North American Menopause Society (NAMS) video series about important midlife health topics: The Timing Hypothesis of HRT

The North American Menopause Society is proud of its comprehensive video series for clinicians about important midlife health topics. All the interviews in the series are hosted by NAMS Board of Trustees Member and Immediate Past President Dr. Marla Shapiro, a Canadian physician, who led this exciting initiative. Dr. Shapiro is also the medical consultant for CTV News.

In this latest video, The Timing Hypothesis, Dr. Shapiro interviews Dr. Peter Schnatz, Past President of NAMS and Associate Chairman and Residency Program Director in the Department of Obstetrics and Gynecology at the Reading Hospital in Reading, Pennsylvania. Dr. Schnatz discusses the benefits of starting women on hormone therapy at the beginning of the menopause transition, along with the cardiovascular health advantages.   

The ELITE:Early Versus Late Intervention Trial With Estradiol also affirms the timing hypothesis in relation to timing of estradiol administration, when a beneficial cardiovascular effect is only seen in women with early, but not later menopause.

Premature or early onset menopause is associated with increased risk of CVD and all-cause mortality.

Clinical pearls:

• Women who had premature menopause are at high risk for CHD, CVD and all-cause mortality.
• With every 1 in 3 women dying due to CVD, identifying those who are high risks for it is important from public health perspective.
• Women with premature menopause can be benefited by pharmacological and life style interventions to prevent the increased all-cause mortality and CVD risk they are put at due to accelerated reproductive aging.

Majority of women around the world undergo menopause between 45 to 55 years of age with the average age being 51 years.[1] According to recent estimates about 5% of women attain natural menopause between the age of 41-45 years and additional 1% of have the last period before the age of 40.  Another 5% have premature menopause due to surgical removal of the ovaries, radiation and chemotherapy for malignancies or smoking.  The age at final menstrual period is of great public health significance and is considered as an important marker for predicting future cardiovascular, bone and overall health of the women. [2]

Women who attain menopause before 45 years of age have shorter total duration of estrogen exposure as compared to women who have menopause in 50s.

Multiple observational and cross sectional studies in the past have tried to assess the effect of loss of ovarian function and increased risk of cardiovascular diseases (CVD) and all-cause mortality in women undergoing premature menopause.

A recent meta-analysis published in JAMA cardiology by Muka et al [3] tried to systemically review and meta-analyze the relationship between age and duration of menopause and increased risk of cardiovascular diseases.

The analysis included 32 studies consisting of 310,329 non-overlapping women in their analysis.

The investigators compared the outcomes between women who entered menopause before 45 years of age to those women who were 45 or older at the onset. It was seen that women in the early menopause group had 1.5 times the risk of overall coronary heart disease, 1.11 times the risk of fatal coronary heart disease,1.23 times the risk for overall stroke, 0.99 for stroke mortality, 1.19 times the risk for CVD mortality, and 1.12 for all-cause mortality as compared to women who had menopause after the age of 45 years.

Women who had menopause between age of 50-54 have decreased risk (.87 times) of suffering from fatal CHD as compared to women who had menopause before 50 years of age. The risk for stroke was comparable in both the groups.

With every 1 in 3 women dying due to CVD, identifying those who are high risks for it might be important from public health perspective. Menopause might be a crucial period in women’s life to evaluate her future risk for CVD and introduce interventions to reduce the risk.

In an invited commentary about the article by Dr JoAnn E Manson (Harvard Medical School, Boston, MA) and D. Teresa K Woodruff (Northwestern University), the authors stress upon the complicated relationship between menopause and CVD. They discuss the findings of the Framingham Heart Study which states that increase in systolic, diastolic blood pressure, cholesterol and other vascular risk factors around pre and peri menopausal years led to an accelerated menopause at a younger age. The data from the study provides an important clue about cardiovascular health being responsible for menopausal timing, but it does not exclude a bidirectional relationship. [4]

An earlier Meta-analysis of observational study showed that bilateral surgical oophorectomy was associated with more than double the risk of CVD (risk ratio=2.62). Women who are put on HRT after the surgery nullify their increased risk for CVD as compared to women with intact ovaries.

