Tag Archives: pregnancy

Managing the sugar blues: Putting the latest gestational diabetes mellitus guidelines into practice

The American College of Obstetricians and Gynecologists (ACOG) published a practice bulletin on gestational diabetes mellitus (GDM) in February 2018,1 just 7 months after publishing a previous bulletin on the same topic.2 According to ACOG, the purpose of the update was to provide additional information on the pharmacologic treatment of gestational diabetes mellitus. This article elucidates the recent changes in ACOG’s bulletin, as well as those in the American Diabetes Association guidelines.3 Continue reading »

Fears surrounding pregnancy and motherhood among women with cystic fibrosis

Recent advances in science and clinical care have changed the characteristics of the population with cystic fibrosis (CF). Half of patients with CF are now adults who want to achieve milestones that were impossible in the past; for women with CF, this may include motherhood. However, these women may have concerns and fears about getting pregnant, being pregnant, and becoming mothers that go beyond those that otherwise healthy women experience. This qualitative study was conducted to ascertain the reproductive health concerns of a small group of women with CF.

Cystic fibrosis (CF) is an autosomal-recessive, multisystem disease affecting about 70,000 persons worldwide.1 In the United States, 1 in 31 persons of Caucasian European descent carries the CF trait, making it the most common genetic disorder in this group.1 A defect on chromosome 7 results in an alteration in the structure and function of the CF transmembrane conductance regulator (CFTR) protein that controls movement of ions across cell membranes.2 As a result of the impaired CFTR protein, the body produces tenacious mucus that obstructs certain organs, particularly the lungs, intestines, and those of the reproductive tract.2

Recent advances have improved overall survival and quality of life (QOL) of patients with CF. For the first time since the CF gene was identified in 1989, about half of patients with the disease survive to adulthood.1 Average life expectancy has risen from 14 years in 1969 to 40+ years today.1,3 Women, who account for about half of the CF population,4 experience poorer health-related QOL than their male counterparts.5 In women with CF, hormonal fluctuations across the lifespan may compromise their overall health.6 Nevertheless, many women with CF wish to experience all of the adult developmental milestones that may not have been possible in the past, when CF was considered a life-limiting disease of childhood.7 One of these milestones is becoming a mother.

The wide variability in disease presentation means that some women with CF can conceive a child naturally and easily, whereas others have impaired fertility or infertility. Thickened cervical mucus can obstruct the Fallopian tubes and/or the cervix, preventing sperm from reaching the egg for fertilization.1 The thickened mucus in the gastrointestinal tract impedes proper absorption of nutrients.1 Adequate body fat and weight are needed for a regular menstrual cycle; as a result, some women with CF who have a suboptimal body mass index (BMI) have irregular ovulation.1 In general, good pulmonary function and a normal BMI predict reproductive success in women with CF.8

Great strides have been made since 1960, when it was reported that a successful pregnancy in a woman with CF ended with maternal death from CF complications 6 weeks after delivery.9 Although exact fertility data are unknown, the CF Foundation Patient Registry indicated that the number of women with CF who became pregnant more than doubled in 24 years, from 116 in 1992 to 270 in 2016.4 With recent CF drug discoveries that target specifi c CF mutations, the personalized approach to care will likely lead to improved patient outcomes, including the ability to become pregnant and deliver healthy infants.

fears pregnancy motherhood cystic fibrosis imageDespite these promising developments, Korzeniewska et al10 reported that only 33% of their sample of women with CF (n = 64) understood how CF affects fertility. Based on semi-structured interviews with 22 women aged 18-30 years with CF, Kazmerski et al11 found that misinformation regarding how CF could affect fertility and pregnancy abounded. In a separate report, Kazmerski et al12 indicated that the women with CF were disappointed by the lack of support from their CF care team when the topic of reproductive health was raised, usually by patients themselves. Both patients and care team members agreed that improvements in this area were needed.

The purpose of the current study was to ascertain the reproductive health concerns of a group of women with CF. These women were part of a larger mixed-methods study (the parent study) that investigated their knowledge of basic fertility concepts and how CF affects the reproductive system, and explored their perceptions regarding whether new CFTR-modulating drugs could affect their reproductive health.7

Parent study

The parent study evaluated broad reproductive health implications of targeted therapy for young women with CF.7 It was approved by the University of Alabama at Birmingham Institutional Review Board and conducted in Alabama in 2015-2016. In brief, 10 women aged 25-34 years with a confirmed diagnosis of CF homozygous F508del mutation and a forced expiratory volume in 1 second ≥40% participated.7 They were recruited from an adult CF center located in a large academic medical center in the southeastern United States.

Participants completed a demographic survey and two questionnaires related to their knowledge of fertility and CF and sat for an audio-recorded, semi-structured interview about the processes of becoming pregnant and a mother. Individual interviews lasting 30-45 minutes were conducted in person or by telephone by two of the authors, who also completed the qualitative analysis for the current study. Participants were asked whether they had been pregnant, whether they felt that CF aff ected their fertility, how and when they learned that CF might affect fertility, what they knew about the effects of the CFTR-modulating drug lumacaftor/ivacaftor (LUM/ IVA) on fertility, and whether they knew about available resources on pregnancy and fertility. Thematic saturation was reached after the eighth interview. Findings from the parent study showed that participants reported needing comprehensive reproductive and sexual health counseling and education from their CF care team, as well as support for their desire to become mothers even though they suspected that their fertility might be impaired.

Current study

Among the 10 women, 7 elaborated on their concerns and possible challenges to becoming pregnant, with 2 also describing their experiences with past or current pregnancies. Qualitative data were analyzed using Braun and Clarke’s approach to thematic analysis, which included these steps: (1) Interview transcripts were read multiple times to look for patterns; (2) Data about fears related to pregnancy and motherhood were coded with descriptive labels; (3) Codes were grouped into preliminary themes; and (4) The final thematic schema was identified.13 Two authors independently reviewed all transcripts and coded the data, and collaborated in developing the final coding schema. Both authors had >90% inter-rater agreement during the coding phase and easily arrived at consensus during the thematic development phase. HyperRESEARCH, a qualitative analysis software, was used to manage and analyze the data.14

Findings

Participants (mean age, 29 years) were Caucasian and highly educated, with 80% having a 4-year college degree. Most were married and had never been pregnant. They hoped that new targeted therapeutics in CF care would help them conceive and carry a healthy pregnancy to term. They expressed different layers of fears as they contemplated their future on the pregnancy continuum. (Pseudonyms are used to protect their identities.) The main theme that emerged from this qualitative analysis was Fears surrounding pregnancy and motherhood. Although most participants said they desired children, they had fears related to getting pregnant, being pregnant, and becoming new mothers— the three subthemes.

Fears before pregnancy

Five participants reported having fears even before attempting pregnancy. One fear was bearing a child with CF. Carly said that it was critical to have her partner tested for the CF gene prior to exploring her options for motherhood because she did not want to risk having a child with CF: We decided [that] if he was a CF carrier, we would adopt. If he was not a CF carrier, we would try [to get pregnant]. Being a mother with a child with CF, it just scared the living crap out of me. Experiencing the daily struggles and treatment burden of CF, Carly did not want the same hardships for her child. Debby echoed the sentiment about her partner carrying the CF gene: We are interested in confirming that he’s not a carrier because if he is a carrier, we know our chance of having a CF baby would be definitely increased. If that is the case, we would want to look at alternative situations, like adoption.

Two participants described financial concerns related to becoming pregnant. Ella said that if she could not get pregnant, she wanted to explore using a gestational carrier. However, she stated: I just don’t think we can afford surrogacy. Anna, who has a school-age child, feared having another child: My fears would be financial concerns, just making sure I can cover all the bases so that my next pregnancy is as smooth, or as close to as smooth, as the first one.

Gia shared concerns related to LUM/IVA, a part of her regimen that benefited her overall health and functioning. Because LUM/IVA’s safety during pregnancy has not been established, Gia feared that she would need to stop her medication if she were to become pregnant. She stated: My biggest concern is how I would feel going off lumacaftor/ ivacaftor. [I would] take a hit to my health, my lung health, [and worry] if that is going to impact the health of a fetus….and [if] somehow I wasn’t able to carry the baby to term.

Fears during pregnancy

Five participants conveyed fears about the pregnancy itself. Most fears centered on keeping themselves as healthy as possible in order to deliver a healthy baby. Betty and Carly described how maintaining their health during pregnancy and afterward was critical in order to care for their infants. Carly, a natural athlete who enjoyed exercise as part of her health regimen, said: My biggest fear with having CF is how uncomfortable [pregnancy] is, and I worry that my athleticism, working out, is gonna have to decrease….that [it] may lead to lower lung function. That scares me. I don’t care about what I look like on the outside for the most part; I care about the lungs.

Ella feared that a pregnancy could compromise her pulmonary status: I worry about [pregnancy] impacting my lung function in a way that could be permanent. When lung function goes down, there could be scarring, and things that occur that make it irreversible. Fran worried about her pulmonary health but had a more positive outlook on pregnancy’s potential effects: I think I’m strong enough to handle it. If I did lose lung function, I would be dedicated to getting it back. That would be a top priority for me. It [having a baby] would be worth a short-term setback. Debbie described how she was proactive about maintaining her treatment regimen and staying healthy to avoid getting sick and harming the baby.

Fears as new mothers

Six participants reported potential fears as new mothers, most of which related to balancing the demands of CF with work, family, and motherhood. Ella reported: I do worry about being able to balance doing all of my treatments and caring for a newborn. Debbie described her fear of being able to care for both herself and a baby: I wanna make sure that I’m able to take care of the baby as well as myself. Gia expressed her worry about being able to balance her job and CF with being a mom: I guess it’s more of the balance of, “Could I keep working and how much?” and maybe needing to downshift. I sometimes worry about CF, [which] is already such a time suck that it’s like, “Oh, let’s throw a baby into the mix and see what happens.”

Two participants expressed worry about their child going to daycare and bringing home contagious infections. Carly said that she was always vigilant about possible infection sources to keep herself healthy: I’m a total germophobe. My biggest fears are just me getting sick and not being able to take care of my baby, because of whatever bugs [he or she] might have. She went on to discuss not being able to be around or care for her baby when he or she got sick: I’m gonna have to quarantine myself into a room… [and not] get sick so I can take care of my baby. Betty discussed getting sick from her baby as a result of going to daycare: They [babies] go there and they get sick. They come back, I get sick.

In thinking about their futures, two participants mentioned the often unspoken fear of dying early of their incurable disease and not being able to be there for their children. Ella said: I think about not being healthy, or putting my child through the trauma of losing a parent. I think about how wonderful my husband is, and my family. If that [death] were to happen, it wouldn’t be as though [my baby] would be left alone in the world. Anna spoke of the fear of dying in a more positive light, as a source of motivation: Yeah, dying early. That’s a big fear. That also keeps me motivated. Other participants voiced the positive aspects of becoming pregnant and being mothers with CF. Anna, who had CF-related diabetes, stated: My A1Cs stayed in the 6’s during my entire pregnancy—the best they’ve been in my life. Carly reflected on her determination to remain healthy despite the daily challenges of having CF: I don’t feel that CF has held me back in any other aspect of my life. I’m certainly not expecting it to here [pregnancy].

