History of Present Illness

A 26-year-old female, gravida 0, presents to your office with her male spouse for advice about becoming pregnant. They were married two months ago and have recently returned from a two-week honeymoon in Rio de Janeiro, Brazil. They desire to become pregnant as soon as possible.

She has no significant past medical history, past surgical history, or social history. Their family genetic screening history reveals no increased risk.

She notes a history of “pink eye” that developed approximately one week ago and has since resolved. She states that she felt like she had a low-grade fever during the last half of her trip, but was uncertain because they spent most of the time in their jungle bungalow. She states that she and her husband both developed a “heat rash” during their trip that resolved after leaving the jungle and returning to their hotel in the city.

She denies recent history of nausea, vomiting, diarrhea, joint pain, bloody stools, epistaxis, bleeding gums, hematuria, cough, and sore throat.

She has predictable menses coming every 27–28 days and lasting 4–5 days since menarche at age 14. Her last menstrual period was 26 days ago.

She was previously using combined oral contraception pills, but stopped them with her last cycle.

Physical Examination

General appearance

Well-developed, well-nourished woman in no discomfort. Alert and oriented

Temperature

37.1°C

Pulse

76 bpm

Blood pressure

116/62 mm Hg

Respiratory rate

16 breaths/min

BMI

24.5 kg/m²

HEENT

Normocephalic, atraumatic head with non-injected and anicteric sclera

Cardiovascular

Regular rate and rhythm, no edema

Pulmonary

Clear to auscultation bilaterally, no crackles or wheezes

Abdomen

Soft, non-tender, no rebound or guarding. No hepatosplenomegaly. Liver edge is non-tender

Skin

No rash, no jaundice, no petechiae

Laboratory:

Urine HCG Negative.

How Would You Manage This Patient?

The patient and her husband have traveled to an area endemic with Zika virus and demonstrate symptomatology consistent with Zika virus infection (conjunctivitis, rash, and subjective fever), with symptom onset within the last two weeks. Testing for Zika RNA by nucleic acid test (NAT) was performed on urine and serum for both the patient and her partner and results were negative for infection. Subsequent testing for Zika virus immune globulin M (IgM) was then performed on the patient and her partner at a follow-up visit two weeks later. The patient’s Zika virus IgM testing was negative for infection, but her partner had a positive titer for Zika virus IgM, which was confirmed with plaque reduction neutralization test (PRNT). Additional testing for dengue and chikungunya IgM was also performed on both partners, and resulted negative for infection.

The patient and her partner were informed of their results, the risks of congenital infection with Zika virus, and the possible methods of transmission. They were advised to continue to use barrier methods for vaginal, anal, or oral intercourse and to avoid conception for three months following the day they left Brazil, which was the last day they were exposed to Zika infection.

Zika Virus

Zika virus is an arthropod-borne virus that is transmitted by mosquitoes of the genus Aedes. Zika virus belongs to the genus Flavivirus, which also contains dengue virus, yellow fever virus, and West Nile virus. It is named after the Ugandan forest where it was first isolated in 1947.

Human infection with Zika was detected as early as 1952 in Uganda and Tanzania and spread throughout equatorial Africa and Asia. The first major recognized outbreak occurred in Micronesia in 2007, when more than 70 percent of the population was infected. Other outbreaks followed in French Polynesia in 2013–2014. Zika was first detected in the Western hemisphere on Easter Island in 2014 with subsequent infections detected in Brazil in May of 2015. By 2017, mosquito-borne disease had spread to include most countries of Central and South America, the Caribbean islands, and locations within the United States (Texas and Florida).

The Zika virus is commonly transmitted through the bite of an infected Aedes mosquito. Additional methods of transmission include vertical transmission from mother to fetus, sexual transmission, laboratory exposure, blood transfusion, and organ transplantation. The virus has been isolated in most body fluids (blood, urine, semen, saliva, female genital tract secretions, amniotic fluid, cerebrospinal fluid, and breast milk) and may be present in semen and cervical mucous even after it has disappeared from the blood. Although the virus has been isolated in breast milk, transmission through breastfeeding has not been documented and the risks of transmission and infection in the newborn are outweighed by the benefits of breastfeeding [1].

Infection with Zika virus is frequently not recognized in the adult population. When it occurs, symptoms appear after a 2- to 14-day incubation period and resolve within 2–7 days. They are mild and typically include low-grade fever, maculopapular rash, arthralgia, and non-purulent conjunctivitis. Less common complaints are myalgia, headache, abdominal pain, nausea, and diarrhea.