A detailed analysis of Women’s Health Initiative study also stressed the beneficial effects of HRT in relation to cardiovascular health when initiated between the ages of 50 to 59 years as compared to older women. [5]

The ELITE: Early Versus Late Intervention Trial With Estradiol also affirms the timing hypothesis in relation to timing of estradiol administration, when a beneficial cardiovascular effect is only seen in women with early, but not later menopause. [6]

To conclude, the findings of the review indicates that women who had premature menopause are at high risk for CHD, CVD and all-cause mortality.

Complex relationship exists between cardiovascular health and accelerated reproductive aging and further research is needed to clarify the issue, but currently women with premature menopause can be benefited by pharmacological and life style interventions to prevent the increased all-cause mortality and CVD risk they are put at due to accelerated reproductive aging.

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[1] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285482/

[2] http://www.cdc.gov/reproductivehealth/infertility/

[3] http://cardiology.jamanetwork.com/article.aspx?articleid=2551981

[4] http://amaprod.silverchaircdn.com/data/Journals/CARDIOLOGY/0/hic160023.pdf.gif

[5] https://www.nhlbi.nih.gov/whi/

[6] https://clinicaltrials.gov/ct2/show/NCT00114517

History of preeclampsia linked to coronary artery calcification 30 years later.

Preeclampsia (PE) is a hypertensive pregnancy disorder complicating 1-5% of all pregnancies, and is a major cause of maternal and fetal morbidity and mortality.

In-fact it is known as the modulator of the offspring health, as many studies have associated it with increased incidence of metabolic syndrome later in the life of the offspring. 

A substantial number of epidemiological studies in recent year have also documented it to be a risk factor for increased cardiovascular and renal diseases for mother later in life. 

Women who have history of preeclampsia have a 2 fold increase in CVD and 5-12 fold in end stage renal  diseases(ESRD).

A recent study by White WM et al in the forthcoming American journal of obstetrics & gynecology concluded that a history of preeclampsia is associated with an increased risk of coronary artery calcification more than 30 years after affected pregnancies, even after controlling individually for traditional risk factors.

This paper was also presented recently at the  Society for Maternal and fetal Medicine (SMFM) 36^th Annual pregnancy meeting at Atlanta Georgia in February, 2016.

This study by White WM et al is important because it is the first prospective cohort study with confirmation of preeclampsia by medical record review.

They recruited 40 women with history of preeclampsia and 40 women without such history were recruited from a large cohort of population in Olmsted County, MN and who delivered between 1976 and 1982.

They were matched for parity and age at the time of index birth. Cat scan was performed to measure the coronary artery calcification in Agatston Units. The mean age at imaging was 59.5 (± 4.6) years.

It was seen that the frequencies of being diagnosed with hypertension (60% v. 20%, p < 0.001) and higher BMI (29.8 vs. 25.3) were both greater in women with H/O preeclampsia.

The frequency of a CAC score > 50 Agatston units was also greater in the preeclampsia group (23% v. 0%, p=0.001). Compared to women without preeclampsia, the odds of having a higher coronary artery calcification score was 3.54 (1.39 - 9.02) times greater in women with prior preeclampsia without adjustment, and 2.61 (0.95 - 7.14) times greater after adjustment for current hypertension.

The presence of coronary artery calcifications may be able to identify those at a particularly high cardiovascular risk, since CAC is  a strong predictor of  CHD.

According to a recent Multi-Ethnic Study of Atherosclerosis (MESA) by Joshi PM et al in the Journal Atherosclerosis showed that a high burden of coronary artery calcium (CAC) is a strong predictor of coronary heart disease (CHD) among persons at low risk.

Recognition of PE as a risk factor for CVD allows identification of a young population of women at high risk of developing of cardiovascular disease.

