Assisted Reproductive Technology is associated with higher risk of Birth Defects!

Since 1981, ART has been used in the United States. Today approximately 1.6% of all infants born in the United States every year are conceived using ART.  According to 2014 data by CDC, 208,786 ART cycles were performed, resulting in 57,332 live births (deliveries of one or more living infants) and 70,352 live born infants.

As the number of infants conceived by ART continues to increase, it was observed that those conceived after Assisted Reproductive Technology (ART) was born with several Birth defects, especially nonchromosomal birth defects as compared to those conceived the natural way! In fact according to CDC, the risk of certain birth defects was 2 to 4 fold as compared to those conceived naturally.

The largest study of its kind was published in April issue of JAMA pediatrics. The researchers linked ART surveillance, birth certificates, and birth defects registry data for 3 states (Florida, Massachusetts, and Michigan) during a period of 10 years from 2000-2010. The exposure studied was ART and certain techniques among ART births. The main outcome measures were prevalence of selected chromosomal and nonchromosomal birth defects that are usually diagnosed at or immediately after birth.

Of the total 4,618,076 live births, 64,861 or (1.4%) were conceived using ART. According to the lead investigator Sheree L. Boulet, DrPH, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia higher prevalence of  nonchromosomal birth defects (59.57 per 10,000) in ART infants compared with non-ART infants (48.40 per 10,000, P<0.001) was reported. Even after adjustment of all the confounders (maternal age), there was 28% higher risk of non chromosomal anomolies with ART.

Infants born after ART were also more likely to be born prematurely, have lower birth weights and mothers who underwent ART were higher educated, nulliparous, career oriented, elderly (>30 Years) and non-Hispanic white. They were also more likely to have Diabetes and Hypertension.

The birth defects most commonly observed were reduction deformity of the lower limbs (P=0.007), rectal and large intestinal atresia/stenosis (P<0.001), and tracheoesophageal fistula/esophageal atresia (P=0.001) compared with those conceived spontaneously. No statistically significant difference in birth defects was seen among fresh vs frozen embryos.

Other systemic reviews, metaanalysis and registry based studies have also concluded that birth defects are more common in infants conceived after ART, and stress upon need of further research according to various sub-groups of ART.

It was also seen that maternal age is inversely related to risk for chromosomal defects in ART, including trisomy 13, trisomy 21 (Down syndrome), and trisomy 18, probably because older mother undergo Preimplantation Genetic Diagnosis (PGD) as compared to younger woman, primarily for aneuploidy.

"It is possible that younger women with an ART-conceived pregnancy were less willing to undergo chorionic villue sampling or amniocentesis because of heightened concerns about risks to the fetus," wrote Boulet and colleagues. "Another potential explanation is that young women undergoing ART have more serious underlying health issues than older women and thus have poorer-quality embryos."

Other studies have found increased incidence of cancer, heart defects, genitourinary malformations and malformations of the eye later in life.

The current study has several limitations; it lacked data on pregnancies that did not end up in live births, so the prevalence of birth defects may be underestimated. Also infants born with ART are closely followed than those born naturally, so the detection of birth defects may be higher!

The study implies that patients should have a good discussion with their physicians about the ART procedure, including detail information on all the birth defects resulting due to the ART. They should also understand that the actual risk for individual family is very small, but the odds are increased. A careful evaluation of long term effects and defects later in life is also necessary by designing studies for long term follow up of such infants.

References:

http://www.cdc.gov/media/pressrel/2008/r081117.htm

http://www.medpagetoday.com/OBGYN/Pregnancy/57161

http://www.ncbi.nlm.nih.gov/pubmed/23449641

http://archpedi.jamanetwork.com/article.aspx?articleid=2506140

http://www.newsmax.com/Health/Health-News/IVF-reproductive-technology-birth/2016/02/04/id/712683/

http://www.reuters.com/article/us-health-ivf-birth-defects-idUSKCN0X122D

http://www.medscape.com/viewarticle/861447

Kelley-Quon L, et al "Congenital malformations associated with assisted reproductive technology: a California statewide analysis" AAP 2012.

Ondansetron Revisited: New and troubling data

Ondansetron

Ondansetron is a 5-HT₃ receptor antagonist manufactured by GlaxoSmithKline in US and is also available in its generic form, ondansetron.

The drug was approved by The U.S. Food and Drug Administration in 1991 for treating nausea and vomiting caused by cancer treatments such as chemotherapy.

However, doctors began using the drug off-label to treat women with morning sickness.

Presently, 97.7% of prescriptions for the treatment of nausea and vomiting in pregnancy in the United States are with medications not labeled for use in pregnancy, not indicated for nausea and vomiting in pregnancy, and not classified as safe in pregnancy by the Food and Drug Administration.

The use of ondansetron for nausea and vomiting in pregnancy has increased from 50,000 monthly prescriptions in 2008 to 110,000 at the end of 2013, despite unresolved issues regarding fetal safety and Food and Drug Administration warnings about serious dysrhythmias.

Sales of antiemetics for NVP in the US, 2008-2014

IMS National Prescription Audit from 2008 to 2014.

Estimates suggest one out of every four pregnant women receive a prescription for ondansetron.