Discussion

These study participants wanted to experience pregnancy and motherhood, but they had certain fears about these life experiences. Even before contemplating becoming pregnant, some expressed concerns about the genetic transmission of CF. They did not want any children they bore to experience a life-limiting disease. They wanted their partners to be tested for CF to rule out the possibility of having a child with CF and to help inform their decision-making with regard to the use of gestational carriers, adoption, or living a child-free life.

Concerns about genetic transmission of CF are understandable; young women with breast cancer who carry the BRCA gene have expressed similar fears. In response, the American Society of Reproductive Medicine has recommended pre-implantation genetic diagnosis (PGD) testing on embryos to look for a specific genetic disorder such as the BRCA mutation.15 In fact, CF is one of the most common indications for PGD testing, enabling couples to transfer an embryo without the CF gene and avoid the difficult decision to terminate a pregnancy.16

The physical stress of pregnancy, combined with potential adverse effects of a medication regimen (or temporarily stopping such a regimen), is challenging for women with a chronic illness such as cancer or diabetes or a history of childhood cancer. They have concerns about potential health setbacks such as a recurrence or the development of secondary cancers or pregnancy-associated cardiomyopathy.17-21 Despite having similar fears, the women with CF in this study expressed hope and determination to experience pregnancy and motherhood.

Many survivors of childhood cancer who are at risk for infertility related to gonadotoxic therapy have misperceptions regarding their personal risk for infertility.22-26 The American Society of Clinical Oncology recommends discussing potential infertility, as well as fertility preservation options, with all young individuals diagnosed with cancer.27 Multidisciplinary programs to address fertility preservation in children and adolescents are emerging.28 The Cystic Fibrosis Foundation aims to provide resources to educate patients, families, and healthcare providers (HCPs) regarding fertility and reproductive health options.29

A sobering challenge of future motherhood for women with CF is the potential for early mortality, which forces them to face an uncertain future for themselves as parents and for their children, who could suffer the loss of their mother at a young age. Confronting these uncertainties appeared to strengthen the resolve of some of the study participants with CF, and could potentially motivate them to remain engaged in health-promoting activities and to maintain strong relationships with their partners and family members.

Limitations

A limitation of the current study was the small and homogenous (all Caucasian) sample, although this demographic characteristic is representative of the CF population. Another limitation is that these women had the same genetic mutation (F508del homozygous), which may have influenced their responses because of the moderate/severe phenotypic presentation of this mutation. Finally, 80% of the participants held a 4-year college degree, compared with 30% of persons with CF nationally, which could limit the generalizability of the findings.4

Implications for practice and future research

Childbearing-age women with CF may benefit from a collaborative care eff ort between the CF care team and reproductive health specialists who can provide individualized education and counseling. All of these HCPs can address patients’ fears and assist them with their reproductive health decisions. Kazmerski et al12 reported that women with CF considered their disease a major factor in deciding whether to become pregnant, and that they were disappointed by the lack of support from their CF care team when the topic of reproductive health was raised, usually by the women themselves. HCP and patient discomfort in initiating reproductive and sexual health discussions may hinder provision of comprehensive care; hence, HCP training and educational resources for reproductive health services, as well as standardization in CF care models, are warranted.11

Additional research is needed to investigate how women with CF decide to pursue a pregnancy versus use a gestational carrier or adopt a child. The different paths to motherhood for women with CF is not well documented; in fact, in the larger (parent) study, these women self-reported a lack of knowledge related to alternative options and their associated costs, both tangible and intangible.7 These findings are consistent with those of Cherven et al,26 who found that only 36% of childhood cancer survivors reported receiving education about the risk for infertility at diagnosis and 39% received it at the end of therapy. Nearly all of these survivors reported that they would have preferred receiving fertility education at diagnosis. However, education at one time point alone may be insufficient. Continuing discussions about fertility need to be targeted to young cancer survivors’ needs and developmental stage, which change over time. Findings from previous work with young cancer survivors may help improve the conversation with patients with CF, who require ongoing education and counseling about reproductive health and fertility options, as well as their associated costs.

Conclusion

Attempting and carrying a pregnancy is a complex challenge for women with CF. If these women can conceive, then they worry about being able to be a full partner in caring for a newborn—while still sustaining their own daily care for CF. As mean survival of patients with CF extends into the fifth decade of life, findings from this current study suggest that women with CF would benefit from individualized education and counseling regarding reproductive health as part of their comprehensive clinical care.

Sigrid Ladores is Associate Professor at the School of Nursing, Leigh Ann Bray is Assistant Professor at the School of Nursing, Wendy Landier is Associate Professor at the School of Medicine, Brooke Cherven is a PhD student at the School of Nursing, and Karen Meneses was Professor and Associate Dean for Research at the School of Nursing, all at the University of Alabama at Birmingham. The authors state that they do not have a fi nancial interest in or other relationship with any commercial product named in this article.

Support

This study was supported by a UAB Faculty Development Grant and the School of Nursing, UAB.

References appear in the downloadable PDF above and below.

WHNP1218_Feature_FearPregnancyMotherhoodCF

Freezing Ovarian Tissue May Be a Promising Fertility Treatment

By 2018, some 76,000 women in the U.S. will freeze their eggs every year to preserve their fertility and increase their odds of getting pregnant later in life. Yet egg freezing is by no means a solid insurance policy. Some estimates suggest that just under 24% of procedures will result in a live birth. The fertility field is looking for other options.

In a new study published in the journal Reproductive Sciences, two fertility experts argue that ovarian tissue freezing—a procedure that removes and freezes ovarian tissue for later use—could offer an alternative, especially for women who can’t undergo egg freezing for medical reasons.

Read more at Time.

Perinatal anxiety disorders: Assessment and management

Key words: pregnancy, perinatal period, perinatal anxiety, generalized anxiety disorder, perinatal anxiety screening scale

Routine assessment for perinatal anxiety disorders, using established diagnostic criteria and standardized tools, can facilitate early diagnosis, guide management, and optimize outcomes for pregnant women and their offspring.

An anxiety disorder can disrupt a woman’s abilities to enjoy life and to self-care. When an anxiety disorder is present during the perinatal period—that is, during pregnancy and/or the first year postpartum—it can change how a woman experiences her pregnancy and how she interacts with and cares for her child.Limited data suggest a possible association between severe perinatal anxiety disorders and adverse pregnancy outcomes such as preterm birth, low birth weight, and postpartum depression.2,3 In addition, maternal anxiety disorders have been linked to developmental and mental health problems in offspring.2-4 Healthcare providers (HCPs) who see women during pregnancy and postpartum need to know the risk factors and signs and symptoms associated with perinatal anxiety disorders so that these disorders can be identified early and treated as needed. This article focuses primarily on assessment for and management of a common anxiety disorder—generalized anxiety disorder (GAD)—in this patient population.

Generalized anxiety disorder

Generalized anxiety disorder (GAD) is a mental disorder characterized by frequent and intense worry or anxiety about many aspects of one’s life (e.g., health, work, family), even if these aspects of life are going well.A person with GAD has difficulty controlling this anxiety, which can interfere with daily functioning.

Prevalence

Approximately 40 million adults in the United States, or 18% of the adult U.S. population, are diagnosed with an anxiety disorder each year, with 22.8% of these cases classified as severe.In addition to GAD, anxiety disorders include phobias, social anxiety disorder, post-traumatic stress disorder (PTSD), panic disorder, and obsessive-compulsive disorder. Many adults have more than one anxiety disorder.GAD, with a prevalence of 3.1% and an average age of onset of 31 years, is twice as common in women as in men,7 Anxiety disorders affect 4%-39% of women during pregnancy and up to 18% during the postpartum period.8

Risk factors

Perceived lack of partner and/or social support, a history of intimate partner violence or other abuse, a personal history of mental illness, having an unplanned or unwanted pregnancy, past or present pregnancy complications, and past pregnancy loss are risk factors for perinatal GAD.Women experiencing a high-risk pregnancy are also at greater risk for developing GAD.10,11 Other risk factors for perinatal GAD include failure to complete high school, unemployment, and nicotine use.12

Symptoms

Some degree of anxiety is common during pregnancy and postpartum, so HCPs should aim to differentiate between “normal” anxiety and GAD. Persons in the general population with GAD may report trembling, twitching, shakiness, muscle aches, sweating, nausea, diarrhea, and an exaggerated startle response.7 In the perinatal period, GAD may manifest as excessive and persistent nervousness, worry, or even panic about pregnancy and childbirth, the infant’s health, and parenting. Physical features—in addition to those listed for GAD in general—may include stomach pain, headaches, dizziness, palpitations, and shortness of breath.13 GAD can exacerbate sleep disturbances and fatigue in women during the perinatal period. Because anxiety and depressive disorders often co-exist, a pregnant or postpartum woman with GAD may exhibit manifestations of depression as well.14

Screening for perinatal GAD

Routine screening is essential for early recognition of GAD, which may otherwise go undetected and untreated in pregnant and postpartum women. Some of the most common clinical features of GAD may be attributed to normal physiologic changes of pregnancy or expected psychosocial adjustments to pregnancy and child care. A woman may be reluctant to report signs/symptoms of GAD for fear of being perceived as an excessive worrier or a hypochondriac.

The American College of Obstetricians and Gynecologists (ACOG) advises screening women at least once during the perinatal period for anxiety and depression using a standardized, validated tool.15 Although ACOG does not provide a recommendation for timing or frequency of this screening, the organization does advise HCPs to closely monitor women who have a history of, or risk factors for, anxiety or depressive disorders.

Two anxiety screening instruments used in both pregnant and postpartum women are the Generalized Anxiety Disorder-7 (GAD-7) and the Perinatal Anxiety Screening Scale (PASS). The GAD-7 is a 7-item self-report questionnaire created to identify essential areas of anxiety (worry, restlessness, irritability, and fear) and its severity in the previous 2 weeks.16,17 The reported internal consistency of the GAD-7 is excellent (Cronbach’s α, .92), and its test/retest reliability is good (intraclass correlation coefficient [ICC], .83). The PASS is useful throughout the perinatal period to assess for a range of anxiety symptoms.18,19 Principal component analyses suggested a 4-factor structure addressing symptoms of acute anxiety and adjustment; general worry and specific fears; perfectionism, control, and trauma; and social anxiety. The PASS is validated for use in hospital, mental health, and community samples and has excellent reliability (Cronbach’s α, .96) and test/retest reliability (ICC, .74). The Box lists various anxiety screens and provides links to them for easy access.

Validated anxiety screening instruments with a postpartum focus include the Postpartum Worry Scale-R (PWS-R) and the Penn State Worry Questionnaire-10 (PSWQ-10). The PWS-R was developed to identify the degree of uncontrollable worry, a major symptom of GAD in postpartum women.20 This revised format of the original PWS includes items related to the mother’s perception of the infant’s well-being in terms of health and development and the mother’s relationship with her child.21,22 The PSWQ-10 measures worry, often described as the cardinal feature of GAD.23  Although the PSWQ-10 cannot distinguish GAD from major depressive disorder, it can track worry, which may affect both treatment and recovery. The Edinburgh Postnatal Depression Scale (EPDS) has an anxiety subscale (EPDS-3A) and can reliably differentiate between depression and anxiety.24 

Making the diagnosis

Establishing rapport with patients facilitates a discussion of the clinical features of anxiety, screening test results, and treatment options.

