Tuesday, April 26, 2016

A Mother's Love- Infertility and Pregnancy Loss

(photo: Sher Institutes)

One could argue that there's nothing more intense than a mother's love, long before her child is even born.

This week we celebrate the National Infertility Awareness Week, a movement that started in 1989.  My interest in Women’s Mental Health and Reproductive Psychiatry began a little less than two decades later, when my husband and I were diagnosed with infertility. Suddenly, this two-physician couple assumed the patient role, with all its emotional and physical pains, challenges and distress. Denial, anger, shock, grief and disbelief, depression and anxiety all followed. A terrifying sense of loss of control marked that turbulent, draining road.

Relationships suffer- marital discord arises, friendships get affected, one’s social life may vanish. Diminished quality of life, complicated grief, major depressive disorder, anxiety disorders, and post-traumatic stress disorder may develop.

Infertility is the inability to achieve pregnancy for one year (or six months if over 35) or being unable to carry a pregnancy to live birth. It is quite common, affecting approximately 1 in 8 couples. One third of infertility is attributed to the female partner, 1/3 attributed to the male partner and 1/3 is unexplained or results from a combination of problems in both partners 

According to Dr. John Rapisarda, Reproductive Endocrinologist and Vice President of Fertility Centers of Illinois, “The most common causes of infertility in women are Polycystic Ovarian Syndrome (PCOS) and other ovulation disorders, blockage of the Fallopian tubes and diminished ovarian reserve while the most common causes of infertility in men are hormonal imbalances, low sperm count, abnormal sperm shape, and poor sperm movement (motility)”.

The frustration, pressure and uncertainty that surround infertility have been shown to cause significant mental stress, particularly anxiety and depression. In addition to that, fertility treatment often involves invasive, time-consuming tests and procedures, and complicated medication schedules that further add to the stress of the diagnosis. That is commonly accompanied by feelings of grief, failure, and guilt. 

The prevalence of depressive symptoms among infertile women has been reported as being twiceas high as that of fertile women. Further, levels of distress and anxiety in infertile women persist over extended periods of time, tending to increase as treatment intensifies and the duration of treatment lengthens. Several factors are involved: 

·         The drugs and hormones that are commonly used to treat infertility often cause a myriad of psychological side effects. Clomiphene citrate (Clomid, Serophene), frequently prescribed because it improves ovulation and increases sperm production, may cause anxiety, sleep interruptions, mood swings, and irritability; Oral contraceptives, often part of the treatment protocols, have higher doses of progesterone, which has been associated with increased depression. GnRH Agonists (Leuprolide/Lupron) are associated with depression, emotional lability, and changes in libido; Steroids and immunosuppresants may also cause depression, mania, anxiety and psychosis. 

·         Financial Difficulties: insurance coverage varies widely, and infertility treatments can be financially draining while still offering disappointing success rates in a lot of cases;

·         Religious ambivalence: fertility treatment goes against several religious doctrines, further adding to feelings of guilt and anxiety or social criticism.

·         Social aspects: patients may find it very distressing to socialize with their friends who are pregnant or have children. They may feel guilty for not being able to fully rejoice with them and end up opting to exclude them from their lives, becoming increasingly withdrawn and seclusive, with fewer support systems at a time when social support could be so helpful.
   


 While it is clear that infertility can affect mental health, researchers are not sure if mental health can affect fertility. Some studies have proposed that high levels of depression, anxiety, and stress can affect some of the hormones that regulate ovulation. The hormonal impact on mood and its correlation with pre-menstrual syndrome, pre-menstrual dysphoric disorder, pregnancy and postpartum depression, and menopause are well-established. The psychological impact of the hormones used in fertility treatments, however, hasn’t been as widely studied.

A Japanese study with 83 women undergoing fertility treatment showed that the rates of anxiety and depression were higher as the age increased. They also found that patients who underwent infertility treatment were more likely to have higher depression scores compared to patients who had not undergone treatment. Additionally, patients whose husbands were infertile had significantly lower total mood and anxiety scores than those whose husbands were not infertile.

“Eliminating psychological stress may be necessary for successful infertility treatment.
Women appear to have a higher rate of infertility-related stress than men. Studies have also found that greater than half of the women receiving infertility treatment feel that infertility is the most stressful experience of their lives", they conclude.


