Postapproval 
Pregnancy Safety 
Studies 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Denise Johnson-Lyles at 301-796-
6169 or (CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 
240-402-8010.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2019 
Clinical/Medical 
48826dft.docx 
04/30/19   
Postapproval 
Pregnancy Safety 
Studies 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, rm. 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2019 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  PHARMACOVIGILANCE  CASE REPORTS AND CASE SERIES .................... 4 
IV.  PREGNANCY REGISTRIES.......................................................................................... 5 
A.  Overview ......................................................................................................................................... 5 
B.  Registry Design Considerations .................................................................................................... 6 
1. Objectives ......................................................................................................................................... 7 
2. Study Population for Inclusion ........................................................................................................ 7 
3. Outcome Definition(s) and Ascertainment ....................................................................................... 7 
4. Sample Size and Statistical Power ................................................................................................... 8 
5. Safety Evaluation When a Pregnancy Registry Is Not Feasible ...................................................... 8 
6. Comparator Selection  Reference Group(s) ................................................................................. 9 
7. Exposure Definition and Ascertainment .......................................................................................... 9 
8. Covariates  Potential Confounders .............................................................................................. 9 
9. Data Collection .............................................................................................................................. 10 
10.  Data Analysis and Presentation ................................................................................................ 10 
11.  Privacy and Human Subject Protection Issues ......................................................................... 11 
12.  Independent Data Monitoring Committee/Scientific Advisory Board ....................................... 11 
13.  Recruitment and Retention Plans .............................................................................................. 11 
a.  Recruitment ............................................................................................................................. 12 
b.  Retention ................................................................................................................................. 13 
14.  Multiproduct Pregnancy Registries ........................................................................................... 14 
15.  Pregnancy Registry Discontinuation ......................................................................................... 14 
16.  Lactation Study Added on to a Pregnancy Registry .................................................................. 14 
V.  COMPLEMENTARY STUDIES .................................................................................. 15 
A.  Electronic Data Sources .............................................................................................................. 15 
1. Methods to Identify Pregnancies ................................................................................................... 16 
2. Estimates of Conception and Gestational Age ............................................................................... 16 
3. Linkages to Offspring ..................................................................................................................... 17 
4. Study Outcome Ascertainment and Validation .............................................................................. 17 
B.  Population-Based Surveillance and National Registries or Registers ..................................... 18 
C.  Population-Based Case Control Studies .................................................................................... 19 
1. Selection of Pregnancy-Related Cases and Controls .................................................................... 19 
2. Exposure Assessment ..................................................................................................................... 20 
3. Examples of Pregnancy Case-Control Studies in the United States .............................................. 20 
REFERENCES ............................................................................................................................ 22 
APPENDIX A:  LIST OF DATA COLLECTION ELEMENTS ........................................... 26 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Postapproval Pregnancy Safety Studies 
2  Guidance for Industry1 
3   
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person 
9  and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the 
10  requirements of the applicable statutes and regulations.  To discuss an alternative approach, 
11  contact the FDA staff responsible for this guidance as listed on the title page. 
12   
13   
14   
15   
16  I.  INTRODUCTION  
17   
18  The purpose of this guidance is to provide sponsors2 and investigators with recommendations on 
19  how to design investigations to assess the outcomes of pregnancies in women exposed to drugs 
20  and biological products regulated by FDA (i.e., pregnancy safety studies).  The goal of 
21  postapproval pregnancy safety studies is to provide clinically relevant human safety data that can 
22  inform health care providers treating or counseling patients who are pregnant or anticipating 
23  pregnancy about the safety of drugs and biological products through inclusion of the information 
24  in a products labeling.   
25   
26  In the years since FDA issued guidance on this topic, pregnancy safety studies required by FDA 
27  have expanded beyond those using data from pregnancy exposure registries (pregnancy 
28  registries)3 to also include other types of epidemiologic studies and pregnancy surveillance 
29  programs.  This guidance should be used in conjunction with other epidemiological literature on 
30  the design, conduct, and interpretation of observational studies.  The development of pregnancy 
31  safety studies requires specialized knowledge in a variety of areas, including expertise in the 
32  fields of epidemiology, clinical teratology, obstetrics, pediatrics, clinical genetics, and statistics 
33  when designing a study.4 
34   
                                                 
1 This guidance has been prepared by the Postapproval Pregnancy Safety Studies working group in the Center for 
Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research and the Office 
of Womens Health in the Office of the Commissioner at the Food and Drug Administration.  
 
