Eating Disorders and Infertility

Twenty million American women (compared to 10 million men), will experience an eating disorder at some point in their lifetimes. Eating disorders come with a slew of medical complications, including infertility. In this post, we will discuss how fertility is affected by 3 common eating disorders--anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED).

Anorexia nervosa
In past editions of the DSM, amenorrhea was listed as a criterion for AN. While it is not included in the DSM-5, the absence of menstruation for >3 months affects about 66-84% of women with AN, while an additional 6-11% of women report light or infrequent menses (oligomenorrhea). Low BMI, high levels of exercise, and low caloric intake are the strongest predictors of amenorrhea. Amenorrhea occurs because food deprivation inhibits the hypothalamic-pituitary-gonadal (HPG) axis, decreasing the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which subsequently decreases the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland, which in turn, decreases the synthesis of estrogen and progesterone. A functioning HPG axis is imperative for ovulation and, thus, fertility. 

Recent research has found that estrogen receptor alpha (ERα), a nuclear receptor activated by estrogen, is also involved in the nutritional regulation of reproduction. Caloric restriction has been shown to decrease liver ERα activity, which disrupts the estrous cycle. However, dietary amino acids prevent this from occurring by promoting hepatic ERα activity. Finally, increased physical activity (over-exercise) is sometimes seen in patients with AN. It's been found that moderate exercise leads to increased fertility; however, exercising to exhaustion leads to a 2.3- to 3-fold increased risk of infertility. This effect of exercise is thought to be independent of body fat stores.

What is the upshot of this? According to a survey by Hassan and Killick, it takes underweight women (BMI <19 kg/m²) 4 times longer to conceive than it does for women with a normal BMI. Specifically, they found that underweight women took an average of 29 months to become pregnant, compared to 6.8 months for women of normal weight.

Bulimia nervosa

About 7-40% of women with BN report amenorrhea and 36-64% report oligomenorrhea. Research has found that women with BN have increased odds of receiving fertility treatments. This is thought to be possibly related to increased rates of polycystic ovarian syndrome (PCOS) in women with BN. The pathophysiology of infertility in PCOS is complex, but strongly associated with insulin resistance, which will be discussed in more detail below. 

Binge eating disorder 

While amenorrhea and oligomenorrhea may not be surprising consequences for patients with AN or BN, patients with BED have also been found to have light, infrequent, or absent menses, even after controlling for conditions like PCOS, or compensatory behaviors like purging. Obesity has been shown to increase the risk of infertility, miscarriage, poor pregnancy outcomes, and impaired fetal well-being. In fact, it's been found that with each unit increase in BMI above 29 kg/m^2, the chance of spontaneous conception decreases by 5%. Studies have found that obesity impairs the HPG axis, and also affects oocyte quality and uterine receptivity.

This decreased fertility in obese women is thought to be multifactorial. Elevated serum free cholesterol concentrations have been associated with reduced fecundity, and dyslipidemia is common in obese patients. Further, abnormal levels of insulin, leptin, and adiponectin in obese patients have been shown reduce fertility.

In obese patients with BED, insulin levels rise, leading to insulin resistance. This insulin resistance is highly correlated with PCOS. High levels of insulin inhibit synthesis of sex hormone-binding globulin (SHBG), leading to increased free testosterone levels, and also increase ovarian androgen synthesis. Insulin resistance has been shown to lead to abnormally high levels of LH. This combination results in a hyperandrogenic state that suppresses ovulation and thus reduces fertility.

Leptin is a hormone produced by adipose tissue that normally works to maintain energy homeostasis by inhibiting hunger/ reducing food intake and regulating pancreatic islet cells. Levels are low in women with AN, but markedly increased in obese patients, who develop a leptin resistance. Leptin affects reproduction by facilitating GnRH secretion in the HPG axis. Leptin-deficient female mice produce low levels of gonadotropins like LH and FSH,  and, consequently, sex steroids, which partly explains the hypogonadotropic hypogonadism in patients with AN. However, high concentrations of leptin, like those seen in obese patients with BED, have been demonstrated to directly interfere with estradiol production and oocyte maturation, which also decreases fertility.

Under physiologic conditions, leptin reduces hunger and food intake. The mouse on the left was leptin-deficient. 

Levels of adiponectin, another hormone secreted by adipose tissue, are low in obese patients. Adiponectin has insulin-sensitizing, anti-atherosclerosis and anti-inflammatory effects, but affects female fertility by stimulating granulosa cell steroidogeneis, and by possibly playing a role in uterine receptivity and embryo development.