In October of 2015, a spike in the number of cases of congenital microcephaly in Brazil was reported to the World Health Organization (WHO). These increases correlated with an outbreak of infection with the Zika virus. Review of outbreaks in French Polynesia in 2013 and 2014 showed a similar correlation. The international science community turned its focus to Zika and the evidence around the infection grew, and continues to grow to this date. The virus has been shown to be able to infect neural stem cells and attenuate their growth [2]. This facilitates the explanation for the devastating effects on the developing neurologic system of infected fetuses.

The WHO, the Centers for Disease Control and Prevention (CDC), and other scientific groups now recognize that Zika virus is a cause of microcephaly [3]. Additional sequelae have also been described, and congenital Zika syndrome has been characterized with the five following features:

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  Severe microcephaly with partially collapsed skull

  
  
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  Thin cerebral cortices with subcortical calcifications

  
  
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  Macular scarring and focal pigmentary retinal mottling

  
  
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  Congenital contractures (e.g., club foot)

  
  
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  Marked early hypertonia and symptoms of extrapyramidal involvement [4]

Other adverse effects noted during pregnancy include fetal loss, intrauterine growth restriction, and hydrops fetalis.

The risk of vertical transmission occurs throughout pregnancy, with the greatest effects on the fetus occurring with infection in the first and second trimesters. The risk of birth defects in fetuses with in utero exposure to Zika appears to be low, but those estimations are confounded by a lack of standard definitions as well as difficulty ascertaining maternal infection rates. The overall risk for adverse outcomes during pregnancies demonstrating maternal infection is also not clearly delineated.

Several countries that have experienced Zika outbreaks have reported increases in cases of Guillain−Barré Syndrome (GBS). Current CDC and WHO research suggests that there is a strong correlation between Zika and GBS, but only a small proportion of people with recent Zika infection get GBS [5, 6]. Other long-term neurologic sequelae have been reported, but have not been substantiated [7].

Testing for the presence of Zika infection can be performed by NATs or detection of Zika IgM. NATs may be used on urine or serum to demonstrate the presence of Zika virus RNA early in the course of illness. If an NAT is positive for Zika virus RNA, infection is confirmed and no further testing is necessary. If the NAT is negative, infection is not excluded and the serum serologic testing for Zika IgM should be performed. The time interval for Zika IgM levels to be detectable is variable. Zika IgM is typically detectable around four days after infection and remains detectable in the serum for 12 weeks. Because of the possibility of persistent IgM positivity, one cannot always reliably distinguish between an infection that occurred during the current pregnancy and one that occurred before the current pregnancy [8]. Zika virus serology may be falsely positive due to infection with other flaviviruses, so positive or equivocal IgM testing should be confirmed with a PRNT. For specimens collected from 7 days to 12 weeks after the onset of symptoms or last exposure, a negative IgM antibody result to Zika rules out recent infection with the virus. Testing is available through the CDC and most state health departments, as well as some commercial laboratories. Care providers should become familiar with where and what type of testing is available in their area [8, 9, 10].

Recommendations for testing, the type of testing performed, and the interpretation of results depend on the presence or absence of symptoms, whether the patient is pregnant or not, and the timing of the clinical presentation or exposure. The CDC recommendations are updated periodically and can be found on its website: www.CDC.gov/zika [11, 12]. The CDC recommends that Zika virus testing be performed on all men and women with Zika virus exposure and symptoms consistent with Zika virus [13]. The CDC previously recommended testing on all women who have been exposed to Zika virus during their pregnancy, regardless of symptomatology [11]. Because of emerging evidence that IgM test results may persist positive past 12 weeks after infection, as of the date of this publication, the CDC recommends that asymptomatic pregnant women who have recent exposure but without possible ongoing exposure not receive routine Zika virus testing [8]. Risk of exposures includes travel to an area with active Zika or having unprotected intercourse (vaginal, oral, or anal) with a partner who has recently traveled to an area with Zika. Patients who have been exposed to Zika virus should be screened for the symptoms typically associated with Zika infection. If a patient has experienced fever, rash, arthralgia, or conjunctivitis, he or she may be exhibiting symptoms of Zika disease. The symptoms of Zika are similar to other flavivirus infections, so providers should consider testing for dengue and chikungunya in those patients who have symptoms of infection but whose Zika NAT is negative [8].