2 For the purposes of this guidance, sponsors refer to persons or entities that conduct or fund studies for approved 
products. 
 
3 A pregnancy registry collects data that are then analyzed to address a safety question.  For the purposes of this 
guidance, pregnancy registry refers to both the data collection and the study that uses the data. 
 
4 The previous guidance for industry Establishing Pregnancy Exposure Registries published August 23, 2002, has 
been withdrawn. 
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35  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
36  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
37  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
38  the word should in Agency guidances means that something is suggested or recommended, but 
39  not required.  
40   
41   
42  II.  BACKGROUND 
43   
44  Pregnant women represent an important segment of the population, with over 6 million 
45  pregnancies occurring per year, based on national vital statistics (Curtin et al. 2015).  Pregnant 
46  women may have chronic conditions, such as diabetes, seizure disorders, or asthma, that need to 
47  be treated during pregnancy, or pregnant women may develop acute or serious medical 
48  conditions during pregnancy that require treatment.  In addition, nearly half of all pregnancies in 
49  the United States may be unintended, which could result in potential inadvertent exposure to 
50  drugs and biological products in pregnancy if a woman is exposed to a drug when she is not 
51  aware she is pregnant (Finer 2016).  Therefore, there is an important need for safety information 
52  on product exposure during pregnancy.   
53   
54  During clinical development of most drugs and biological products, pregnant women are actively 
55  excluded from trials, and if pregnancy does occur during a trial, the usual procedure is to 
56  discontinue treatment and monitor the women to assess pregnancy outcomes.  Consequently, at 
57  the time of a drug or biological products initial marketing, except for drugs and biological 
58  products developed to treat conditions unique to pregnancy, there are no or limited human data to 
59  inform the safety of a drug or biological product taken during pregnancy.   
60   
61  Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 
62  355(o)(3)), added by section 901 of the Food and Drug Administration Amendments Act of 2007 
63  authorizes FDA to require certain postmarketing studies or clinical trials for prescription drugs 
64  approved under section 505(b) of the FD&C Act and biological products approved under section 
65  351 of the Public Health Service Act (42 U.S.C. 262).  Under section 505(o)(3), FDA can require 
66  such studies or trials at the time of approval to assess a known serious risk related to the use of 
67  the drug, to assess a signal of serious risk related to the use of the drug, or to identify an 
68  unexpected serious risk when available data indicates the potential for a serious risk.  Under 
69  section 505(o)(3), FDA can also require such studies or trials after approval if FDA becomes 
70  aware of new safety information.5  Postapproval studies using data collected in pregnancy 
71  registries may be required to assess potential serious risks to the pregnancy that may affect the 
72  health of the fetus or the woman due to drug or biological product use during pregnancy.6  
73  However, gaps in safety data in pregnant women still exist.  
                                                 
5 Defined at section 505-1(b)(3) of the FD&C Act. Also see the guidance for industry Postmarketing Studies and 
Clinical Trials  Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (April 2011).  
We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
6 See the guidance for industry Postmarketing Studies and Clinical Trials  Implementation of Section 505(o)(3) of 
the Federal Food, Drug, and Cosmetic Act.   
 