Current guidelines recommend cardiovascular screening and treatment for formerly preeclamptic women. However, these recommendations are based on low levels of evidence due to a lack of studies on screening and prevention in formerly preeclamptic women.

The American Heart association guidelines have listed preeclampsia as an independent risk factor for CHD, as strong as a failed stress test— but larger studies are still needed to understand the underlying mechanism. 

The current study strongly advocates the need for research on mechanisms of late disease manifestations, and on effective screening and therapeutic strategies aimed at reducing the late disease burden in formerly preeclamptic women. Identification of women with CAC score > 50 carries significant potential therapeutic implications.

 References:

http://www.ncbi.nlm.nih.gov/pubmed/26841074

http://www.ajog.org/article/S0002-9378%2816%2900287-8/abstract

http://www.ncbi.nlm.nih.gov/pubmed/26792940

Oral contraceptives use around and during pregnancy does not appear to be teratogenic.

Image in the public domain, courtesy of Wikimedia Commons

2010 saw the 50^th anniversary of the contraceptive pill.

‘The pill’ as it is commonly known was a key player in building women’s current economic role in society as it gave women an unprecedented control over their own fertility.

Oral contraceptives remain the most common method of contraception in most part of the world. According to a CDC Faststats:

• Leading contraceptive method among women aged 15-29: Pill
• Percent of women aged 15-44 currently using the pill: 17.1%

Although the failure rate is 0.1 percent when pills are taken perfectly (same time every day, no missed pills), the actual failure rate is 9 percent over the first year, due primarily to the missed pills, drug interactions, forgetting to restart the pill after the seven-day pill-free interval or illness and results in what is known as breakthrough pregnancy.

photo courtesy: http://www.catholicmatch.com

Studies conducted in the past with high dose preparations have linked various birth defects with first trimester exposure to oral contraceptives. These birth defects involved the vertebrae, anus, heart, trachea, esophagus, kidney and limbs (VACTERL syndrome) (Nora et al, 1976).

After thorough investigation in the later years, these associations have not been substantiated. These studies were mainly focused on use of the OC during the first trimester.  No studies were found that studied the effect of exogenous hormones immediately before and around the time of conception or immediately after conception.

This prospective observational cohort study conducted by Brittany M Charlton from the Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts and her colleagues from Denmark was published on line on January 6, 2016 in British Medical Journal and aims to study the association between use of oral contraceptives around pregnancy time and resulting congenital malformations in the fetus.

They used Medical Birth Register records from 1997 to 2011 (880,694 live births) and Danish National Prescription Register and collected prescription data on the use of oral contraceptives. The investigators assumed that women who filled their prescriptions were exposed to oral contraceptives.

The women were divided into 4 groups, No oral contraceptive exposure, >3 months before pregnancy onset (reference group), 0-3 months before pregnancy onset (that is, recent use), and after conception. The two primary exposures of interest were after conception and recent use before pregnancy onset.

Any major birth defect was the primary outcome and subgroups of major birth defects categorized by organ system were the secondary outcomes.

Previous studies have observed associations between oral contraceptive exposure and 4 subgroups of congenital anomalies of hypoplastic left heart syndrome, gastroschisis, limb defects, and urinary tract anomalies.

Logistic regression was used to o estimate prevalence odds ratios of any major birth defect as well as categories of birth defect subgroups.

It was seen that the prevalence of major birth defect was consistent at 25 per 1000 live births across all the four groups. The study did not find any increase in the 4 birth defects that earlier studies have shown a link with.

The study lacked the statistical power for different formulations of oral contraceptives and specific subgroup of birth defects, but was very strong when it comes to examining the association between birth defects and the timing of oral contraceptives use.

It also stands at par with other studies conducted earlier, documenting no increase in birth defects after the use of oral contraceptives.

It also assures the patients and healthcare providers about no association between the oral contraceptive use and increased risks of malformation, as estimated 9% of oral contraceptive users become pregnant in the first year of use; many more women will stop using oral contraceptives when planning a pregnancy and conceive within a few menstrual cycles.