(Un)safety of Marijuana in Pregnancy

Over 180 million people use cannabis for recreational or medical purposes globally, which is becoming a worsening public health issue in light of its recent legalization battles for both medicinal and recreational purposes and its ubiquitous use among adolescents and young adults, several of whom continue using it during pregnancy. Cannabis is, in fact, the most commonly illicit drug used during pregnancy with a self-reported prevalence ranging from 2% to 5% in most studies but increases to 15–28% among young, urban, socioeconomically disadvantaged women.

It is estimated that 48–60% of marijuana users continue use during pregnancy, with many women believing that it is relatively safe to use during pregnancy and less expensive than tobacco. In reality, though, we’ve been learning that cannabis in pregnancy isn’t benign and it has been reported that healthcare providers don’t routinely counsel their patients on the potential risks.

Tetrahydrocannabinol (THC), one of the psychoactive substances found in marijuana, is distributed rapidly to the brain and fat. It is known to cross the placenta, producing fetal plasma levels that were approximately 10% of maternal levels after acute exposure.

Marijuana has been associated with several adverse pregnancy outcomes, including:

•  Central Nervous System Effects: It has been shown to disrupt normal brain development and function. Animal models demonstrate that endocannabinoids play key roles in normal fetal brain development, including in neurotransmitter systems, and neuronal proliferation, migration, differentiation, and survival. Human fetuses exhibit central nervous system cannabinoid receptor type 1 as early as 14 weeks of gestation, with increasing receptor density with advancing gestational age, which suggests a role for endocannabinoids in normal human brain development;
• A Hungarian study just published this month on Biological Psychiatry points out to the correlation of prenatal marijuana exposure and the neuropsychiatric outcome in the offspring. They reviewed data from human and experimental studies to show that long-term and heavy cannabis use during pregnancy can impair brain maturation and predispose the offspring to neurodevelopmental disorders.  “Endocannabinoids regulate brain development via modulating neural proliferation, migration, and the differentiation of lineage-committed cells. In the fetal nervous system, endocannabinoid-sensing receptors and the enzymatic machinery of endocannabinoid metabolism exhibit a cellular distribution map different from that in the adult, implying distinct functions”.
•  This Dutch study emphasizes that, “Besides its well-known involvement in specific brain functions, such as control of movement, memory and emotions, the endocannabinoid system plays an important role in fundamental developmental processes such as cell proliferation, migration and differentiation. For this reason, changes in its activity during stages of high neuronal plasticity, such as the perinatal and the adolescent period, can have long-lasting neurobehavioral consequences”.
• It has repeatedly been correlated with impaired cognition and increased sensitivity to drugs of abuse; (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988557/)
• The National Institute on Drug Abuse emphasizes that “human studies have shown that some babies born to women who used marijuana during their pregnancies respond differently to visual stimuli, tremble more, and have a high-pitched cry, which could indicate problems with neurological development. In school, children prenatally exposed to marijuana are more likely to show gaps in problem-solving skills, memory, and the ability to remain attentive. Establishing marijuana’s effects on prenatal development is important, because roughly half of U.S. pregnancies are unplanned, with the rate considerably higher for teens and young adults, so many women may use marijuana without knowing they are pregnant. Furthermore, breastfeeding mothers are cautioned that some research suggests that THC is excreted into breast milk in moderate amounts. Researchers do not yet know what this means for the baby developing brains”.
• Women who use cannabis are more likely to experience intimate partner violence; (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686908/)
• Children who were exposed to marijuana in utero had lower scores on tests of visual problem solving, visual-motor coordination, and visual analysis than children who were not exposed to marijuana in utero (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975798/ and http://www.ncbi.nlm.nih.gov/pubmed/8727237);
• It is associated with decreased attention span and behavioral problems and is an independent predictor of marijuana use by age 14 years (http://www.ncbi.nlm.nih.gov/pubmed/16911731, http://www.ncbi.nlm.nih.gov/pubmed/10840176, http://www.ncbi.nlm.nih.gov/pubmed/1469105); and
•  Poorer reading and spelling scores and lower teacher-perceived school performance (http://www.ncbi.nlm.nih.gov/pubmed/15203174).
• At least one study showed that THC was significantly associated with stillbirth (odds ratio 2.34, 95% CI, 1.13–4.81), though this finding was somewhat confounded by the effect of cigarette smoking. It has also been shown to increase the risk of intrauterine growth restriction and low birth weight.

In light of all the evidence above, The American College of Obstetricians and Gynecologists (ACOG) issued an official recommendation in 2015 advising ob-gyns to urge their patients who are pregnant or contemplating pregnancy to discontinue marijuana use.

