0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Viewpoint |

Pregnancy in the Time of Zika Addressing Barriers for Developing Vaccines and Other Measures for Pregnant Women FREE

Saad B. Omer, MBBS, MPH, PhD1; Richard H. Beigi, MD, MSc2
[+] Author Affiliations
1Departments of Global Health, Epidemiology, and Pediatrics, Emory University, Atlanta, Georgia
2Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women’s Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
JAMA. 2016;315(12):1227-1228. doi:10.1001/jama.2016.2237.
Text Size: A A A
Published online

Three recent infectious disease outbreaks of global importance—H1N1 influenza, Ebola, and now Zika—have had specific implications for pregnant women. For the H1N1 pandemic, pregnant women and their infants were high-risk groups for severe complications and death. During the Ebola outbreak, there were concerns about worse outcomes among pregnant women and specific concerns regarding vertical transmission of infection to newborns. The current Zika outbreak, with its ostensible association with microcephaly, has direct and highly concerning implications for pregnant women and women of reproductive age.

Yet the global public health community again lacks the optimal tools for dealing with a disease that has specific and important implications for pregnant women. There are substantial knowledge gaps in current understanding of Zika, irrespective of the affected population. However, Zika’s association with adverse fetal outcomes requires that pregnant women be a priority group for developing and evaluating vaccines and other measures. There are several current scientific and structural barriers to developing vaccines for pregnant women. These barriers challenge the ability to prepare and respond to epidemics and are particularly highlighted during a public health emergency that has pregnant women and their unborn fetuses as the primary affected population.

One barrier is a lack of a broadly accepted ethical framework for guiding clinical research during pregnancy. For example, the term minimal risk1—a concept that informs ethical review of research—is not well defined for research in pregnancy. Therefore, institutional review boards (IRBs) often resort to categorizing most intervention research in pregnancy as high risk, often without a balanced consideration of the risks of not performing the research. Moreover, the risks and benefits to the fetus also need to be considered along with risks and benefits to the mother, adding to the challenge. This lack of a broadly accepted ethical framework has a chilling effect on both academic and industry-led clinical research in pregnancy.2,3 Therefore, there is a need for development and articulation of a pregnancy-specific ethical framework that can offer guidance to investigators and IRBs.

Pregnancy is a physiologically dynamic state. The immune profile of a pregnant woman is responsive to the changing levels of sex hormones and evolves through the course of pregnancy.4 However, most of the current knowledge base for vaccine response is derived from observational studies conducted in the latter part of pregnancy, with limited data available from the first and early second trimester or from randomized clinical trials. On the other hand, clinical, practical, and public health considerations require that vaccine use not be restricted to women with advanced gestational age. Given that a substantial portion of Zika’s teratogenic effects may occur in the earlier phase of pregnancy, administration of any forthcoming Zika vaccine will be most beneficial prior to or during the early parts of pregnancy. The knowledge gap for early pregnancy vaccine responses and safety will make the task of developing and recommending an effective Zika vaccine for use across pregnancy challenging.

Until recently, the pregnancy and lactation sections of US Food and Drug Administration (FDA)-approved labels for vaccines and pharmaceuticals contained ambiguous information with limited clinical utility. For example, the labels were required to contain determination of letter risk categories (A, B, C, D, or X) for pregnancy. These categories were an attempt to summarily convey risk of reproductive and developmental adverse effects. However, the categories were somewhat simplistic and challenging to translate into practice in a clinically meaningful manner.

After years of deliberations, revisions, and public comment, FDA recently issued the Pregnancy and Lactation Labeling Rule (PLLR).5 This rule will enable inclusion of clinically relevant and interpretable information in drug and vaccine labels and creates a consistent format for communicating information on risks as well as benefits relevant to pregnant and lactating women and for males and females of reproductive potential. Moreover, the new rule allows for incorporating information about risk and benefits from a variety of sources, including non–industry-sponsored epidemiological and interventional studies. Although the release of the PLLR is important and holds promise to provide more clinically useful information, its implementation faces many logistical challenges. For example, there is a need for a “mock label” (ie, a sample label providing examples of information to be included in the sections relevant to pregnancy and lactation) to provide guidance for inclusion and format of pregnancy-related information in sections relevant to pregnant women.

General understanding of the new categorization system is insufficient among clinicians who provide obstetrical care. Therefore, it will take concerted efforts to phase in this categorization. Having clarity regarding vaccine (and drug) labeling related to pregnancy will help ensure that clinicians have a higher level of confidence in pregnancy-related vaccines and could provide a road map for conducting research that can inform labeling and hence clinical decisions.

Robust safety evaluation is a cornerstone of any vaccine development and deployment program. There has been an increase in the number of studies evaluating the safety of currently recommended maternal vaccines, such as influenza and pertussis vaccines.6 Despite increased attention on the evaluation of safety of immunization in pregnancy, barriers remain. For example, a review commissioned by the World Health Organization highlighted the lack of standard definitions of outcomes, and standards for measurement of these outcomes, relevant to evaluation of vaccines in pregnancy.7 This lack of standardization poses a challenge for conduct of clinical trials, generalizability of safety data, and merging of large safety data sets. This last point is critical because large multilocation data sets could optimize the evaluation of rare but clinically important outcomes, such as microcephaly.

Moreover, safety assessment for pharmaceutical interventions against emerging public health threats requires real-time assessment of risk vs benefit. Baseline outcome rates are an essential input for such an assessment. The value of baseline rates was recognized during the H1N1 pandemic.8 Since then, there has been little progress in ascertaining baseline rates in different geographic locations of outcomes such as first trimester miscarriages. Ascertainment of baseline rates of outcomes is even more important when a disease emerges in the context of other infections (eg, malaria) that are associated with adverse birth outcomes.

