Caffeine and Pregnancy. How much is too much?

Last week news shows such as Today announced results from a recent study from the National Institute of Child Health and Human Development that associates caffeine consumption with early pregnancy loss. Headlines stated “drinking three or more caffeinated beverages a day raised the risk of early pregnancy loss.”  These headlines further confuse the already confusing question about how much caffeine intake is “okay” if you are trying to conceive or already pregnant.

The study published in Fertility and Sterility followed 344 expectant couples and examined lifestyle factors and the rate of early pregnancy loss. The study measured the number of caffeinated beverages partners drank as well as multivitamin use before they conceived through the seventh week of pregnancy. Researchers concluded that drinking three or more caffeinated beverages a day (before conception or during pregnancy) raised the risk of early pregnancy loss by 74 percent. Male preconception consumption of caffeinated beverages was found to be just as strongly associated with pregnancy loss as females.  The study however found that if a woman took multivitamin while she was trying to become pregnant through the first seven weeks of pregnancy  there was nearly a 80 percent reduction in the risk of miscarriage.

The study however only looked at an association, meaning it doesn't prove a cause and effect relationship.  It does not prove that caffeine intake itself leads to miscarriage. Another limitation is that the study examined the number of caffeinated beverages rather than measure total caffeine intake.  Caffeine content of caffeinated beverages can vary wildly between beverages. Nor did the study control for other confounding factors (exercise, sleep, or recreation drug use).  Individuals who drink more then 3 cups of coffee a day may be different that those who do not drink coffee. If these factors are not controlled for results can be misleading. For instance, high caffeine drinkers may have higher levels of subjective stress with poorer sleep habits etc. which may contribute to fertility loss.  Cigarette smoking, alcohol consumption, and a less health conscious lifestyle have all been linked to increased coffee consumption .

A previous 2011 systematic review  published in Birth Defects Research Part B of Developmental and Reproductive Toxicology  examined  both human and animal studies and  he risk of spontaneous abortion from caffeine exposure. They  concluded there was fair to good evidence that consumption of caffeinated beverages during pregnancy at a level ≤5 to 6 mg/kg body weight/day does not increase the risk of spontaneous abortion. Very very high caffeine intake in some animal studies demonstrates some increased risk however woman drinking  over a dozen cups of coffee in a day would not approach this level of caffeine intake.

Previous publications report an association between caffeine use in pregnancy and low birth weight and preterm birth.  For instance a  2014 meta-analysis of 100,000+ women reported that increases in maternal caffeine intake during pregnancy is associated with increased risk of delivering low birth weight infants (in a dose dependent manner).  However a randomized double blind trial that analyzed the effect of reducing caffeine intake found no effect on birth weight or preterm  birth when caffeine intake was decreased by 50% in women drinking 3+ cups a day prior to study enrollment. A 2010 systematic review similarly did not demonstrate a significant association between maternal caffeine intake anytime in pregnancy and preterm birth.

Given the knowledge of literature the American College of Gynecology states there is insufficient evidence to support reducing caffeine use below 200mg/day.

For hopeful or expecting mothers the first step is to determine how much caffeine you are consuming.  Caffeine is most associated with coffee, tea, soft drinks, and energy drinks. Content and can vary dramatically between products and brands.  For example the same size coffee at Starbucks has double the caffeine content compared to McDonalds. 

Caffeine can be also be present in unexpected places such some prescription and over the counter medications such as those for flu/cold, allergy, and headaches as well as diet pills and diuretics.   Caffeine content of popular items can be found here.

Dr. Williams of the Albert Einstein College of Medicine and a spokesman for the American College of Obstetricians and Gynecologists  warns " what I do end up seeing not infrequently, an effort to really be as thorough as possible, a lot of women will go cold turkey on caffeine. And what ends up happening is invariably these women will then develop rebound headaches and take medications to treat the headaches. Those medications may be harmful.”

