Month: December 2017

Is Advil Preventing You From Getting Pregnant?

This month, I’m taking a break from diet to explore another important area in health and wellness: fertility. Any girl who’s ever turned to Google or Pinterest in search of increasing fertility has no doubt encountered hundreds of tips and tricks. As usual, some are reliable and others are based on myth and anecdote.

Eat vegan. Eat Paleo. Eat whole-30. No smoking. No alcohol. Some alcohol. No caffeine. Some caffeine. Prenatal vitamins. Ovulation predictors. Work out more. Work out less. Yoga. Acupuncture. Hypnosis. Basal body temperature. Do it every day. Don’t do it every day. Test for STDs. Get a semen analysis. Test your tubes. Test for endometriosis.

One recommendation in particular caught my attention. I came across a headline saying that NSAIDs (non-steroidal anti-inflammatory drugs) can prevent ovulation. I had never heard about this before and decided to take a deeper look.

NSAIDs are over-the-counter pain medications that work by blocking enzymes that make prostaglandins (which cause swelling and are interpreted as pain). Many people take these medications fairly often for headaches, backaches, joint pain, menstrual cramps, toothaches, other injuries, and even heart disease.

Some common OTC NSAIDs are: Aspirin (Bayer, Excedrin), Ibuprofen (Advil, Motrin, Nuprin), Ketoprofen (Actron, Orudis), and Naproxen (Aleve). Others are available with a prescription.

The Claim: Taking NSAIDs can reduce fertility by preventing ovulation.

Initial Search: A quick Google search came up with the following results:

WebMD: NSAIDs may hinder ovulation and lower levels of the female hormone progesterone. They cite a study by Sami Salman, MD, from the University of Baghdad. This study is available below in the peer-reviewed research section. Essentially, he studied 39 women taking either an NSAID or a placebo for 10 consecutive days, beginning on day 10 of the menstrual cycle. Ovulation was reduced by 75-93% depending on which drug the patients were taking compared to the control group. He stated that progesterone levels also dropped for the experimental groups. After discontinuing treatment, all of the women ovulated normally during their next cycle. Dr. Salman even proposed that these findings could help them develop a new contraceptive.

Medscape: Pharmacist Darrell Hullsz describes how some side effects of NSAIDs are well known including gastrointestinal, cardiovascular, and renal problems as well as problems toward the end of pregnancy. He says that problems with ovulation have been reported for several decades, but that these problems are still not widely known. An enzyme, COX-2, that is active in the ovaries during follicular development, is blocked by NSAIDs. This prevents the follicule from rupturing (egg from being released). Women see all the other signs of ovulation including elevated body temperature and progesterone levels, but the egg is never released. He goes a step further stating that COX-2 inhibitors may also disrupt fertilization, implantation, and establishment of the placenta. He references the study mentioned above by WebMD as well as two other studies listed below in the peer-reviewed section that oppose the claim by suggesting that delayed follicular rupture is unlikely to cause infertility.

Many other popular health news websites also cite Dr. Salman’s study including: ScienceDaily, Daily Mail, Pharmaceutical Journal, Holistic Primary Care, TheraSpecs, and many fertility blogs and centers.

Follow-up Questions:

If NSAIDs really do affect fertility, does timing and dosage matter? Would it be ok to take NSAIDs during your period, but avoid it during the middle and end of your cycle? Is a lower dose safer?

Are there other painkillers that are safer to take when trying to conceive?

Peer reviewed Research:

These are all of the relevant studies I found. Most did not have full text available. I have provided abstracts with the most important findings from each study in bold.

 

Abstract

Background: NSAIDs are popular and used as analgesics, antipyretics and anti-inflammatory agents for more than a century. They are sold without a prescription and taken by millions of patients every day all over the world. There has been recent concerns as to their use in females at child bearing age, as many animal studies showed unfavourable effects on ovulation.

Objectives: To study the effects of short term use of NSADs at their conventional dosages on ovulation.

Methods: Thirty nine women at fertile age were chosen as volunteers to take part in this study, they visited the Rheumatology consultation clinic in Baghdad Hospital, suffering from minor backpain and received one of the three test drugs (diclofenac 100mg once daily, naproxen 500mg twice daily & etoricoxib 90mg once daily). Treatment with the above drugs was given for ten days starting at day ten of the onset of the menstrual cycle. A blood sample was taken from each patients for hormonal analysis (progesterone level) together with an ultra sonsography to assess the mean diameter of the dominant follicle. At day twenty the patient came back for another ultra sonography & to give a blood sample for another check for progesterone level. A fourth group served as controls, who received no treatment (control volunteers).