One study of 200 couples seen at a fertility clinic, for example, found that half of the women and 15% of the men said that infertility was "the most upsetting experience" of their lives. Another study of 488 American women who filled out a standard psychological questionnaire before undergoing a stress reduction program concluded that women with infertility felt as anxious or depressed as those diagnosed with cancer, hypertension, or recovering from a heart attack.

Despite the evidence that infertility has a profound impact on mood and anxiety, mental health care during this treatment is often neglected. A couple dealing with infertility may benefit from several treatment approaches observing the biopsychosocial model. Those include counseling and psychotherapy, relaxation techniques, yoga, meditation and exercises (see our post about that here) and psychiatric medications that may alleviate mood and anxiety symptoms. The prevalence of antidepressant use has been reported to comprise as much as 4 and 11% of women undergoing infertility treatment according to some studies.

But is there any evidence that antidepressants increase the fertility rates? 

A study published this year on the Journal of Psychosomatics Research by a Canadian group did a systematic review of databases from January 1950 to November 2015 and did not find that antidepressant use by women receiving fertility therapy impacted gamete quality or pregnancy success. “Collectively, the findings of the four studies meeting inclusion criteria reflect no differences between antidepressant users and comparators in assisted reproductive outcomes (i.e., peak serum FSH or estradiol levels, oocyte retrieval, or embryo maturation, transfer and implantation rates). This is consistent with Worly and Gur's findings that clinical studies have yet to demonstrate a deleterious effect of psychotropic medications on oocyte quality or reproductive success”.

A Swedish nation-wide study including 23,557 nulliparous women undergoing their first IVF cycle between January 1, 2007 and December 31, 2012 found no statistically significant associations between SSRI treatment and IVF outcomes. Conversely, women treated with non-SSRI antidepressants had reduced odds of pregnancy (Adjusted Odds Ratio (AOR): 0.41; 95% CI: 0.21, 0.80) and live birth (AOR: 0.27; 95% CI: 0.11, 0.68) and an increased likelihood of miscarriage (AOR: 3.56; 95% CI: 1.06, 11.9). These risks were also significant for untreated individuals in pregnancy (AOR: 0.58; 95% CI: 0.41, 0.82) and live birth (AOR: 0.60; 95% CI: 0.41, 0.89) but not miscarriage (AOR = 1.28; 95% CI: 0.49, 3.39).

It is crucial to note, however, that each patient should be treated according to the severity of her symptoms and medications are often required to ensure safety and well-being. In fact, a recent study on suicidal risk among infertile women undergoing in-vitro fertilization found that being "childless, depressive and non-positive reappraisal predict suicide risk" and stressed that suicidal risk is recommended for women in the course of IVF.

“The incidence of suicide risk was 9.4%. Suicidal women were more likely to be childless or had fewer children and experienced higher levels of depressive symptoms. In addition, they reported more frequently on denial, social withdrawal and self-blame coping strategies compared to participants without suicidal risk”. 





Perinatal loss (miscarriage, stillbirth) is another major risk factor for depression and other psychiatric issues. A recently-published study entitled “Infertility and Perinatal Loss: When the Bough Breaks” does a comprehensive review on the correlation between pregnancy loss, depression, suicidality and trauma:

"Young women, who lack social supports, have experienced recurrent pregnancy loss or a history of trauma and / or preexisting psychiatric illness are at a higher risk of experiencing psychiatric illnesses or symptoms after a perinatal loss or during infertility.

