ASRM 2013 Update: ART Safety: Singleton pregnancy

October 21, 2013Carole 3 Comments »

This is the second part of a two part series on ART Safety. Read the first part here.

Okay, if we take twinning off the table as a cause for  the increased risk of perinatal complications seen in  ART babies, are there any risks to having a singleton ART baby compared to having a singleton spontaneously conceived? Well, yes, there are some additional risks.

Higher monozygotic twinning rates after ART. Monozygotic twinning is a big word for saying that a single fertilized egg splits into two somewhere along the line, creating a twin pregnancy from one fertilized egg. This seems to be 2.25 fold more common in ART conceived babies  (0.9% incidence) compared to the identical twins made in the bedroom (0.4%).

So what’s the big deal. Identical twins are fun, right? Well, the problem comes if they have to share the same amniotic fluid and same placenta. One twin may get the lion’s share of the nutrients and the other twin may not grow very well. Their umbilical cords can become tangled around each other, causing problems with getting enough oxygen to the developing fetuses. Sometimes “twin-to-twin” transfusion syndrome can occur where one twin gets too many red blood cells and the other two few, an unhealthy situation for both, possibly leading to heart failure and fetal death.

What is it about ART that increases the chances of having monozygotic twins? We don’t know but here are some possibilities that have been suggested:

  • Ovarian stimulation may increase the number of available eggs that are prone to splitting.
  • The outer shell of the egg (the zona pellucida) may be altered by ART, increasing the chance of splitting embryos.
  • We know that the zona pellucida may become hardened from some protocols (like freezing eggs or older media formulations) which may encourage splitting.
  • Culture media may play a role in increasing the twinning rate.
  • Implantation of more than one embryo- could some sort of group effect encourage twinning?

Studies have noted that increased twinning of single zygotes after IVF seems to be more common:

  • when transferring more advanced blastocyst stage embryos– increases the risk 4.25 fold
  • When ICSI, assisted hatching and day 5 culture are used-  increases the monozygotic twinning risk by two fold

Are there any other increased obstetrical risks for ART singleton pregnancies compared to  spontaneous conception singletons?

Although singletons from ART have an obstetrical advantage simply by having a room to themselves in the uterus, there is some data that suggests that the risk of placenta previa is 3.8 fold greater in ART singletons compared to population data from all spontaneously conceived pregnancies. Placenta previa is a condition in which the placenta forms in an awkward spot in the uterus so that it blocks the cervix and can cause heavy bleeding. This is a problem for natural delivery because the baby must exit via the cervix. A C-section would be needed for this condition. Keep in mind, that the baseline incidence for placenta previa is less than a fraction of one percent ( 3-5 pregnancies of every 1000 pregnancies) so even a 3.8 fold increase does not make it likely that you will have this problem because at four-fold increase, at most 20 out of 1000 ART pregnancies would be affected- still a very low rate.

Placental abruption , or a peeling away of the placenta from the uterine wall is another even more severe complication that seems to be two-fold more likely with ART babies.  Placental abruption requires emergency treatment to save mother and child because severe bleeding occurs. Before you get too alarmed about these fold increases, remember that the actual risk of experiencing placental abruption in the general population is very small- 1% of all singleton pregnancies. If you risk of something happening is 1%, that means that one person in 100 persons will have that thing happen. If you then find out that your risk is increased two-fold to two in one hundred people, your risk, though increased, is still small. Ninety-eight out of one-hundred people won’t have this problem.

Birth defects seem to be similar with ART singletons and spontaneously conceived singletons–meaning there appears to be no increased risk from using ART in general for most kinds of birth defects. A large study of birth registry data from over 500,000 ART babies born in Sweden, Norway , Finland and Demark, suggest that birth defects in three organ systems may be elevated for ART singletons. Congenital heart malformations were increased by 1.2 fold,  GI malformations by 1.56 fold and urogenital malformations by 1.49 fold. (The risk of Congenital Malformations in Children born after assisted reproduction is only increased in some organ systems:A Nordic study from the Conartas Group, Oral Abstract 326, presented at ASRM Meeting)

Unfortunately the ART category in this study didn’t distinquish between use of ICSI and conventional IVF. There is some conflicting data about the use of ICSI specifically, and the risk of birth defects. Some studies suggest there might be a small increase over background incidence of birth defects when ICSI is used. Other studies do not find any difference. The confounding factor with ICSI is that it is often used to help males with very severe make factor which may be due to an  underlying genetic abnormalities. For instance, some causes of male factor are due to massive deleted regions in the Y chromosome where huge amounts of DNA sequence are completely missing.  It’s possible some of the birth defects have more to do with genetic problems due to passing on abnormal DNA than the ICSI protocol per se. So it is hard to tease out ART-related problems due to the use of ICSI itself, compared to problems arising from the fact that a subset of the infertility population who is more likely to have some genetic mutations are the ones who need ICSI.