Results: There was significant inhibition of ovulation in patients treated with diclofenac, naproxen & etoricoxib. Diclofenac was the highest inhibitor of ovulation compared to the other two drugs (naproxen & etoricoxib). A significant decrease in progesterone level in all three groups in compared to the control group was found. Functional cysts have been observed in one third of patients by the end of the treatment period with diclofenac, naproxen & etoricoxib due to unruptured follicles these disappeared at the next cycle.

Conclusions: The findings may serve as an alarm of the harmful effects of these drugs on female fertility and be taken into consideration in females planning to have a child. The above results may open the door for looking for an emergency contraceptive safer than those at use.

 

Abstract

Ovulation constitutes the central event in ovarian physiology, and ovulatory disfunction is a relevant cause of female infertility. Non-steroidal anti-inflammatory drugs (NSAIDs), widely used due to their analgesic and anti-inflammatory properties, consistently inhibit ovulation in all mammalian species investigated so far, likely due to the inhibition of cyclooxygenase 2 (COX-2), the inducible isoform of COX, that is the rate-limiting enzyme in prostaglandin (PG) synthesis. COX-2 inhibition has major effects on ovulation, fertilization and implantation, and NSAID therapy is likely implicated in human infertility and could be an important, frequently overlooked, cause of ovulatory disfunction in women. Although there is compelling evidence for a role of PGs in ovulation, the molecular targets and the precise role of these compounds in the ovulatory process are not fully understood. Morphological studies from rats treated with indomethacin (INDO), a potent inhibitor of PG synthesis, provide evidence on the actions of NSAIDs in ovulation, as well as on the possible roles of PGs in the ovulatory process. Cycling rats treated with INDO during the preovulatory period show abnormal ovulation, due to disruption of the spatial targeting of follicle rupture at the apex. Noticeably, gonadotropin-primed immature rats (widely used as a model for the study of ovulation) show age-dependent ovulatory defects similar to those of cycling rats treated with INDO. These data suggest that NSAID treatment disrupts physiological mechanisms underlying spatial targeting of follicle rupture at the apex, which are not fully established in very young rats. We summarize herein the ovulatory defects after pharmacologic COX-2 inhibition, and discuss the possible mechanisms underlying the anti-ovulatory actions of NSAIDs.

 

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed to women of child-bearing age. Three case series highlight the possibility of a link between NSAIDs and reversible infertility. The pharmacological target of NSAIDs is cyclo-oxygenase (COX), which catalyses the first rate-limiting step in the production of prostaglandins. COX-2, one of two isoenzymes, is active in the ovaries during follicular development. Its inhibition is thought to cause luteinised unruptured follicle (LUF) syndrome, an anovulatory condition characterised by clinical signs of ovulation but in the absence of follicular rupture and ovum release. The evidence linking regular NSAID use to reversible LUF syndrome comes from animal studies and three clinical studies. COX-2-deficient mice have severely compromised ovulation in the presence of apparently normal follicular development. Experimental administration of prostaglandins induced ovulation in rabbits and this was blocked by the administration of indomethacin. The three clinical studies demonstrated the induction of delayed follicular rupture or LUF in previously ovulating women by the administration of NSAIDs. A link can therefore be identified between NSAID use and reversible female infertility and NSAID withdrawal should be considered prior to or concurrent with fertility investigations.

 

Abstract

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors may interfere with ovulation and the rupture of the follicle, causing reversible infertility.

METHOD: Literature review.

RESULTS: Reversible infertility is shown both in animal and human studies of these drugs. As determined by ultrasound, the drugs may delay or inhibit ovulation. These findings are also confirmed by a few randomized controlled studies showing an increase in time from the luteinizing hormone surge to rupture of the follicle and an increased size of the unruptured follicle. Most of the hormone analyses show values in accordance with the ovulation/menstrual cycle. Also, two epidemiological studies have shown an association between NSAID use and spontaneous abortion. These studies have methodological weaknesses and their findings have to be elucidated in future studies.

