52 1.33, 1.75 316 2.0 1,596 1.8 1.26 1.11, 1.43 1.24 1.07, 1.43 LGA, termd 2,104 8.0 11,846 6.6 1.31 1.25, 1.38 1.33 1.26, 1.41 1,557 10.0 11,342 12.5 0.88 0.83, 0.93 0.89 0.83, 0.95 Birth Outcome Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Unadjusted Adjusteda Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) Unadjusted Adjusteda No. % No. % OR 95% CI OR 95% CI No. % No. % OR 95% CI OR 95% CI Pretermb 3,947 15.1 20,338 11.4 1.40 1.35, 1.46 1.32 1.27, 1.38 3,068 19.7 11,919 13.2 1.65 1.58, 1.73 1.57 1.48, 1.65 SGAc 2,737 10.5 21,660 12.1 0.85 0.81, 0.88 0.81 0.77, 0.85 1,271 8.2 5,674 6.3 1.27 1.19, 1.36 1.22 1.14, 1.31 LGAc 2,446 9.3 13,461 7.5 1.27 1.21, 1.33 1.30 1.23, 1.37 1,873 12.0 12,938 14.3 0.86 0.81, 0.90 0.87 0.82, 0.92 SGA, pretermd 408 1.6 2,585 1.5 1.10 0.99, 1.23 1.01 0.89, 1.15 229 1.5 694 0.8 2.04 1.75, 2.37 1.89 1.60, 2.24 SGA, termd 2,329 8.9 19,075 10.7 0.86 0.82, 0.90 0.83 0.79, 0.88 1,042 6.7 4,980 5.5 1.29 1.20, 1.38 1.26 1.16, 1.36 AGA, pretermd 3,197 12.2 16,138 9.0 1.44 1.39, 1.51 1.39 1.32, 1.46 2,523 16.2 9,629 10.6 1.70 1.62, 1.78 1.61 1.52, 1.71 LGA, pretermd 342 1.3 1,615 0.9 1.54 1.36, 1.73 1.52 1.33, 1.75 316 2.0 1,596 1.8 1.26 1.11, 1.43 1.24 1.07, 1.43 LGA, termd 2,104 8.0 11,846 6.6 1.31 1.25, 1.38 1.33 1.26, 1.41 1,557 10.0 11,342 12.5 0.88 0.83, 0.93 0.89 0.83, 0.95 Abbreviations: AGA, appropriate for gestational age; CI, confidence interval; LGA, large for gestational age; OR, odds ratio; SGA, small for gestational age. a Adjusted for patient age, infertility diagnosis (tubal factor, history of endometriosis, uterine factor, ovulatory disorder, diminished ovarian reserve, male infertility, unexplained infertility), parity, number of prior cycles of assisted reproductive technology, and year of cycle. Models also incorporated a hybrid fixed-effects approach with clusters (clinic) included as random effects and cluster means of the percentage of donor cycles included as a fixed effect. b Compared with term births. c Compared with AGA births. d Compared with AGA term births. Table 2. Association Between Use of Donor Oocytes and Adverse Perinatal Outcomes According to Embryo Status Among Singleton Births at 24–42 Weeks’ Gestation, United States, 2006–2015 Birth Outcome Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Unadjusted Adjusteda Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) Unadjusted Adjusteda No. % No. % OR 95% CI OR 95% CI No. % No. % OR 95% CI OR 95% CI Pretermb 3,947 15.1 20,338 11.4 1.40 1.35, 1.46 1.32 1.27, 1.38 3,068 19.7 11,919 13.2 1.65 1.58, 1.73 1.57 1.48, 1.65 SGAc 2,737 10.5 21,660 12.1 0.85 0.81, 0.88 0.81 0.77, 0.85 1,271 8.2 5,674 6.3 1.27 1.19, 1.36 1.22 1.14, 1.31 LGAc 2,446 9.3 13,461 7.5 1.27 1.21, 1.33 1.30 1.23, 1.37 1,873 12.0 12,938 14.3 0.86 0.81, 0.90 0.87 0.82, 0.92 SGA, pretermd 408 1.6 2,585 1.5 1.10 0.99, 1.23 1.01 0.89, 1.15 229 1.5 694 0.8 2.04 1.75, 2.37 1.89 1.60, 2.24 SGA, termd 2,329 8.9 19,075 10.7 0.86 0.82, 0.90 0.83 0.79, 0.88 1,042 6.7 4,980 5.5 1.29 1.20, 1.38 1.26 1.16, 1.36 AGA, pretermd 3,197 12.2 16,138 9.0 1.44 1.39, 1.51 1.39 1.32, 1.46 2,523 16.2 9,629 10.6 1.70 1.62, 1.78 1.61 1.52, 1.71 LGA, pretermd 342 1.3 1,615 0.9 1.54 1.36, 1.73 1.52 1.33, 1.75 316 2.0 1,596 1.8 1.26 1.11, 1.43 1.24 1.07, 1.43 LGA, termd 2,104 8.0 11,846 6.6 1.31 1.25, 1.38 1.33 1.26, 1.41 1,557 10.0 11,342 12.5 0.88 0.83, 0.93 0.89 0.83, 0.95 Birth Outcome Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Unadjusted Adjusteda Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) Unadjusted Adjusteda No. % No. % OR 95% CI OR 95% CI No. % No. % OR 95% CI OR 95% CI Pretermb 3,947 15.1 20,338 11.4 1.40 1.35, 1.46 1.32 1.27, 1.38 3,068 19.7 11,919 13.2 1.65 1.58, 1.73 1.57 1.48, 1.65 SGAc 2,737 10.5 21,660 12.1 0.85 0.81, 0.88 0.81 0.77, 0.85 1,271 8.2 5,674 6.3 1.27 1.19, 1.36 1.22 1.14, 1.31 LGAc 2,446 9.3 13,461 7.5 1.27 1.21, 1.33 1.30 1.23, 1.37 1,873 12.0 12,938 14.3 0.86 0.81, 0.90 0.87 0.82, 0.92 SGA, pretermd 408 1.6 2,585 1.5 1.10 0.99, 1.23 1.01 0.89, 1.15 229 1.5 694 0.8 2.04 1.75, 2.37 1.89 1.60, 2.24 SGA, termd 2,329 8.9 19,075 10.7 0.86 0.82, 0.90 0.83 0.79, 0.88 1,042 6.7 4,980 5.5 1.29 1.20, 1.38 1.26 1.16, 1.36 AGA, pretermd 3,197 12.2 16,138 9.0 1.44 1.39, 1.51 1.39 1.32, 1.46 2,523 16.2 9,629 10.6 1.70 1.62, 1.78 1.61 1.52, 1.71 LGA, pretermd 342 1.3 1,615 0.9 1.54 1.36, 1.73 1.52 1.33, 1.75 316 2.0 1,596 1.8 1.26 1.11, 1.43 1.24 1.07, 1.43 LGA, termd 2,104 8.0 11,846 6.6 1.31 1.25, 1.38 1.33 1.26, 1.41 1,557 10.0 11,342 12.5 0.88 0.83, 0.93 0.89 0.83, 0.95 Abbreviations: AGA, appropriate for gestational age; CI, confidence interval; LGA, large for gestational age; OR, odds ratio; SGA, small for gestational age. a Adjusted for patient age, infertility diagnosis (tubal factor, history of endometriosis, uterine factor, ovulatory disorder, diminished ovarian reserve, male infertility, unexplained infertility), parity, number of prior cycles of assisted reproductive technology, and year of cycle. Models also incorporated a hybrid fixed-effects approach with clusters (clinic) included as random effects and cluster means of the percentage of donor cycles included as a fixed effect. b Compared with term births. c Compared with AGA births. d Compared with AGA term births. Among thawed embryo transfers, use of a donor oocyte was also associated with increased odds of preterm birth (aOR = 1.57, 95% CI: 1.48, 1.65). However, in contrast with fresh embryo transfers, donor oocyte births following a thawed embryo transfer had increased odds of being SGA (aOR = 1.22, 95% CI: 1.14, 1.31) and decreased odds of being LGA (aOR = 0.87, 95% CI: 0.82, 0.92) compared with autologous oocyte births. Furthermore, odds of SGA preterm (aOR = 1.89, 95% CI: 1.60, 2.24), SGA term (aOR = 1.26, 95% CI: 1.16, 1.36), AGA preterm (aOR = 1.61, 95% CI: 1.52, 1.71), and LGA preterm (aOR = 1.24, 95% CI: 1.07, 1.43) births were higher for donor versus autologous oocyte births, while odds of LGA term birth were lower (aOR = 0.89, 95% CI: 0.83, 0.95). Observed associations for women <40 years of age were similar to those for the entire population (Web Table 1), as were estimates when maternal body mass index was included as a covariate (Web Table 2). DISCUSSION Our results suggest that use of donor versus autologous oocytes was associated with increased odds of preterm birth for singleton births conceived using either fresh or thawed embryos. However, embryo status modified the association between use of donor oocytes and fetal growth. For example, whereas donor oocyte births from fresh embryo transfers had a lower rate of SGA birth than autologous oocyte births, donor oocyte births from thawed embryo transfers had a higher rate of being SGA compared with autologous oocyte births. In addition, when fetal growth outcomes for singleton births from fresh embryo transfers were further classified by length of gestation, donor oocyte births were less likely than autologous oocyte births to be SGA and term but more likely to be