Liquorice in Pregnancy: All Sorts to Think About

When I was just entering the second trimester of pregnancy, I started experiencing very low blood pressure and accompanying fainting spells. While there’s no conclusive evidence to show that low blood pressure during pregnancy is dangerous for you or your baby [1], it can leave you feeling a bit tired and washed out. So I asked my obstetrician what I could do about it. I wasn’t entirely surprised when he ‘prescribed’ the unusual remedy of a piece of liquorice every morning and evening, having been advised something similar by a medical student when my low blood pressure prevented me from donating blood in university. But now I was pregnant – it was time to find out whether this liquorice thing really works, if so, how and (although recommended by my doctor) whether there were any concerns in pregnancy.

I was somewhat surprised to find out the answer to “Does Liquorice Raise Blood Pressure?” is yes! Far from being a quirky old wives’ tale, several studies have shown that the active ingredient, glycyrrhizin, works by mimicking some of the actions of the hormone cortisol [2,3]. Cortisol is commonly known for being released by your body when you are stressed, and most people will be familiar with the rise in blood pressure that accompanies this. That is roughly the same way in which liquorice works. However, the quantities needed to achieve this effect in a measurable way are only for the liquorice lovers – around 300mg of glycyrrhizin is required, meaning one to two 125g bags of liquorice every day! [2,3] (although an effect can be seen at lower doses).

I’m a fan of liquorice, so thought it no hardship to ‘endure’ a bag of liquorice a day to help boost my BP. But first, a quick check on pregnancy risks was in order. This time, I was shocked to find the conclusion that liquorice is clearly to be avoided during pregnancy. It turns out that the same effects that cause a rise in blood pressure also inhibit the placenta’s barrier to maternal cortisol. This can allow circulating stress hormone cortisol to reach the growing baby [4]. Over sustained periods of time, this exposure to maternal glucocorticoids means the baby’s own hormonal ‘axis’ (the hypothalamic-pituitary-adrenal axis) is permanently re-programmed [5, 6]. This mechanism has been studied for the last two decades, and several studies focusing on liquorice in pregnancy have shown that babies born to moms who love a bag or two a day have a higher chance of pre-term birth and babies with higher BMIs, lower IQs, poorer memory, a higher likelihood of attention/hyperactivity disorders and aggression problems and experience early puberty [4, 6, 7, 8].

Most of us get told about avoiding runny eggs and undercooked meat when pregnant. It may not be a common dietary feature, but the evidence is even stronger for avoiding liquorice while pregnant – better to find another way to satisfy your sweet tooth!

REFERENCES:

[1] Zhang J, Klebanoff MA, (2001), “Low Blood Pressure During Pregnancy and Poor Perinatal Outcomes: An Obstetric Paradox”, American Journal of Epidemiology, Vol 153 (7), pp 642 – 646, https://doi.org/10.1093/aje/153.7.642

[2]Hautaniemi EJ et al. (2017) “Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance.”, Scientific Reports (Nature), Vol 7(1): 1094 -7 doi: 10.1038/s41598-017-11468-7

[3] Sigurjonsdottir HA et al. (2001) “Liquorice-induced rise in blood pressure: a linear dose-response relationship.” Journal of Human Hypertension, Vol 15(8): 549 – 52.

[4] Raikkonen K et al. (2009) “Maternal licorice consumption and detrimental cognitive and psychiatric outcomes in children.” American Journal of Epidemiology, Vol 170 (9): 1137 – 46 . doi: 10.1093/aje/kwp272

[5] Raikkonen K et al. (2010) “Maternal prenatal licorice consumption alters hypothalamic-pituitary-adrenocortical axis function in children.” Psychoneuroendocrinology, Vol 35(10): 1587 – 93 doi: 10.1016/j.psyneuen.2010.04.010

[6] Reynolds RM, (2013) “Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis.” Psychoneuroendocrinology, Vol 38(1): 1 – 11

[7] Raikkonen K et al. (2017) “Maternal Licorice Consumption During Pregnancy and Pubertal, Cognitive and Psychiatric outcomes in children”, American Journal of Epidemiology, Vol 185 (5): 317 – 328 doi: 10.1093/aje/kww172

[8] Strangberg TE et al. (2001) “Birth outcome in relations to licorice consumption during pregnancy.”, American Journal of Epidemiology, Vol 153(11): 1085 – 8