The study also postulate that future research could examine the different formulations of oral contraceptives as other health outcomes, such as breast cancer risk have varied by formulation—with triphasic levonorgestrel formulations driving the increased breast cancer risk.

References:

http://www.webmd.com/sex/birth-control/news/20141211/the-pill-remains-most-common-method-of-birth-control-us-report-shows

http://www.cdc.gov/nchs/fastats/contraceptive.htm

http://www.uptodate.com/contents/hormonal-methods-of-birth-control-beyond-the-basics

http://www.bmj.com/content/352/bmj.h6712

Mosher WD, Jones J. Use of contraception in the United States: 1982-2008. Vital Health Stat 23 2010:1-44.

Skouby SO. Contraceptive use and behavior in the 21st century: a comprehensive study across five European countries. Eur J Contracept Reprod Health Care 2004;9:57-68.

http://prospect.rsc.org/blogs/cw/2011/01/11/my-hero-carl-djerassi/#more-6286

http://cebp.aacrjournals.org/content/19/10/2496

Few decisive articles in obstetrics from 2015

Role of progesterone in preventing recurrent preterm births (PTB)

It is widely accepted that progesterone supplementation in pregnancy reduces the risk of recurrent preterm birth. But, according to a secondary analysis of data  from Maternal-Fetal Medicine Units Network Trial of hydroxyprogesterone caproate for prevention of recurrent preterm birth before 37wks concluded that the drug may not be effective in women with a BMI>30 kg/m^2. The cut off weight is 168 pounds or 75 kg. This finding may be due to subtherapeutic serum levels in women with increased BMI or weight. Further larger and planned studies in women with BMI >30 kg/m² are warranted and also the universal use of progesterone in women independent of BMI also deserves reassessment.

Heyborne KD et al - Does 17-alpha hydroxyprogesterone caproate prevent recurrent preterm birth in obese women?

Am J Obstet Gynecol. 2015 Aug;

Maternal Hypertension in Pregnancy predisposes the offspring for higher risks of Congenital Heart Disease

According to a systemic review and metaanalysis published in the journal of pediatric cardiology robust associations were observed between maternal hypertension and overall CHDs, irrespective of being treated or untreated. The authors identified 16 studies that met the study criteria. The effect was also uniform across all the subtypes of CHDs. The results were also similar for various type of antihypertensive medications used.

The authors propose to understand the mechanisms to design strategies to reduce the risks..

Ramakrishnan A et al- Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis.

Pediatr Cardiol. 2015 Oct;36(7):1442-51. Epub 2015 May 8.

The downside of improved control of malaria.

We are recently seeing improved malaria control in many endemic areas worldwide, leading to a decrease in immunity in the population. A large observational study carried out in Mozambique assessed the prevalence of Plasmodium falciparum infection among 1819 Mozambican women who delivered infants between 2003 and 2012.

A major decline in maternal level of antimalarial IgG antibodies were seen in pregnant women both for pregnancy specific parasitic lines as well as general parasitic lines.

It was also seen that those women who developed malaria antenatally had a larger reduction in hemoglobin levels as well as the neonatal birthweight as the immunity declined.

Mayor A et al- Changing Trends in P. falciparum Burden, Immunity, and Disease in Pregnancy. N Engl J Med. 2015 Oct 22;373(17):1607-17.

Uterine exteriorization at cesarean delivery

Uterine exteriorization vs in situ repair has always been a topic of debate among obstetricians.  In A large meta-analysis of 16 studies amounting to a total of 19,439 subjects 9,736 underwent exteriorization, 9,703 had in situ uterine repair. It was seen that the estimated blood loss was not statistically significant between the two groups as well as other perioperative outcomes. Individual preferences and individual intraoperative circumstances should guide the decision.

Zaphiratos V et al- Uterine exteriorization compared with in situ repair for Cesarean delivery: a systematic review and meta-analysis.