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Recommendations

The American College of Obstetricians and Gynecologists recommends the following:

• Before pregnancy and in early pregnancy, all women should be asked about their use of tobacco, alcohol, and other drugs, including marijuana and other medications used for nonmedical reasons.
• Women reporting marijuana use should be counseled about concerns regarding potential adverse health consequences of continued use during pregnancy.
• Women who are pregnant or contemplating pregnancy should be encouraged to discontinue marijuana use.
• Pregnant women or women contemplating pregnancy should be encouraged to discontinue use of marijuana for medicinal purposes in favor of an alternative therapy for which there are better pregnancy-specific safety data.
• There are insufficient data to evaluate the effects of marijuana use on infants during lactation and breastfeeding, and in the absence of such data, marijuana use is discouraged.

“It is important to emphasize that the purpose of screening is to allow treatment of the woman’s substance use, not to punish or prosecute her. Seeking obstetric–gynecologic care should not expose a woman to criminal or civil penalties for marijuana use, such as incarceration, involuntary commitment, loss of custody of her children, or loss of housing. Addiction is a chronic, relapsing biological and behavioral disorder with genetic components, and marijuana use is addictive in some individuals. Drug enforcement policies that deter women from seeking prenatal care are contrary to the welfare of the mother and fetus”, ACOG concludes.

DON'T Pump and Dump!

Few things can be more painful for a mother than to discard her precious liquid gold. Successful breastfeeding often requires a great level of commitment and dedication, and seeing a woman throw away the product of that effort after a drink or two is really disturbing given the evidence that, in the great majority of cases, she wouldn’t need to do it. Current research says that occasional use of alcohol (1-2 drinks) does not appear to be harmful to the nursing baby. As long as the mother feels neurologically normal, the concentration of alcohol in breast milk is negligible. “That means if you are sober enough to drive, you are sober enough to breastfeed”, according to this article.

Sometimes a new mother finds herself in a situation where she may want to drink: it can be a date night (they’re so common in the postpartum period, right?), a wedding, or just to see how beer or wine tastes after 40 weeks of abstinence. While the harmful consequences of alcohol in pregnancy are well-established (the current recommendation is to completely avoid alcohol during pregnancy), its consumption in lactation remains unclear and women continue to receive very conflicting advice on it.

The American Academy of Pediatrics places emphasis on increasing breastfeeding in the United States and their Committee on Drugs considers alcohol compatible with breastfeeding.

The concentration of alcohol in the breast milk equilibrates with the mother’s blood concentration; it does not accumulate (it is not "trapped") in the milk. Pumping and dumping breast milk doesn't speed the elimination of alcohol from your body.

It is wise to avoid breast-feeding until alcohol has completely cleared your breast milk, which typically takes two to three hours for 12 ounces (355 milliliters) of 5 percent beer, 5 ounces (148 milliliters) of 11 percent wine or 1.5 ounces (44 milliliters) of 40 percent liquor, depending on your body weight.

The American Academy of Pediatrics Section on Breastfeeding notes: “ingestion of alcoholic beverages should be minimized and limited to an occasional intake but no more than 0.5 g alcohol per kg body weight, which for a 60 kg mother is approximately 2 oz liquor, 8 oz wine, or 2 beers. Nursing should take place 2 hours or longer after the alcohol intake to minimize its concentration in the ingested milk.”

Factors that influence alcohol metabolism and its concentration in the milk are:

• Your baby's age
• A newborn has an immature liver, and will be more affected by alcohol
• Up until around 3 months of age, infants metabolize alcohol at about half the rate of adults
• An older baby can metabolize alcohol more quickly than a young infant
• Your weight
• A person's size has an impact on how quickly they metabolize alcohol
• A heavier person can metabolize alcohol more quickly than a lighter person
• Amount of alcohol
• The effect of alcohol on the baby is directly related to the amount of alcohol that is consumed
• The more alcohol consumed, the longer it takes to clear the mother's body
• Will you be eating
• An alcoholic drink consumed with food decreases absorption

(source: http://www.llli.org/faq/alcohol.html)

Note that we’re talking about the occasional social drinker (i.e., 1-2 drinks on special occasions). Chronic and heavy consumption of alcohol has been shown to cause impairment on motor and cognitive development, weight gain/failure to thrive and sleep patterns. References here. 

Substantial consume may cause drowsiness, sleep irregularities, weakness and decreased growth in the infant. Very importantly, the effects of alcohol may impair judgement and affect the ability of the mother care for her child and to be aware of her baby’s needs, whether she is breastfeeding or not. If you drink heavily, it is safest to arrange for extra supervision for your baby and it may be best not to breastfeed.

