The Real Risks With IVF That Everyone Should Know

Special Guest Dr. Jie Deng

I’m honored to have Dr. Jie Deng as a guest on this episode of The Egg Whisperer Show. She is not only an Obgyn and Maternal Fetal Medicine specialist (did extra training studying high risk pregnancies), she is also a fertility doctor at Stanford University finishing up her Reproductive Endocrinology and Infertility Fellowship.

Jie Deng, M.D., PhD, joined Stanford University fellowship program in July 2018. She graduated from Sun Yat-Sen University of Medical Science in China, where she received her M.D. and Ph.D. She relocated to the United States in 2008 when she was awarded a California Institute of Regenerative Medicine Training Grant and worked in the field of stem cell research at University of California in San Diego. Subsequently she completed her residency in Obstetrics and Gynecology at Wayne State University. After residency she was trained and worked as a Maternal-fetal Medicine specialist at Yale University. She has been interested in and actively involved in scientific research. She published a variety of peer-reviewed articles in the fields of genetics, epigenetics, and stem cells in journals such as Nature Genetics, Nature Methods, Genome Research, Cell Stem Cell and Molecular Cells. She is also productive in translational research and authored peer-reviewed articles in journals such as Nature Medicine, Fertility & Sterility, Journal of Assisted Reproduction and Genetics, Molecular Human Reproduction and Prenatal Diagnosis.

I’m so happy to have her on my show to talk about this topic.

Dr. Aimee: What’s the pregnancy risk for women over age 40 or 45?

Dr. Deng: According to a 2019 report from the CDC, birth rates for women aged 40–44 has been rising almost continuously since 1985. Then again, you often hear this and that person or some celebrities had babies born after age 45 or during perimenopause.

In this age group, especially between age 40–44, if women conceived by using their own eggs, they will have an increased risk of miscarriage or having a baby with abnormal chromosomes. At age 40, the chance to have a baby with Down’s syndrome is about 1 in 100 and at age 45, the chance is 1 in 25. So once a woman gets pregnant, both screening and diagnostic testing can be done to ensure that the baby’s chromosome is normal, if the women wants to find out that information.

For women between age 45–50, the likelihood to get pregnant with own eggs are very small. So many women will use donor eggs to get pregnant. With donor eggs the age-related genetics are of the donor — so that if a 45-year old woman is carrying a pregnancy from a 30-year old women’s donated egg, the risk of Down syndrome is that of the 30-year old, which is only 1 in 800. In that case, the chance to have a chromosomal abnormal baby is low.

However, regardless of how women conceived, naturally or with IVF, IUI or other interventions, being pregnant at age 40 or beyond have increased risk of certain specific medical complications. For example, pregnant women aged 45 years and older had a 1.5–2 fold greater risk of experiencing gestational diabetes, preeclampsia compared to younger women (age 30–34). It may not always be women’s age that caused the problems, but because as the older we get, we have conditions like diabetes or hypertension more frequently, and these potential health issues become magnified with pregnancy. Advanced age also appeared to shorten pregnancies. More than one in five of 45 years or older mothers delivered their babies at less than 37 weeks’ pregnancy (a normal pregnancy lasts 40 weeks), compared to only one in 10 of all the women. In addition, 80% of mother age beyond 45 delivered their babies by Cesarean section — more than twice the overall rate.

With that being said, most women who are in their 40’s even close to 50 had healthy deliveries and babies, if they received the health care they need. But it’s important to be aware of the risks and to make sure that you do everything you can to minimize them.

Dr. Aimee: What should women over age 45 do to prepare for pregnancy?

Dr. Deng: Prior to conception, women should work with their primary care doctors to manage chronic medical conditions such as hypertension and diabetes, and to get in the best shape possible. Often time they will be referred to a Maternal-fetal medicine specialist who will assess their medical conditions, review the safety data of any medication they might be on to see if medication are safe or not to take during pregnancy. Doctors might order an EKG to check their cardiac function. Because during pregnancy, the heart has to work harder to adapt the change of pregnancy. So, if someone has marginal heart function in the non-pregnant state, she might not be able to tolerate the added stress of the pregnancy. Sometimes women may benefit from taking baby aspirin to reduce the risk of preeclampsia.

Meanwhile, stay as healthy as you can. Make sure you take prenatal vitamin with folic acid. Quit smoking and taper down the amount of alcohol intake and keep as close to your ideal body weight as possible.

Dr. Aimee: What extra care do they expect when they are pregnant?

Dr. Deng: Start prenatal care as early as possible. In early pregnancy, women will be scheduled for routine prenatal testing, including NIPT for fetal chromosomal conditions, or chorionic villus sampling (CVS) or amniocentesis to ensure the chromosome of the baby is normal.