HCPs need to determine the extent to which anxiety, worry, and/or the physical manifestations of anxiety are causing impairment in social, occupational, or other areas of functioning.

Once perinatal anxiety is identified and diagnosed, the next step is to determine whether an underlying condition might be causing the signs/symptoms or exacerbating their severity (e.g., substance misuse/abuse, a physical health condition), as well as whether co-existing psychiatric conditions such as depression, substance abuse, bipolar disorder, psychosis, schizophrenia, or PTSD might be complicating the picture. Referral to a mental health specialist is imperative when a pregnant woman has suicidal ideation, a co-existing psychiatric condition, or need for a complex medication regimen. HCPs providing perinatal care should have resources available for initiating a multidisciplinary team approach in treating perinatal anxiety.25,26 

Management

If perinatal anxiety is determined to be the primary problem, cognitive behavioral therapy (CBT), the first-line treatment for anxiety in the general population, is a reasonable first approach.27  Although less studied in women with perinatal anxiety, CBT has been shown to be effective in treating postpartum depression.28,29 Additional nonpharmacologic options include mindfulness-based cognitive therapy, interpersonal therapy, psychodynamic therapy, acupuncture, and massage.30 When nondrug therapies are ineffective or only partially effective, medication may be indicated. In these cases, HCPs and patients should weigh the risks of not fully treating the anxiety disorder, the potential risks to a fetus exposed to the medications chosen, and the potential benefits of easing the anxiety disorder.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line drugs for the treatment of moderate or severe anxiety disorders.31 The Table lists commonly prescribed SSRIs and SNRIs, as well as their recommended daily doses and side effects.31 Taken together, data obtained over several years suggest that SSRIs and SNRIs are not teratogenic or associated with adverse pregnancy outcomes. Studies of the use of the SSRIs sertraline, fluoxetine, and citalopram during pregnancy provide the largest databases indicating no teratogenic effects.32,33 Although study results are conflicting, some reports have suggested a small increased risk for congenital heart defects associated with use of paroxetine during pregnancy.34,35 No teratogenic effects have been reported with use of SNRIs during pregnancy, although these agents may be associated with a small increased risk for pre-eclampsia.36

The SSRIs fluoxetine and paroxetine and the SNRI venlafaxine, if taken around the time of birth, have been most closely associated with postnatal adaptation syndrome (PNAS).37 However, a recent study found that these agents did not cross the placenta to a greater extent than other antidepressants.37 Maternal use of SSRIs in late pregnancy may also be associated with a potentially increased risk of persistent pulmonary hypertension of the newborn.38 The absolute risk is small, and, according to a recent study, the increased risk appears more modest than that suggested in previous studies.38

Both SSRIs and SNRIs may be used for treatment of an anxiety disorder in a woman who is breastfeeding.34,39 Infants whose mothers are using the SSRIs fluvoxamine, paroxetine, or sertraline or the SNRI venlafaxine have been found to have low or undetectable serum drug levels, and no adverse effects have been reported.40

In the general population, use of benzodiazepines should be reserved for acute anxiety on a short-term basis because of the multiple associated risks: worsening of depressive symptoms, possible dependence, and possible overdose.32 Benzodiazepine use should be avoided in pregnancy because of these risks. Some data show a small increased risk for preterm birth, low birth weight, and floppy infant syndrome (hypotonia) in infants whose mothers used benzodiazepines during pregnancy. Data are inconclusive in terms of any teratogenic effect. If benzodiazepines are considered for women who are breastfeeding, those with a shorter half-life such as lorazepam and oxazepam are preferred because they are reported to result in low levels in breast milk and because they do not cause adverse effects in breastfed infants.34,41 Alprazolam and diazepam, with longer half-lives than some of the other benzodiazepines, should be avoided because of reports of infant sedation.34,41

Implications for practice

Perinatal anxiety is fairly common, and, when severe, has been linked to adverse pregnancy outcomes and to developmental and mental health problems in offspring. Early identification of and intervention for perinatal anxiety can help alleviate signs and symptoms, improve the perinatal experience, and reduce the risk for adverse outcomes. HCPs need to screen women for anxiety both during pregnancy and postpartum. When anxiety is identified, HCPs should conduct further assessment to determine whether the patient has a co-existing psychiatric disorder that merits referral and collaboration with a mental health specialist. Nonpharmacologic treatments such as CBT should be considered as first-line treatment, although some women may require medication to manage symptoms adequately. Risks and benefits of using medications to treat anxiety during the perinatal period should be considered on an individualized and ongoing basis.

Marian L. Farrell is Professor of Nursing at the University of Scranton in Scranton, Pennsylvania. She is also in private practice as a psychiatric nurse practitioner and clinical nurse specialist. The author states that she does not have a financial interest in or other relationship with any commercial product named in this article.

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24. Matthey S, Fisher J, Rowe H. Using the Edinburgh postnatal depression scale to screen for anxiety disorders: conceptual and methodological consideration. J Affect Disord. 2013;146(2):224-230.

25. Ali NS, Azam IS, Ali BS, et al. Frequency and associated factors for anxiety and depression in pregnant women: a hospital-based cross-sectional study. Scientific World Journal. 2012;2012:653098.

26. Dunkel Schetter C, Tanner L. Anxiety, depression and stress in pregnancy: implications for mothers, children, research, and practice. Curr Opin Psychiatry. 2012;25(2):141-148.

27. Otte C. Cognitive behavior therapy in anxiety disorders: current state of the evidence. Dialogues Clin Neurosci. 2011;13(4):413-421.

28. Sockol LE, Epperson CN, Barber JP. A meta-analysis of treatments for perinatal depression. Clin Psychol Rev. 2011;31(5):839-849.

29. Stuart S, Koleva H. Psychological treatments for perinatal depression. Best Pract Res Clin Obstet Gynaecol. 2014;28(1):61-70.

30. Kittel-Schneider S, Reif A. Treatment of mental disorders in pregnancy and lactation: psychotherapy and other non-drug therapies. Neurologist. 2016;87(9):967-973.

31. Stahle S. Stahl’s Essential Psychopharmacology Prescriber’s Guide. 5th ed. New York, NY: Cambridge University Press; 2014.

32. Woo TM, Robinson MV. Pharmacotherapeutics for Advanced Practice Nurse Prescribers. Philadelphia, PA: F.A. Davis; 2016.

33. Rubinchik SM, Kablinger AS, Gardner JS. Medications for panic disorder and generalized anxiety disorder during pregnancy. Prim Care Companion J Clin Psychiatry. 2005;7(3):100-105.

34. Malm H, Artama M, Gissler M, Ritvanen A. Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstet Gynecol. 2011;118(1):111-120.

35. Stephansson O, Kieler H, Haglund B, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality. JAMA. 2013;309(1):48-54.

36. Palmsten K, Setoguchi S, Margulis AV, et al. Elevated risk of preeclampsia in pregnant women with depression: depression or antidepressants? Am J Epidemiol. 2012;175(10):988-997.

37. Ewing G, Tatarchuk Y, Appleby D, et al. Placental transfer of antidepressant medications: implications for postnatal adaptation syndrome. Clin Pharmacokinet. 2015;54(4):359-370.

38. Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151.

39. Ellfolk M, Malm H. Risks associated with in utero and lactation exposure to selective serotonin reuptake inhibitors. Reprod Toxicol. 2010;30(2):249-260.

40. LactMed: A Toxnet Database.

41. Brucker MC, King TL. Pharmacology for Women’s Health. 2nd ed. Burlington, MA: Jones & Bartlett Learning; 2017.

Web resources

A. integration.samhsa.gov/clinical-practice/GAD708.19.08Cartwright.pdf

B. drsarahallen.com/wp-content/uploads/2015/10/PerinatalAnxietyScreeningScale2.pdf

C. link.springer.com/article/10.1007/s00737-013-0380-9

D. outcometracker.org/library/PSWQ.pdf

USPSTF: Screen All Pregnant Women for Pre-eclampsia

All pregnant women should be screened for preeclampsia with blood pressure measurements throughout their pregnancy, according to the U.S. Preventive Services Task Force (USPSTF).

There is “adequate evidence” that screening for preeclampsia has a “substantial benefit” for both mother and infant and that any harms resulting from screening and treatment are “no greater than small,” stated Kristen Bibbins-Dimingo, PhD, MD, of the USPSTF, and colleagues.

Read more at MedPage Today.

Researchers provide new insights into age-related female infertility

 

Researchers at the University of Montreal Hospital Research Center (CRCHUM) have discovered a possible new explanation for female infertility. Thanks to cutting-edge microscopy techniques, they observed for the first time a specific defect in the eggs of older mice. This defect may also be found in the eggs of older women. The choreography of cell division goes awry, and causes errors in the sharing of chromosomes. These unprecedented observations are being published today in Current Biology. Read more.

 

CMV virus is way more common than Zika. But expectant mothers don’t know their babies are at risk.

WHEAT RIDGE — When Megan Wiedel was pregnant with her second child, she did just as her doctor told her to.

No raw fish. No soft cheeses. No lunch meat.

All along, a much bigger risk — one that her doctor never told her about — loomed.

So, unaware, when Wiedel’s first daughter sniffled, she held her. When Wiedel herself caught a cold in the second trimester, she shrugged it off. And when her second daughter, Anna, was born — at only 5 pounds, full term — and then failed the newborn hearing test, Wiedel and her husband tried not to worry as the pediatrician ordered more tests.

Two weeks later, the results came back. Anna would be deaf for the rest of her life. She might never be able to walk or even hold her head up. It was because she had a virus called CMV.

Wiedel hung up the phone and thought to herself: Why had she never heard about CMV?

“When you talk about it, it seems like it’s really rare,” Wiedel said. “But it’s not. A lot of kids have CMV.”

“That’s the hardest piece for me is that this is a preventable, prevalent, quiet disease.”

But, now, a small community of mothers and medical workers are trying to make CMV awareness a little less quiet.

Cytomegalovirus, or CMV, is the most common nongenetic cause of childhood deafness in the country. Every year, approximately 30,000 babies are born in the United States infected with CMV, and as many as 8,000 of those children suffer lifetime consequences from the disease — which can also include blindness, cognitive delays and microcephaly. As many as 400 infants die every year from CMV, according to the National CMV Foundation.
It is vastly more common than the Zika virus, which prompted alarm last summer for its potential to cause birth defects. But, while Congress invested $1.1 billion in fighting Zika, funding for CMV lags behind, and numerous studies show that as many as 85 percent of expectant mothers have no idea what CMV is. The American College of Obstetricians and Gynecologists does not advise doctors to talk to expectant mothers about CMV — despite the fact that it is an easily spread virus that is present in nearly every elementary school and day care center in the country.

At Children’s Hospital Colorado, physician assistant Shannon Hughes has developed an outpatient clinic for kids dealing with the aftereffects of CMV. The clinic has served about 40 kids in the past two years. Nearly all of the parents she meets had never heard of CMV before finding out that it would forever alter their children’s lives.