If you decide to cut caffeine “cold turkey” you may experience withdrawal symptoms such as headache, anxiety/irritability, constipation/diarrhea, low mood, low energy, sweating, or shakiness. Most symptoms dissipate in few days but can last as long as two weeks for heavy drinkers. Gradually decreasing caffeine content over 1-2 weeks can minimize the risk of withdrawal symptoms. Strategies for decreasing caffeine content include transitioning to decaf, switching out tea for coffee, or drinking tea with a lower caffeine content.

Do I have PMS? PMDD?

Discussions of premenstrual syndrome (PMS) cannot ignore the fact that it's partly a social construct, used in popular culture to explain women's increased emotionality--whether it be sadness or anger or anxiety--when it's "that time of the month." But for some women, the symptoms are much more severe than what is typically portrayed. As one woman wrote, "Every month I battle a monster. I gird myself with a healthful diet and a couple of pills, but the personality switch comes, like a lamp switched on, three weeks into my menstrual cycle. If most women get a little bloated, a little cranky, maybe a little confused, I swell an entire dress size and try to ban my husband from any room I'm in. Deciding what to eat for dinner so overwhelms me that I've broken down crying in the frozen food aisle."

In the psychiatric community, PMS's severe manifestation is called premenstrual dysphoric disorder (PMDD). The diagnosis is made using the following criteria from the DSM-5: 

It's a bit wordy, so here's a brief summary: PMDD is diagnosed by 1) the presence of at least 5 symptoms in the luteal phase of the cycle (including at least 1 mood symptom like irritability or mood swings), 2) the symptoms must be confirmed by prospectively monitoring at least 2 cycles, and 3) the symptoms must interfere with the woman's work, relationships, or other activities.

The American College of Obstetrics and Gynecology has a slightly different way of describing this condition, using the phrase "moderate to severe PMS" (rather than PMDD) and the diagnostic criteria of at least one psychological or physical symptom that causes significant impairment and is confirmed by prospective ratings.  Approximately 5-8% of women with hormonal cycles would be classified as having moderate to severe PMS, or PMDD.

The etiology of PMDD is unclear. Given the cyclicity of symptoms, it's long been thought to be related to the ovarian cycle, a brief overview of which is below:

There are 2 main phases--the follicular phase, and the luteal phase. In the follicular phase, an egg follicle in the ovary prepares to release an egg; this phase terminates with ovulation. During the luteal phase, the corpus luteum develops from the ovarian follicle and produces progesterone and estrogen. As you can see from the chart, estrogen levels peak prior to ovulation (while there is a smaller peak during the luteal phase), and progesterone levels rise significantly during the luteal phase. It's thought that the fluctuations in hormone levels--rather than a hormonal imbalance--may trigger PMS or PMDD symptoms, and that some women are more sensitive to these fluctuations than others.

However, hormones like estrogen and progesterone are not the full story; in fact, research has shown that the neurotransmitter serotonin modulates, or dampens, the impact of sex steroids on behavior, while sex steroids also affect serotonin transmission in the brain. We will be discussing the treatment of PMDD in a later post.

Exercise for Mood and Anxiety

Among the several treatment options for depression and anxiety, I find physical exercises to be the most underrated. People are always talking about how exercises help a multitude of physical conditions, but there is much less awareness of mental health outcomes. For the past few years, extensive research has been done about the impact of exercises on depression and anxiety, their mechanisms of action, ideal duration, intensity, type, and frequency.

An obvious mood-enhancement feeling is usually perceived within a few minutes of moderate exercises, and it turns out that it may last much longer than that. Study after study, both epidemiological and experimental, has shown the efficacy of exercises in the treatment of chronic depression and other mood and anxiety symptoms related to various women’s reproductive stages, such as pregnancy, postpartum and menopause. 

Regular workouts may also improve outcomes in women struggling with infertility. According to a study in Obstetrics & Gynecology,  “Women who exercised 30 minutes or more daily had a reduced risk of infertility due toovulation disorders”, says Robert Brzyski, MD, PhD, professor of obstetrics and gynecology at the University of Texas Health Science Center at San Antonio and chair of the ethics committee of the American Society of Reproductive Medicine (ASRM).