In January 2012, a study from the Center for Birth Defects Research and Prevention identified a twofold increased risk for cleft palate associated with ondansetron exposure used for Nausea Vomiting in Pregnancy (NVP) in the first trimester. The study used data from the National Birth Defects Prevention Study, looking at the association between NVP and treatments for NVP and cleft palate, and other noncardiac birth detects.

In 2013, a Danish study by Pasternak B et al compared pregnancy outcomes among almost 2,000 women exposed to ondansetron in pregnancy, and women not exposed to the drug between 2004 and 2011. Exposure to ondansetron was not associated with an increased rate of major malformations (at about 3%), or other adverse fetal outcomes, including stillbirth, preterm delivery, and low birth weight, compared with the unexposed pregnancies

Following this in August 2013, at the International Society of Pharmacoepidemiology meeting in Montreal, the results of a different group of Danish researchers using data from the same national registries employed in the study published in February, but with more pregnancies (almost 900,000) over a longer period (1997 to 2010), detected a twofold increase in congenital heart defects associated with ondansetron during the first trimester of pregnancy.

Overall, the risks associated with ondansetron exposure during the first trimester of pregnancy remain unclear. Most observational research suggests that ondansetron is unlikely to increase the risk for miscarriage, stillbirth, or major birth defects. The few studies evaluating the effect of ondansetron on specific birth defects associate ondansetron exposure early in pregnancy with a small but significant risk for cleft palate and heart defects.

There are also potential maternal risks associated with taking Ondansetron  especially in pregnant women with electrolyte imbalance due to severe nausea and vomiting. These risks include the Serotonin Syndrome which is a triad of cognitive or behavioral changes including confusion, agitation, autonomic instability, and neuromuscular changes.

With these recent studies, we are left with contradictory results regarding the risk of birth defects associated with ondansetron exposure in the first trimester, and more studies may be needed.

Prescribing ondansetron as a first line option is not consistent with American Professors in Gynecology and Obstetrics and American College of Obstetricians and Gynecologists evidence-based recommendations for the management of NVP.

Ondansetron is not recommended by current guidelines as a first-line option for nausea and vomiting in pregnancy. Initial treatments are lifestyle and dietary modifications. If drug therapy is required, doxylamine/pyridoxine is FDA-approved and guideline-endorsed for the treatment of nausea and vomiting in pregnancy. 

In conclusion, with the availability of a safe and effective FDA-approved drug for NVP, there is no reason for women to be exposed to a drug of unproven maternal and fetal safety, which has not been labeled for NVP. 

Given the current evidence, ondansetron should be avoided in the first trimester of pregnancy unless other treatments are ineffective.

Several families filed lawsuits after their children suffered a number of defects, including: mental problems, vision issues, heart defects, cleft palate and lip, clubbed foot and skull deformities.

One of the suits, filed in July 2015 by Angela and Brian Kutzer, claims Glaxo paid doctors to promote and prescribe Zofran and made “false representations about the safety and efficacy” of the drug.

As of October 2015, these lawsuits were consolidated into a multidistrict legislation in the Eastern District of Pennsylvania.

References:

• http://www.drugwatch.com/2015/11/24/study-links-zofran-to-birth-defects/ Accessed December 08, 2015.
• Treating morning sickness in the United States - Changes in prescribing are needed. Koren G. (2014) American Journal of Obstetrics and Gynecology, 211 (6), pp. 602-606.
• http://www.obgynnews.com/single-view/ondansetron-new-and-troubling-data/00595b8bf7a0ec96a0d280e28af9edd6.html Accessed December 15, 2015.
• Mayhall EA, Gray R, Lopes V, Matteson KA. Comparison of antiemetics for nausea and vomiting of pregnancy in an emergency department setting. Am J Emerg Med. 2015;33:882-886. Abstract
• American College of Obstetricians and Gynecologists. ACOG (American College of Obstetrics and Gynecology) Practice Bulletin: nausea and vomiting of pregnancy. Obstet Gynecol. 2004; 103:803-814. Abstract
• American Professors in Gynecology and Obstetrics (APGO) Educational Series on Women's Health. Nausea and vomiting of pregnancy. American Professors in Gynecology and Obstetrics. 2015.
• https://www.apgo.org/images/nvp/nvp_monograph_040215_final.pdf Accessed December 08, 2015.

·        Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G. The safety of ondansetron for nausea and vomiting of pregnancy: A prospective comparative study. BJOG. 2004;111:940-943. Abstract

·        Colvin L, Gill AW, Slack-Smith L, Stanley FJ, Bower C. Off-label use of ondansetron in pregnancy in Western Australia. Biomed Res Int. 2013;2013:909860.

·        Pasternak B, Svanstrom H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013;368:814-823. Abstract

·        http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm351864.htm

• Anderka, M., Mitchell, A.A., Louik, C., Werler, M.M., Hernández-Diaz, S., and Rasmussen, S.A. National Birth Defects Prevention Study. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2012; 94: 22–30
• http://www.utswmedicine.org/stories/articles/year-2015/zofran-pregnancy.html Accessd December 08, 2015.
• http://www.fertilitycenter.com/fertility_cares_blog/fda-warns-against-zofran-use-in-pregnancy/ Accessd December 08, 2015