“Obviously, that has a big impact on them emotionally that they think they did something wrong and should have prevented it,” she said.

Neonatal nurse practitioner Erin Mestas, who also works at Children’s as well as at Poudre Valley Hospital, is also trying to raise awareness among both mothers and health care workers about CMV.

“There needs to be more education about CMV risk reduction,” Mestas said. “I think childbearing women need to be more educated.”

In some ways, CMV’s ubiquity accounts for its invisibility.

Most adults have been exposed to CMV at some point in their lifetimes, meaning they have antibodies to fight off a new CMV infection. For women with CMV antibodies, then, being exposed to the virus while pregnant is usually no big deal.

Read more at The Denver Post

 

Collaborative care in a rural setting for a pregnant woman with heroin addiction

How can a nurse practitioner help a young woman addicted to heroin safely carry her pregnancy to term and deliver a healthy infant?

ATa 23-year-old woman, presents to the obstetrician’s office in her rural hometown. As a nurse practitioner (NP) enters the examination room, AT cries out to her, “I can’t lose another baby!”

Three weeks previously, after learning that she was pregnant, AT voluntarily admitted herself to an inpatient treatment program at a regional medical center located 50 miles from her home. AT had been injecting heroin daily for the past 1.5 years. At the inpatient treatment program, AT insisted on undergoing detoxification from heroin because she knew that she would not be able to keep appointments for maintenance medication management.

She underwent medicated detoxification over 2.5 days. After a 5-day stay, she was discharged from the medical center and instructed to follow up with counseling services nearer to her home.

At the office visit, AT acknowledges to the NP that she has thought about heroin every minute since her discharge from the inpatient treatment program, and that her boyfriend, with whom she lives, is still using heroin. She admits that she has relapsed twice since the discharge, taking a hydrocodone/acetaminophen tablet one time and injecting methamphetamine one time. The NP wonders how she can best help AT safely carry her pregnancy to term and deliver a healthy infant.

How common is heroin addiction today?

Most heroin addictions begin with prescription opioid abuse. In 2010, approximately 210 million prescriptions were written for opioids in the United States.1 Twenty percent of the U.S. population have admitted using prescription opioids for nonmedical reasons. Opioid users who become addicted to the drugs but can no longer get them legally may turn to heroin because it is less costly on the black market.1 In 2013, more than 500,000 persons in this country admitted using heroin, an increase of 100% since 2006.1

Heroin has infiltrated small rural areas as well as urban areas because of its easy availability and relatively low cost.1-5 In fact, data indicate that heroin use has increased significantly in recent years among rural adolescents and young adults, with a report from the National Institute on Drug Abuse and the CDC describing a shift in heroin use from urban to rural areas.6-8

The demographics of heroin users are changing in other ways. Nowadays, a typical user may be a woman in a high income bracket living in a suburban area with private health insurance or she may be a woman living in poverty in a rural or urban area.1,5,8 In 2012, 34% of persons receiving treatment for heroin addiction in the U.S. were women.2,9 Women fortunate enough to be treated for heroin addiction will likely undergo psychological counseling, with or without maintenance therapy with an opioid agonist.2, 9-11 By contrast, many women living in rural areas have limited access to treatment.7

How can an NP providing care in a rural community meet the needs of AT?

The NP reviews AT’s health history, including her recent hospitalization information. She asks AT if they can have an honest conversation about her heroin use and her life situation so that they can plan for the best care for her and the fetus.

AT has complex health and social problems that have led to and complicated her current situation. Her health history includes depression and anxiety. She was the victim of a sexual assault at age 14. Her parents were both heavy drinkers, and her three siblings have addictions to alcohol, drugs, or both. At age 20, AT was prescribed hydrocodone/acetaminophen after a back injury and became addicted to the opioid, which eventually led to her heroin use. She has had many failed attempts to quit using heroin on her own. As a result, AT has not been able to get or keep a job. She has no home or car and has been charged with two felony possessions in the past year. The year before, the Division of Family Services removed her two children from her care because of her addiction—prompting her outcry to the NP about her fear of losing another child.

When she learned she was pregnant with her third child, AT and her boyfriend were homeless. It was only after AT’s detoxification and hospital stay that her boyfriend’s mother agreed to let them stay with her as long as they both remained drug free. Her boyfriend, who is the father of her other two children as well, can hold odd jobs, but he spends most of his income on drugs.

AT’s initial physical examination and routine prenatal laboratory test findings are all normal. Test results for HIV, hepatitis C, chlamydia, gonorrhea, and syphilis are negative. AT completed the hepatitis B vaccination series with her previous pregnancy. A urine drug screen is negative. Ultrasonography (USG) confirms that she is at 10 weeks’ gestation.

The NP tells AT about an outpatient treatment program at the local hospital that provides free transportation to and from visits. AT agrees to be evaluated at the program and to consider maintenance therapy. An appointment is made for the next day. The NP also describes the healthcare providers (HCPs) who will be important team members in AT’s care. She will receive chemical dependency counseling, other mental health counseling, and management of her maintenance medication dosage at the outpatient treatment program. The NP will collaborate with the obstetrician at the office to provide her prenatal care and will consult regularly with maternal–fetal healthcare specialists at the regional medical center where she was previously hospitalized. AT provides written consent for all healthcare team members to have access to her electronic health record so that her care can be coordinated.

How is heroin addiction treated during pregnancy?

Chronic heroin use during pregnancy is associated with spontaneous abortion, placental insufficiency, intrauterine growth restriction, premature labor and/or birth, chorioamnionitis, preeclampsia, abruption placentae, oligohydramnios, premature rupture of membranes, intrauterine death, higher rates of cesarean sections, postpartum hemorrhage, and longer hospital stays. Newborns are at risk for neonatal abstinence syndrome (NAS).12-14

Opioid-assisted maintenance therapy (OAMT), the standard treatment for heroin addiction during pregnancy, can reduce the risks for obstetric and neonatal complications.15 In addition, the use of OAMT during pregnancy can prevent complications of illicit opioid use, narcotic withdrawal, and relapse; encourage prenatal care and drug treatment; reduce criminal activity; and avoid risks to the patient of associating with a drug culture.15, 16

Methadone, a full opioid agonist, is the most commonly used medication for OAMT during pregnancy. Methadone maintenance must be prescribed and dispensed on a daily basis by an addiction treatment specialist in a registered methadone treatment program. Buprenorphine, a partial opioid agonist, is another option for treatment during pregnancy. Buprenorphine may be prescribed in an office setting by a physician or NP who has undergone specific credentialing and in accordance with federal and state regulations. Advantages of treatment with buprenorphine over methadone include lower risk of overdose, ability to have outpatient treatment without required daily visits to a treatment program, and evidence of less severe NAS.15,16 Disadvantages include higher discontinuation rates, risks for sharing or selling the drug, and lack of long-term data on the effects of the medication on children exposed to it in utero.15,16

Medication dosages may need to be adjusted during pregnancy to avoid withdrawal symptoms that can cause fetal stress and may lead to maternal heroin use relapse. This need is especially true in the third trimester, when the woman may have a more rapid metabolism.15,16

How does the NP manage AT’s ongoing care?

The NP sees AT every 2 weeks over the next 6 weeks to establish rapport, offer support, and evaluate concerns. The NP consults with maternal– fetal healthcare specialists at the regional medical center to discuss a plan to monitor fetal well-being throughout the pregnancy. A USG schedule is established to evaluate fetal anatomy at 19 weeks and then every 6 weeks in the third trimester to monitor fetal growth.

AT and her addiction specialist decide that buprenorphine is an appropriate maintenance medication for her. AT attends individual and group counseling sessions at the outpatient treatment program 5 days a week and sees the addiction specialist weekly for her buprenorphine prescription for the first month of her treatment. The psychiatrist at the treatment center evaluates AT for depression and anxiety and prescribes sertraline to treat depression and quetiapine to aid sleeping. Over time, AT is able to reduce her counseling sessions to 3 days a week and her appointments for buprenorphine prescription to once monthly.

After the first few weeks of frequent visits, AT sees the NP every 4 weeks until 26 weeks’ gestation, every 2 weeks until 36 weeks’ gestation, and then weekly. The USG at 19 weeks shows normal fetal anatomy and growth. USGs at 28 and 34 weeks show fetal growth within normal limits. All routine laboratory test results are normal.

The NP and obstetrician discuss birthing plans with AT. She decides to remain on buprenorphine through labor and delivery, with a planned epidural for pain management. The pediatrician is available to oversee management of any NAS in the newborn. The maternal–fetal healthcare specialists at the regional medical center remain available for consultation.

At 38 weeks’ gestation, AT has an uncomplicated labor and vaginal birth of a baby girl weighing 6 lb 15 oz. Although breastfeeding is encouraged, AT decides to bottle feed. A social worker from the division of family services approves AT to take her baby home. AT and her daughter are discharged after 48 hours to stay with her boyfriend at his mother’s home. She decides she will use an intrauterine contraceptive so that she can continue to get her life in order without worrying about another pregnancy.

Should AT be encouraged to breastfeed?

Breastfeeding is encouraged for mothers receiving OAMT as long as they abstain from the use of illicit substances.15,17 Breastfeeding supports mother–infant bonding and may reduce the severity and duration of NAS symptoms.18,19 Minimal levels of methadone or buprenorphine are found in breast milk, regardless of the maternal dosage.15,16 Both medications are considered safe during breastfeeding.15

The safety of illicit substances during breastfeeding is not possible to determine. Maintaining open lines of communication between the mother and her HCPs is essential so that she feels comfortable letting them know if she does relapse. If relapse does occur, the mother should be provided with assistance to transition to bottle feeding and guidance on how to taper milk production to prevent mastitis.17

Reflection

Although AT was successful in stopping heroin and staying drug free for most of her pregnancy, she admitted having two occasions of illegal drug use during treatment. Her boyfriend initiated treatment, but he stopped after 2 weeks and started using heroin again. AT moved into a shelter for homeless pregnant women for a month, until her boyfriend returned to treatment. The motivation to have a healthy baby she could keep and easy access to a treatment center near home were vital to AT’s success.

Implications for NPs

Nurse practitioners providing care for reproductive-aged women may encounter some with heroin addiction, including during a pregnancy. NPs need to screen all women for alcohol and drug abuse at least annually and all pregnant women early in pregnancy. A nonjudgmental and supportive approach is important. Goals for pregnant women are to encourage regular prenatal care and drug treatment that includes OAMT and counseling. A collaborative approach includes prenatal care providers, addiction treatment specialists, mental health professionals, maternal–fetal healthcare specialists, and neonatal specialists. Using this collaborative approach, NPs in rural health settings can safely manage the care of pregnant women with heroin or opioid addiction.

Corinne Ann Coppinger is a women’s health nurse practitioner atMercy Hospital-Washington in Washington, Missouri. The author states that she does not have a financial interest in or other relationship with any commercial product named in this article.

References

1. Kane-Willis K, Schmitz SJ, Bazan M, Narloch VF. A multiple indicator analysis of heroin and opiate use in Missouri: 2001-2011. Missouri Recovery Network. March 2013.