AGA and preterm, LGA and preterm, or LGA and term. In contrast, among thawed embryo transfers, use of donor oocytes was associated with nearly 2-fold higher odds of being SGA and preterm but was protective for LGA term birth. Our finding, that use of donor oocytes was associated with an increased overall risk for preterm birth irrespective of embryo status, is consistent with several other studies (10, 12, 14). It has been suggested that the association between use of donor oocytes and adverse perinatal outcomes such as preterm birth and hypertensive disorders of pregnancy may be due to abnormal placental development caused by maternal immune response to fetal antigens from a donor oocyte pregnancy (12, 26). Given that women using donor oocytes tend to be older or have a history of prior failed IVF cycles (1), unmeasured factors related to advanced maternal age, nulliparity, and premature ovarian insufficiency may also contribute to elevated risks for adverse perinatal outcomes (13, 27). Increases in LGA incidence after cryopreservation of embryos have also been also observed previously, particularly for autologous oocytes, for which the odds of being SGA decrease from fresh to thawed while the odds of being LGA increase (20, 21, 28). This may be due to either a treatment effect on the growth axis of autologous embryos or a reduction in the survivorship of autologous embryos with the propensity to be SGA. Of the few studies that compared rates of SGA birth for donor versus autologous oocyte births, most suggest little or no association (5, 6, 10, 11). However, unlike the present study, prior investigations typically combined fresh and thawed embryos, which may have contributed to biased estimates. Our results suggest that associations between use of donor oocytes and SGA birth differ by embryo status, a finding that has not, to our knowledge, been previously reported. The mechanism for this association is not known. It has been hypothesized that the supraphysiologic doses of gonadotropins used during controlled ovarian stimulation may negatively affect endometrial receptivity, resulting in the lower rates of implantation, clinical pregnancy, and live birth that have been reported for fresh, autologous transfers, as compared with cycles in which no ovarian stimulation is performed (both frozen autologous embryo transfers (19, 28) and fresh donor embryo transfers (29)). This etiology may explain our finding of lower rates of SGA birth in donor-oocyte births following fresh embryo transfer. However, in thawed embryo transfers, the uterine environment is ostensibly similar for pregnancies conceived using donor and autologous oocytes because ovarian stimulation was not performed. The increased rate of being SGA for donor oocyte births among thawed embryo transfers observed in our study might thus be more representative of the maternal response to donor oocytes, because the competing risks resulting from ovarian stimulation are absent. In other words, it is possible that the uterine environment had a greater influence on growth restriction in fresh embryo transfer cycles than did the use of donor oocytes. The primary strength of our study is the use of a national database with detailed, high-quality information on ART procedures and sufficient sample size to assess both preterm and SGA births among donor oocyte births following fresh and thawed embryo transfer. Also, by limiting our analysis to singleton infants from single-gestation pregnancies, we were able to reduce the potential impact of confounding due a vanishing twin on perinatal outcomes. However, our findings are subject to several limitations. First, we were unable to assess the frequency of pregnancy complications, most notably hypertensive disorders of pregnancy. Although these factors likely fall on the causal pathway, information on their co-occurrence with preterm and SGA birth would provide important evidence on potential etiology of the outcomes studied in this analysis, especially given the potential for common biological mechanisms related to maternal immune response and placental pathology (26, 30). In addition, we were unable to distinguish between iatrogenic and spontaneous preterm birth and could not evaluate growth restriction among fetal deaths or for infants born before 24 weeks’ gestation. Furthermore, the measures of fetal growth used in this study represent the outcomes of infants born at a particular gestational age, whereas valid assessments of fetal growth require serial measurements over the course of pregnancy. Finally, unmeasured confounding may have affected our estimates. In conclusion, we found that the use of donor oocytes was associated with increased odds of preterm delivery among singleton births conceived using both fresh and thawed embryo transfer. In addition, rates of being SGA were higher for donor oocyte births than for autologous oocyte births but only among thawed embryo transfers, suggesting that changes in the uterine environment associated with controlled ovarian stimulation may have a greater influence on perinatal outcomes in the context of fresh embryo transfer. More research is needed to better understand the pathologies that may underlie maternal and fetal complications of donor oocyte pregnancies as well as the potential for adverse long-term outcomes. ACKNOWLEDGMENTS Author affiliations: Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia (Sheree L. Boulet, Jennifer F. Kawwass, Sara Crawford, Dmitry M. Kissin); Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia (Jennifer F. Kawwass); and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (Michael J. Davies). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Conflict of interest: none declared. Abbreviations AGA appropriate for gestational-age aOR adjusted odds ratio ART assisted reproductive technology CI confidence interval LGA large for gestational age IVF in vitro fertilization SGA small for gestational age REFERENCES 1 Kawwass JF , Monsour M , Crawford S , et al. . Trends and outcomes for donor oocyte cycles in the United States, 2000–2010 . JAMA . 2013 ; 310 ( 22 ): 2426 – 2434 . 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Pregnancy rates in donor oocyte cycles compared to similar autologous in vitro fertilization cycles: an analysis of 26,457 fresh cycles from the Society for Assisted Reproductive Technology . Fertil Steril . 2014 ; 102 ( 2 ): 399 – 404 . Google Scholar CrossRef Search ADS PubMed 30 Redline RW . Placental inflammation . Semin Neonatol . 2004 ; 9 ( 4 ): 265 – 274 . Google Scholar CrossRef Search ADS PubMed Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Epidemiology Oxford University Press

Preterm Birth and Small Size for Gestational Age in Singleton, In Vitro Fertilization Births Using Donor Oocytes

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Oxford University Press
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Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2018.