INTERPRETATION: Women with fertility problems should avoid not only the selective cyclooxygenase-2 inhibitors, but also the traditional NSAIDs. However, women with rheumatic disease responding well to therapy should consult their physicians before stopping treatment. Reduced dose of a NSAID and temporary stop of drug treatment early in the menstrual cycle, or alternative drug treatment, may be a solution. NSAIDs should not be used in the last eight weeks of pregnancy.

  • 5. Reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs. (1996) https://www.ncbi.nlm.nih.gov/pubmed/8646437

 

Abstract

The case histories of three young women with ankylosing spondylitis, rheumatoid arthritis and a seronegative inflammatory polyarthritis undergoing investigations for infertility are presented. In each, non-steroidal anti-inflammatory drug (NSAID) therapy was associated with the recurrent development of luteinized unruptured ovarian follicles and normal ovulation following drug withdrawal. It is suggested that NSAID therapy may be an important and frequently overlooked cause of anovulation and infertility.

 

Abstract (1) There have been isolated reports of reversible female infertility linked to NSAIDs. The likely mechanism is ovulatory failure due to non rupture of mature follicles. (2) If a woman who presents with infertility is found to be taking a NSAID, the role of the drug should be considered before launching costly, invasive investigations or starting medically assisted reproduction.

 

Abstract

OBJECTIVE: To highlight the possible association between infertility and treatment with long-term non-steroidal anti-inflammatory drug (NSAIDs). NSAIDs act mainly through the inhibition of cyclooxygenase, the enzyme that catalyses the synthesis of prostaglandins, which are essential mediators of ovulation, implantation and placentation of the conceptus.

METHODS: Case reports of four women suffering from severe arthritis, on long-term NSAIDs and undergoing extensive investigation and treatment for infertility.

RESULTS: During the last 2 yr, four out of five women with severe arthritis and difficulty conceiving were counselled to stop NSAIDs, and they successfully conceived shortly after the withdrawal of NSAIDs.

CONCLUSION: NSAIDs, used largely for the treatment of rheumatological conditions, may be responsible for some cases of infertility.

 

Abstract: Non-steroidal anti-inflammatory drugs are widely used in the treatment of inflammatory joint diseases. Many patients suffering from these disorders are young women during their childbearing years. We report three cases of infertility where the cause may have been NSAID-induced ‘luteinized unruptured follicle’ syndrome. This phenomenon is well recognized in obstetric circles, and we would like to bring it to the attention of rheumatologists since it is not documented in the rheumatological literature.

 

Abstract

STUDY QUESTION: Does use of commonly used over-the-counter (OTC) pain medication affect reproductive hormones and ovulatory function in premenopausal women?

SUMMARY ANSWER: Few associations were found between analgesic medication use and reproductive hormones, but use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for potential confounders.

WHAT IS KNOWN ALREADY: Analgesic medications are the most commonly used OTC drugs among women, but their potential effects on reproductive function are unclear.

STUDY DESIGN, SIZE, DURATION: The BioCycle Study was a prospective, observational cohort study (2005-2007) which followed 259 women for one (n = 9) or two (n = 250) menstrual cycles.

PARTICIPANTS, SETTING, METHODS: Two hundred and fifty-nine healthy, premenopausal women not using hormonal contraception and living in western New York state. Study visits took place at the University at Buffalo.

MAIN RESULTS AND THE ROLE OF CHANCE: During study participation, 68% (n = 175) of women indicated OTC analgesic use. Among users, 45% used ibuprofen, 33% acetaminophen, 10% aspirin and 10% naproxen. Analgesic use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for age, race, body mass index, perceived stress level and alcohol consumption (OR 0.36 [0.17, 0.75]). Results remained unchanged after controlling for potential confounding by indication by adjusting for ‘healthy’ cycle indicators such as amount of blood loss and menstrual pain during the preceding menstruation. Moreover, luteal progesterone was higher (% difference = 14.0, -1.6-32.1, P = 0.08 adjusted) in cycles with follicular phase analgesic use, but no associations were observed with estradiol, LH or FSH.

LIMITATIONS, REASONS FOR CAUTION: Self-report daily diaries are not validated measures of medication usage, which could lead to some classification error of medication use. We were also limited in our evaluation of aspirin and naproxen which were used by few women.

