In the past 40 years, since the first human in-vitro fertilization (IVF) live birth, the utilization and efficiency of assisted reproductive technologies (ART) have increased significantly. As the success of these treatments improved, patient safety and achieving healthy pregnancy outcomes became a new focus of research and discussion . The main goal of this newfound focus has been to decrease the rate of multiple gestations, and much effort has been devoted to the research regarding elective single embryo transfer (eSET) .
Another area of great interest is the long-term outcome of ART pregnancies, such as adult-onset diseases . Unfortunately, many of these outcomes are confounded by other obstetrical complications, including low birth weight (LBW) and preterm birth (PTB), which are thought to be risk factors for several cardiometabolic conditions including type 2 diabetes (Barker's hypothesis) [4–6], as well as inevitably linked with each other. Importantly, a number of reports showed an increased risk of LBW and PTB with ART .
The American Congress of Obstetricians and Gynecologists (ACOG) identifies birth under 37 weeks gestational age as preterm, with further classification into late (34 weeks and above) and early (under 34 weeks) preterm births . The WHO defines LBW as birth weight under 2500 g. It is further categorized into LBW (<2500 g), very low birth weight (VLBW) (<1500 g), and extremely low birth weight (ELBW; <1000 g) . It is important to distinguish between LBW and small for gestational age (SGA), since the definition of the latter may vary by region and is subject to accurate determination of gestational age. Although SGA infants account for a number of LBW infants, LBW is a more reliable parameter compared with SGA, and it is easily obtained at birth. Aside from conception via ART, birth weight can be affected by a myriad of other risk factors, including maternal smoking during pregnancy, multiple gestations, prematurity, intrauterine growth restriction, socioeconomic factors, genetic predisposition, infections, and maternal nutritional status .
LOW BIRTH WEIGHT INCIDENCE IN NATURALLY CONCEIVED PREGNANCIES: THE BENCHMARK
The Centers for Disease Control and Prevention (CDC) annually publish the National Vital Statistics Report, which includes the incidence of prematurity and LBW in the United States. As expected, said publication shows that LBW is more prevalent amongst multiple births (59.9%) than singleton births (8.0%) . The CDC also publishes the Assisted Reproductive Technology Surveillance, which analyzes ART-conceived pregnancies. Its data shows that ART-conceived pregnancies have a higher incidence of LBW (25.5%) compared with the incidence in all births (8.1%). There is also a large difference in rates of prematurity: 31.2% of ART-conceived versus 9.7% in all births. When focusing on singleton births, these differences are reduced substantially (LBW: 8.7 versus 6.4%; PTB 13.4 versus 7.9%, for ART-conceived and spontaneous singleton births, respectively). This report concludes that reducing the number of embryos transferred and increasing the use of elective SET (eSET) will reduce multiple births and their related adverse outcomes .
Although this data is very informative because of its vast sample size and inclusivity, no distinction is made as to the effect of the individual factors of each ART treatment – such as the use of intracytoplasmic sperm injection (ICSI), eSET or multiple embryo transfer (MET), fresh or frozen embryo transfer (FET), and so forth – on LBW and PTB. Therefore, a thorough review and breakdown of the individual factors related to the ART process is necessary to determine how these factors may contribute to LBW and PTB.
NUMBER OF EMBRYOS TRANSFERRED MATTERS: ELECTIVE SINGLE EMBRYO TRANSFER VERSUS DOUBLE EMBRYO TRANSFER
Double embryo transfer (DET) is far more likely to result in multiple gestations, therefore, increasing the risk of LBW and PTB . Given the dramatic effect of multiple gestations on LWB and prematurity described in the previous section, it is necessary to analyze these pregnancy outcomes separately. As previously mentioned, significant emphasis has been placed on reducing the number of multiple pregnancies, mainly through elective SET . Therefore, in this review we focus on the outcomes of singleton births.
Martin et al. studied incidence of LBW and PTB in singleton births following fresh SET versus DET and compared them to those of the general population. The results showed that DET result in a higher incidence of LBW and PTB than non-ART singleton births [adjusted OR (aOR) 1.59–2.17 and 1.38–1.58, respectively]. No difference was seen between SET singletons and non-ART births . A literature search revealed no publications comparing singleton LBW incidence after SET and DET after adjusting for prematurity.
IS FROZEN EMBRYO TRANSFER BETTER THAN FRESH EMBRYO TRANSFER? CONTROVERSIES REGARDING THE PROTECTIVE EFFECT OF CRYOPRESERVATION
Two publications (a retrospective cohort study and a meta-analysis) comparing fresh versus frozen–thawed embryo transfers attributed a lower risk of LBW to cryopreserved embryos (adjusted relative risk 0.73–0.82), while finding no difference in PTB [15,16▪]. The retrospective cohort study also highlighted the possibility of an ‘overcorrection’ effect, pointing to an increased incidence of high and very-high birth weight (defined as >4000 g and >4500 g, respectively) after FET. Similarly, the meta-analysis indicated a RR of 1.58 for having a large for gestational age birth (LGA) after FET compared with a fresh transfer. Furthermore, it reported a RR of perinatal mortality of 0.88 with FET compared with fresh transfers. Notable limitations of these two articles include the lack of adjustment for gestational age in the case of the retrospective study  and the reported heterogeneity of the analyzed studies in the meta-analysis, including differences in the cryopreservation method used [16▪].