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0002-9262
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1476-6256
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10.1093/aje/kwy051
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Abstract

Abstract We used 2006–2015 US National Assisted Reproductive Technology Surveillance System data to compare preterm birth and fetal growth for liveborn singletons (24–42 weeks’ gestation) following in vitro fertilization with donor versus autologous oocytes. Using binary and multinomial logistic regression, we computed adjusted odds ratios and 95% confidence intervals for associations between use of donor oocytes and preterm delivery, being small for gestational age (SGA), and being large for gestational age (LGA), stratified by fresh and thawed embryo status and accounting for maternal characteristics and year of birth. There were 204,855 singleton births from fresh embryo transfers and 106,077 from thawed embryo transfers. Among fresh embryo transfers, donor oocyte births had higher odds of being preterm (adjusted odd ratio (aOR) = 1.32, 95% confidence interval (CI): 1.27, 1.38) or LGA (aOR = 1.27, 95% CI: 1.21, 1.33) but lower odds of being SGA (aOR = 0.81, 95% CI: 0.77, 0.85). Among thawed embryo transfers, donor oocyte births had higher odds of being preterm (aOR = 1.57, 95% CI: 1.48, 1.65) or SGA (aOR = 1.22, 95% CI: 1.14, 1.31) but lower odds of being LGA (aOR = 0.87, 95% CI: 0.82, 0.92). Use of donor oocytes was associated with increased odds of preterm delivery irrespective of embryo status; odds of being SGA were increased for donor versus autologous oocyte births among thawed embryo transfers only. assisted reproduction, donor egg, in vitro fertilization, perinatal outcomes, preterm, small for gestational age In the United States, use of donor oocytes for in vitro fertilization (IVF) procedures has increased over time largely due to delayed childbearing and the concomitant decline in the number and quality of eggs with advancing female age (1). In 2014, donor oocyte cycles accounted for over 9% of all assisted reproductive technology cycles and resulted in over 8,500 live births (2). The literature on the association between donor oocyte cycles and adverse perinatal outcomes is equivocal; results from some but not all studies suggest higher rates of obstetrical complications such as first-trimester vaginal bleeding (3, 4), hypertensive disorders of pregnancy (5–12), induction of labor (13), cesarean delivery (5, 8, 10, 12, 13), and postpartum hemorrhage (5, 10) for IVF conceptions from donor oocytes compared with autologous oocytes. Likewise, use of donor oocytes has been variably associated with increased risk for low birth weight (5, 6, 10, 12, 14–16) and preterm delivery (5, 6, 8, 10, 12, 14–16) when compared with births from IVF using autologous oocytes, even when restricted to singletons. Although there is some evidence of higher proportions of births from donor versus autologous oocytes being small for gestational age (SGA, <10th percentile of birth weight for gestational age), the associations tend to be smaller in magnitude and lack statistical significance (5, 6, 10, 12, 17). Studies of the potential associations between use of donor oocytes and infant outcomes may be complicated by the frequent use of frozen-thawed embryos in donor cycles. In 2014, 58% of donor cycles used frozen-thawed embryos compared with 38% of autologous cycles (2). Infants born following thawed autologous embryo transfer have been found to have higher average birth weights and lower odds of preterm and SGA birth compared with those conceived following a fresh embryo transfer (18–21); however, none of these studies compared infant outcomes for births from donor and autologous oocytes stratified by embryo status (fresh versus frozen-thawed embryo transfer). The aim of this study was to examine patterns of preterm birth and being SGA for singleton births resulting from donor oocyte IVF versus autologous oocyte IVF and to explore the role of embryo status as a potential effect measure modifier. We hypothesized that donor oocyte infants would have higher rates of preterm birth and growth restriction than autologous oocyte infants but that the associations would be attenuated for frozen-thawed cycles, given prior report of improved perinatal outcomes following frozen-thawed transfer. METHODS Study cohort The data used for this study were derived from the Center for Disease Control and Prevention’s National Assisted Reproductive Technology Surveillance System (NASS), which collects information on nearly all (98%) assisted reproductive technology (ART) cycles performed in US fertility clinics, as mandated by the Fertility Clinic Success Rates and Certification Act (22). Since 1995, NASS has collected data on patient demographic factors, obstetrical and medical history, ART treatment procedures, and resultant pregnancies and births. Each year, a random sample of fertility clinics that submitted data to NASS is selected for data validation, in which trained abstractors visit the clinics and compare data reported to NASS with medical records. Discrepancy rates were <5.6% for all fields evaluated in 2015 (23). We included all IVF cycles performed between 2006 and 2015 that resulted in a singleton gestation (1 fetal heart observed on ultrasound prior to 7 weeks’ gestation) and a liveborn singleton infant (n = 333,113). We excluded cycles using donated embryos (n = 2,837), cryopreserved eggs (n = 2,833, only reported for fresh embryo transfers from 2013 onward), or a gestational carrier (n = 8,215). Infants with gestational ages <24 weeks and >42 weeks (n = 7,798) and those with implausible birth weight and gestational age combinations (n = 498) (24) were also excluded. The study was approved by the institutional review board of the Centers for Disease Control and Prevention. Assessment of exposure Information on type of oocytes and embryos was ascertained from clinic-reported data on oocyte source and embryo state (autologous oocyte with a fresh embryo transfer, donor oocyte with a fresh embryo transfer, autologous oocyte with thawed embryo transfer, donor oocyte with thawed embryo transfer). Assessment of outcomes For fresh embryo transfers with information on date of oocyte retrieval, gestational week was calculated as: (date of delivery − date of oocyte retrieval + 14 days)/7. When date of oocyte retrieval was missing, gestational week was calculated as (date of delivery − date of embryo transfer + 17 days)/7 and assumed that the average time in embryo culture was 3 days during the study period. Information on infant birth weight was collected by clinics and was based on clinician or patient report. Using gestational age and birth weight information, we classified births as preterm (<37 weeks of gestation), SGA (<10th percentile of birth weight for gestational age), appropriate for gestational age (AGA; 10th–90th percentile of birth weight for gestational age), or large for gestational age (LGA; >90th percentile of birth weight for gestational