Put another way, what further complicates understanding the safety data around ART is that the population of people who use ART are are not necessarily at the same risk to start with compared to the general population for birth defects or other complications from pregnancy. Here is an example of what I mean. Infertility has multiple origins- both structural and genetic- and  infertility is not like an on or off switch for most people, but runs along a gradient, meaning that most people exist somewhere along a range of less to more fertile, having some personal factors that make them more fertile, and others that make them less fertile. Many people who use ART might well become pregnant eventually on their own but it would take longer than the more fertile person next to them on the gradient.

If you take the time to conceive as a barometer for how fertile or infertile someone is, you could ask whether the time to conceive –by itself–is correlated with more or less obstetrical risks (eg. preterm birth) in the general population that hasn’t used ART. It turns out that increased time to conceive (more than one year) was correlated with an increased risk of pre-term birth compared to those in the population who conceived in less than one year.  In fact, mothers who needed more than one year to conceive  spontaneously had similar risks for pregnancy complications and birth defects as ART mothers.

So this raises the question of whether some innate causes to infertility (for example, genetic causes) go hand-in-hand with an increased risk of obstetrical complications, regardless of whether ART is used or not. This commingling of causes (ART and inherent) make it harder to tease out whether some ART-related safety issue that could be attributed to ART may also be attributable to underlying genetic issues that are inherent to the patient population. The take-home lesson here is that ART does not heal the causes of infertility, but rather makes it possible for less fertile couples to conceive – more quickly or at all–and now their increased risk of birth defects or obstetrical complications is revealed.  The increased risk may always have been  there but invisible because they didn’t get pregnant.

When looking at ART patients versus the general population, ART mothers are usually older, more likely to be childless, less likely to smoke, are more likely to be affluent, tend to have a higher BMI and are less reproductively-healthy. When you correct for some of these differences in BMI, age, years of infertility and so on, the risks are much more similar between ART singletons and spontaneous conception singletons.

When the IVF registry data from other countries is followed over many years, the good news is that the most recently conceived  IVF babies seem healthier than the  IVF babies conceived years ago, so perhaps  even if there are ART protocol induced risks,  ART protocols are becoming more similar to the natural conditions we are trying to mimic, and hopefully becoming safer over time.

A series of studies looked at what happened when a mother had two pregnancies, one spontaneous and one ART.  For whatever reason, women tend to have heavier babies with each subsequent pregnancy. However, when the second baby was an ART baby, this wasn’t the case. The second ART baby often had a lower birth weight than the first spontaneously conceived child. The study authors concluded that controlled ovarian stimulation  and in-vitro lab protocols seen to effect (lower) the birth weight of the ART baby compared to their spontaneously conceived sibling, even when the maternal environment is the same. It was previously shown that the average weight of ART singletons is less than the average weight of spontaneously conceived singletons., but this showed that even in the same maternal environment, this phenomenon persists, suggesting there may be some ART-related causes, in addition to any genetic based infertility causes for the lower birth weights in ART singletons. Oddly enough, one ART intervention, achieving pregnancy from a frozen embryo transfer cycle, seemed to produce heavier than average babies. Why this could be is not understood.

Studies on medical issues in human populations are incredibly hard to  understand and come up with clear signals because there are so many confounding variables. But a few conclusions can be made with confidence:

Take home messages:

  • Perinatal risks are slightly increased in ART singletons vs. spontaneously conceived singletons (but still much lower than risks from any type of TWIN pregnancy).
  • Time to pregnancy of greater than one year increases perinatal risks, even in spontaneously conceived children.
  • Based on sibling studies, there does seem to be an ART protocol (possibly ovarian stimulation or lab protocols) that decreases birth weights. It is still inconclusive whether culture media type or length of culture may have an effect.
  • Overall, perinatal outcomes for ART singletons are reassuring, because risks are low, even if slightly increased relative to spontaneous conceived singletons.
  • TWINNING Is still the most important health risk factor.
  • IVF Safety appears to be increasing over time (perhaps as protocols improve?) compared to 30 years ago.








© 2013, Carole. All rights reserved.

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