Dr. Aimee: If women had pregnancy after PGT-A, is prenatal genetic testing still needed?

Dr. Deng: Yes, because PGT uses only a few cells from the early embryo, and misdiagnosis is possible although it is uncommon. ACOG recommends that all patients who have had PGT still should be offered traditional diagnostic testing or screening for chromosomal abnormalities.

Women will have a detailed ultrasound for the baby’s anatomy at around 18–20 weeks. All pregnancies after IVF will have additional ultrasound to look at the detailed structure of baby’s heart because the chance of have fetal congenital cardiac anomaly is higher in IVF pregnancies.

Dr. Aimee: How high is the chance that an IVF baby will have congenital cardiac anomalies?

Dr. Deng: The fetal congenital cardiac anomalies are 1% in IVF pregnancies, which is double the risk in pregnancies that conceived naturally.

Women might also need early glucose screening testing, and be closely monitored for high blood pressure and preeclampsia. Women may need additional ultrasounds in their 2nd and 3rd trimesters to monitor the baby’s growth, since low birth weight is another pregnancy complication that is more common in older expectant moms.

Dr. Aimee: Many people ask for twins during IVF treatment. What are the risks of twin pregnancies?

Dr. Deng: In the early days of IVF before we have good tools to select the best potential embryos, doctors transferred two or three or even more embryos to increase the chance of pregnancy. Nowadays, PGT-A can select the chromosomally normal embryos, which usually provides an average live birth rate of 60%. In this case, if we transfer more than one normal embryo, that will dramatically increase multi-pregnancies without increasing the overall live birth rates with a comparable magnitude.

Twin pregnancy is associated with almost all maternal and neonatal complications except big size babies. Babies are likely to be born prematurely. Only 40% of twin pregnancies go full term. Prematurity may lead to a number of problems. Newborn may need respiratory support and feeding support because of immature of lungs and GI system. And depends on GA at birth, babies who survive extreme prematurity are at risk for long-term effects which may include developmental delays, cerebral palsy, vision problems or hearing loss. For the Mom, the preclampsia and GDM risk in twin pregnancies is three to four times the rate in singleton pregnancies. Because of these potential complications of multi-pregnancies, the whole REI professional world has been dedicated to single embryo transfer, especially when we transfer D5 or 6 genetically normal embryos.

Dr. Aimee: Does IVF or ICSI increase risk of congenital anomalies?

Dr. Deng: It’s such an important question but answering that question is not simple.

Although most pregnancies conceived by IVF have healthy outcomes, there have been some reports of increased risk for birth defects in babies conceived with IVF. However, these studies and findings have not been consistent. In 2016, CDC used national ART surveillance data linked with information from vital records and birth defects registries for three states (Florida, Massachusetts, and Michigan), and studied ART and birth defects in 4 million infants. Data from this large population showed that, if we don’t look at congenital anomalies that are associated with abnormal chromosomes, the overall chance of having non-chromosomal defects was 5.8% per 1000 for ART infant, which is slightly higher than 4.7 per 1000 for non-ART infants. Babies conceived using ART were more likely to have congenital defects such as cleft lip, cleft palate or a congenital heart defect. In addition to the structural birth defects, some evidence links IVF to two genetic diseases: Beckwith-Weidemann syndrome and Angelman syndrome. However, whether these outcomes are due to the ART treatment or whether it is due to the inherent problem that has led to the couple being unable to conceive naturally and having to use ART is unclear. Also, we have to remember that the absolute risk of having these defects are very low. For example, even IVF babies have ten times higher chance to have Beckwith-Weidemann syndrome or Angelman syndrome, that chance would still be 1 in 1300 or 1 in 1000. Of course, all these findings deserve more research attention, but based on observed data, IVF is considered safe and does not have much greater risks than those of natural conceptions.

Dr. Aime: Would ICSI affect intelligence of offspring?

Dr. Deng: ICSI procedure involves more manipulations of egg and sperm. Given the potential stresses of such handling, there have been concerns about this procedure, even though many of them are theoretical. As we just discussed, in light of the reassuring congenital malformation rates among IVF and ICSI babies, many follow-up studies switched their focus to the developmental outcomes of these children. Although several early studies with small samples suggested increased risk of mild developmental delay, 2% in ICSI children vs 1% in natural conceived children at 1 yr old age, data from many larger studies did not show difference in developmental outcomes when compared to the general population. Studies from Denmark examined the academic performance in over 8,000 children conceived by ART between 1995 and 2000 confirmed that ART-born children are just as intelligent as their spontaneously conceived peers — not super kids, but certainly not worse off. This was supported by other multi-center studies in which children’s development and behavior at 5 yrs and 10 years were studied. The differences in some ICSI children were likely due to influence of parental cognitive ability and education levels. ICSI procedure itself did not affect the psychological well-being, IQ or cognitive development of children.