2. Substance Abuse and Mental Health Services Administration. Behavioral Health Trends in the United States: Results from the 2014 National Survey on Drug Use and Health. September 2015.

3. Kane-Willis K, Schmitz SJ, Bazan M, Narloch VF. Heroin use: National and Illinois Perspectives, 2008-2010. Roosevelt University. Institute for Metropolitan Affairs. August 2012.

4. U.S. Department of Justice Drug Enforcement Administration. National Drug Threat Assessment Summary. November 2014. info.

5. Substance Abuse and Mental Health Service Administration. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. September 2014.

6. Havens JR, Young AM, Havens CE. Nonmedical prescription drug use in a nationally representative sample of adolescents: evidence of greater use among rural adolescents. Arch Pediatr Adolesc Med. 2011;165(3):250-255.

7. Keyes KM, Cerdá M, Brady JE, et al. Understanding the rural-urban differences in nonmedical prescription opioid use and abuse in the United States. Am J Public Health. 2014;104(2):e52-e59.

8. CDC. Today’s Heroin Epidemic. Updated July 7, 2015.

9. Substance Abuse and Mental Health Service Administration. Substance Abuse Treatment Admissions by Primary Substance of Abuse, According to Sex, Age Group, Race, and Ethnicity. 2013.

10. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. J Addict Med. 2015;9(5):358-367.

11. National Institute on Drug Abuse. Principles of Drug Addiction Treatment: A Research-Based Guide (Third Edition). Updated December 2012.

12. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville, MD: Substance Abuse and Mental Health Services Administration (US); 2004.

13. Kaltenbach K, Berghella V, Finnegan L. Opioid dependence during pregnancy. Effects and management. Obstet Gynecol Clin North Am. 1998;25(1):139-151.

14. Maeda A, Bateman BT, Clancy CR, et al. Opioid abuse and dependence during pregnancy: temporal trends and obstetrical outcomes. Anesthesiology. 2014;121(6):1158-1165.

15. American College of Obstetricians and Gynecologists. Committee Opinion. Opioid Abuse, Dependence, and Addiction in Pregnancy. May 2012.

16. Wong S, Ordean A, Kahan M;Society of Obstetricians and Gynecologists of Canada. SOGC clinical practice guideline: substance use in pregnancy. Int J Gynaecol Obstet. 2011;114(2):190-202.

17. Reece-Stremtan S, Marinelli KA.ABM clinical protocol # 21: guidelines for breastfeeding and substance use or substance use disorder, revised 2015. Breastfeed Med. 2015;10(3):135-141.

18. McQueen KA, Murphy-Oikonen J, Gerlach K, Montelpare W. The impact of infant feeding method on neonatal abstinence scores of methadone- exposed infants. Adv Neonat Care. 2011;11(4):282-290.

19. Pritham UA. Breastfeeding promotion for management of neonatal abstinence syndrome. J Obstet Gynecol Neonat Nurs. 2013;42(5):517-526.

Drugs in pregnancy, lactation, and reproductive health: Standards for prescribers

In June 2015, the FDA updated its recommendations for the labeling of drugs with respect to their use by pregnant women, lactating women, and females and males of reproductive potential. Healthcare providers caring for these populations, many of whom are taking prescription medications and biologics, need to be alert to these labeling changes.

Between 64% and 94% of pregnant women use a prescribed medication during their gestation.1,2 Among pregnant women who take prescribed medications, 80% do so during the first trimester,3 when fetal organ systems and structures are being formed. For many women who are managing chronic diseases, discontinuing the medications is not an option. In addition, because more than 50% of pregnancies in the United States are unintended,4 a large group of women are exposing their fetus to medications before they even realize that they are pregnant.

For postpartum patients on medications for chronic conditions, the choice to breastfeed their infant may pose a dilemma. Many of these women are advised to bottle-feed their infants instead, even if they are using medications safely taken by lactating women.5 Likewise, women who become ill during the lactation period may be counseled to stop breastfeeding their child if they need to take certain medications. According to the Centers for Disease Control and Prevention, 77% of infants born in the United States in 2010 were breastfed.6 During the same year, breastfeeding rates were 49% at 6 months and 27% at 1 year. Because many breastfeeding mothers are using prescription medications, these statistics translate to hundreds of thousands of infants potentially being exposed to these same medications for prolonged periods of time.

For reproductive-aged women who could become pregnant, counseling with regard to the potential impact of prescription or over-the-counter medications on pregnancy is often lacking. In the case of drugs that are known teratogens, past research indicates that women who had them prescribed, compared with women for whom safer medications were prescribed, did not receive contraceptive counseling in greater numbers.7 The impact of certain drugs on fertility, including chemotherapeutic medications, may not be discussed unless the effects are catastrophic. Finally, there is scant information on the need for reproductive health counseling for men in terms of medication use. Available counseling has often focused on the impact of illicit drugs on male factor infertility.8

Role of the FDA

The thalidomide tragedy, as it developed in the late 1950s and early 1960s in Europe, provided the impetus for tighter regulation of drugs by the FDA in the United States. In 1979, the FDA adopted a labeling system  hat rated drugs for pregnant women using the well-known letter system: A, B, C, D, or X. At the time, the FDA did not provide a risk classification system for drugs taken during lactation. Pregnant women and nursing mothers were considered under the precaution areas of the counseling for medication use.9

Early in 1996, the FDA determined that the letter system was too simplistic.3 In addition, many drugs were allocated to different risk categories, depending on how the results of safety studies were being interpreted,10 resulting in confusion for healthcare providers (HCPs) and patients alike. The Teratology Society asked the FDA to develop a more comprehensive risk counseling strategy that would encompass all stages of the childbearing process.Changes to the system were proposed in 2008, and multiple public hearings and comment periods ensued. The Pregnancy and Lactation Labeling Rule (PLLR) was adopted and published in December 2014. Immediate compliance with the labeling rule has been required for all prescription drug and biologic products submitted to the FDA after June 30, 2015; phased-in compliance over 3-5 years is required for previously approved prescription drugs and biologics.11

The 2015 Pregnancy and Lactation Labeling Rule.12

The PLLR requires changes to the content and format for information presented in prescription drug labeling in the Physician Labeling Rule format to assist HCPs in assessing benefit versus risk and in subsequent counseling of pregnant women and nursing mothers who need to take medication, thereby enabling them to make informed decisions for themselves and their children. Subsections for pregnancy, lactation, and females and males of reproductive potential are required in the Use in Specific Populations section. Pregnancy letter categories have been removed.

Pregnancy subsection

Specific subheadings required in the pregnancy subsection include contact information for a pregnancy exposure registry for the drug (if one is available), a risk summary, clinical considerations, and available human and animal data. Some subheadings may be excluded if no relevant information is available.

Risk summary

This subheading is always required. If a drug is contraindicated in pregnancy, this fact must be listed first. Statements that describe risks for adverse developmental outcomes based on relevant human data, animal data, and the drug’s pharmacology are required. A cross-reference to additional details in the data subheading is included when applicable. Drugs not absorbed systemically following a particular route of administration include a statement that maternal use is not expected to result in fetal exposure to the drug. Drugs with more than one route of administration must include information related to each route.

Clinical considerations

This subheading provides information to further assist HCPs in prescribing decisions and risk–benefit counseling. When relevant, this subheading includes information about disease-associated maternal and/or embryo/fetal risk, dose adjustments during pregnancy and postpartum, maternal adverse reactions, fetal/neonatal adverse reactions, and labor/delivery. Inclusion of any disease -associated maternal and/or embryo/fetal risks is important for patient counseling and informed decision making. After all, HCPs and patients need to weigh the risks and benefits of not treating a disease/condition in pregnancy (e.g., depression, hyperlipidemia) versus the risks and benefits of taking a given drug during pregnancy.

When pharmacokinetic data support dose adjustment during pregnancy and/or postpartum, a summary of this information is provided. When applicable, cross-referencing to other labeling sections (e.g., Clinical Pharmacology, Dosage and Administration) for additional information is included.

Drug-associated adverse reactions that are unique to pregnancy or that occur with increased frequency or severity in pregnant women are described. When available, information on any clinical interventions to monitor or reduce maternal drug-associated adverse reactions is provided.

The fetal/neonatal adverse reactions described in this subsection are those based on the drug’s pharmacologic activity. The potential severity and reversibility of the adverse reaction, as well as interventions for monitoring and mitigation of the adverse reaction, are included.

If a drug is expected to affect labor or delivery, the labeling must provide available information about the drug’s effects on the mother, the fetus/neonate, and the duration of labor and delivery. An example is the use of an opioid during labor that may cause respiratory depression in the neonate. The labeling information includes the effect of dose, timing, and duration of exposure on the risk to the neonate and the use of naloxone to mitigate the reaction.

Data

Data that provide the scientific basis for the information in the risk summary and clinical consideration subheadings are included. Human and animal data are presented separately. Data regarding adverse developmental outcomes, adverse reactions, and other adverse events related to the drug must be included.

Lactation subsection

This subsection must include a risk summary, applicable clinical considerations, and any available human and animal data. The term lactation refers to the biologic state during which the body produces and excretes milk. The term breastfeeding is used to refer to all human milk, whether received directly from the breast or as expressed milk.

Risk summary

This subheading is always required. If a drug is contraindicated during breastfeeding (e.g., radioisotopes), this fact must be stated first. Drugs not absorbed systemically by the mother following a particular route of administration must include a statement that maternal use is not expected to result in the child’s exposure to the drug during breastfeeding. Drugs with more than one route of administration must include information related to each route. For drugs absorbed systemically, available information on whether the drug and/or its active metabolites are present in human milk, effects of the drug on the breastfed child, and effects of the drug on milk production and/or excretion must be included. If a drug and/or its active metabolites are present in human milk, detailed information on actual or estimated infant daily dose based on exclusive breastfeeding  must be provided. The risk summary must acknowledge when data are lacking.

Clinical considerations

A description of ways to minimize exposure of the breastfed child to systemically absorbed drugs that are used intermittently, in a single dose, or short term must be included. This description may include information on timing of administration of the drug relative to feeding, pumping sessions, or expressing for discarding. Specified time periods are based on the half-life of the drug and/or its active metabolite(s). Information on monitoring for adverse reactions must be included if available.

Data

As with the pregnancy subheading, data on which the risk summary and clinical considerations are based for lactation and breastfeeding are provided.

Females and males of reproductive potential subsection

This subsection is included if there are human or animal study data of potential drug-associated effects on fertility and/or pre-implantation loss. Recommendations for pregnancy testing and/or contraception may be based on concerns for adverse developmental outcomes if the drug is taken during pregnancy.

Relevance to practice

Healthcare providers can use the information provided in the new labeling to be better informed and enhance discussions about the benefits and risks of specific drugs with women who are pregnant or lactating or with patients of reproductive potential. The information contained in the PLLR may or may not be the same as that included in patient drug information.

Providers can utilize websites, mobile apps, and reference texts to focus counseling or answer patients’ questions (Table). These resources may be especially useful until the PLLR changes are fully implemented, as well as for supplemental information. As always, HCPs can consult with pharmacists regarding the pharmacokinetics and pharmacodynamics of a drug.