Getting pregnant with PCOS using Metformin (Glucophage) and Clomiphene Citrate (Clomid)

It is unknown whether insulin resistance is a cause of PCOS or a symptom, but regardless one of the large contributing factors to my infertility due to PCOS is/was insulin resistance. When you have insulin resistance, the cells in the body are resistant to insulin, thus they don’t take up glucose from the blood easily; and the body increases the amount of insulin produced, to force the sugar into the cells [1]. High insulin levels affect the ovaries and cause them to produce too much LH (Luteinising Hormone) which then disrupts the cycle and prevents ovulation [2]. Thus in order to ovulate, your insulin levels have to be lowered and more regulated. There are a few ways in which to do this, you can change your diet (follow a low-carb/ketogenic diet) and/or you can take an insulin-sensitizer such a metformin. Sometimes your menstrual cycles will right themselves after some weight loss (about 5% of your body mass) or after being on the metformin for at least 6 months.

Clomiphene Citrate (Clomid) is often the first suggested therapy for anovulation (not ovulating like in PCOS). However many women are Clomiphene resistant (don’t ovulate no matter what the dose). In this case it is recommended that both Metformin and Clomiphene are taken, as the metformin can possibly reduce the clomiphene resistance [3].

In my case I had only been on a low dose of Metformin before I was put on 50mg of Clomid, and I didn’t ovulate. I then decided to give myself 6 months on a higher dose of Metformin (recommended level is over 1500mg/day, I use 2 x 850mg tablets per day) before trying another cycle of Clomid, and the next Clomid cycle I ovulated at 50mg! In total to conceive my son, I did 5 rounds of Clomid (all at 50mg) and got pregnant twice (one miscarriage and one live birth). I truly think I would be resistant to the Clomid if I didn’t take a high dose of Metformin.

Women with PCOS have an incredibly high early miscarriage rate (1st trimester) of between 30-50% (per pregnancy) versus 10-15% for non-PCOS women [4]. Luckily you can take Metformin throughout your pregnancy and drop your chance of early miscarriage to the regular 10-15% as well as decreasing your chances of premature-birth [5, 6].

So after all the wonderful stuff Metformin can do for you why isn’t everyone taking it? Metformin can cause some unfortunate gastro-intestinal side effects (mostly diarrhoea). However by starting at a low dose and slowly increasing it or by using the extended-release version most people eventually tolerate it [7]. In fact, according to [8], although about 25% of people will experience some GI issues until they get used to the drug, only 5% of people are completely unable to tolerate metformin.

 

[1] Roberts CK, Hevener AL, Barnard RJ, “Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training. “, Comprehensive Physiology. Vol. 3(1), pp.1-58, 2013 https://dx.doi.org/10.1002%2Fcphy.c110062

[2] Franks S, Gilling-Smith C, Watson H and Willis D, “Insulin action in the normal and polycystic ovary.”, Endocrinol Metab Clin North Am. Vol 28(2), pp. 361-78, 1999 https://www.ncbi.nlm.nih.gov/pubmed/10352923

[3] Dasari P, Pranahita G. “The efficacy of metformin and clomiphene citrate combination compared with clomiphene citrate alone for ovulation induction in infertile patients with PCOS.”, Journal of Human Reproductive Sciences.Vol 2(1), pp.18-22, 2009 http://www.jhrsonline.org/text.asp?2009/2/1/18/51337

[4] Kamalanathan S, Sahoo JP, Sathyapalan T. “Pregnancy in polycystic ovary syndrome.”, Indian Journal of Endocrinology and Metabolism;Vol.17(1), pp.37-43. 2013 http://www.ijem.in/text.asp?2013/17/1/37/107830

[5] Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA and Nestler JE., “Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.”, J Clin Endocrinol Metab. Vol. 87(2), pp.524-9, 2002 https://doi.org/10.1210/jcem.87.2.8207

[6] Feng L, Lin XF, Wan ZH, Hu D, Du YK, “Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis.” Gynecol Endocrinol. Vol. 31(11), pp. 833-9, 2015 https://doi.org/10.3109/09513590.2015.1041906

[7] Hostalek U, Gwilt M and Hildemann S. “Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention.” Drugs. Vol. 75(10), pp.1071-1094, 2015 https://dx.doi.org/10.1007%2Fs40265-015-0416-8