Dr. Madhukar Trivedi, MD, a psychiatrist at the University of Texas Southwestern Medical College, and colleagues studied exercise as a secondary treatment for patients with major depressive disorder who hadn't achieved remission through drugs alone. They evaluated two exercise doses: One group of patients burned four kilocalories per kilogram each week, while another burned 16 kilocalories per kilogram weekly. They found both exercise protocols led to significant improvements, though the higher-dose exercise program was more effective for most patients (Journal of Clinical Psychiatry, 2011).

During pregnancy, it’s been reported that about 20% of women meet criteria for major depression or generalized anxiety disorder, and those are linked to bad outcomes such as preterm birth and low birth weight. A recent study from Spain analyzed 167 healthy pregnant women- 90 were assigned to a supervised exercise program and 77 were in the control group. Significant differences were found between the two groups at the end of the study: the percentage of women who were depressed was much lower in the exercise group (12.2%) as compared to the control group (24.7%).

This is particularly relevant given that a lot of women feel even more anxious to take psychiatric medication during pregnancy, due to fears they might harm the fetus.

A study by Heh and colleagues (2008) randomly assigned 80 women with a 6-week postpartum EPDS score >10 (signifying postpartum depression) to one of two exercise groups: 3 exercise sessions/week, or the patient’s usual treatment (control group).  Women who were in the exercise group had a significant improvement in mood by five months postpartum when compared to the control group.

However, a lot of women worry that an exercise routine may be potentially harmful to their babies.

The same group analyzed 200 pregnant women and found out that regular and moderate exercise is safe throughout pregnancy and is not a risk to maternal and fetal well-being, and it helps to control excessive weight gain.

Additionally, they found that exercise throughout pregnancy does not cause preterm delivery. 

The American College of Obstetricians and Gynecologists advises pregnant women to participate in 30 minutes of moderate exercise on most days, unless other health conditions preclude this recommendation (Artal and O’Toole, 2003). Here you can find the complete guidelines for exercise during pregnancy and the postpartum period, including absolute and relative contraindications and warning signs to terminate exercises during pregnancy: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1724598/pdf/v037p00006.pdf

Other forms of mind-body interventions, such as yoga, have been gaining popularity during pregnancy and in the post-partum period and can be a wonderful way to substantially improve bonding/ attachment with your newborn! Several places are now offering Yoga and Pilates classes for mom & baby. If you’re unable to join one, there are great DVDs and YouTube videos and you can practice even at home.  ('Yoga for prenatal depression: a systematic review and meta-analysis'. Gong H et al (2015). BMC Psychiatry 15(1):14. [Pract Midwife. 2015])

Randomized controlled trials have also shown that exercise training is effective in alleviating vasomotor and other menopausal symptoms. Sternfeld and colleagues studied 248 women dividing them in an exercise group and a group that maintained their usual activity level. By 12 weeks, the exercise group reported greater improvement in insomnia, subjective sleep quality, and depressive symptoms. 

But how does it work in the brain? Biologically, exercises work by increasing serotonin (the neurotransmitter targeted by antidepressants) or brain-derived neurotrophic factor (which supports the growth of neurons), decreasing cortisol (a stress hormone) and regulating sleep, which is known to have protective effects on the brain,  helping with the fatigue and lack of motivation that are commonly seen in people with depression. Psychologically, they allow people to engage in a new meaningful activity and bring them the feeling that they’re taking good care of themselves, with consequent improvement on self-esteem and self-confidence. Socially, it makes one get out of the house and meet new people and sometimes engage in group sports and activities.

It's important that clinicians talk about the benefits of exercise with their patients, not only the physical ones, but the impact that exercise may have on mental health.  

So let’s sweat away the blues and take advantage of exercise's low cost, easy accessibility, minimal side effects, and extensive health benefits.  

Helpful links to some related studies:

Dunn, A.L., Trivedi, M.H., Kampert, J.B., Clark, C.G., Chambliss, H. G., 2005. Exercise treatment for depression: efficacy and dose response. Am. J. Prev. Med. 28: 1-8.

Koltyn, K.F., Schultes, S.S., 1997. Psychological effects of an aerobic exercise session and a rest session following pregnancy. J. Sports Med. Phys. Fitness 37 (4), 287-291.