Drug and vaccine development and evaluation in children may provide some context for the current outbreak response. Pediatricians and child health researchers recognized many parallel challenges in the amount and quality of data available for the care of children. The term therapeutic orphans was coined for children, stressing the concept of the lack of information available to prevent and treat disease in children. To address these challenges, efforts were mobilized around the conceptualization and passing of legislation (Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act). These efforts have contributed to improving the quantity and quality of research that has been conducted in children.9 A similar approach may also be relevant to fostering research in pregnancy.

Pregnant women have been a high-risk group requiring special consideration for several recent global public health emergencies. Currently, pregnant women and their unborn children are the focal point of the Zika outbreak. Although there are several barriers for developing vaccines and other measures for pregnant women, these barriers are surmountable with concerted efforts and leadership. Strategic planning and action have allowed for advances in pediatric drug development and provide a good model. However, the time to act is now, before the next epidemic takes its toll.

ARTICLE INFORMATION

Corresponding Author: Saad B. Omer, MBBS, MPH, PhD, 1518 Clifton Rd NE, Room 7017 (CNR Bldg), Atlanta, GA 30322 (somer@emory.edu).

Published Online: February 24, 2016. doi:10.1001/jama.2016.2237.

Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Beigi reported having received research funding from Novavax and Novartis Vaccines for maternal immunization research. No other disclosures were reported.

REFERENCES

Shah  S, Whittle  A, Wilfond  B, Gensler  G, Wendler  D.  How do institutional review boards apply the federal risk and benefit standards for pediatric research? JAMA. 2004;291(4):476-482.
PubMed   |  Link to Article
Trannoy  E.  Will ethical and liability issues and public acceptance allow maternal immunization? Vaccine. 1998;16(14-15):1482-1485.
PubMed   |  Link to Article
Paradiso  PR.  Maternal immunization: the influence of liability issues on vaccine development. Vaccine. 2001;20(suppl 1):S73-S74.
PubMed   |  Link to Article
Kourtis  AP, Read  JS, Jamieson  DJ.  Pregnancy and infection. N Engl J Med. 2014;370(23):2211-2218.
PubMed   |  Link to Article
Gruber  MF.  The US FDA pregnancy, lactation, and labeling rule: implications for maternal immunization. Vaccine. 2015;33(47):6499-6500.
PubMed   |  Link to Article
Jackson  LA, Campbell  JD, Frey  SE,  et al.  Effect of varying doses of a monovalent H7N9 influenza vaccine with and without AS03 and MF59 adjuvants on immune response: a randomized clinical trial. JAMA. 2015;314(3):237-246.
PubMed   |  Link to Article
Fulton  TR, Narayanan  D, Bonhoeffer  J, Ortiz  JR, Lambach  P, Omer  SB.  A systematic review of adverse events following immunization during pregnancy and the newborn period. Vaccine. 2015;33(47):6453-6465.
PubMed   |  Link to Article
Black  S, Eskola  J, Siegrist  CA,  et al.  Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines. Lancet. 2009;374(9707):2115-2122.
PubMed   |  Link to Article
Ren  Z, Zajicek  A.  Review of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act: what can the obstetric community learn from the pediatric experience? Semin Perinatol. 2015;39(7):530-531.
PubMed   |  Link to Article

Figures

Tables

References

Shah  S, Whittle  A, Wilfond  B, Gensler  G, Wendler  D.  How do institutional review boards apply the federal risk and benefit standards for pediatric research? JAMA. 2004;291(4):476-482.
PubMed   |  Link to Article
Trannoy  E.  Will ethical and liability issues and public acceptance allow maternal immunization? Vaccine. 1998;16(14-15):1482-1485.
PubMed   |  Link to Article
Paradiso  PR.  Maternal immunization: the influence of liability issues on vaccine development. Vaccine. 2001;20(suppl 1):S73-S74.
PubMed   |  Link to Article
Kourtis  AP, Read  JS, Jamieson  DJ.  Pregnancy and infection. N Engl J Med. 2014;370(23):2211-2218.
PubMed   |  Link to Article
Gruber  MF.  The US FDA pregnancy, lactation, and labeling rule: implications for maternal immunization. Vaccine. 2015;33(47):6499-6500.
PubMed   |  Link to Article
Jackson  LA, Campbell  JD, Frey  SE,  et al.  Effect of varying doses of a monovalent H7N9 influenza vaccine with and without AS03 and MF59 adjuvants on immune response: a randomized clinical trial. JAMA. 2015;314(3):237-246.
PubMed   |  Link to Article
Fulton  TR, Narayanan  D, Bonhoeffer  J, Ortiz  JR, Lambach  P, Omer  SB.  A systematic review of adverse events following immunization during pregnancy and the newborn period. Vaccine. 2015;33(47):6453-6465.
PubMed   |  Link to Article
Black  S, Eskola  J, Siegrist  CA,  et al.  Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines. Lancet. 2009;374(9707):2115-2122.
PubMed   |  Link to Article
Ren  Z, Zajicek  A.  Review of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act: what can the obstetric community learn from the pediatric experience? Semin Perinatol. 2015;39(7):530-531.
PubMed   |  Link to Article
CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

15,786 Views
1 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
Jobs
JAMAevidence.com

The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
Detecting the Likelihood of Pregnancy

The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
Original Article: Is This Patient Pregnant?