Can J Anaesth. 2015 Nov;62(11):1209-1220.

The best time to perform External Cephalic Version (ECV)

The optimum age to perform ECV has always been a debatable issue.

External cephalic version (ECV) of the breech fetus at term (after 37 weeks) has been shown to be effective in reducing the number of breech presentations and caesarean sections, but the rates of success are relatively low. This systemic review of Cochrane Data base examines studies initiating ECV prior to term (before 37 weeks' gestation).

Pooled results suggested that early ECV reduced the risk of non-cephalic presentation at birth, failure to achieve vaginal cephalic birth, and vaginal breech delivery. However there was no statistical significant difference in Caesarean Section rate between the two groups. There was evidence that risk of preterm labour was increased with early ECV compared with ECV after 37 weeks. Future research reporting infant morbidity outcomes in these late preterm births is warranted.

Hutton E.K et al- External cephalic version for breech presentation before term.

Cochrane Database Syst Rev. 2015 Jul 29;7:CD000084.

Limited value of fetal ST-segment analysis

STAN S31 is a one-of-a-kind fetal monitor which exclusively combines standard CTG technology with ST-Analysis of the fetal ECG (FECG) during labour. The combined analysis of the CTG and fetal ECG helps to detect a fetus that is exposed to hypoxia and which needs remedial action, and also provides reassurance when no intervention is required.

However, It is not clear whether use of STAN 31 as an adjunct to other conventional fetal heart rate monitor improves the intrapartum and neonatal outcome.

This Multicenter RCT of about 11,108 subjects included women with a single fetus undergoing vaginal delivery at more than 36 weeks of gestation with cervical dilation of 2 to 7 cm. They were randomly assigned to "open" or "masked" monitoring with fetal ST-segment analysis. The masked system functioned as a normal fetal heart-rate monitor (FHR). The open system functioned as both FHR as well as fetal ECG monitor.

The primary outcome was a composite of intrapartum fetal death, neonatal death, an Apgar score of 3 or less at 5 minutes, neonatal seizure, an umbilical-artery blood pH of 7.05 or less with a base deficit of 12 mmol per liter or more, intubation for ventilation at delivery, or neonatal encephalopathy.

It was observed that fetal ECG monitoring along with FHR  did not improve perinatal outcome or decreased the rate of caesarean delivery. The primary outcome occurred in 52 fetuses or neonates of women in the Fetal ECG group  and 40 fetuses or neonates of women in the FHR  group.

Belfort M.A- A Randomized Trial of Intrapartum Fetal ECG ST-Segment Analysis.

N Engl J Med. 2015 Aug 13;373(7):632-41.

Expectant management of mild preeclampsia near term is feasible.

There is little guidelines for the management of women with mild preeclampsia with stable maternal and fetal conditions at 34 to 36 weeks of gestation. The study by Broekhuijsen K et al in Lancet 2015, investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. This open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands confirmed that most patients will reach term without progressing into severe disease and the expectant management buys us valuable time for optimum neonatal maturity without any harm to the mother.

References:

• Relation of body mass index to frequency of recurrent preterm birth in women treated with 17-alpha hydroxyprogesterone caproate.Co AL, Walker HC, Hade EM, Iams JD. Am J Obstet Gynecol. 2015 Aug; 213(2):233.e1-5
• Ramakrihnan A et al- Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis.Pediatr Cardiol. 2015 Oct;36(7):1442-51
• Mayor A et al- Changing Trends in P. falciparum Burden, Immunity, and Disease in Pregnancy. N Engl J Med. 2015 Oct 22;373(17):1607-17.
• Zaphiratos V et al- Uterine exteriorization compared with in situ repair for Cesarean delivery: a systematic review and meta-analysis.Can J Anaesth. 2015 Nov;62(11):1209-1220.
• http://www.news-medical.net/Stan-S31-Fetal-Monitor-from-Neovent
  
  

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