age). In addition, we further categorized SGA, AGA, and LGA births according to preterm and term (37–42 weeks) delivery. Assessment of patient and treatment characteristics The patient and treatment characteristics included in the study were reported by clinics as part of routine ART surveillance. They included female patient age at cycle start, age of oocyte source at retrieval, race/ethnicity, prepregnancy body mass index, parity, previous preterm birth, reason for ART, number of prior ART cycles, number of oocytes retrieved, oocyte donor age at retrieval, embryo stage at transfer, number of embryos transferred, number of embryos cryopreserved, use of assisted hatching, use of intracytoplasmic sperm injection, and use of donor sperm. Statistical analyses We examined the distribution of patient and treatment characteristics for singleton births from donor and autologous oocytes, stratified by use of a fresh or thawed embryo transfer. χ2 tests were used to test for differences in distributions of characteristics for births from donor versus autologous oocytes. We calculated the 10th, 50th, and 90th percentiles of birth weight for gestational age for singleton births according to oocyte source (autologous or donor) and embryo status (fresh or thawed) for all births and stratified by male and female sex. Cubic splines were used to smooth gestational age–specific birth weight values. Finally, we used binary and multinomial logistic regression models to compute unadjusted and adjusted odds ratios and 95% confidence intervals for associations between use of donor oocytes and preterm delivery (binary) and fetal growth categorized as a 3-level (SGA, AGA, and LGA) or 6-level (SGA preterm, SGA term, AGA preterm, AGA term, LGA preterm, and LGA term) outcome. The birth weight–gestational age thresholds (SGA, AGA, and LGA) accounted for infant sex. The interaction of use of donor oocytes and embryo status (fresh or thawed) was included in the models, and stratified results are reported. Covariates for the adjusted model were selected a priori and included female patient age, infertility diagnosis (tubal factor, history of endometriosis, uterine factor, ovulatory disorder, diminished ovarian reserve, male factor infertility, and unexplained infertility), parity, number of prior ART cycles, and year of cycle start. To account for variation in use of donor oocytes among clinics, we used a hybrid fixed-effects approach with cluster mean values for proportion of donor cycles included as a fixed effect and clinic included as a random effect (25). This approach accounts for clinic-level variation in the outcome and the exposure and adjusts the other covariates for clinic-level differences related to use of donor oocytes (25). Because women using donor oocytes tend to be older and because advanced maternal age is associated with increased risk for adverse perinatal outcomes, we conducted a sensitivity analysis limiting the study population to births to women <40 years of age. Also, because we were unable to include body mass index in the models due to a high proportion of missing values (>40%), we included an additional sensitivity analysis restricted to records with information on body mass index. Analyses were conducted using SAS, version 9.4 (SAS Institute, Inc., Cary, North Carolina). P values of <0.05 were considered statistically significant. RESULTS After exclusions, the final sample included 310,932 singleton births at 24–42 weeks’ gestation that resulted from IVF cycles initiated between 2006 and 2015. Of those, 57.5% (n = 178,654) were conceived using fresh embryos with autologous oocytes, 8.4% (n = 26,201) used fresh embryos with donor oocytes, 29.1% (n = 90,494) used thawed embryos with autologous oocytes, and 5.0% (n = 15,583) used thawed embryos with donor oocytes. Regardless of embryo status, women who used donor oocytes tended to be older, had a history of 2 or more prior ART cycles, and were more frequently diagnosed with diminished ovarian reserve than women using autologous oocytes. (Table 1) Among births from fresh embryo transfers, the proportion of births following the transfer of 2 or more embryos was lower for those using donor versus autologous oocytes (8.0% versus 23.3%, respectively); similarly, the proportion of births where assisted hatching was used was lower for donor oocyte births (18.6% versus 34.3%, respectively). Table 1. Characteristics of Embryo Transfers Resulting in Singleton Births at 24–42 Weeks Gestation, United States, 2006–2015 Characteristic Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) No. % No. % No. % No. % Patient age, years  <30 688 2.6 28,931 16.2a 339 2.2 11,713 12.9a  30–34 2,237 8.5 70,161 39.3 1,112 7.1 35,419 39.1  35–39 5,405 20.6 62,291 34.9 2,672 17.2 33,168 36.7  ≥40 17,871 68.2 17,271 9.7 11,460 73.5 10,194 11.3 Age of oocyte source at retrieval, yearsb  <30 17,192 82.3 28,931 16.2a 7,300 82.2 14,474 21.9a  30–34 3,213 15.4 70,161 39.3 1,270 14.3 27,992 42.4  35–39 412 2.0 62,291 34.9 238 2.7 19,694 29.8  ≥40 66 0.3 17,271 9.7 77 0.9 3,906 5.9  Missing 5,318 0 6,698 24,428 Race/ethnicity  Non-Hispanic white 12,684 74.9 85,923 74.8a 6,968 72.3 41,387 71.7a  Non-Hispanic black 885 5.2 6,172 5.4 558 5.8 3,102 5.4  Hispanic 1,284 7.6 9,548 8.3 620 6.4 4,424 7.7  Asian/Pacific Islander 2,055 12.1 12,973 11.3 1,476 15.3 8,690 15.1  Other 23 0.1 226 0.2 21 0.2 117 0.2  Missing 9,270 63,812 5,940 32,774 Parityc  0 18,584 71.5 127,614 71.7a 8,063 52.0 50,247 55.8a  1 5,270 20.3 38,530 21.7 5,677 36.6 31,327 34.8  ≥2 2,138 8.2 11,843 6.7 1,773 11.4 8,489 9.4 No. of previous preterm deliveriesc  0 25,105 97.0 172,108 97.1 14,177 91.6 82,837 92.3a  1 697 2.7 4,611 2.6 1,204 7.8 6,389 7.1  ≥2 81 0.3 530 0.3 99 0.6 492 0.6 Body mass indexd  <18.5 450 2.7 3,671 2.9a 309 3.0 2,215 3.3a  18.5–24.9 9,907 58.9 72,655 57.4 6,009 58.2 39,842 59.7  25.0–29.9 4,029 24.0 29,424 23.2 2,390 23.1 14,916 22.4  ≥30.0 2,424 14.4 20,941 16.5 1,624 15.7 9,752 14.6  Missing 9,391 51,963 5,251 23,769 Reason for ART  Tubal factor 1,705 6.5 27,482 15.4 1,009 6.5 12,782 14.1a  History of endometriosis 1,561 6.0 20,051 11.2a 880 5.7 9,147 10.1a  Uterine factor 1,098 4.2 6,805 3.8a 774 5.0 4,369 4.8  Ovulatory disorder 1,096 4.2 29,973 16.8a 675 4.3 19,017 21.0a  Diminished ovarian reserve 20,208 77.1 27,668 15.5a 12,280 78.8 12,216 13.5a  Male infertility 4,796 18.3 71,906 40.3a 2,633 16.9 34,848 38.5a  Unexplained infertility 914 3.5 27,528 15.4a 538 3.5 12,530 13.9a  Other reason 4,578 17.5 20,951 11.7a 2,973 19.1 15,598 17.2a No. of prior ART cycles  0 11,256 43.0 113,656 63.7a 1,790 11.5 5,041 5.6a  1 4,597 17.6 31,488 17.6 4,147 26.6 43,052 47.7  ≥2 10,340 39.5 33,430 18.7 9,635 61.9 42,230 46.8 No. of oocytes retrievede  <5 339 1.3 12,636 7.1a  5–9 2,413 9.2 47,227 26.4  10–20 12,239 46.7 90,120 50.4  >20 11,210 42.8 28,671 16.1 Embryo stage, dayse  2–3 6,958 26.6 81,324 45.5a  5–6 18,700 71.4 93,719 52.5  Other 543 2.1 3,611 2.0 No. of embryos transferred  1 7,666 29.3 38,502 21.6a 6,613 42.4 41,182 45.5a  2 16,451 62.8 98,570 55.2 7,166 46.0 39,590 43.8  >2 