There is no known cure for Zika virus infection. If a woman planning pregnancy has been exposed to Zika virus, she should either wait for a sufficient time for the virus to clear from her bloodstream or have serologic testing performed. If the testing is positive, or if no testing is performed, she should be advised to wait for eight weeks after the last possible exposure (if asymptomatic) or after the onset of symptoms (if symptomatic). Zika virus RNA can be detected in semen when it is no longer detectable in blood, so even if serologic testing of a male is negative, the chance of transmission through semen still exists. The ability to culture Zika virus from semen is not widely available, so couples who are planning pregnancy should be counseled to avoid conception for at least three months after the last possible exposure or symptoms onset. Couples should be advised to use barrier methods of contraception during vaginal, anal, and oral sex during this time period in order to prevent transmitting the virus to their sexual partners. These may be used in conjunction with more effective methods of contraception to avoid pregnancy [14].

Based on what is known from similar viruses, an infection with Zika virus likely provides individual protection from reinfection with Zika. This may account for the delayed association between Zika and congenital microcephaly. The populations where Zika has been endemic for years may exhibit immunity to infection by the time they enter child-bearing years, thus demonstrating a lower prevalence of microcephaly. There currently is no vaccine to prevent Zika infection, but pharmaceutical companies and the scientific community are actively researching the development of a vaccine [15].

Preconception counseling for all patients should include a discussion of their travel plans, including an overview of the areas that are endemic for Zika. Women and/or their partners who are planning pregnancy should be advised to avoid travel to Zika endemic areas if possible. If a woman or her partner travels to a Zika endemic area, the best method to avoid infection is to prevent mosquito bites. The use of Environmental Protection Agency (EPA)–registered insect repellents is proven to be a safe and effective method for avoiding mosquito bites, even for pregnant and breastfeeding women. Other methods include wearing long-sleeved shirts and long pants, wearing permethrin-treated clothing, using screens on windows and doors to keep mosquitoes outside, using air-conditioning or a mosquito bed net, and emptying collections of standing water that may provide a hatchery site for mosquito eggs [16].

The evidence behind Zika virus and the effects of its infection in humans is growing, as is the area where Zika is endemic. Health-care providers should use up-to-date resources such as the CDC, the American Congress of Obstetricians and Gynecologists, and the WHO to keep abreast of the growing scientific knowledge about Zika transmission and disease [17, 18, 7].

Key Teaching Points

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  Zika virus has been associated with congenital microcephaly and other neurologic sequelae in fetuses and newborns with in utero exposure to Zika.

  
  
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  The most common symptoms of infection in the adult population include:

  
  
  
  
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    Low-grade fever

    
    
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    Maculopapular rash

    
    
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    Arthralgia

    
    
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    Non-purulent conjunctivitis

  
  
  
  
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  Patients planning on conceiving should be educated about the method of transmission of Zika virus, the risks of Zika infection to pregnancy, and methods to avoid transmission.

  
  
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  Women who have positive testing for Zika virus or who have been exposed to Zika virus and have not been tested should be advised to wait for at least eight weeks after symptom onset (if symptomatic) or last exposure to the virus (if asymptomatic) prior to attempting conception.

  
  
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  Men who have been exposed to Zika virus should be advised to wait for at least three months after symptom onset (if symptomatic) or last exposure to the virus (if asymptomatic) prior to attempting to get their partner pregnant. During this time, barrier methods of contraception should be used during intercourse to prevent transmitting the virus to their sexual partners.

  
  
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  Because of the rapidly expanding body of evidence on Zika virus infection, health-care providers should use up-to-date resources such as the CDC, the American Congress of Obstetricians and Gynecologists, and the WHO to stay informed on how to screen, diagnose, and counsel patients on the disease.

History of Present Illness

A 26-year-old nulligravida presents to her gynecologist for preconception counseling. She has no significant medical history other than a history of mental illness. At the age of 18, she was diagnosed with major depressive disorder after she was hospitalized for ingesting a large amount of acetaminophen. She had no medical sequelae from the overdose, and received psychiatric care during the admission. She was successfully treated with a combination of psychotherapy and pharmacotherapy. She experienced a relapse three years later when she discontinued her medication, and was again hospitalized for severe depressive symptoms. She was again successfully treated and maintained on pharmacotherapy.

She currently takes 40 mg of citalopram daily, which is prescribed by her family practitioner, and she sees a therapist once monthly. In the last three years, her mood has been stable and she is symptom-free. Earlier this year, she married her partner of two years. She is excited to start a family and is planning to discontinue her oral contraceptive in hope of conceiving soon.

She has no gynecological complaints and notes regular menstrual periods each month. She has been monogamous with her current partner for the past two years and has no history of sexually transmitted diseases. Aside from her citalopram and combination oral contraceptive, her only other medication is a multivitamin. She used to smoke one pack per day, but quit soon after her marriage. She denies any illicit substance use and drinks one to two alcoholic drinks most weekends. Neither she nor her husband has a family history of mental retardation, genetic disorders, or birth defects.