Polman, R., Kaiseler, M, Borkoles, E., 2007. Effect of a single bout of exercise on the mood of pregnant women. J. Sports Med. Phys. Fitness 47 (1), 103-111.

Heh, S.S., Huang, L.H., Ho, S.M., Fu, Y.Y., Wano, L.L., 2008.  Effectiveness of an exercise support program in reducing the severity of postnatal depression in Taiwanese women. Birth . 35 (1), 60-65.

Artal, R., O’Toole, M., 2003. Guidelines of the American College of Obstetricians and Gynecologists for exercise during pregnancy and the postpartum period. Br. J. Sports Med. 37 (1), 6-12

http://www.ncbi.nlm.nih.gov/pubmed/15626549?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

https://www.essa.org.au/wp/wp-content/uploads/Exercise-and-Mental-Health-An-Exercise-and-Sports-Science-Australia-Commissioned-Review.pdf

Is Lamictal safe in pregnancy?

Lamictal, also known as lamotrigine, is an anticonvulsant medication that is frequently used in psychiatry. It has been shown to be an effective maintenance medication in bipolar disorder--that is, studies have found evidence of its effectiveness in preventing depressive episodes in people with bipolar disorder. There is weaker evidence for its effectiveness in treating acute depressive episodes. Many of our patients have asked us about whether or not Lamictal is safe in pregnancy. 

The data that are available suggest that lamotrigine monotherapy is relatively safe in pregnancy. In 1992, a lamotrigine pregnancy registry was created to monitor for major congenital malformations (i.e., birth defects) in children of mothers who took lamotrigine during the first trimester. The registry collected data from 1,558 pregnancies over 18 years, and found that major congenital malformations occurred in 2.2% of exposures, which is very similar to the baseline rate of birth defects in the general population (frequently cited as between 2-4% of all pregnancies). On the other hand, the rate of birth defects in children exposed to both Lamictal and valproic acid (also known as Depakote), was 10.7%. A prospective study found evidence that the dosage of lamotrigine used affects rates of congenital malformations, with higher doses (>300 mg/ day) leading to a birth defect rate of 4.5%, but lower doses (<300 mg/day) leading to a rate of 2.0%. 

One of frequently cited risks of taking lamotrigine during the first trimester is the development of cleft lip or palate. The formation of the palate occurs between weeks 6 and 11 of gestation. The North American AED registry looked at 684 infants exposed to lamotrigine during the first trimester and found that the risk of developing cleft palate, lip, or both, was 0.73% in the exposed population, compared to 0.07% in the unexposed population. While 0.73% is 10.4x greater than 0.07%, it's important to note that the 0.73% absolute risk of developing a cleft palate or lip with lamotrigine exposure is still quite low, provided the results are accurate. Further, it's important to take the results with a grain of salt for several other reasons, including the relatively small number of women in the study population, and the lack of addressing possible confounding variables like maternal race, habits like smoking or alcohol use, exposure to other medications, and other medical problems. 

One important consideration for a patient who does decide to use Lamictal in pregnancy is that serum levels of the drug will decrease in pregnancy. Estrogen has been shown to increase the clearance, or elimination, of Lamictal, and in pregnancy, clearance increases by 250% on average. One way that this is monitored in patients who use lamotrigine for seizure control is that serum levels are obtained prior to pregnancy, and the dosage of the drug is increased during pregnancy so that serum levels remain above 65% of the pre-pregnancy level. Obtaining levels prior to and during pregnancy is not always necessary in patients who take Lamictal for bipolar disorder, but of course, could be helpful. 

The discerning reader may wonder that if estrogen increases the clearance of Lamictal, then perhaps oral contraceptives that contain estrogen will also lead to decreased Lamictal levels. That is correct! For more on this, please click here. 

I'm taking antidepressants while pregnant. Does that mean my child will develop autism?

Recently, an article linking antidepressant use in pregnancy with the risk of autism spectrum disorder in children was published in JAMA Pediatrics. What followed was a flurry of news reports like this and this, claiming that women who take SSRIs in pregnancy increase their child's risk of autism "by as much as 87%" (according to the Newsweek article). Scary news. In our clinic, many women who are either pregnant or preparing for pregnancy have asked us about whether taking antidepressant medications during pregnancy will increase the risk of autism in their children exposed in utero, so we think it's an important topic to cover.