2,084 8.0 41,582 23.3 1,804 11.6 9,722 10.7 No. of embryos cryopreserved  0 6,312 24.1 88,492 49.5a 14,941 95.9 87,310 96.5a  1–2 5,189 19.8 35,275 19.7 426 2.7 1,937 2.1  >2 14,700 56.1 54,887 30.7 216 1.4 1,247 1.4 Assisted hatching  Yes 4,864 18.6 61,350 34.3a 8,934 57.3 47,114 52.1a  No 21,337 81.4 117,304 65.7 6,649 42.7 43,380 47.9 ICSIc,e  Yes 19,882 75.9 132,603 74.3a  No 6,309 24.1 45,896 25.7 Donor sperme  Yesf 2,582 9.9 7,494 4.2  No 23,606 90.1 171,104 95.8 Characteristic Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) No. % No. % No. % No. % Patient age, years  <30 688 2.6 28,931 16.2a 339 2.2 11,713 12.9a  30–34 2,237 8.5 70,161 39.3 1,112 7.1 35,419 39.1  35–39 5,405 20.6 62,291 34.9 2,672 17.2 33,168 36.7  ≥40 17,871 68.2 17,271 9.7 11,460 73.5 10,194 11.3 Age of oocyte source at retrieval, yearsb  <30 17,192 82.3 28,931 16.2a 7,300 82.2 14,474 21.9a  30–34 3,213 15.4 70,161 39.3 1,270 14.3 27,992 42.4  35–39 412 2.0 62,291 34.9 238 2.7 19,694 29.8  ≥40 66 0.3 17,271 9.7 77 0.9 3,906 5.9  Missing 5,318 0 6,698 24,428 Race/ethnicity  Non-Hispanic white 12,684 74.9 85,923 74.8a 6,968 72.3 41,387 71.7a  Non-Hispanic black 885 5.2 6,172 5.4 558 5.8 3,102 5.4  Hispanic 1,284 7.6 9,548 8.3 620 6.4 4,424 7.7  Asian/Pacific Islander 2,055 12.1 12,973 11.3 1,476 15.3 8,690 15.1  Other 23 0.1 226 0.2 21 0.2 117 0.2  Missing 9,270 63,812 5,940 32,774 Parityc  0 18,584 71.5 127,614 71.7a 8,063 52.0 50,247 55.8a  1 5,270 20.3 38,530 21.7 5,677 36.6 31,327 34.8  ≥2 2,138 8.2 11,843 6.7 1,773 11.4 8,489 9.4 No. of previous preterm deliveriesc  0 25,105 97.0 172,108 97.1 14,177 91.6 82,837 92.3a  1 697 2.7 4,611 2.6 1,204 7.8 6,389 7.1  ≥2 81 0.3 530 0.3 99 0.6 492 0.6 Body mass indexd  <18.5 450 2.7 3,671 2.9a 309 3.0 2,215 3.3a  18.5–24.9 9,907 58.9 72,655 57.4 6,009 58.2 39,842 59.7  25.0–29.9 4,029 24.0 29,424 23.2 2,390 23.1 14,916 22.4  ≥30.0 2,424 14.4 20,941 16.5 1,624 15.7 9,752 14.6  Missing 9,391 51,963 5,251 23,769 Reason for ART  Tubal factor 1,705 6.5 27,482 15.4 1,009 6.5 12,782 14.1a  History of endometriosis 1,561 6.0 20,051 11.2a 880 5.7 9,147 10.1a  Uterine factor 1,098 4.2 6,805 3.8a 774 5.0 4,369 4.8  Ovulatory disorder 1,096 4.2 29,973 16.8a 675 4.3 19,017 21.0a  Diminished ovarian reserve 20,208 77.1 27,668 15.5a 12,280 78.8 12,216 13.5a  Male infertility 4,796 18.3 71,906 40.3a 2,633 16.9 34,848 38.5a  Unexplained infertility 914 3.5 27,528 15.4a 538 3.5 12,530 13.9a  Other reason 4,578 17.5 20,951 11.7a 2,973 19.1 15,598 17.2a No. of prior ART cycles  0 11,256 43.0 113,656 63.7a 1,790 11.5 5,041 5.6a  1 4,597 17.6 31,488 17.6 4,147 26.6 43,052 47.7  ≥2 10,340 39.5 33,430 18.7 9,635 61.9 42,230 46.8 No. of oocytes retrievede  <5 339 1.3 12,636 7.1a  5–9 2,413 9.2 47,227 26.4  10–20 12,239 46.7 90,120 50.4  >20 11,210 42.8 28,671 16.1 Embryo stage, dayse  2–3 6,958 26.6 81,324 45.5a  5–6 18,700 71.4 93,719 52.5  Other 543 2.1 3,611 2.0 No. of embryos transferred  1 7,666 29.3 38,502 21.6a 6,613 42.4 41,182 45.5a  2 16,451 62.8 98,570 55.2 7,166 46.0 39,590 43.8  >2 2,084 8.0 41,582 23.3 1,804 11.6 9,722 10.7 No. of embryos cryopreserved  0 6,312 24.1 88,492 49.5a 14,941 95.9 87,310 96.5a  1–2 5,189 19.8 35,275 19.7 426 2.7 1,937 2.1  >2 14,700 56.1 54,887 30.7 216 1.4 1,247 1.4 Assisted hatching  Yes 4,864 18.6 61,350 34.3a 8,934 57.3 47,114 52.1a  No 21,337 81.4 117,304 65.7 6,649 42.7 43,380 47.9 ICSIc,e  Yes 19,882 75.9 132,603 74.3a  No 6,309 24.1 45,896 25.7 Donor sperme  Yesf 2,582 9.9 7,494 4.2  No 23,606 90.1 171,104 95.8 Abbreviations: ART, assisted reproductive technology; ICSI, intracytoplasmic sperm injection. aP < 0.01 for comparison of donor versus autologous oocyte births (χ2 test). b For autologous cycles, age at oocyte retrieval is patient’s age at the time oocytes were retrieved. For donor cycles, age at oocyte retrieval is donor’s age at the time oocytes were retrieved. c Data for categories does not sum to total due to missing data (≤1%). d Body mass index was calculated as weight (kg)/height (m)2. e Data not reported consistently for frozen embryo cycles. f Includes donor sperm and mixed (donor and partner) sperm. Table 1. Characteristics of Embryo Transfers Resulting in Singleton Births at 24–42 Weeks Gestation, United States, 2006–2015 Characteristic Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) No. % No. % No. % No. % Patient age, years  <30 688 2.6 28,931 16.2a 339 2.2 11,713 12.9a  30–34 2,237 8.5 70,161 39.3 1,112 7.1 35,419 39.1  35–39 5,405 20.6 62,291 34.9 2,672 17.2 33,168 36.7  ≥40 17,871 68.2 17,271 9.7 11,460 73.5 10,194 11.3 Age of oocyte source at retrieval, yearsb  <30 17,192 82.3 28,931 16.2a 7,300 82.2 14,474 21.9a  30–34 3,213 15.4 70,161 39.3 1,270 14.3 27,992 42.4  35–39 412 2.0 62,291 34.9 238 2.7 19,694 29.8  ≥40 66 0.3 17,271 9.7 77 0.9 3,906 5.9  Missing 5,318 0 6,698 24,428 Race/ethnicity  Non-Hispanic white 12,684 74.9 85,923 74.8a 6,968 72.3 41,387 71.7a  Non-Hispanic black 885 5.2 6,172 5.4 558 5.8 3,102 5.4  Hispanic 1,284 7.6 9,548 8.3 620 6.4 4,424 7.7  Asian/Pacific Islander 2,055 12.1 12,973 11.3 1,476 15.3 8,690 15.1  Other 23 0.1 226 0.2 21 0.2 117 0.2  Missing 9,270 63,812 5,940 32,774 Parityc  0 18,584 71.5 127,614 71.7a 8,063 52.0 50,247 55.8a  1 5,270 20.3 38,530 21.7 5,677 36.6 31,327 34.8  ≥2 2,138 8.2 11,843 6.7 1,773 11.4 8,489 9.4 No. of previous preterm deliveriesc  0 25,105 97.0 172,108 97.1 14,177 91.6 82,837 92.3a  1 697 2.7 4,611 2.6 1,204 7.8 6,389 7.1  ≥2 81 0.3 530 0.3 99 0.6 492 0.6 Body mass indexd  <18.5 450 2.7 3,671 2.9a 309 3.0 2,215 3.3a  18.5–24.9 9,907 58.9 72,655 57.4 6,009 58.2 39,842 59.7  25.0–29.9 4,029 24.0 29,424 23.2 2,390 23.1 14,916 22.4  ≥30.0 2,424 14.4 20,941 16.5 1,624 15.7 9,752 14.6  Missing 9,391 51,963 5,251 23,769 Reason for ART  Tubal factor 1,705 6.5 27,482 15.4 1,009 6.5 12,782 14.1a  History of endometriosis 1,561 6.0 20,051 11.2a 880 5.7 9,147 10.1a  Uterine factor 1,098 4.2 6,805 3.8a 774 5.0 4,369 4.8  Ovulatory disorder 1,096 4.2 29,973 16.8a 675 4.3 19,017 21.0a  Diminished ovarian reserve 20,208 77.1 27,668 15.5a 12,280 78.8 12,216 13.5a  Male infertility 4,796 18.3 71,906 40.3a 2,633 16.9 34,848 38.5a  Unexplained infertility 914 3.5 27,528 15.4a 538 3.5 12,530 13.9a  Other reason 4,578 17.5 20,951 11.7a 2,973 19.1 15,598 17.2a No. of prior ART cycles  0 11,256 43.0 113,656 63.7a 1,790 11.5 5,041 5.6a  1 4,597 17.6 31,488 17.6 4,147 26.6 43,052 47.7  ≥2 10,340 39.5 33,430 18.7 9,635 61.9 42,230 46.8 No. of oocytes retrievede  <5 339 1.3 12,636 7.1a  5–9 2,413 9.2 47,227 26.4  10–20 12,239 46.7 90,120 50.4  >20 11,210 42.8 28,671 16.1 Embryo stage, dayse  2–3 6,958 26.6 81,324 45.5a  5–6 18,700 71.4 93,719 52.5  Other 543 2.1 3,611 2.0 No. of embryos transferred  1 7,666 29.3 38,502 21.6a 6,613 42.4 41,182 45.5a  2 16,451 62.8 98,570 55.2 7,166 46.0 39,590 43.8  >2 2,084 8.0 41,582 23.3 1,804 11.6 9,722 10.7 No. of embryos cryopreserved  0 6,312 24.1 88,492 49.5a 14,941 95.9 87,310 96.5a  1–2 5,189 19.8 35,275 19.7 426 2.7 1,937 2.1  >2 14,700 56.1 54,887 30.7 216 1.4 1,247 1.4 Assisted hatching  Yes 4,864 18.6 61,350 34.3a 8,934 57.3 