Physical Examination

General appearance

Well kempt, with appropriate affect

Pulse

80 beats/min

Blood pressure

100/60 mmHg

Height

65 inches

Weight

130 lb

BMI

21.6 kg/m²

HEENT

No thyromegaly or thyroid nodules present

Neurological exam

No motor or sensory deficits, no tremor or gait disturbance

Extremities

Multiple old linear scars on upper thighs bilaterally consistent with cutting

Genitourinary

Normal pelvic examination with non-tender anteverted uterus, nulliparous cervix, and no adnexal masses

TSH

1.82

Urine toxicology

Negative

Rubella and varicella titers consistent with immunity

How Would You Manage This Patient?

This woman has a history of severe depression with relapse and is now in remission for over a year on a selective serotonin reuptake inhibitor (SSRI). Given that she is feeling well with stable mood, this would be an appropriate time to conceive, with a lower risk for relapse during pregnancy. However, she is still at risk for relapse of depression, which could result in significant incapacity that would put both her health and that of her fetus at risk.

Her physician has a frank discussion with her about the risks and benefits of continuing antidepressant medication in the preconception period and in pregnancy. They discuss the possible effects of the use of SSRIs during pregnancy on the fetus and on the neonate after delivery, as well as the potential harms of being depressed while pregnant. After considering the multiple factors involved, she decides to continue using citalopram. Shortly afterward, she returns to the office for prenatal care newly pregnant. Her physician reviews her interval mood and health status and confirms that she is doing well on her present dose. Over the course of her pregnancy, he continues to assess her mood and well-being at each visit, and also encourages her to renew contact with her psychotherapist when she is feeling depressed. After she delivers a healthy full-term infant, he counsels her about signs of postpartum exacerbation to look out for, and arranges a postpartum visit to screen for such change.

Preconception Counseling for Women with a History of Depression

Depression is one of the most common disorders that clinicians who counsel women preconceptionally are likely to encounter. Twenty percent of women will experience an episode of major depressive disorder during their lifetimes, and the most common age of onset is between 20 and 40 years, the prime age for bearing children [1]. Many more women will experience minor episodes of depressed mood or reactive affective disorders that are not as severe as the experience described in the case, but who are nonetheless prescribed antidepressant medication. In the United States, 13 percent of women are exposed to an SSRI in the first trimester [2].

Counseling women with a history of major depression who are planning pregnancy is complex. The medical literature is conflicting and recommendations are difficult to generalize. Counseling and treatment are further complicated by the stigma attached to mental health issues. Providers may not recognize the gravity of the effects of depression in pregnancy and not give it the same consideration as treatment for other chronic illness such as hypertension or diabetes. Family members also fail to recognize the importance of treatment and may not be supportive of a patient’s decision. The result is that women seeking treatment for depression in pregnancy may feel guilty or ashamed during a highly vulnerable time [3].

The decision to initiate or continue treatment for depression in the preconception period and in pregnancy involves balancing risks of untreated disease and relapse with risks of medical treatment. Enumerating the effects of depression on pregnancy is difficult due to conflicting reports that are confounded by factors associated with mental health issues such as poor prenatal care, drug and alcohol abuse, and the wide variation in symptom severity. In a meta-analysis of 29 prospective studies that specifically examined the effects of antenatal depression on birth outcomes, both preterm birth and low birth weight were significantly associated with depression [4]. Another review and meta-analysis analyzed a wider assortment of outcomes and included subgroup analyses to assess the effects of potential confounders. This review identified a 37 percent increase in risk for depressed women to deliver preterm relative to nondepressed women, though the association with low birth weight was not significant [5].

Although these studies failed to show significant risks of other birth outcomes, they do not account for many other adverse effects that depressed mood may have on the mother and the infant. Women who discontinue antidepressant medication during pregnancy have a 68 percent chance of relapsing depression, compared with 26 percent of women who continue antidepressant medication. Depression may lead to less compliance in prenatal care and less investment in the care of pregnancy, which may lead to unhealthy practices such as substance abuse and poor nutrition. When depression continues into the postpartum period, there may be downstream effects on the infant, including delayed cognitive and linguistic skills and impaired emotional development. In its most severe form, maternal depression can lead to suicide [1]. Although suicide in pregnancy is rare, it accounts for 20 percent of postpartum deaths [6].