Kathleen M. Mahoney is a perinatal clinical nurse specialist at Robert Wood Johnson University Hospital in New Brunswick, New Jersey. The author states that she does not have a financial interest in or other relationship with any commercial product named in this article.

References

1. Ramoz LL, Patel-Shori NM. Recent changes in pregnancy and lactation labeling: retirement of risk categories. Pharmacotherapy. 2014;34(4):389-395.

2. Fantasia H, Harris A. Changes to pregnancy and lactation risk labeling for prescription drugs. Nurs Womens Health. 2015;19(3):266-270.

3. Mazur-Amirshahi M, Samiee-Zafarghandy S, Gray G, Van den Anker JN. Trends in pregnancy labeling and data quality for US-approved pharmaceuticals. Am J Obstet Gynecol. 2014;211(6):690e1-11.

4. Guttmacher Institute. Unintended Pregnancy in the United States. March 2016.

5. Saha MR, Ryan K, Amir LH. Postpartum women’s use of medicines and breastfeeding practices: a systemic review. Int Breastfeed J. 2015;10(28):1-10.

6. Centers for Disease Control and Prevention. Breastfeeding Report Card, 2013.

7. Schwartz EB, Postlethwaite DA, Hung YY, Armstrong MA. Documentation of contraception and pregnancy when prescribing potentially teratogenic medications for reproductive age women. Ann Intern Med. 2007;147(6): 370-376.

8. Fronczak CM, Kim ED, Barqawi AB. The insults of illicit drug use on male fertility. J Androl. 2012;33(4):515- 528.

9. Mosley JF 2nd, Smith LL, Dezan MD. An overview of upcoming changes in pregnancy and lactation labeling information. Pharm Pract (Granada). 2015;13(2):605.

10. Addis A, Sharabi S, Bonati M. Risk classification systems for drug use during pregnancy: are they a reliable source of information? Drug Saf. 2000;23(3):245-253.

11. Food and Drug Administration. Pregnancy and Lactation Labeling (Drugs) Final Rule. December 3, 2014.

12. Food and Drug Administration. Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products — Content and Format. Washington, DC: Food and Drug Administration; 2015.

Web resources

A. reprotox.org

B. toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

C. mothertobaby.org/fact-sheets-parent

Hypothyroidism in pregnancy

Thyroid disorders are fairly common in pregnancy, with the most common being hypothyroidism. Undiagnosed or inadequately treated hypothyroidism during pregnancy can have devastating consequences on the developing fetus. By contrast, early recognition and effective management of thyroid disorders in pregnancy can minimize risk for both maternal and neonatal complications.

Approximately 4% of women seeking prenatal care have previously been diagnosed with hypothyroidism.In iodine-sufficient areas such as the United States, the major cause of hypothyroidism in women of childbearing age is chronic autoimmune thyroiditis (Hashimoto’s disease).However, worldwide, iodine deficiency remains the most important cause of thyroid insufficiency.2,3 In addition, prior thyroidectomy; radioiodine therapy; use of medications such as amiodarone, anti-thyroid drugs, or lithium; and pituitary or hypothalamic disease can result in hypo-thyroidism.2

The prevalence of hypothyroidism diagnosed during pregnancy is 0.3%-0.5% for overt hypothyroidism and 2%-3% for subclinical hypothyroidism.Unrecognized or inadequately treated hypothyroidism during pregnancy has been associated with spontaneous abortion, preeclampsia, intrauterine fetal demise, preterm birth, low birth weight, postpartum hemorrhage, and irreversible detrimental effects on fetal neurodevelopment.2,4 The degree of neurocognitive deficit is related to the severity, duration, and gestational age at which hypothyroidism occurs.2,4,5

To reduce pregnancy complications and enhance optimal pregnancy outcomes, nurse practitioners (NPs) need to understand normal thyroid physiology, changes in thyroid physiology and laboratory values during pregnancy, fetal thyroid development and functioning, and strategies for effective pharmacologic management and thyroid monitoring for women with hypothyroidism during pregnancy. The purpose of this article is to increase this understanding.

Synthesis and regulation of thyroid hormones

The follicular cells are the functional cells of the thyroid gland. The follicular cells, in combination with iodine and the amino acid tyrosine, synthesize and secrete thyroid hormone (TH). TH synthesis is also controlled by serum iodide levels. The first step in TH synthesis is the concentration of iodide within the thyroid. Iodide is the inorganic form of iodine and the form in which iodine enters the thyroid. Iodide is oxidized to iodine by the enzyme thyroidal peroxidase (TPO) in the follicular cells.6

Thyroglobulin, a large glycoprotein synthesized by the follicular cells, is the precursor of TH. Thyroglobulin contains the amino acid tyrosine and is joined with one or two iodine molecules within the follicular cells. This joining, facilitated by TPO, results in the formation of iodotyrosine complexes.6 Two of these iodotyrosine complexes form the active THs: tri-iodothyronine (T3), which has three iodine molecules, and thyroxine (T4 ), which has four iodine molecules.

Thyroid hormone is stored in the thyroid as a colloid compound until needed. Of the TH that is synthesized, 90% is T4 , although T3 is physiologically more potent. Only a small amount of T3 is synthesized in the thyroid, with about 80% formed in the liver, kidneys, and muscles from de-iodination of T4 . T3 and T4 are transported in the circulation for the most part bound to thyroxine-binding globulin (TBG) and other plasma proteins such as albumin.6 Proteinbound TH acts as a reservoir, with free TH released as needed. Only free TH can enter target receptor cells, where it then influences a variety of metabolic processes in the body.

Thyroid hormone is regulated through a negative feedback loop involving the hypothalamus-pituitary- thyroid (HPT) axis. Thyrotropin-releasing hormone (TRH), synthesized in the hypothalamus, circulates via the hypothalamic-pituitary portal system to the anterior pituitary, where it stimulates release of thyroid-stimulating hormone (TSH).6 TRH is released in response to cold, stress, and decreased levels of free T4 (FT4 ). TSH, in turn, binds with receptors on the plasma membrane of the thyroid follicular cells and causes an immediate release and increase in synthesis of TH (Figure).6 

Thyroid changes during pregnancy

In response to increased metabolic needs during pregnancy, thyroid activity and hormone production increase. The thyroid typically enlarges moderately due to hyperplasia of glandular tissue and increased vascularity. Human chorionic gonadotropin (hCG) secreted by the placenta, similar in structure to TSH, directly stimulates the maternal thyroid to produce TH. TBG levels increase beginning at about 20 weeks’ gestation as a result of increased estrogen levels. These two changes—that is, hCG stimulation of TH synthesis and increased TBG levels—lead to a decrease in TSH levels in the first trimester, with a return to baseline in the second trimester, and an increase in total TH levels* throughout pregnancy. Table 1 shows the physiologic changes in thyroid function during pregnancy.4,8,9

*Total TH includes both free and protein-bound forms; the increase in total TH is due mainly to the increased protein-bound forms of the hormone. The free circulating form of TH remains relatively unchanged throughout pregnancy.7,8

Nurse practitioners should note that non-pregnancy laboratory reference ranges do not apply to pregnant women. In fact, reference ranges change throughout pregnancy to reflect the physiologic changes occurring in thyroid function. Therefore, NPs should use trimester-specific, assay-specific normal ranges. If these ranges are unavailable, then these ranges for TSH should be used:3,4

• First trimester: 0.1-2.5 mIU/L

• Second trimester: 0.2-3.0 mIU/L

• Third trimester: 0.3-3.0 mIU/L

In addition, the elevated TBG seen in pregnancy interferes with immunoassays for FT4 levels. TSH is the most sensitive indicator of thyroid status in pregnant women.7

Fetal thyroid development and function

Fetal thyroid development and function can be divided into three overlapping phases: embryogenesis (phase I), functional development (phase II), and maturation (phase III) (Table 2).5,9,10 The thyroid is the first fetal endocrine gland to develop. It starts as a thickening at the base of the tongue and migrates down the neck to reach its final position in front of the trachea by 7 weeks’ gestation.9,10 Follicle cells form and begin thyroglobulin production by 8 weeks’ gestation. Although the fetal thyroid is able to start concentrating iodine and synthesizing iodothyronines by about 10 weeks’ gestation, little TH synthesis occurs until about 18 weeks’ gestation.During fetal development, T4 is the major TH being produced; T3 is not detected until the third trimester.9,10

The fetal hypothalamus is visible by 7 weeks’ gestation, with levels of TRH detectable by 9 weeks.10 The fetal pituitary is visible by 4 weeks, with TSH starting to become detectable at 10-12 weeks.10 The fetal HPT axis begins to function mid-gestation (18-20 weeks), with the fetus beginning to implement feedback mechanisms for TH production.9,10 During this time, fetal receptors for TRH and TSH become responsive. Further maturation of the HPT axis continues throughout the remainder of pregnancy.10

Maternal hypothyroidism is particularly harmful to the fetal brain  in the first half of pregnancy, when fetal T4 production is low. TH is critical for neuron development and neural pathway organization.5,9 It is the transplacental transfer of T4 and iodine in the first trimester that promotes fetal brain development until the fetal thyroid becomes functional.5 Even during the second and third trimesters, when the fetal thyroid is producing T4 , much of the Tneeded for development is still of maternal origin.5,9

Overt hypothyroidism

Overt hypothyroidism (OH) in pregnancy, evidenced by elevated TSH and low serum FT4, is linked to adverse fetal/obstetric outcomes. Stillbirth, preterm delivery, postpartum hemorrhage, and infants with neuropsychological and cognitive impairment have been reported in women with inadequately treated OH.2,4,5 OH should be treated with levothyroxine (LT4), with the goal of normalizing trimester-specific TSH values.Women who have been euthyroid on their LT4 dosages pre-pregnancy will need dosage changes throughout pregnancy in order to maintain the euthyroid state.

Subclinical hypothyroidism

Subclinical hypothyroidism (SH) is by far the most frequent thyroid dysfunction occurring during pregnancy.11 SH is associated with elevated TSH and normal FT4. SH represents early, mild thyroid dysfunction. Sixty percent to 80% of these cases demonstrate the presence of antithyroid peroxidase antibodies, a marker of chronic thyroiditis (Hashimoto’s disease).12 Because of limited and conflicting data, controversy exists regarding the effects of SH on fetal/obstetric outcomes, including the need to screen or treat women with SH. Several obstetric complications have been associated with SH, with pregnancy loss being one of the most frequent.11,12 Other reported complications include gestational hypertension, preeclampsia, low birth weight, placental abruption, and postpartum hemorrhage, albeit at lower frequencies than those recorded in pregnant women with untreated OH.11,12

Early studies reported impaired cognitive development in infants born to mothers whose SH was inadequately treated, but not in infants born to women with adequately treated SH.12,13 However, in 2012, a large randomized controlled trial, the Controlled Antenatal Thyroid Screening Study, revealed no difference in the neurocognitive development of infants born to women who were screened and treated for SH versus those whose SH status was not revealed until after delivery.14 As a result, the American Congress of Obstetricians and Gynecologists (ACOG), the Endocrine Society, and the American Thyroid Association (ATA) do not recommend universal screening for thyroid disease in pregnancy.4,7 Instead, screening is recommended only in women who are at increased risk for OH, those with symptoms of thyroid disease, and those with a personal history of thyroid disease.