Meanwhile, other articles dispute these claims and report no difference in LBW after fresh or frozen cycles. Sekhon et al. analyzed 202 SETs in donor oocyte cycles and concluded that there was no difference in LBW between fresh and vitrified euploid SETs. Comparison with 2760 autologous euploid vitrified SETs also yielded no difference in LBW . Another retrospective study compared 516 cycles undergoing FET or fresh embryo transfer after ICSI for male infertility, and no difference was found in incidence of LBW . Although both studies were well designed, they had smaller sample sizes than their previously cited counterparts.
Another interesting study compared the birth weight and gestational age of consecutive sibling singletons of oocyte donation cycles after fresh embryo transfer or FET. No difference was observed in birth weight or gestational age. Notably, this article compared means for each analyzed parameter, as opposed to other studies, which compared incidence of LBW or PTB .
Although cryopreservation may indeed have an effect on birth weight and prematurity, this is difficult to isolate from other advantages of cryopreservation, such as aneuploidy screening with preimplantation genetic testing for aneuploidy (PGT-A) and the increasing proportion of cryopreserved embryos transferred as SET. Only one of the aforementioned studies adjusted for these confounders, albeit being confined exclusively to oocyte donation cycles .
THE EFFECT OF THE ENVIRONMENT: NATURAL VERSUS ARTIFICIAL ENDOMETRIAL PREPARATION
Aside from the processes related to embryo fertilization and culture, the endometrial environment hosting said embryo may also have an effect on the healthy development of the pregnancy and, ultimately, on perinatal outcomes. Since the introduction of FETs in the 1980s, the question arose as to whether it was better to transfer an embryo during a natural cycle or to prepare the endometrium for implantation artificially. Currently, four strategies are commonly used for endometrial preparation: natural cycles with no stimulation, in which luteinizing hormone is measured to schedule the transfer; natural cycles scheduled by administration of hCG; artificial cycles with hormone replacement therapy composed of estrogen, progesterone, with or without GnRH analogs; and artificial cycles with low-dose gonadotropins . Although several studies have been undertaken in an attempt to establish the best method to improve pregnancy rates , only one includes birth weight and gestational age in its results, showing no significant difference (n = 161) . Of note, similarly to one of the previously mentioned articles, this article does not compare categories such as LBW or PTB, but rather compares the means of birth weight and gestational age.
CHANGES IN ASSISTED REPRODUCTIVE TECHNOLOGIES: HAS BIRTH WEIGHT CHANGED OVER THE YEARS?
Interestingly, although several of the mentioned studies make use of large datasets constituting many years of data, we found only one evaluating trend in birth weight after ART over the years. This retrospective cohort of 7295 singletons from fresh and frozen cycles found no significant difference in the average birth weight over the 18-year period constituting 1996 through 2013. The same study found higher mean birth weights in frozen versus fresh cycles, and no difference in ICSI versus conventional IVF or day 3 versus day 5 transfers. One limitation of this study was the difference in size of the fresh and frozen groups (6625 and 1030, respectively), which limited the number of LBW infants born from frozen cycles to less than 10 per studied year .
With the increasing prevalence and success of ART, there has been an increased interest in understanding and preventing the potential adverse effects that these treatments may have on the resulting offspring. One of the main negative effects of ART is the three-fold incidence of LBW in newborns conceived after ART when compared with all live births.
The difference in LBW between ART and naturally conceived newborns is largely attributable to the increased rate of twin and higher order gestations as a result of multiple embryo transfers. This issue is being addressed via a global effort to better identify the ideal candidates for eSET, thus reducing the number of transferred embryos.
This review outlines some of the many studies that have been devoted to elucidating the causes of the problem of LBW and prematurity in ART singletons. In them, we observe several interesting trends that could shed some light on the issue. When comparing SET to DET resulting in singleton births, the latter is associated with worse perinatal outcomes. However, there are no articles comparing both groups that adjust for prematurity or account for FETs, which are increasingly becoming the mainstay of clinical practice.
In regards to the question of fresh versus cryopreserved embryo transfer, there is some controversy as to whether this affects birth weights, with large sample size articles indicating that FET is indeed better for achieving a birthweight similar to that observed in spontaneous pregnancies. In this matter, it is also important to highlight the difficulty in addressing this issue in an isolated matter, as SETs are more prevalent in frozen–thawed cycles and aneuploidy screening is also almost exclusive to this modality.
Of the articles comparing different endometrial preparation strategies to optimize ART outcomes, our literature search yielded only one mentioning of perinatal outcomes, such as PTB or LBW, which revealed no difference between the studied groups. The one study analyzing the birth weight trend over time showed no significant difference in 18 years, other than that attributable to whether the cycle was fresh or frozen.
In conclusion, the attempts to increase the proportion of eSET cycles are ongoing and more data is being gathered in regards to the long-term outcomes of ART-conceived newborns. In the meantime, it becomes necessary to clarify exactly, which factors – and to which degree – contribute to the higher LBW and PTB incidence seen in ART pregnancies. Although several studies have reported on birth weight and prematurity, it is important to note that many of them do so as a secondary outcome, having the substantial design limitations and underpowering for said outcome that this entails. Hence, further research is necessary that specifically addresses the issues of birth weight and prematurity, as these are very likely associated with long-term conditions of adulthood of ART-conceived offspring.
Financial support and sponsorship
Conflicts of interest
E.S. is a consultant and receives research funding from the Foundation for Embryonic Competence. A.R. has no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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