Also, the popular idea that alcohol improves milk production is a myth. Studies show that alcohol actually decreases milk production and that the presence of alcohol in breast milk causes babies to drink about 20 percent less breast milk (Mennella & Beauchamp 1991, 1993; Mennella 1997, 1999) or inhibit let-down (Coiro et al 1992; Cobo 1974). 

(For a complete of the amount of drugs that are transferred into human milk please read: http://pediatrics.aappublications.org/content/pediatrics/108/3/776.full.pdf)

Dr. Jack Newman, member of the LLLI Health Advisory Council, says this in his handout "More Breastfeeding Myths":

“Reasonable alcohol intake should not be discouraged at all. As is the case with most drugs, very little alcohol comes out in the milk. The mother can take some alcohol and continue breastfeeding as she normally does. Prohibiting alcohol is another way we make life unnecessarily restrictive for nursing mothers.”

In summary: "As alcohol leaves the bloodstream, it leaves the breast milk. Pumping and dumping will not remove it. Pumping and dumping, drinking a lot of water, resting, or drinking coffee will not speed up the rate of the elimination of alcohol from your body".

Mothers who are intoxicated should not breastfeed until they are completely sober, at which time most of the alcohol will have left the mother's blood (which may take up to three hours). Drinking to the point of intoxication,binge drinking, or drinking daily has not been adequately studied and is not advised in concurrence with breast feeding.

What Medications Can I take for Insomnia During Pregnancy?

Insomnia during pregnancy is extremely common--a 1998 poll done by the National Sleep Foundation found that 78% of women report experiencing insomnia during pregnancy. There is a lot of information available about behavioral changes to improve insomnia while pregnant, and in fact, strategies like establishing a bedtime routine, avoiding stimulating substances like caffeine, and using pillows for support may solve the problem for many women. However, some pregnant women with severe insomnia require medications, which we will discuss below.

Choosing the right medication first depends on the cause of insomnia, and there are many. In the first trimester, rising progesterone levels lead to daytime fatigue and disturbed sleep at night; further, breast tenderness, nausea, and increased nighttime urination also interfere with a good night's sleep. In the third trimester, the size of the growing fetus makes it difficult to lie down comfortably, puts pressure on the bladder, and also increases the risk of obstructive sleep apnea (OSA) and gastroesophageal reflux disease (GERD). In the third trimester there is also an increased risk of restless leg syndrome. And throughout pregnancy, many women experience an increase in anxiety, due to concerns about labor and delivery, changes in relationships after the birth of a child, financial strain, childcare, etc. 

In psychiatry, frequently used medications for sleep include antidepressants, sedative-hypnotics (e.g., Ambien, Sonata, Lunesta, and benzodiazepines), and antihistamines (e.g., Benadryl).

Antidepressants
The topic of antidepressant safety in pregnancy is very broad. The results of research are often mixed, and based on observational studies (rather than randomized controlled trials, which more clearly demonstrate cause and effect). In general, the SSRIs (like escitalopram, sertraline, fluoxetine) have not been consistently shown to lead to specific congenital malformations (birth defects) with the possible exception of paroxetine (Paxil) and cardiac malformations, but there likely are associations between taking antidepressants during pregnancy and preterm birth, and between antidepressants and neonatal adaptation syndrome. The effects are generally small, and serious consequences are very rare. Sedating tricyclic antidepressants that are often used for insomnia (like amitriptyline or nortriptyline) have not been clearly shown to lead to any increased risk of congenital malformations above baseline rates in the general population. The topic of antidepressants and possible increased risk of autism is discussed in this blog post.

Sedative-hypnotics
In terms of the safety of sedative-hypnotics in pregnancy, it has long been thought that benzodiazepines lead to an increased risk of cleft lip/ palate. However, more recent studies, including a large population-based study conducted in the UK, have shown that there is no clear evidence that taking benzodiazepines and non-benzodiazepine hypnotics during the first trimester of pregnancy leads to an increased risk of major birth defects. However, there is a possible increased risk of preterm birth, low birth weight, and neonatal adaptation syndrome, similar to antidepressants.

Antihistamines
A 2014 review of the safety of antihistamines in pregnancy found no clear association between prenatal antihistamine exposure led and birth defects. More research exists for older, H1 blockers like diphenhydramine, promethazine or hydroxyzine, which are commonly used for sleep, and these are generally thought to be safer in pregnancy. 

Stimulants and ADHD in Pregnancy

Attention-deficit hyperactivity disorder (ADHD) is one of the most common conditions of childhood and approximately 30% of patients are estimated to continue pharmacologic treatment into adulthood (approximately 4% of the adult population suffers from ADHD). First line medications most often used to treat ADHD in adults are Dextroamphetamine (Dexedrine, Adderall) and Methylphenidate (Concerta, Ritalin, Metadate).