WIDER IMPLICATIONS OF THE FINDINGS: The observed associations between follicular phase analgesic use and higher progesterone and a lower probability of sporadic anovulation indicate that OTC pain medication use is likely not harmful to reproduction function, and certain medications possibly improve ovulatory function.

 

Abstract

OBJECTIVE: To assess the effect of ibuprofen, a nonspecific inhibitor of prostaglandin synthesis, on ovulation.

DESIGN: Prospective, randomized, double-blind, placebo-controlled cross-over study.

SETTING: University Medical Center.

PATIENT(S): Twelve normally cycling women between ages 20 and 40.

INTERVENTION(S): Subjects were randomized to either oral ibuprofen (800 mg) or placebo three times per day, beginning when the maximum diameter of the leading follicle reached 16 mm by ultrasound, and continuing for 10 days total. The second cycle was a washout period, and in the third cycle, the subjects were crossed over to the alternate regimen from the first cycle. The probability of delayed follicular collapse was determined using the binomial distribution, and changes in P levels were compared using the paired t test.

MAIN OUTCOME MEASURE(S): Urinary LH surge, follicular collapse by serial transvaginal ultrasonography, and serum midluteal P levels.

RESULT(S): Eleven of 12 subjects detected an LH surge with both ibuprofen and placebo. Five of 11 women demonstrated a >or=2-day increase in time interval from detection of the LH surge to follicular collapse, and 3 of those 5 had been randomized to ibuprofen. This represents a 27% (3 of 11; 95% confidence limits: 1%, 53%) rate of delay for follicular collapse for ibuprofen. There was no difference in average midluteal P levels for ibuprofen or placebo.

CONCLUSION(S): If ibuprofen inhibits follicular collapse, this effect is seen in a small group of study subjects, and this information should be clinically reassuring to patients who take nonsteroidal anti-inflammatory drugs. Serum midluteal P levels were unaffected by administration of ibuprofen.

What we know and don’t know

The research I found doesn’t give us a very definitive answer. 8 out of the 10 studies or reviews point to a strong association between NSAIDs and ovulation problems. However, in most of these studies, subjects took high doses for an extended period of time (at least 10 consecutive days). Some of them used NSAIDs that are unpopular or unavailable in the US. 1 out of the 10 studies suggests a weak association between NSAIDs and ovulation problems and 1 out of the 10 studies actually suggests that NSAIDs can improve ovulation.

Here is a table to help make the findings more clear

Study number Number/description of subjects Type of study Outcome with NSAIDs
1 39 women Control trial (non-random) poor
2 rats Unsure, review? poor
3 3 women Case studies poor
4 unsure Review poor
5 3 women Case studies poor
6 “isolated reports” Review poor
7 4 women Case studies poor
8 3 women Case studies poor
9 259 women Control trial (non-random) good
10 12 women Randomized control trial Poor in a small group

 

The majority of studies reporting poor outcomes are case studies involving 3 or 4 women. They may even be citing the same 3 or 4 women in multiple articles. It is difficult to know details (such as exactly which medications the women were taking and for how long) from the abstracts. However, we do know that in study 1 most of the women were taking medications not available in the US. In study 9 however, the women were mostly using Advil. This might make findings from study 9 more relevant. Study 10 is the highest quality in terms of research design, but with only 12 subjects, the results may not be reliable.

The possible mechanism responsible for ovulation problems while using NSAIDs is well described and seems plausible. According to this research, it has been observed in all mammals. However, studies involving mice and rats may still not be relevant to humans.

Conclusions

Overall, it seems like there is some good evidence to suggest that taking NSAIDs regularly can cause problems with ovulation. Unfortunately, there is still some controversy. I wasn’t able to find any good information on lower doses or the importance of timing, but subjects in these studies all took the medications around the time of ovulation.

I was also unable to find any information on good alternatives. Study 9, which claimed painkillers do not cause ovulation problems, didn’t separate out NSAIDs and acetaminophen. A quick Google search suggests that acetaminophen (like Tylenol) is safe during pregnancy, but may reduce estrogen and luteinizing hormones in the body. This could affect fertility.  I have yet to look deeper into this claim.

Applications

My recommendation would be for anyone who has had unexplained infertility for more than 3 months to stop taking NSAIDs and use Tylenol for mild/occasional pain relief (unless your doctor doesn’t think this would be safe). Fertility treatments are often very expensive and might be avoided by simply switching pain medication.

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