ASD is a developmental disorder characterized by impaired communication and social interactions. More information can be found here. Right now, there is no known single cause, but we do know that risk factors for ASD include particular genetic variants, de novo mutations, maternal disease (like diabetes), and--importantly--maternal history of psychiatric disorders.   

Here's a brief summary of the JAMA article: it was a study that looked at all pregnancies that occurred in Quebec between 1/1/98 and 12/31/09. Data from from several databases were linked with unique personal identifiers to provide information about medical services, prescription drugs, hospitalization, and demographics. The researchers defined antidepressant (AD) exposure as having at least 1 prescription filled at any time during pregnancy or a prescription filled before pregnancy that overlapped with the first day of gestation. The outcome variable was whether or not children had a medical service claim or hospitalization with a diagnosis of ASD between birth and the end of follow-up. The researchers determined crude and adjusted hazard ratios (HRs) which are the expression of the hazard, or chance, of events occurring in the treatment arm as a ratio of the hazard, or chance, of the events occurring in the control arm. Basically, the HR could be expressed as follows:

The researchers found that the hazard ratio for the use of antidepressants during the second and/ or third trimester was 1.87, which is where various news sites got the 87% increased risk of ASD statistic. On the surface, this HR indicates that there is a higher chance of children being diagnosed with ASD in women who used ADs in the second and/ or third trimester than the chance of children being diagnosed with ASD in women who did not. The study authors suggest that this means that the use of antidepressants is associated with an 87% increased risk of ASD, even after taking into account particular confounders. (Of note, the hazard ratio for the use of ADs in the first trimester was 0.84.) However, when we look more closely at the study, we see a few problems with this conclusion: 

1.  The biggest problem is that maternal psychiatric illness, in particular, depression, is known to be associated with an increased risk of ASD in offspring. The study had no reliable measures of depression severity. Therefore, there is no way to tell whether the children were at higher risk for developing ASD because their mothers were taking antidepressants, or because their mothers had more severe depression. In Alison Stuebe's fantastic article on this topic in the Huffington Post, she writes the following: "The key problem is that women who take a medication when they are pregnant have a reason for taking it. Blaming the outcome on the medication, without considering the underlying disease, is like saying that umbrellas cause flooding. Taking away the umbrellas -- "not treating the rain" -- does not prevent flooding; it just means that people get soaked."
   
2.  Another problem with the author's conclusion about an 87% increased risk of autism is that the number is very misleading. If the average child has a 1.5% risk of autism (according to the CDC, the prevalence was 1.5% in 2010), then the children exposed to antidepressants in the second and/ or third trimester in this study had a risk of 2.8%, which is an absolute risk increase of 1.3%, a much more modest value than 87%. 
3. A sensitivity analysis that restricted the study population to children with ASD diagnosis confirmed by a psychiatrist of a neurologist found that the association between the use of antidepressants in the second and or third trimester and risk of ASD was no longer statistically significant (the confidence interval included 1). This means that it's important to realize that the study did not show an increased risk of ASD diagnosis in children of mothers who took antidepressants, but rather, an increased risk of a billing code (which could just indicate an evaluation) for ASD. 

Whether or not to continue taking antidepressants during pregnancy is a very personal decision, and best discussed with your clinician. It's important to remember that there are significant risks of untreated depression or anxiety in pregnancy, including prematurity, intrauterine growth restriction, and low birth weight, as well as higher rates of impulsivity, and cognitive, emotional, and behavioral problems in children. Mothers with untreated depression in pregnancy have significantly higher rates of relapse of their depression if they do not take their medications (68% compared to 26% in women who did continue taking medications during pregnancy), according to a large NIH study looking at mothers with severe depression. To put this in context, if 1000 women with severe depression stop taking their medications during pregnancy, then 680 of them would experience a relapse in major depression, while only 13 of the women would avoid an evaluation of their child for autism.