47,114 52.1a  No 21,337 81.4 117,304 65.7 6,649 42.7 43,380 47.9 ICSIc,e  Yes 19,882 75.9 132,603 74.3a  No 6,309 24.1 45,896 25.7 Donor sperme  Yesf 2,582 9.9 7,494 4.2  No 23,606 90.1 171,104 95.8 Characteristic Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) No. % No. % No. % No. % Patient age, years  <30 688 2.6 28,931 16.2a 339 2.2 11,713 12.9a  30–34 2,237 8.5 70,161 39.3 1,112 7.1 35,419 39.1  35–39 5,405 20.6 62,291 34.9 2,672 17.2 33,168 36.7  ≥40 17,871 68.2 17,271 9.7 11,460 73.5 10,194 11.3 Age of oocyte source at retrieval, yearsb  <30 17,192 82.3 28,931 16.2a 7,300 82.2 14,474 21.9a  30–34 3,213 15.4 70,161 39.3 1,270 14.3 27,992 42.4  35–39 412 2.0 62,291 34.9 238 2.7 19,694 29.8  ≥40 66 0.3 17,271 9.7 77 0.9 3,906 5.9  Missing 5,318 0 6,698 24,428 Race/ethnicity  Non-Hispanic white 12,684 74.9 85,923 74.8a 6,968 72.3 41,387 71.7a  Non-Hispanic black 885 5.2 6,172 5.4 558 5.8 3,102 5.4  Hispanic 1,284 7.6 9,548 8.3 620 6.4 4,424 7.7  Asian/Pacific Islander 2,055 12.1 12,973 11.3 1,476 15.3 8,690 15.1  Other 23 0.1 226 0.2 21 0.2 117 0.2  Missing 9,270 63,812 5,940 32,774 Parityc  0 18,584 71.5 127,614 71.7a 8,063 52.0 50,247 55.8a  1 5,270 20.3 38,530 21.7 5,677 36.6 31,327 34.8  ≥2 2,138 8.2 11,843 6.7 1,773 11.4 8,489 9.4 No. of previous preterm deliveriesc  0 25,105 97.0 172,108 97.1 14,177 91.6 82,837 92.3a  1 697 2.7 4,611 2.6 1,204 7.8 6,389 7.1  ≥2 81 0.3 530 0.3 99 0.6 492 0.6 Body mass indexd  <18.5 450 2.7 3,671 2.9a 309 3.0 2,215 3.3a  18.5–24.9 9,907 58.9 72,655 57.4 6,009 58.2 39,842 59.7  25.0–29.9 4,029 24.0 29,424 23.2 2,390 23.1 14,916 22.4  ≥30.0 2,424 14.4 20,941 16.5 1,624 15.7 9,752 14.6  Missing 9,391 51,963 5,251 23,769 Reason for ART  Tubal factor 1,705 6.5 27,482 15.4 1,009 6.5 12,782 14.1a  History of endometriosis 1,561 6.0 20,051 11.2a 880 5.7 9,147 10.1a  Uterine factor 1,098 4.2 6,805 3.8a 774 5.0 4,369 4.8  Ovulatory disorder 1,096 4.2 29,973 16.8a 675 4.3 19,017 21.0a  Diminished ovarian reserve 20,208 77.1 27,668 15.5a 12,280 78.8 12,216 13.5a  Male infertility 4,796 18.3 71,906 40.3a 2,633 16.9 34,848 38.5a  Unexplained infertility 914 3.5 27,528 15.4a 538 3.5 12,530 13.9a  Other reason 4,578 17.5 20,951 11.7a 2,973 19.1 15,598 17.2a No. of prior ART cycles  0 11,256 43.0 113,656 63.7a 1,790 11.5 5,041 5.6a  1 4,597 17.6 31,488 17.6 4,147 26.6 43,052 47.7  ≥2 10,340 39.5 33,430 18.7 9,635 61.9 42,230 46.8 No. of oocytes retrievede  <5 339 1.3 12,636 7.1a  5–9 2,413 9.2 47,227 26.4  10–20 12,239 46.7 90,120 50.4  >20 11,210 42.8 28,671 16.1 Embryo stage, dayse  2–3 6,958 26.6 81,324 45.5a  5–6 18,700 71.4 93,719 52.5  Other 543 2.1 3,611 2.0 No. of embryos transferred  1 7,666 29.3 38,502 21.6a 6,613 42.4 41,182 45.5a  2 16,451 62.8 98,570 55.2 7,166 46.0 39,590 43.8  >2 2,084 8.0 41,582 23.3 1,804 11.6 9,722 10.7 No. of embryos cryopreserved  0 6,312 24.1 88,492 49.5a 14,941 95.9 87,310 96.5a  1–2 5,189 19.8 35,275 19.7 426 2.7 1,937 2.1  >2 14,700 56.1 54,887 30.7 216 1.4 1,247 1.4 Assisted hatching  Yes 4,864 18.6 61,350 34.3a 8,934 57.3 47,114 52.1a  No 21,337 81.4 117,304 65.7 6,649 42.7 43,380 47.9 ICSIc,e  Yes 19,882 75.9 132,603 74.3a  No 6,309 24.1 45,896 25.7 Donor sperme  Yesf 2,582 9.9 7,494 4.2  No 23,606 90.1 171,104 95.8 Abbreviations: ART, assisted reproductive technology; ICSI, intracytoplasmic sperm injection. aP < 0.01 for comparison of donor versus autologous oocyte births (χ2 test). b For autologous cycles, age at oocyte retrieval is patient’s age at the time oocytes were retrieved. For donor cycles, age at oocyte retrieval is donor’s age at the time oocytes were retrieved. c Data for categories does not sum to total due to missing data (≤1%). d Body mass index was calculated as weight (kg)/height (m)2. e Data not reported consistently for frozen embryo cycles. f Includes donor sperm and mixed (donor and partner) sperm. Figure 1 depicts the 10th, 50th and 90th percentiles of birth weight according to gestational age after smoothing for all singleton IVF births from autologous and donor oocyte embryos, stratified by embryo status. Among fresh embryo transfers, the 10th-percentile values between 25 and 41 weeks were higher for donor oocyte births compared with those using autologous oocytes (Figure 1A), although differences were minimal (<5%) at gestational ages beyond 32 weeks. Likewise, gestational age–specific birth weights at the 90th percentile were slightly higher for donor oocyte births than autologous oocyte births from 25 weeks onward. In contrast, among thawed embryo transfers, the 10th-percentile values for donor oocyte births were lower than autologous oocyte births for nearly every gestational age, and the 90th-percentile values were lower after 27 weeks’ gestation (Figure 1B). Similar trends were observed using sex-specific growth curves. (Web Figures 1 and 2, available at https://academic.oup.com/aje). Figure 1. View largeDownload slide Smoothed 10th, 50th, and 90th percentiles of birth weight for singleton births by oocyte source for fresh embryo transfers (A) and thawed embryo transfers (B), United States, 2006–2015. Figure 1. View largeDownload slide Smoothed 10th, 50th, and 90th percentiles of birth weight for singleton births by oocyte source for fresh embryo transfers (A) and thawed embryo transfers (B), United States, 2006–2015. P values for the interaction of the use of donor oocytes and embryo status were <0.0001 for all models with the exception of preterm birth in the sensitivity analysis restricted to women <40 years of age. Among fresh embryo transfers, use of a donor oocyte was associated with increased odds of preterm birth (adjusted odd ratio (aOR) = 1.32, 95% confidence interval (CI): 1.27, 1.38). (Table 2) Donor oocyte births also had decreased odds of being SGA compared with autologous oocyte births (aOR = 0.81, 95% CI: 0.77, 0.85) but increased odds of being LGA (aOR = 1.30, 95% CI: 1.23, 1.37). When fetal growth was further classified according to preterm and term birth, use of donor oocytes was associated with reduced odds of SGA term birth (aOR = 0.83, 95% CI: 0.79, 0.88) but not SGA preterm birth (aOR = 1.01, 95% CI: 0.89, 1.15). In addition, odds of being AGA and preterm, LGA and preterm, or LGA and term were all higher for donor versus autologous oocyte births. Table 2. Association Between Use of Donor Oocytes and Adverse Perinatal Outcomes According to Embryo Status Among Singleton Births at 24–42 Weeks’ Gestation, United States, 2006–2015 Birth Outcome Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Unadjusted Adjusteda Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) Unadjusted Adjusteda No. % No. % OR 95% CI OR 95% CI No. % No. % OR 95% CI OR 95% CI Pretermb 3,947 15.1 20,338 11.4 1.40 1.35, 1.46 1.32 1.27, 1.38 3,068 19.7 11,919 13.2 1.65 1.58, 1.73 1.57 1.48, 1.65 SGAc 2,737 10.5 21,660 12.1 0.85 0.81, 0.88 0.81 0.77, 0.85 1,271 8.2 5,674 6.3 1.27 1.19, 1.36 1.22 1.14, 1.31 LGAc 2,446 9.3 13,461 7.5 1.27 1.21, 1.33 1.30 1.23, 1.37 1,873 12.0 12,938 14.3 0.86 0.81, 0.90 0.87 0.82, 0.92 SGA, pretermd 408 1.6 2,585 1.5 1.10 0.99, 1.23 1.01 0.89, 1.15 229 