Congenital Anomalies and Low Birth Weight Associated With Assisted Reproductive Technologies

Peter Kovacs, MD

Disclosures

Introduction

Several recently published studies address the issue of congenital anomalies and low birth weight in connection with assisted reproductive technologies (ART), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI).[1,2,3] Although it is only 24 years since the birth of the first baby using IVF, tens of thousands of babies have subsequently been born worldwide as a result of IVF or ICSI. Thus, any implication of an increased risk of congenital anomalies among babies conceived by such techniques has widespread repercussions.

Initially, IVF was used for the treatment of tubal infertility, but the field has advanced rapidly and the number of indications for IVF has expanded. Most of our safety information derives from retrospective case-control and cohort studies from databases in countries in which there are mandatory or voluntary registries that collect ART procedure and pregnancy-related data, along with information on perinatal outcome. These studies typically have observed an increased risk of congenital anomalies with IVF/ICSI when crude numbers were compared, but after controlling for maternal age, multiple gestation, year of birth, and gestational age, the relative risk became comparable to that for the general population.[4,5,6,7,8] However, after controlling for many potential confounding variables, Australian investigators discovered a 2-fold increased risk of major congenital anomalies with ART, not only in multiple gestations but in singletons and even in those infants born at term.[1]

There are a number of important points that need to be made as one evaluates the available information. In the United States, on average 2% to 3% of births in the general population are affected by congenital anomalies.[9] Many known factors are associated with an increased incidence of congenital anomalies: advanced maternal age, certain maternal medical conditions (eg, diabetes), certain medications (eg, antiepileptic agents), substance-abuse habits of the mother, environmental toxic effects, infections (eg, rubella), genetic abnormalities, multiple gestations, and prematurity. Certain anomalies are more common in male or female infants.

If one wants to compare the incidence of congenital anomalies associated with ART with that in the general population, it is important to find appropriate population controls. Women undergoing ART tend to be older. There are more multiple gestations, and there is a higher rate of prematurity with ART. These factors must be taken into account. If a nonlethal anomaly is identified during early gestation after IVF or ICSI, the pregnancy is possibly less likely to be terminated, because of the couple's limited options to achieve pregnancy. .

Thus, it is important to know the number of terminations for anomalies in the study and control groups. It is important to compare the sex ratio between newborns born after ART and in the control group. No studies have controlled for possible environmental toxic exposure (urban vs rural residence), maternal medical conditions, or medication use. Moreover, there may be other key differences between fertile and infertile populations that have an effect on the risk of anomalies but are unknown. If an increased incidence of congenital anomalies after IVF or ICSI is attributed to ovarian stimulation or the drugs used for that purpose, it becomes important to know how many women in the control group used the same drugs in order to conceive. Specifically, it is important to control for the type and dose of any drugs used to achieve pregnancy, independent of whether IVF, ICSI, or any other ART method was involved. This information is unavailable from these cohort studies.

Congenital anomalies are typically identified using the International Code of Diagnosis (ICD) criteria, but in some studies anomalies are defined as abnormalities found at birth that resulted in "malfunction" or "required surgical correction".[1,10] Not all anomalies are evident at birth, and several centers have made an effort to perform a more detailed physical evaluation (eg, routine cardiac ultrasounds) of the newborns after ART than is usually performed in the general population. This detection bias could lead to an overestimation of anomalies in the IVF/ICSI cohort.

Finally, it is unclear from these studies what the biological mechanism for the increased congenital anomalies might be. It could be the drugs, changes in the hormonal and growth factor/cytokine levels that occur as a result of ovarian stimulation, the laboratory handling of oocytes and spermatozoa, the infertility itself, or special maternal or paternal factors. This could be further analyzed by including only cycles with or without male factor infertility, cycles in which donor gametes are used, cycles in which a gestational carrier is used, or by the analysis of fresh vs frozen embryo transfer cycles.

When the currently available information is shared with couples who are planning to undergo ART cycles, it is important to put the absolute risk in perspective for them. Even if the higher 8% to 9% risk is the true risk, 91% to 92% of the offspring will be free of anomalies as compared with 96% to 97% of the offspring in the general population. With more women delaying childbearing, it is likely that more couples will need the help of an infertility specialist when they decide to start a family. It is important to collect further information not just on the risk of congenital anomalies but also on the later development of children born after IVF or ICSI. Over the next few years, some of the offspring born after IVF and ICSI will try to have their own families, so we will be able to collect data on their reproductive potential as well.

Although the studies that evaluate the incidence of low birth weight after IVF or ICSI face the same design difficulties as those that try to evaluate the risk of congenital anomalies, they seem to come up with similar results. Reports on the incidence of low birth weight with ART are less controversial, however.[2,6,7,11] There are a number of factors (eg, genetic, nutritional, gestational age, maternal medical conditions, and order of the pregnancy) that determine the birth weight of a newborn. To be sure, the risk of preterm birth and low birth weight is increased with ART. Most of this increase is due to the increased prevalence of multiple gestations. However, even singletons tend to be delivered at an earlier gestational age, and the rate of cesarean sections is also much higher.

These studies do not discuss whether elective labor induction as a result of real or perceived complications during pregnancy play a role in the earlier deliveries. Subgroup studies investigating fresh vs frozen embryo transfer, gamete donor cycles, male infertility, and gestational carrier, for example, might identify any special maternal, paternal, uterine, or hormonal characteristics that could explain the lower birth weight. Long-term follow-up of a large number of these children is necessary to see whether they are at risk for chronic medical conditions (diabetes, hypertension, coronary artery disease) later in life.

In summary, a recent report suggests that the risk of congenital anomalies with IVF or CSI is about 2-fold higher than the risk associated with unassisted conception.[1] If this is true, couples undergoing ART have to consider a small increase in the absolute risk. Perhaps these findings indicate that a more detailed in utero evaluation is necessary to provide couples with all available options, including the possibility of pregnancy termination. However, most congenital anomalies are not life-threatening and can be corrected once the baby is born. Critically, these studies are fraught with a number of potential confounders that could bias the results and overestimate the actual relationship between ART and the likelihood of a congenital anomaly. Before declaring any such putative relationship as established, more work must be done to correct for potential confounders and provide the least biased estimates of risk for clinicians to use in discussions with their patients.

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