However, a lack of consensus exists regarding the need to treat SH in pregnant women. ACOG recommends against treatment for pregnant woman with SH because of a lack of research showing benefit.7 However, the Endocrine Society and the ATA recommend LTtherapy for all women with SH.4,7

Levothyroxine therapy

Levothyroxine, a Pregnancy Category A medication, remains the  drug of choice for the treatment of all types of hypothyroidism. In typical cases, the LT4 dosage is increased as the pregnancy advances because of the hypermetabolic state that pregnancy induces.3,4 In fact, dosage requirements may increase by as much as 30%-50% during pregnancy, and these increases may be needed as early as the fifth week of gestation.3 Replacement therapy in dosages of 1-2 mcg/kg/day, or about 100 mcg/day, is recommended.12,137 NPs should check patients’ TSH levels every 4-6 weeks during pregnancy so that dosages can be adjusted as necessary. The goal is to maintain maternal serum TSH in the trimester-specific range.3,4 Because only minimal amounts of LT4 cross the placenta after the first trimester, the fetus is not at risk for thyrotoxicosis from maternal LT4 replacement.4,8

Because of differences, albeit subtle, in bioavailability among LT4 formulations, patients should stay with one formulation when possible. NPs should educate patients to take LT4 on an empty stomach—45 minutes before consumption of food, beverages, or other medications—for optimal absorption.3,15 Prenatal vitamins, calcium, and iron can interfere with the absorption of LT4 and should be avoided within 4 hours of taking LT4.3 Likewise, medications used to treat gastroesophageal reflux, including histamine-2 blockers, proton pump inhibitors, and antacids, can decrease LT4 absorption.15 Finally, NPs need to ascertain whether pregnant women are using any herbal products that contain lemon balm, also known as bee balm, honey plant, or sweet balm.16 Lemon balm, used as a tea or oil to treat anxiety, insomnia, and indigestion, is known to have anti-TSH effects, and can prevent T4 absorption from the small intestine.15,16

After delivery, the LT4 requirement drops immediately; women who were on LT4 prior to pregnancycan revert to their pre-pregnancy dosage.3,5 Women who were started on LT4 to treat OH during their pregnancy can likely reduce their dosage to half that taken just before delivery.3,4,7 If they were receiving LT4 to treat SH, the medication can be stopped and thyroid function tests performed in 6 weeks to determine whether further treatment is required.3,4,7 LT4 is considered safe to use during lactation.3,17

Iodine requirements and pregnancy

Iodine is a critical trace element required for TH synthesis; both maternal and fetal TH production depends on an adequate dietary intake of iodine.7 Iodine deficiency may be a factor contributing to concurrent maternal and fetal hypothyroidism. In the United States, iodized salt is an important source of iodine. (About 70% of salt sold for household use is iodized.) Other common dietary sources of iodine in the U.S. are dairy products, seafood, eggs, meat, and poultry.The prevalence of iodine deficiency is lowest in the Americas (10%) and highest in Europe (59.9%).3,8

In pregnancy, because of an increase in renal excretion of iodine and transfer of iodine to the placenta and fetus, the thyroid triples its uptake of iodine.8 Dietary iodine requirements are therefore increased during pregnancy. Although most U.S. women have adequate iodine intake to meet the increased demand for both maternal and fetal TH production, it is difficult to identify those who are at risk for or who may have mild to moderate iodine deficiency.4

In cases of mild to moderate iodine deficiency, the thyroid decreases synthesis of T4 in favor of T3 , the T3 levels remain normal, and circulating TSH does not rise. Thyroid function tests may indicate euthyroidism even though the amount of T4 available to the fetus may be insufficient.3 Severe iodine deficiency in pregnancy can cause hypothyroidism, poor pregnancy outcome, irreversiblemental retardation, and cretinism. Recent studies show that even mild iodine deficiency has been associated with impaired neurologic outcomes in children.3,8,9

The World Health Organization recommends an intake of 250 mcg/day of iodine during pregnancy and breastfeeding.4,18,19 To achieve this level, the ATA recommends that women in North America who are planning pregnancy or are pregnant or breastfeeding take a daily supplement containing 150 mcg of iodine.1,4 Among the roughly 200 prenatal vitamin brands marketed in the U.S., only half contain iodine, and among the products that do contain iodine, not all contain the recommended dose.4 In addition, studies have shown about 20% of pregnant woman do not take their prenatal vitamin supplement.1,4 NPs need to educate their pregnant patients about why they need to take all the supplements that are prescribed for them.

Conclusion

The normal physiologic changes in the thyroid during pregnancy occur to compensate for increased maternal metabolic demands and to provide adequate TH and iodine for fetal brain development. Hypothyroidism in pregnant women presents unique challenges related to these changes. The physiologic changes affect both interpretation of thyroid studies and dosing of LT4 during pregnancy. The goal of treatment is to restore euthyroidism as soon as possible and to maintain TSH in the trimester-specific reference range. NPs need to consider these key practice points:

• Thyroid disease is the second most common endocrine disorder of pregnancy (following diabetes).

• Iodine requirements increase in pregnancy and lactation. Women should be advised to take a prenatal vitamin that contains 150 mcg of iodine in its formulation.

• Under ideal circumstances, women with hypothyroidism should have their LT4 dose optimized prior to pregnancy and then reviewed each trimester.

• The dosage of LT4 needed to maintain a euthyroid state increases during pregnancy.

• Women with OH should be treated to maintain serum TSH in the trimester-specific goal range.

• Controversy exists regarding whether SH in pregnant women should be treated.

• T4 drops immediately following delivery; the LT4 dosage will need to be readjusted.

Carol A. Botwinski is Director/Chair of the Department of Nursing at the University of Tampa in Tampa, Florida. The author states that she does not have a financial interest in or other relationship with any commercial product named in this article.

References

1. Haddow JE. The new American Thyroid Association Guidelines for thyroid disease during pregnancy and postpartum: a blueprint for improving prenatal care. Thyroid. 2011;21(10): 1047-1048.

2. Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011; 25(6):927-943.

3. Klubo-Gwiezdzinska J, Burman K, Van Nostrand D, Wartofsky L. Levothyroxine treatment in pregnancy: indications, efficacy, and therapeutic regimen. J Thyroid Res. 2011;1-12.

4. Stagnaro-Green A, Abalovich M, Alexander E, et al; American Thyroid Association Taskforce on Thyroid Disease during Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1081-1104.

5. Mann N. Congenital hypothyroidism – what’s new? Paediatr Child Health. 2011;21:295-300.

6. Matfin G. Disorders of endocrine control of growth and metabolism. In: Porth C, ed. Essentials of Pathophysiology4th ed. Philadelphia, PA: Wolters Kluwer; 2015:767-792.

7. American College of Obstetricians and Gynecologists. Practice bulletin No. 148: Thyroid disease in pregnancy. Obstet Gynecol. 2015; 125(4):996-1005.

8. Girling J, Sykes L. Thyroid disorders and other endocrinological disorders in pregnancy. Obstet Gynaecol Reprod Med. 2013;23:171-179.

9. Blackburn S. Maternal, Fetal, & Neonatal Physiology: A Clinical Perspective4th ed. St. Louis, MO: Saunders; 2012.

10. Rose S. Thyroid disorders. In: Martin R, Fanaroff A, Walsh M, eds. Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant. 9th ed. St. Louis, MO: Elsevier; 2011:1556-1584.

11. McLeod D, McIntyre H. Subclinical hypothyroidism and related biochemical entities in pregnancy: implication and management. Obstet Med. 2010;3:139-144.

12. Cooper D, Biondi B. Subclinical thyroid disease. Lancet. 2012; 379(9821):1142-1154.

13. Behrooz HG, Tohidi M, Mehrabi Y, et al. Subclinical hypothyroidism in pregnancy: intellectual development of offspring. Thyroid. 2011;21(10): 1143-1147.

14. Lazarus JH, Bestwick JP, Channon S, et al. Antenatal thyroid screening and cognitive function. N Engl J Med. 2012:366(6):493-501.

15. Eligar P, Eligar V. Levothyroxine: factors affecting its intestinal absorption and metabolism. W London Med J. 2011;3:9-14.

16. University of Maryland Medical Center. Lemon Balm. Updated May 7, 2013.

17. National Institute of Health. Toxnet. Substance Name: Levothyroxine.

18. World Health Organization. Iodine Supplementation in Pregnant and Lactating Women. 2015.

19. World Health Organization. Joint statement by the WHO and UNICEF: Reaching optimal iodine nutrition in pregnant and lactating women and young children. 2007.

Fertility preservation for young cervical cancer survivors

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By Aimee Chism Holland, DNP, WHNP-BC, FNP-BC, RD; Deborah Kirk Walker, DNP, FNP-BC, NP-C, AOCN; Sigrid Ladores, PhD, PNP; and Karen Meneses, PhD, RN, FAAN

About 68% of invasive cervical cancer cases diagnosed in the United States involve women of childbearing age. Current treatment options for young patients with cervical cancer may cause hormonal and/or structural modifications to the reproductive system that could compromise pregnancy potential. Although clinical guidelines are available to help preserve fertility in these patients, gaps in practice remain, suggesting that the fertility-sparing needs of cervical cancer survivors are not routinely met. The authors provide nurse practitioners with current evidence about fertility-sparing treatments and with counseling considerations for young cervical cancer survivors.

Key words: cervical cancer survivor, fertility-sparing treatment, pregnancy, infertility, conization, trachelectomy

Cervical cancer was once the leading cause of gynecologic cancer in the United States. Following introduction of the use of the Pap smear in the 1940s, the incidence of cervical cancer has declined dramatically.<sup.1 Because use of the Pap smear is so effective and so widespread, the diagnosis of cervical cancer, when it is found, is usually made when a woman is younger (and still fertile) and when the disease is at an earlier stage (and therefore more easily treated).

In 2014, the American Cancer Society projected that 12,360 new cases of cervical cancer would be diagnosed in the U.S.2 Approximately 68% of cervical cancer cases are diagnosed in women of childbearing age.3,4 For young women, a diagnosis of cervical cancer once meant a hysterectomy and loss of the ability to bear a child. Today, fertility-sparing treatment (FST) options exist for women with early-stage cervical cancer, as well as more advanced fertility preservation and assisted reproductive technology (ART) approaches for those who are not candidates for FST.5

Young cervical cancer survivors may not know about FST options, and thus fear that treatment for cancer may compromise their future ability to conceive.6 Survivors also tend to be anxious about pregnancy outcomes after completing cancer treatment.7,8 Evidence suggests that they will want to discuss future fertility options with their healthcare provider (HCP).9 The American Society of Clinical Oncology (ASCO) and the American Society of Reproductive Medicine have published guidelines recommending that, prior to treatment, HCPs educate patients diagnosed with cervical cancer about the treatment’s potential effects on their fertility, along with fertility-preservation options.10,11 However, many HCPs are uninformed themselves and do not routinely offer fertility-preservation counseling prior to cancer treatment.12,13 The purpose of this article is to provide HCPs with current evidence about FST for cervical cancer and with counseling recommendations for young cervical cancer survivors.

