1. Infants conceived via natural In Vitro Fertilization (IVF) cycles (no controlled ovarian hyperstimulation) were less likely to be low birthweight at delivery compared to those conceived via standard IVF cycles.
2. This association did not remain significant after adjusting for gestational age.
Evidence Rating Level: 2 (Good)
Study Rundown: A growing number of pregnancies in the United States are conceived following Assisted Reproductive Technologies (ART) treatments. This increase in ART treatments has been attributed to advances in science and technology as well as the social and cultural phenomenon of delayed childbearing and age-related infertility. While ART poses only minimal risk to healthy women and their potential offspring, studies have identified that infants conceived by ART treatments experience an increased risk of adverse perinatal outcomes, including preterm delivery and low birthweight. The most common complications related to ART treatments are related to an increased risk of multifetal gestation. Low birthweight is classically defined as birthweight <2500 grams and unlike the diagnosis of small-for-gestational age, is not gestational age-specific. In this way, use of low birthweight can be confounded by preterm delivery since preterm infants are more likely to weigh less but are not necessarily growth restricted or small-for-gestational age. In Vitro Fertilization (IVF) involves timed ovulation followed by egg retrieval, in vitro fertilization of the egg by ejaculated sperm followed by embryo transfer of the fertilized egg on day 3-5 after fertilization. In an IVF cycle, ovulation can occur naturally or as a result of stimulation. Stimulated cycles involve ovulation induction or controlled ovarian hyperstimulation achieved using gonadotropins (e.g. follicle-stimulating hormone, luteinizing hormone) to stimulate folliculogenesis followed by injection of an LH-analogue (typically hCG or GnRH analogue) to stimulate ovulation. In natural cycle IVF, women are allowed to ovulate “naturally” such that only the egg she would have ovulated is retrieved for use in the IVF cycle. While there are pros and cons to both approaches, certain populations would not be candidates for natural cycle IVF, including women with ovulatory disorders who do not ovulate in a predictable manner if at all. Previous cohort studies in international populations suggest that compared to infants born after standard IVF, those born following natural cycle IVF are less likely to be low birthweight.
In the first study of its kind in the United States, researchers in Colorado compared pregnancy and perinatal outcomes between infants conceived via natural compared to standard IVF. Results demonstrate that while infants conceived via natural IVF were less likely to be low birthweight, this difference did not remain significant after adjusting for gestational age. These results imply that while natural cycle IVF babies are less likely to be low birthweight, this may be confounded by a higher incidence of multiple gestations and/or preterm delivery with stimulated IVF cycles. Strengths of this study included single center cohort, which minimized variability in stimulation protocols and retrieval and transfer technique. However, these findings are limited by retrospective study design and associated risk of bias as well as inability to account for potential confounders such as ethnicity or parental height. Additional investigation is required to determine whether differences in neonatal outcomes by stimulation protocol are driven by a causal association or are instead related to side effects of stimulation (e.g. multiple gestations) or to pre-existing conditions (e.g. diminished ovarian reserve) that necessitate a stimulated cycle.
Relevant Reading: Implications of ART on term singleton birth weight
In-Depth [retrospective cohort study]: All singleton live births from fresh IVF-embryo transfer cycles from 2007-2013 at one IVF center were included in the analysis. Perinatal outcomes (including length of gestation, birthweight, preterm delivery, and size for gestational age) were compared between stimulated (n = 174) and unstimulated (or natural) (n = 190) IVF cycles. Women in the natural group were older (35 vs. 34.2 years, p < 0.05), but had similar parity and prior ART history.
Infants born to natural IVF cycles were less likely to be low birthweight (<2500 g) than those born following stimulated cycles (1% vs. 8.6%, p < 0.005). This lower incidence of low birthweight infants in the natural cycle group remained significant after adjusting for maternal age, infertility diagnosis, use of intracytoplasmic sperm injection, and number of embryos transferred (OR: 0.07, 95% CI: 0.01-0.4) but did not remain significant after adjusting for gestational age (OR: 0.11, 95% CI: 0.01-1.0). There were fewer preterm infants in the natural cycle group.
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