1.5 694 0.8 2.04 1.75, 2.37 1.89 1.60, 2.24 SGA, termd 2,329 8.9 19,075 10.7 0.86 0.82, 0.90 0.83 0.79, 0.88 1,042 6.7 4,980 5.5 1.29 1.20, 1.38 1.26 1.16, 1.36 AGA, pretermd 3,197 12.2 16,138 9.0 1.44 1.39, 1.51 1.39 1.32, 1.46 2,523 16.2 9,629 10.6 1.70 1.62, 1.78 1.61 1.52, 1.71 LGA, pretermd 342 1.3 1,615 0.9 1.54 1.36, 1.73 1.52 1.33, 1.75 316 2.0 1,596 1.8 1.26 1.11, 1.43 1.24 1.07, 1.43 LGA, termd 2,104 8.0 11,846 6.6 1.31 1.25, 1.38 1.33 1.26, 1.41 1,557 10.0 11,342 12.5 0.88 0.83, 0.93 0.89 0.83, 0.95 Birth Outcome Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Unadjusted Adjusteda Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) Unadjusted Adjusteda No. % No. % OR 95% CI OR 95% CI No. % No. % OR 95% CI OR 95% CI Pretermb 3,947 15.1 20,338 11.4 1.40 1.35, 1.46 1.32 1.27, 1.38 3,068 19.7 11,919 13.2 1.65 1.58, 1.73 1.57 1.48, 1.65 SGAc 2,737 10.5 21,660 12.1 0.85 0.81, 0.88 0.81 0.77, 0.85 1,271 8.2 5,674 6.3 1.27 1.19, 1.36 1.22 1.14, 1.31 LGAc 2,446 9.3 13,461 7.5 1.27 1.21, 1.33 1.30 1.23, 1.37 1,873 12.0 12,938 14.3 0.86 0.81, 0.90 0.87 0.82, 0.92 SGA, pretermd 408 1.6 2,585 1.5 1.10 0.99, 1.23 1.01 0.89, 1.15 229 1.5 694 0.8 2.04 1.75, 2.37 1.89 1.60, 2.24 SGA, termd 2,329 8.9 19,075 10.7 0.86 0.82, 0.90 0.83 0.79, 0.88 1,042 6.7 4,980 5.5 1.29 1.20, 1.38 1.26 1.16, 1.36 AGA, pretermd 3,197 12.2 16,138 9.0 1.44 1.39, 1.51 1.39 1.32, 1.46 2,523 16.2 9,629 10.6 1.70 1.62, 1.78 1.61 1.52, 1.71 LGA, pretermd 342 1.3 1,615 0.9 1.54 1.36, 1.73 1.52 1.33, 1.75 316 2.0 1,596 1.8 1.26 1.11, 1.43 1.24 1.07, 1.43 LGA, termd 2,104 8.0 11,846 6.6 1.31 1.25, 1.38 1.33 1.26, 1.41 1,557 10.0 11,342 12.5 0.88 0.83, 0.93 0.89 0.83, 0.95 Abbreviations: AGA, appropriate for gestational age; CI, confidence interval; LGA, large for gestational age; OR, odds ratio; SGA, small for gestational age. a Adjusted for patient age, infertility diagnosis (tubal factor, history of endometriosis, uterine factor, ovulatory disorder, diminished ovarian reserve, male infertility, unexplained infertility), parity, number of prior cycles of assisted reproductive technology, and year of cycle. Models also incorporated a hybrid fixed-effects approach with clusters (clinic) included as random effects and cluster means of the percentage of donor cycles included as a fixed effect. b Compared with term births. c Compared with AGA births. d Compared with AGA term births. Table 2. Association Between Use of Donor Oocytes and Adverse Perinatal Outcomes According to Embryo Status Among Singleton Births at 24–42 Weeks’ Gestation, United States, 2006–2015 Birth Outcome Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Unadjusted Adjusteda Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) Unadjusted Adjusteda No. % No. % OR 95% CI OR 95% CI No. % No. % OR 95% CI OR 95% CI Pretermb 3,947 15.1 20,338 11.4 1.40 1.35, 1.46 1.32 1.27, 1.38 3,068 19.7 11,919 13.2 1.65 1.58, 1.73 1.57 1.48, 1.65 SGAc 2,737 10.5 21,660 12.1 0.85 0.81, 0.88 0.81 0.77, 0.85 1,271 8.2 5,674 6.3 1.27 1.19, 1.36 1.22 1.14, 1.31 LGAc 2,446 9.3 13,461 7.5 1.27 1.21, 1.33 1.30 1.23, 1.37 1,873 12.0 12,938 14.3 0.86 0.81, 0.90 0.87 0.82, 0.92 SGA, pretermd 408 1.6 2,585 1.5 1.10 0.99, 1.23 1.01 0.89, 1.15 229 1.5 694 0.8 2.04 1.75, 2.37 1.89 1.60, 2.24 SGA, termd 2,329 8.9 19,075 10.7 0.86 0.82, 0.90 0.83 0.79, 0.88 1,042 6.7 4,980 5.5 1.29 1.20, 1.38 1.26 1.16, 1.36 AGA, pretermd 3,197 12.2 16,138 9.0 1.44 1.39, 1.51 1.39 1.32, 1.46 2,523 16.2 9,629 10.6 1.70 1.62, 1.78 1.61 1.52, 1.71 LGA, pretermd 342 1.3 1,615 0.9 1.54 1.36, 1.73 1.52 1.33, 1.75 316 2.0 1,596 1.8 1.26 1.11, 1.43 1.24 1.07, 1.43 LGA, termd 2,104 8.0 11,846 6.6 1.31 1.25, 1.38 1.33 1.26, 1.41 1,557 10.0 11,342 12.5 0.88 0.83, 0.93 0.89 0.83, 0.95 Birth Outcome Fresh Embryo Transfer Thawed Embryo Transfer Donor Oocyte (n = 26,201) Autologous Oocyte (n = 178,654) Unadjusted Adjusteda Donor Oocyte (n = 15,583) Autologous Oocyte (n = 90,494) Unadjusted Adjusteda No. % No. % OR 95% CI OR 95% CI No. % No. % OR 95% CI OR 95% CI Pretermb 3,947 15.1 20,338 11.4 1.40 1.35, 1.46 1.32 1.27, 1.38 3,068 19.7 11,919 13.2 1.65 1.58, 1.73 1.57 1.48, 1.65 SGAc 2,737 10.5 21,660 12.1 0.85 0.81, 0.88 0.81 0.77, 0.85 1,271 8.2 5,674 6.3 1.27 1.19, 1.36 1.22 1.14, 1.31 LGAc 2,446 9.3 13,461 7.5 1.27 1.21, 1.33 1.30 1.23, 1.37 1,873 12.0 12,938 14.3 0.86 0.81, 0.90 0.87 0.82, 0.92 SGA, pretermd 408 1.6 2,585 1.5 1.10 0.99, 1.23 1.01 0.89, 1.15 229 1.5 694 0.8 2.04 1.75, 2.37 1.89 1.60, 2.24 SGA, termd 2,329 8.9 19,075 10.7 0.86 0.82, 0.90 0.83 0.79, 0.88 1,042 6.7 4,980 5.5 1.29 1.20, 1.38 1.26 1.16, 1.36 AGA, pretermd 3,197 12.2 16,138 9.0 1.44 1.39, 1.51 1.39 1.32, 1.46 2,523 16.2 9,629 10.6 1.70 1.62, 1.78 1.61 1.52, 1.71 LGA, pretermd 342 1.3 1,615 0.9 1.54 1.36, 1.73 1.52 1.33, 1.75 316 2.0 1,596 1.8 1.26 1.11, 1.43 1.24 1.07, 1.43 LGA, termd 2,104 8.0 11,846 6.6 1.31 1.25, 1.38 1.33 1.26, 1.41 1,557 10.0 11,342 12.5 0.88 0.83, 0.93 0.89 0.83, 0.95 Abbreviations: AGA, appropriate for gestational age; CI, confidence interval; LGA, large for gestational age; OR, odds ratio; SGA, small for gestational age. a Adjusted for patient age, infertility diagnosis (tubal factor, history of endometriosis, uterine factor, ovulatory disorder, diminished ovarian reserve, male infertility, unexplained infertility), parity, number of prior cycles of assisted reproductive technology, and year of cycle. Models also incorporated a hybrid fixed-effects approach with clusters (clinic) included as random effects and cluster means of the percentage of donor cycles included as a fixed effect. b Compared with term births. c Compared with AGA births. d Compared with AGA term births. Among thawed embryo transfers, use of a donor oocyte was also associated with increased odds of preterm birth (aOR = 1.57, 95% CI: 1.48, 1.65). However, in contrast with fresh embryo transfers, donor oocyte births following a thawed embryo transfer had increased odds of being SGA (aOR = 1.22, 95% CI: 1.14, 1.31) and decreased odds of being LGA (aOR = 0.87, 95% CI: 0.82, 0.92) compared with autologous oocyte births. Furthermore, odds of SGA preterm (aOR = 1.89, 95% CI: 1.60, 2.24), SGA term (aOR = 1.26, 95% CI: 1.16, 1.36), AGA preterm (aOR = 1.61, 95% CI: 1.52, 1.71), and LGA preterm (aOR = 1.24, 95% CI: 1.07, 1.43) births were higher for donor versus autologous oocyte births, while odds of LGA term birth were lower (aOR = 0.89, 95% CI: 0.83, 0.95). Observed associations for women <40 years of age were similar to those for the entire population (Web Table 1), as were estimates when maternal body mass index was included as a covariate (Web Table 2). DISCUSSION Our results suggest that use of donor versus autologous oocytes was associated with increased odds of preterm birth for singleton births conceived using either fresh or thawed embryos. However, embryo status modified the association between use of donor oocytes and fetal growth. For example, whereas donor oocyte births from fresh embryo transfers had a lower rate of SGA birth than autologous oocyte births, donor oocyte births from thawed embryo transfers had a higher rate of being