These risks must be balanced with the risk of using antidepressant medication in the preconception period and in pregnancy. The most commonly prescribed medications for treatment of depression are the SSRIs, a medication class for which there is the greatest amount of research on use in pregnancy. Although studies have linked their use in early pregnancy to an increased rate of miscarriage, this risk is no greater than that of depressed women who discontinue treatment prior to conception [2]. Observational studies have suggested a link between SSRI use and a variety of adverse effects, including preeclampsia, postpartum hemorrhage, perinatal death, and neonatal seizures [7]. However, the absolute increase in risk for these events was small, and the studies showed only associations that may have been confounded by other factors in prescribing these medications. Multiple large cohort studies have demonstrated that SSRIs are not associated with congenital malformations. The possible exception is paroxetine, which has been linked to an increased risk of cardiac anomalies in first-trimester exposure in some studies. Some, but not all, studies have also shown an increased risk of persistent pulmonary hypertension in newborns whose mothers use SSRIs in late pregnancy. Infants born to mothers who use SSRIs in pregnancy commonly display a neonatal adaptation syndrome characterized by tremors, jitteriness, and irritability. These symptoms usually resolve within days, and there appears to be no impact of SSRI use on long-term neurological development [8].

Other classes of medication may also be considered. Tricyclic antidepressants have not been shown to increase the rate of structural malformations, though they can cause a temporary withdrawal syndrome in infants similar to that seen with SSRIs. Dosage for these medications usually needs to increase in the second half of pregnancy due to increased plasma volume and metabolism. Atypical antidepressants such as bupropion, mirtazapine, and trazodone have not been extensively studied in pregnancy, and there is limited information available about their effects in pregnancy [1].

Non-pharmacologic treatment for depression in the preconception period and in pregnancy may be effective in selected women. Both interpersonal psychotherapy and cognitive-behavioral therapy have been demonstrated to be helpful for women with mild to moderate depression. Wellness strategies such as stress reduction and exercise promotion may be helpful, and mind–body modalities such as relaxation and yoga have limited evidence of successful treatment in mild depression.

Counseling and management should also take into consideration that relapse is affected by the interval since the prior episode of depression and its severity. Women who have experienced more severe depression symptoms when not taking medication are more likely to relapse with discontinuation. Prior response to treatment is important, as success with any agent is highly individualized. Consequently, there is no single agent or dose that is considered preferable or recommended at the time of conception. Switching from a drug of known efficacy to one of unknown efficacy is not recommended, because it may increase the rate of relapse since there is no proven benefit in safety profile of one agent over another [9]. The patient’s own opinions about how well she is able to cope without pharmacological intervention are also important.

In 2009, the American College of Obstetricians and Gynecologists and the American Psychiatric Association convened a panel of experts to develop best practices for counseling women about managing depression in pregnancy [10]. They suggest that women with mild to moderate depression should preferentially be offered non-pharmacologic therapy, and those on antidepressant medication may consider weaning prior to conception. Women with a recent exacerbation of symptoms should consider waiting to conceive until they achieve 6–12 months of stability. The panel considered it acceptable for women to continue medication if they have a history of severe or recurrent depression, poor prior response to psychotherapy alone, or a strong desire to continue medication.

Some mental health professionals have advocated the use of decision aids that involve the individual patient’s input and desires. Such tools explain the risks and benefits of treatment and provide the patient with a stepwise assessment to help them decide what is most important to them. A particularly helpful example, which is currently undergoing clinical trials, is available at Healthwise.net [11]. Figure 58.1 illustrates a simple algorithm for counseling patients about medication use during pregnancy.

Figure 58.1 An algorithm to aid in counseling patients about treatment for depression during pregnancy.

It is important to recognize that a patient’s needs and priorities may change over the course of the preconception time and during pregnancy. Regular follow-up assessments are important to gauge the effect of treatment, screen for worsening symptoms, and evaluate the need for adjustments in therapy. Such assessments may be made by the primary obstetrical provider or by a mental health professional depending on the patient’s needs and preferences and the provider’s comfort level.

Key Teaching Points

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  Untreated depression may have significant adverse effects on pregnancy, including preterm birth, substance abuse, poor nutrition, and suicide.

  
  
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  Antidepressant medication is not generally considered teratogenic, but SSRIs are associated with increased risks of persistent pulmonary hypertension and neonatal adaptation syndrome.

  
  
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  Psychotherapy without medication is preferable and can be an effective treatment for women with mild to moderate depression.

  
  
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  Women with severe or recurrent depression, poor prior response to psychotherapy alone, or a strong desire to continue medication may be encouraged to continue medication to treat depression during the preconception period and in pregnancy.