Perinatal Outcomes by Mode of Assisted Conception and Sub-Fertility in an Australian Data Linkage Cohort

Abstract

BackgroundFertility treatment is associated with increased risk of major birth defects, which varies between in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), and is significantly reduced by embryo freezing. We therefore examined a range of additional perinatal outcomes for these exposures.MethodsAll patients in South Australia receiving assisted conception between Jan 1986–Dec 2002 were linked to the state-wide perinatal collection (all births/stillbirths ≥20 weeks gestation or 400 g birth weight, n = 306 995). We examined stillbirth, mean birth weight, low birth weight (<2500 g, <1500 g), small size for gestational age (<10th percentile, <3rd percentile), large size for gestational age (>90th percentile), preterm birth (32–<37 weeks, <32 weeks gestation), postterm birth (≥41 weeks gestation), Apgar <7 at 5 minutes and neonatal death.ResultsRelative to spontaneous conceptions, singletons from assisted conception were more likely to be stillborn (OR = 1.82, 95% Confidence Interval (CI) 1.34–2.48), while survivors as a group were comprehensively disadvantaged at birth, including lower birth weight (−109 g, CI −129–−89), very low birth weight (OR = 2.74, CI 2.19–3.43), very preterm birth (OR = 2.30, CI 1.82–2.90) and neonatal death (OR = 2.04, CI 1.27–3.26). Outcomes varied by type of assisted conception. Very low and low birth weight, very preterm and preterm birth, and neonatal death were markedly more common in singleton births from IVF and to a lesser degree, in births from ICSI. Using frozen-embryos eliminated all significant adverse outcomes associated with ICSI but not with IVF. However, frozen-embryo cycles were also associated with increased risk of macrosomia for IVF and ICSI singletons (OR = 1.36, CI 1.02–1.82; OR = 1.55, CI 1.05–2.28). Infertility status without treatment was also associated with adverse outcomes.ConclusionsBirths after assisted conception show an extensive range of compromised outcomes that vary by treatment modality, that are substantially reduced after embryo freezing, but which co-occur with an increased risk of macrosomia.

Increased risk of large-for-gestational age birthweight in singleton siblings conceived with in vitro fertilization in frozen versus fresh cycles

“…These analyses indicate that frozen embryo state [4][5][6][7][8][9][10][11][12][13] is associated with an increased risk for LGA, and blastocyst embryo stage is associated with a decreased risk for SGA. The magnitude of the increase we found in the 2nd birthweight in the fresh/frozen pairs of siblings of +222 g is in accord with prior studies (+244 g 4 in an Australian population, +250 g 10 and +286 g 6 in Danish populations), and far exceeds the +81 g attributable only to an increase in parity.…”

“…Prior studies have also consistently reported an excess of large-for-gestational age (LGA) birthweights among children born from frozen embryos; [4][5][6][7][8][9][10][11][12] longer embryo culture of fresh embryos has also been implicated as a potential cause of LGA [13].…”

“…Most often studies compare women treated with IVF to fertile women, but this approach has limitations: the two groups usually differ on a range of important characteristics such as age, socioeconomic status, and education, as well as reproductive history. Several studies have compared women treated with IVF to women with a history of subfertility and no IVF treatment [11,15,16] in an effort to quantify the contribution of the IVF treatment to adverse perinatal and infant outcomes.…”

Independent factors influencing large-for-gestation birth weight in singletons born after in vitro fertilization

“…Several studies have shown that singletons born after FET have a perinatal outcome more comparable to those born after natural conception than to those born after fresh embryo transfer (fresh ET), having higher birth weight and less pregnancy complications [2][3][4][5][6][7][8][9][10]. However, higher risk for birth of a singleton being large for gestational age (LGA) has been revealed after FET [2,3,7,8,[11][12][13][14].…”

“…The influences of the culture media [21][22][23], culture period [24,25], hormonal protocols [26], and infertility [12,14,27] on the IVF singleton birth weight have already been considered. There are several studies confirming that IVF placentas differ from spontaneous placentas in their size, shape, weight, and abnormality rate [3,6,7,[28][29][30][31], and that placentation following FET differ from the placentation following fresh ET [3,6,7,13] In this study, we analyzed the connection of IVF procedure type and maternal background factors to LGA risk.…”