SGA compared with autologous oocyte births. In addition, when fetal growth outcomes for singleton births from fresh embryo transfers were further classified by length of gestation, donor oocyte births were less likely than autologous oocyte births to be SGA and term but more likely to be AGA and preterm, LGA and preterm, or LGA and term. In contrast, among thawed embryo transfers, use of donor oocytes was associated with nearly 2-fold higher odds of being SGA and preterm but was protective for LGA term birth. Our finding, that use of donor oocytes was associated with an increased overall risk for preterm birth irrespective of embryo status, is consistent with several other studies (10, 12, 14). It has been suggested that the association between use of donor oocytes and adverse perinatal outcomes such as preterm birth and hypertensive disorders of pregnancy may be due to abnormal placental development caused by maternal immune response to fetal antigens from a donor oocyte pregnancy (12, 26). Given that women using donor oocytes tend to be older or have a history of prior failed IVF cycles (1), unmeasured factors related to advanced maternal age, nulliparity, and premature ovarian insufficiency may also contribute to elevated risks for adverse perinatal outcomes (13, 27). Increases in LGA incidence after cryopreservation of embryos have also been also observed previously, particularly for autologous oocytes, for which the odds of being SGA decrease from fresh to thawed while the odds of being LGA increase (20, 21, 28). This may be due to either a treatment effect on the growth axis of autologous embryos or a reduction in the survivorship of autologous embryos with the propensity to be SGA. Of the few studies that compared rates of SGA birth for donor versus autologous oocyte births, most suggest little or no association (5, 6, 10, 11). However, unlike the present study, prior investigations typically combined fresh and thawed embryos, which may have contributed to biased estimates. Our results suggest that associations between use of donor oocytes and SGA birth differ by embryo status, a finding that has not, to our knowledge, been previously reported. The mechanism for this association is not known. It has been hypothesized that the supraphysiologic doses of gonadotropins used during controlled ovarian stimulation may negatively affect endometrial receptivity, resulting in the lower rates of implantation, clinical pregnancy, and live birth that have been reported for fresh, autologous transfers, as compared with cycles in which no ovarian stimulation is performed (both frozen autologous embryo transfers (19, 28) and fresh donor embryo transfers (29)). This etiology may explain our finding of lower rates of SGA birth in donor-oocyte births following fresh embryo transfer. However, in thawed embryo transfers, the uterine environment is ostensibly similar for pregnancies conceived using donor and autologous oocytes because ovarian stimulation was not performed. The increased rate of being SGA for donor oocyte births among thawed embryo transfers observed in our study might thus be more representative of the maternal response to donor oocytes, because the competing risks resulting from ovarian stimulation are absent. In other words, it is possible that the uterine environment had a greater influence on growth restriction in fresh embryo transfer cycles than did the use of donor oocytes. The primary strength of our study is the use of a national database with detailed, high-quality information on ART procedures and sufficient sample size to assess both preterm and SGA births among donor oocyte births following fresh and thawed embryo transfer. Also, by limiting our analysis to singleton infants from single-gestation pregnancies, we were able to reduce the potential impact of confounding due a vanishing twin on perinatal outcomes. However, our findings are subject to several limitations. First, we were unable to assess the frequency of pregnancy complications, most notably hypertensive disorders of pregnancy. Although these factors likely fall on the causal pathway, information on their co-occurrence with preterm and SGA birth would provide important evidence on potential etiology of the outcomes studied in this analysis, especially given the potential for common biological mechanisms related to maternal immune response and placental pathology (26, 30). In addition, we were unable to distinguish between iatrogenic and spontaneous preterm birth and could not evaluate growth restriction among fetal deaths or for infants born before 24 weeks’ gestation. Furthermore, the measures of fetal growth used in this study represent the outcomes of infants born at a particular gestational age, whereas valid assessments of fetal growth require serial measurements over the course of pregnancy. Finally, unmeasured confounding may have affected our estimates. In conclusion, we found that the use of donor oocytes was associated with increased odds of preterm delivery among singleton births conceived using both fresh and thawed embryo transfer. In addition, rates of being SGA were higher for donor oocyte births than for autologous oocyte births but only among thawed embryo transfers, suggesting that changes in the uterine environment associated with controlled ovarian stimulation may have a greater influence on perinatal outcomes in the context of fresh embryo transfer. More research is needed to better understand the pathologies that may underlie maternal and fetal complications of donor oocyte pregnancies as well as the potential for adverse long-term outcomes. ACKNOWLEDGMENTS Author affiliations: Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia (Sheree L. Boulet, Jennifer F. Kawwass, Sara Crawford, Dmitry M. Kissin); Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia (Jennifer F. Kawwass); and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia (Michael J. Davies). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Conflict of interest: none declared. Abbreviations AGA appropriate for gestational-age aOR adjusted odds ratio ART assisted reproductive technology CI confidence interval LGA large for gestational age IVF in vitro fertilization SGA small for gestational age REFERENCES 1 Kawwass JF , Monsour M , Crawford S , et al. . Trends and outcomes for donor oocyte cycles in the United States, 2000–2010 . JAMA . 2013 ; 310 ( 22 ): 2426 – 2434 . 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Pregnancy rates in donor oocyte cycles compared to similar autologous in vitro fertilization cycles: an analysis of 26,457 fresh cycles from the Society for Assisted Reproductive Technology . Fertil Steril . 2014 ; 102 ( 2 ): 399 – 404 . Google Scholar CrossRef Search ADS PubMed 30 Redline RW . Placental inflammation . Semin Neonatol . 2004 ; 9 ( 4 ): 265 – 274 . Google Scholar CrossRef Search ADS PubMed Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Journal

American Journal of EpidemiologyOxford University Press

Published: Aug 1, 2018

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