Similarly to what applies to most drugs, the use of stimulants in pregnancy should be individually and carefully assessed, weighing their pros and cons, risks and benefits for each woman and her needs.  In several cases of mild to moderate ADHD, the soon-to-be mother can function reasonably well without stimulants, with some behavioral modifications and/or non-stimulant medications. In more severe cases, however, they must continue on pharmacologic treatment in order to function.

We talked about the use of caffeine in pregnancy on a previous blog post. 

Alternative pharmacologic treatment options include tricyclic antidepressants, bupropion and clonidine, which have more evidence to support their safety in pregnancy than stimulants. However, large population studies have shown that the number of women who take stimulants during pregnancy has been getting progressively higher within the last decade, exposing a troubling lack of information regarding potential fetal risks in humans and urging for more post-marketing research.

A group from Boston University reviewed data from the Slone Epidemiology Center’s Birth Defects Study (BDS), an ongoing case-control surveillance effort focused on birth defects in relation to antenatal medication use in 29,540 women (19,811 cases and 9,729 controls) who were interviewed between 1998 and 2014. They noted that “In animal studies, methylphenidate has not produced teratogenic effects in mice or rats; in rabbits, only doses that were about 40 times the maximum recommended human dose resulted in an increased risk of spina bifida. Amphetamines given orally in doses approximately 1.5 and 8 times the normal human dose to both pregnant mice and rabbits had no apparent effects on fetal development, although parenteral doses at approximately 6 times the human dose resulted in fetal malformations in mice. However, it is important to note that animal studies are not predictive of human effects; teratogenicity in animals does not imply the same effect in humans, and lack of teratogenicity in animals does not ensure no effect in humans”, they conclude, adding that “The few human studies that have explored possible effects of these drugs on the fetus included only small numbers of subjects or were primarily focused on methylphenidate, while our experience indicates that amphetamine mixed salts is by far the most common (and most rapidly increasing) ADHD medication used by pregnant women in the United States”, says Louik and colleagues.

Most of the data we currently have derives from large Danish population studies. In one of them, Pottegård and colleagues evaluated data of 222 exposed and 2,220 unexposed pregnancies from 2005 to 2012 and found no statistically significant difference between the two groups in terms of risk for major congenital malformations. The same group also studied a total of 180 children exposed to methylphenidate in utero during first trimester (among whom four children with major malformations were observed) and concluded that methylphenidate exposure during pregnancy does not appear to be associated with a substantially (i.e. more than twofold) increased risk of congenital malformations.

A large cohort study monitoring 50,282 women with medication exposure during pregnancy with 367 women taking Dextroamphetamine and 215 unspecified Amphetamines in the first trimester demonstrated no increase in the risk of malformation in exposed infants. 

Based on these studies, the available data for methylphenidate suggest no increase in the risk of malformation when used at therapeutic doses.

However, there is some evidence that these infants may be at increased risk for low birth weight, preterm birth, growth retardation and neonatal withdrawal symptoms, but those findings are based on very small studies with several confounding limitations.

Good 2010 did a chart review including 267 women who had positive urine tests for methamphetamine compared to a control group of women with negative urine tests, and found a higher risk of  preterm delivery (52% vs. 17%), low Apgar scores (6% vs. 1–2%), and neonatal mortality (4% vs. 1%).

A study by Bro et al, published on the Journal of Clinical Epidemiology in 2015 on the adverse pregnancy outcomes after exposure to methylphenidate or atomoxetine during pregnancy looked at 989,932 pregnancies, in which 186 (0.02%) women used MPH/ATX and 275 (0.03%) women had been diagnosed with ADHD but who did not take MPH/ATX. They found that exposure to MPH/ATX was associated with an increased risk of spontaneous abortion but also found that women with ADHD who did not take MPH/ATX also carried an increased risk. MPH/ATX was however associated with low Apgar scores <10, an association not found among women with ADHD who did not use MPH/ATX.

 In conclusion, the data on use of stimulant medications in pregnancy are too scarce to allow definitive conclusions about their reproductive safety. Available data for amphetamines suggest no increase in the risk of malformation when used at therapeutic doses, while infants might have slightly lower birth weights and lower Apgar scores.  Whenever possible, the clinician should attempt to manage ADHD symptoms through non-pharmacological strategies (e.g., behavioral modification), treat comorbidities that may aggravate the ADHD picture (mood and anxiety symptoms, sleep difficulties, alcohol and substance use), or use alternative medications that have more supporting evidence in pregnancy.

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.