Perinatal loss is the non-voluntary end of pregnancy or death of the baby from conception until 28 days into a newborns life. The term perinatal loss includes miscarriage, stillbirth, and neonatal death.
Psychological Aspects of Perinatal Loss Understanding and addressing psychological aspects of perinatal loss is critical because of the psychological reactions of women (grief, depression, anxiety, PTSD, suicide) and the impact on subsequent pregnancies and relationships with partners and surviving siblings. The grief that follows miscarriage often declines significantly by 6 months for both men and women, yet sometimes persists for up to 2 years. Perinatal loss leads to complicated grief more frequently than other losses. Several factors may contribute to this. Pregnancy loss is often sudden and unexpected. The grief that parents experience after early pregnancy loss is often not openly acknowledged or socially supported. Perinatal loss is associated with guilt or self-blame, and women may feel that their bodies have failed. Predictors of complicated grief following perinatal loss include lack of social support, previous loss, major depression, ambivalence about pregnancy, and termination of pregnancy for fetal anomaly. Termination of pregnancy for fetal anomaly is associated with higher levels of self-blame, guilt, and social isolation. Other factors that have been reported as predictive in some, but not all studies include older maternal age, having viewed an ultrasound, having experienced quickening (fetal movement), having named the baby or bought things for the baby, and length of gestation.  Whether miscarriage is managed medically or surgically does not have a bearing on the intensity or duration of grief. The presence of living children is protective against grief after perinatal loss. The perinatal loss of a co-twin or a higher order pregnancy is associated with unique challenges such as enduring the trauma of prolonged hospitalization for the surviving twin. Grief following perinatal loss is a normal phenomenon. Nonetheless, women, especially those with risk factors, should be monitored for prolonged or complicated grief and persistence of depression, anxiety, or posttraumatic symptoms. Women who experience a perinatal loss have fourfold higher odds than women with a live birth of screening positive for depression. Risk factors for persisting depression/ psychological distress after miscarriage are infertility treatment, recurrent pregnancy loss, prior history of depression, prior PTSD, intimate partner violence (IPV), and high levels of distress immediately after miscarriage. There is also a higher risk of inpatient or outpatient psychiatric treatment 12 months after fetal death. The highest risk is for women with a loss occurring after 20 weeks of gestation, and the most commonly reported psychiatric disorder is adjustment disorder. However, 5 to 18 years after intrauterine fetal death (IUFD), there are no significant increases in depression scores. Thus, while women with recurrent miscarriages and a past history of depression and fetal death after 20 weeks of gestation are at a high risk of depression/ adjustment disorder in the year following perinatal loss, this risk declines subsequently.
Post-Traumatic Stress Disorder (PTSD) rates are increased after all types of perinatal loss—miscarriage, termination of pregnancy, stillbirth, and neonatal death. Risk factors for PTSD include younger age, lower education, previous trauma, and mental health problems. Longer gestational ages are associated with greater severity of PTSD. Even 9 months after a stillbirth or neonatal death, women have a sevenfold higher rate for screen positive PTSD when compared with women with live births. It is important to encourage the use of available social support because having a support network is associated with less depression and PTSD. The mean annual suicide rate is higher (18.1 per 100,000) in the first year after miscarriage than after live birth (5.9) or in the general population (11.3)”.


They proceed to commenting on the guidelines for the management of psychological responses after stillbirth, which remain controversial, “especially surrounding the parent’s decision to hold the baby. Although there is a dearth of randomized controlled trials of bereavement counseling or specialized psychotherapy for mothers, fathers, and families after perinatal death, there is evidence from studies using other study designs. Some studies have found that holding the baby may increase the risk of depression, anxiety, and PTSD in the mother, sometimes up to 7 years after stillbirth. However, other studies have found that parents appreciate time and contact with their deceased infant, and that parents who see and hold their baby report fewer poor mental health outcomes. Encouragement of parents to see and hold their deceased baby may be best done under guidance from experienced staff , always emphasizing the importance of respecting culturally diverse approaches to neonatal death. In the case of termination of pregnancy for fetal anomaly, observing a deformed baby can be traumatic, but it may also help to reduce guilt if observing the baby convinces the mother that she made the right decision. Other approaches to supporting parents grieving after a stillbirth have included supportive DVDs, internet-based cognitive behavior therapy and mindfulness-based therapy. Physical activity may help as shown in a recent study, which found that in women within a year of stillbirth, those who reported higher levels of physical activity reported lower levels of depressive symptoms. There is a dearth of studies or reviews specifically examining the use of SSRIs or other psychotropics in the aftermath of perinatal loss. However, it is worth noting that the association between SSRI use and miscarriage is controversial, and there is no association between SSRI use and stillbirth. Although all women may not need preventive psychosocial interventions after miscarriage, stillbirth, or neonatal death, it is important that they be monitored, especially if they have established risk factors. Given the lack of evidence for any specific approach, we recommend a customized treatment plan based on the individual’s preferences.



Couples dealing with infertility and pregnancy loss eventually come to some form of resolution achieved through biological children, adopted children, surrogacy, embryo/egg/sperm donation, or a decision to have a life without children. Whatever the outcome is, the experience will change some of the most important aspects of who you are- you may reframe your self-identity and self-perception, strengths and weaknesses, relationships, and even your global view of existence.









Monday, April 25, 2016

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.

Friday, April 15, 2016

(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.


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.

Wednesday, April 13, 2016

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.



Tuesday, April 12, 2016

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. 

Monday, April 11, 2016

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.