There is also concern about the association of autism with ICSI. But from a 2 million newborn data in the registry, the chance to have autism is 19.0 per 100,000 in children born with ISCI, which is not significantly higher than naturally conceived children.

Dr. Aimee: How about medical health? Can IVF treatment increase cancer risk in childhood?

Dr. Deng: In December last year, one article involving data from 1,085,172 children suggested that there was increased risk of childhood cancer after frozen embryo transfer. After that article is published, many internet articles appeared with alarming titles such as “Freezing embryos doubles risk of IVF kids developing childhood cancer”; or “Children born from frozen eggs twice as likely to develop cancer”. This caused a lot of anxiety and calls from infertility pt who had children with FET or is planning to get pregnant with frozen embryos. Just two weeks ago, one article published on JARG pointed out significant flaws in the methodology and interpretation of this study. Basically, when you use a large sample database to do ‘data mining’ or ‘data fishing’, some dubious findings will turn up. You will find something that shows statistical significance, but these findings might not be valid due to misinterpretation of data or might not translate into clinical significance. In that study, women who conceived through FET were compared with those who conceived spontaneously. There are so many cofounding factors between two groups, which differed not only in the usage of FET, but also distributions of parental age, diagnosis of infertility, use of fertility drugs and ART, embryo cryopreservation etc. In order to prove an association between IVF and childhood cancer, ideally, we would hope to have two groups of children who are identical in every feature, except for the utilization of IVF. However, it is impossible to find such a control group in which children were born naturally by infertile parents. So it is almost impossible to confirm that the outcome was derived from the IVF technique itself. In addition, due to the very low absolute childhood cancer risk, hundreds or thousands of FETs would have to be avoided in order to “prevent” one case of childhood cancer. There are numerous benefits of FET, such as providing the opportunity for embryo banking and preimplantation genetic testing, decreasing the risk of OHSS and improve clinical pregnancy rate in some populations. We cannot take away FET because of this small dubious “risk”. Of course, we may be limited by the biological knowledge of the day, and the study observations deserve more attention, but so far, there is no good evidence supporting an association between FET and childhood cancer.

Dr. Aimee: Does IVF treatment increase risk of breast cancer or ovarian cancer?

Dr. Deng: During IVF treatment, the level of estrogen is much higher than normal physiological levels. The treatment also involves exposure to exogenous hormones that stimulate follicle growth and multiple ovarian punctures. That’s why people concern about the risks of breast, uterine cancer, and ovarian cancers after such exposures.

Studies investigating breast cancer risks in women who underwent IVF treatment are inconsistent. Most studies do not show an overall increase of breast cancer in exposed women. In 2018, one study linked data of 2.2 million person years of observation and risks of ovarian, breast, and uteri cancer in women treated with assisted reproductive technology in Great Britain.

No increased risk of corpus uteri or invasive breast cancer was detected in women who had had assisted reproduction. They observed increased borderline ovarian tumors but when they broke down patients’ characteristics, they found that increased risks of ovarian tumors were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumor in women treated because of only male factor or unexplained infertility, which suggested that ovarian tumor risks could be due to patients’ underling health problems rather than assisted reproduction itself.

For patients who were diagnosed breast cancer, data showed that egg freezing, or IVF treatment did not worsen the prognosis of cancer, or change the course of treatment, or result in relapse of cancer. Of course, due to the theoretical concern that estrogen can potentially stimulate cancer cell growth we do use some medication for example LTZ to lower the estrogen level during ovarian stimulation, especially in those estrogen-dependent Br Ca patients. But overall, IVF is considered safe. For breast cancer patients especially those who need to preserve their fertility before chemotherapy, they should not avoid fertility preservation treatment because of the fear that IVF treatment will worsen cancer status.

Dr. Aimee: Thank you Dr. Deng for being a guest on my show. Where can people find you?

Dr. Deng: I invite everyone to follow me on Instagram.

Catch more of me, and topics like this through The Egg Whisperer Show. Episodes are live-streamed on YouTube, Facebook, Twitter, IGTV and Apple Podcasts on Wednesdays at 7PM PST. Sign up to get my newsletter. Tune in to The Egg Whisperer Show on YouTube. and Sign up for The Egg Whisperer School.

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