[8] McCreight LJ, Bailey CJ and Pearson ER. “Metformin and the gastrointestinal tract.”, Diabetologia.;Vol. 59:pp 426-435, 2016 https://dx.doi.org/10.1007%2Fs00125-015-3844-9

Anti-inflammatories and Ovulation

As someone who suffers from an autoimmune disease, anti-inflammatories (or more specifically NSAIDs Non-Steroidal Anti-Inflammatory Drugs) are often my best friend. I’ve been on and off them for probably close on 15 years and have often relied on them to help me make it through the day. So when my husband and I were trying to conceive I kept on popping them without a thought, while weaning myself off of all the hectic autoimmune disease drugs such as methotrexate that I was advised to get off of before conception (you need to be off of methotrexate for at least 4 months before you conceive). Then because things were taking a little longer than I would of hoped, I started to investigate the effect of the NSAID I was still taking on fertility. I was stunned by what I found, even more so because not one of my doctors had mentioned it.

NSAIDs can interrupt, delay or stop ovulation due to the action of the NSAID on the cox-2 enzyme and its role in the development of prostaglandins (a fatty molecule involved in the regulation of inflammation) [1]. If you think about ovulation, it is essentially an inflammatory process with the follicle on the ovary swelling and eventually bursting to release the egg. If you don’t allow for this inflammation then ovulation cannot occur.

In fact some NSAIDs are so good at stopping ovulation that they have been investigated for their use as contraceptives or as morning-after pills [2, 3]! Unfortunately it is not just prescription anti-inflammatories (such as Arcoxia and Celebrex, Mypaid and Myprodol) that can cause this, anti-inflammatories available over the counter are responsible as well (such as Voltaren, Cataflam, Nurofen , Advil) [4].

So if you are trying to conceive, think carefully about popping a pill for a headache or backache.

 

[1] M. Gaytán, C. Morales, C. Bellido, J.E. Sánchez-Criado and F. Gaytán, “Non-steroidal anti-inflammatory drugs (NSAIDs) and ovulation: lessons from morphology”, Histol Histopathol Vol. 21, pp. 541-556, 2006 http://europepmc.org/abstract/med/16493584

[2] Edelman AB, Jensen JT, Doom C, Hennebold JD, “Impact of the prostaglandin-synthase 2 inhibitor celecoxib on ovulation and luteal events in women. “, Contraception, 87(3), pp. 352-357, 2013 https://www.ncbi.nlm.nih.gov/pubmed/22902348

[3] McCann NC, Lynch TJ, Kim SO and Duffy DM, “The COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates”. Contraception. 88, 2013 https://www.ncbi.nlm.nih.gov/pubmed/24120248

[4] Salman S, Sherif B & Al-Zohyri A, “Effects of some non-steroidal anti-inflammatory drugs on ovulation in women with mild musculoskeletal pain.” Annual European Congress of Rheumatology, 2015 http://www.pharmaceutical-journal.com/news-and-analysis/nsaid-use-may-prevent-fertile-women-from-ovulating/20068779.article

 

Welcome to Evidence Based Moms

As the old trope goes, Babies don’t come with a manual! And neither does getting pregnant with those babies or dealing with them as they grow out of babyhood. Many people claim to have the answers, online forums, parenting articles, your parents and in-laws (and especially random people you meet in the supermarket). But if everyone’s advice is different, how do you know which is correct?

This is when we turn to science. Modern medicine is based on the practice of being evidence based, which means that you can’t claim something works unless you can prove that it works. Proving something works is not that easy, as you have to show repeatable, predictable results in enough people that you can extrapolate to the general population and then publish this work so that others can read it and critique it and act upon it. The Internet is filled with journals, white papers and conference proceedings outlining all this work.

So if all this information is available why don’t people access it? The primary reason is because you generally have to have multiple years of graduate level education to cut through the jargon and understand what the information is about. This is what we hope to do on this blog. We want to take the questions that we come up against in our everyday parenting lives and answer them to the best of our ability with the latest science and medicine has to offer. We also want to make sure that everyone who stumbles onto our blog can understand and take out actionable points of information.

Please note that we are providing the latest information to the best of our abilities, however we are NOT your medical doctor! Any information you find on this blog that you find interesting, wish to implement etc should be thoroughly discussed with your health care provider before you do anything. We are not here to diagnose or advise, we are just providing information which may or may not be relevant to you.