Diagnosis and staging of cervical cancer

A Pap smear is used to screen for cervical cancer but not to make the diagnosis. A histology report from a cervical biopsy confirms the diagnosis and type of cervical cancer. After diagnosis, a workup is done to determine disease stage (Table 1).5

A clinical staging system is used for cervical cancer (rather than the surgical criteria used for most other gynecologic cancers). Two different staging systems are available. The International Federation of Gynecology and Obstetricsn (FIGO) staging system is based on a physical examination, diagnostic procedures, and imaging studies. Stages IA1, IA2, and IB1 are con­sidered early stages of cervical cancer.5,14 In stages IA1 and IA2, cancer is confined to the cervix and diagnosed only microscopically. Stage IB1 describes cancer confined to the cervix with a clinically visible tumor ?4 cm, stromal invasion that further describe tissue involvement (Table 2).5,15,16

Fertility-sparing cervical cancer treatment

The National Comprehensive Cancer Network (NCCN) recommends cone biopsy or radical trachelectomy for treatment for up to cervical cancer stage IB1 in women who want to preserve their fertility.5 This recommendation has not always existed; trends in surgical management of low-risk early-stage lesions have changed over the past 20 years. Hysterectomy was the only cure for cervical cancer stage IB1 until Dargent developed the fertility-sparing radical vaginal trachelectomy (RVT) technique in 1994.,sup>17 Prior to RVT, women with stage IA1 or IA2 lesions were the only cervical cancer survivors able to preserve their fertility.15

Cone biopsy

This term refers to a wedge-shaped excision of cervical tissue for both diagnostic evaluation and removal of abnormal tissue. Two methods of obtaining a cone biopsy with fertility sparing in mind are cold knife conization (CKC) and the loop electrosurgical excision procedure (LEEP). Cone biopsy is used to treat small lesions when there is no risk of dissecting across a gross neoplasm.5 Given that adequate margins and correct orientation are obtained, CKC and LEEP are appropriate measures for cervical cancer stage IA1 without lymphovascular space invasion.5 Negligible risks exist for cervical cancer stage IA1 recurrence following this treatment.5

Potential risks regarding future fertility following a cone biopsy include cervical stenosis and preterm delivery.18,19 Cervical stenosis occurs in 2%-3% of patients after CKC and in 3%-4% post-LEEP.19 Because of scar tissue formation that can occur after a cone biopsy, fertility may be compromised until the tissue is removed from the cervix. Long and Leeman19 reported that a history of a cone biopsy increased the odds of a preterm delivery by 2.19 (95% confidence interval, 1.93-2.49); risk correlated with the depth of the transformation zone removed. In this study, a greater risk existed for preterm delivery when a cone biopsy sample was thicker than 1.2 cm and larger than 6 cm2. However, Bevis and Biggio18 reported that evidence for the effects of conization procedures on fertility was conflicting because of the different types of procedures performed and the varying quality of control groups.

Fanfani et al20 performed a multicenter retrospective analysis of reproductive outcomes in 23 early-stage cervical cancer survivors who had undergone coni­zation treatment. Among 10 patients who tried to conceive, 6 achieved a spontaneous pregnancy and 4 received conception assistance via in vitro fertilization and embryo transfer (1 of whom achieved a pregnancy). In total, 70% of the young survivors achieved a pregnancy after cone biopsy treatment.

Trachelectomy

This fertility-sparing surgical procedure is performed to eradicate cervical cancer. In an RVT, the uterine corpus, ovaries, and Fallopian tubes are preserved, but the cervix, upper portion of the vagina, and the supporting ligaments are removed. A cerclage is placed at the location of the isthmus to close the opening of the uterus.7 RVT is an option for patients with stage IA2 or IB1 lesions 2 cm and ?4 cm, and provides a larger resection of the parametria.5

Most women who undergo RVT are able to conceive spontaneously, but a small number will require conception assistance.21 The 5-year cumulative pregnancy rate for women trying to conceive post-RVT is 52.8%; the cervical cancer recurrence rate after the procedure continues to be low.7 Potential risks of either trachelectomy procedure with regard to future fertility include miscarriage, preterm delivery, anovulation, and isthmic stenosis.7,21

Koh et al5 reported that, worldwide, more than 300 pregnancies have been confirmed following a trachelectomy for cervical cancer. Risk for second trimester miscarriage following a trachelectomy is 10%. However, 72% of women have carried a pregnancy to term. Park et al22 conducted a retrospective chart review of 55 young early-stage cervical cancer survivors who underwent laparoscopic abdominal trachelectomy. Ten of 18 patients attempting a pregnancy conceived; 6 of the 10 experienced preterm delivery. Overall, 55.6% of the survivors achieved a pregnancy, with 60% delivering preterm.

Fertility preservation procedures

Most women with cervical cancer at stage IB2 or greater are not candidates for FST. Radiation therapy is most often used for patients with higher stage IB disease, often called bulky disease. Radiation therapy is also used following a primary radical hysterectomy or in conjunction with chemotherapy in advanced disease. Radiation that includes the ovaries can damage oocyte quality and sex hormone production. Chemotherapy is not used in patients with milder forms of cervical cancer who are considering FST options.

Women planning to undergo radiation still have fertility preservation options, including the ART procedures of oocyte or embryo cryopreservation prior to cancer treatment.23 Cryopreservation of unfertilized oocytes, as opposed to embryos, may be considered for patients who do not have a male partner, do not wish to use donor sperm, or have religious or ethical reasons for avoiding embryo freezing. Because oocytes are highly sensitive to radiation injury, a procedure called ooph­oropexy (ovarian transposition) may be used. With ooph­oropexy, ovaries are sutured to the posterior uterus to protect them during pelvic radiation.

Before or after cancer treatment, survivors may benefit from ovarian stimulation medications that help promote follicular development. However, guidelines from both the American Congress of Obstetricians and Gynecologists and ASCO indicate insufficient evidence regarding the effectiveness of gonadotropin-releasing hormone analogs to suppress and protect ovarian function during cytotoxic treatment.24

Counseling before treatment

These counseling recommendations concerning fertility preservation were issued by ASCO: (1) Assume that patients with cancer want to discuss fertility preservation; address the possibility of infertility before cancer treatment starts and work with an interdisciplinary team to formulate a plan and make appropriate referrals; (2) Present oocyte and embryo cryopreservation as established fertility preservation methods; (3) Discuss the option of ooph­oropexy when pelvic radiation will be performed; (4) Inform patients of their individual risk for infertility, based on disease stage and treatment, as high, medium, low, or nonexistent; and (5) Inform patients about the use of conservative gynecologic surgery and radiation options.11

Several organizations and advocacy groups are available for young cervical cancer survivors with fertility concerns both before and after treatment (Table 3). ASCO created a video that can educate young patients about fertility preservation options and support networks.

Counseling after treatment

A woman who has undergone FST for cervical cancer faces many challenges. She may experience distress, depression, anxiety, and/or fear, and, depending on her own innate coping ability and her support system, may require psychological assessment and referral. HCPs can evaluate patients for these psychological reactions with tools such as the Functional Assessment of Cancer Therapy-Cervical Cancer Subscale and the NCCN Distress Thermometer for Patients, and make referrals as needed.

Cervical cancer and its treatment can adversely affect sexual health, causing problems such as decreased libido, fatigue, vaginal stenosis, and dyspareunia (Table 4).25-27 Many women hesitate to mention sexual problems on their own, so HCPs need to inquire about them and make referrals to a counselor who specializes in sex therapy, a gynecologist, or a physical therapist who specializes in pelvic pain and sexual dysfunction.* Many of the physical and psychological complaints involving sexual function resolve with-in the first year after treatment but may last up to 2 years or long­er.25,26

With regard to dyspareunia in particular, asking patients whether they experience it is the first step in helping resolve the problem. Nonpharmacologic and pharmacologic treatments, along with alternate positioning during intercourse, can be offered. HCPs can recommend over-the-counter vaginal moisturizers and lubricants to assist with vaginal dryness, dyspareunia, and sexual stimulation. In addition, prescription-strength topical lidocaine, estradiol vaginal cream, or ospemifene may help.

Undergoing ART can be arduous for women who endure painful and costly treatments. As of 2008, only 15 states have mandates that require health insurance carriers to provide full or partial coverage of costs related to infertility treatments.28 Most couples or individual women pay for infertility treatments out of pocket. Each ART cycle requires a woman to invest her body, mind, time, and money to realize her dream of motherhood, and she may be placing herself at risk for developing anxiety and depression.29-31

Even if a woman succeeds in achieving pregnancy through ART, the process is often fraught with anxiety.32,33 Young female cancer survivors have reported that they have a hopeful yet worried outlook on fertility and motherhood.34 This worry is especially true for cervical cancer survivors who have had trachelectomy surgery, as reported by Lloyd et al,7 wherein several participants described how they were fearful during pregnancy and attempted to be “model” pregnant women who followed every recommendation to reduce risks associated with preterm labor and miscarriage.

Consultations with specialists in reproductive endocrinology and/or high-risk obstetrics may be helpful. Pregnancy loss after infertility treatment can be devastating to these women, who view their pregnancy as “precious” and a “miracle,” and can have a profound impact on their psychological well-being.7 HCPs should prompt­ly refer these cancer survivors to mental health counselors who specialize in infertility and pregnancy loss.

Conclusion

Sixty-eight percent of cervical cancer cases diagnosed in the U.S. involve reproductive-aged women.2 Many of these women desire future pregnancies and want to discuss treatment options and future fertility. An interdisciplinary care approach for these women is necessary, with an emphasis placed on both successful cancer treatment and fertility preservation. FST options are available for women with early-stage cancer up to IB1. Fertility preservation procedures are available for women who are not candidates for FST. National guidelines are available regarding treatment and counseling for reproductive-age women with cervical cancer. The role of HCPs such as women’s health nurse practitioners is to educate young cervical cancer patients and survivors about their treatment options, manage pre- and post-treatment care, and provide referrals to specialists as needed.

Aimee Chism Holland is Assistant Professor, Coordinator of the Dual Adult/Gerontology Primary Care and Women’s Health Nurse Practitioner Specialty Track; Deborah Kirk Walker is Assistant Professor; Sigrid Ladores is Assistant Professor; and Karen Meneses is Professor and Associate Dean for Research, all at the School of Nursing at The University of Alabama at Birmingham. The authors state that they do not have a financial interest in or other relationship with any commercial product named in this article.

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*Editor’s Note: In the current issue of Women’s Healthcare: A Clinical Journal for NPs, Tammy M. DeBevoise, PT, DPT; Angela F. Dobinsky, PT, DPT; Caitlin B. McCurdy-Robinson, PT, DPT; Christina M. McGee, PT, DPT, ATC, LAT; Cody E. McNeely, PT, DPT; Sara K. Sauder, PT, DPT; and Kimberlee D. Sullivan, PT, DPT, WCS, BCB-PMD present a feature-length article on pelvic floor physical therapy.