 
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74   
75  FDA held a 2-day public meeting in 2014 where stakeholders, including birth defect experts 
76  from academia, industry, professional organizations, and patient groups, discussed the conduct of 
77  pregnancy registries and epidemiologic studies using different study designs.7  In addition, FDA 
78  conducted reviews of pregnancy registries listed on the FDAs Office of Womens Health web 
79  page (Gelperin et al. 2017).  Based on FDA reviews and the 2014 public meeting, FDA 
80  understands that pregnancy registry data have contributed to labeling changes and clinical 
81  guidelines, but their potential has not been fully realized, often because of feasibility issues.   
82   
83  Pregnancy registries remain an important tool for safety data collection in the postmarketing 
84  setting because of the prospective design and the ability to collect detailed patient level data.  
85  However, because of the recurring challenges of achieving sufficient enrollment, pregnancy 
86  registries generally are not sufficient by themselves to assess the safety of products during 
87  pregnancy; therefore, other study methods capable of appropriately assessing the occurrence of 
88  specific major congenital malformations (MCMs) (e.g., birth defects and congenital anomalies)8 
89  and other pregnancy outcomes are needed.  In addition, use of complementary approaches may 
90  help address the limitations inherent to a specific study design and provide greater confidence in 
91  the conclusions.  Input received from the 2014 public meeting and findings from FDA reviews 
92  were used to develop this guidance.  
93   
94  The following sections describe three general approaches (pharmacovigilance, pregnancy 
95  registries, and complementary data sources) that can be used in the postmarket setting to evaluate 
96  drug or biological product safety during pregnancy.  These approaches are not intended to imply 
97  a hierarchy of evidence from the different study methods.  Rather, each approach may uniquely 
98  contribute to the overall safety assessment of a product during pregnancy.  When considering 
99  postmarketing approaches, the selection of any one or combination of these assessments and 
100  timing of initiation may vary by drug or biological product.  Consideration can be given to 
101  experience with similar drugs and biological products, knowledge of the underlying disease and 
102  its risks (maternal and fetal), potential use of the drug or biological product in females of 
103  reproductive potential and pregnant women, existing knowledge of a safety concern, and the 
104  potential for capturing the same pregnancy in two different assessments (double counting).  
105  Moreover, evaluation of the strengths and limitations inherent to each type of assessment allows 
106  FDA to recommend or require the appropriate method of postapproval risk assessment.9   
107   
                                                 
7 See transcripts from the FDA public meeting Study Approaches and Methods to Evaluate the Safety of Drugs and 
Biological Products During Pregnancy in the Post-Approval Setting, May 28-29, 2014, at 
https://www.fda.gov/Drugs/NewsEvents/ucm386560.htm.  
 
8 For the purposes of this guidance, the following terms are used interchangeably:  congenital malformations, 
congenital anomalies, and birth defects, and are referred to as MCM throughout this guidance. 
 
9 The authority to require a responsible person to conduct a postapproval study or studies or clinical trial(s) of a drug 
under section 505(o)(3) includes the authority for FDA to set parameters for the study or trial to be conducted, 
including how the study or trial is to be done and the population and indication.  In other words, under section 
505(o)(3), we can require a study or clinical trial that is well designed and adequate to address the serious safety 
concern.  Our current thinking on this and other matters is set forth in the guidance for industry Postmarketing 
Studies and Clinical Trials  Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act.   
 
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108   
109  III.  PHARMACOVIGILANCE  CASE REPORTS AND CASE SERIES 
110   
111  Good pharmacovigilance practice involves the collection of comprehensive data on adverse 
112  pregnancy outcomes to detect safety signals and develop a case series for analysis.  Sources can 
113  include spontaneous reports submitted to the sponsor and FDA, as well as case reports from the 
114  medical literature or clinical studies.  Well-documented and informative case reports can be used 
115  to identify a signal, particularly if the pregnancy outcome is rare in the absence of drug exposure.  
116  Safety signals generally indicate the need for further investigation, which may or may not lead to 
117  the conclusion that the product caused the outcome or increased the risk of the outcome.  The 
118  importance of astute clinicians and clinical judgment in identifying a distinctive and unique 
119  pattern of congenital malformations associated with a particular pregnancy exposure has been 
120  critical in identifying teratogens (Shepard 1994; Obican and Scialli 2011).  The quality of the 
121  reports is critical for appropriate evaluation of the potential relationship between the product and 
122  adverse outcomes.  FDA recommends that sponsors make a reasonable effort to obtain complete 
123  information for case assessment during initial contacts and subsequent follow-up.   
124   
125  Case reports are the most common source of reports of adverse pregnancy outcomes but can 
126  often be challenging to interpret because information is often incomplete or there are additional 
127  risk factors for the adverse pregnancy outcome, which case reports may not address.  In addition, 
128  one needs to consider the background rates of adverse pregnancy outcomes.  Good case reports 
129  include numerous important elements for conducting adequate pharmacovigilance.  Specific 
130  critical factors in evaluating the effects of product exposure in human pregnancies may include, 
131  but are not limited to, the following:10 
132   
133    A detailed description of the adverse pregnancy outcome 
134   
135    A detailed description of the exposure including the specific medication, the dose, 
136  frequency, route of administration, and duration 
137   
138    The timing of the exposure in relation to the gestational age 
139   
140    The maternal age, medical and pregnancy history, and use of concomitant medications, 
141  supplements, and other substances 
142   
143    Exposures to known or suspected environmental teratogens 
144   
145  FDA has occasionally considered case reports and case series to be adequate data sources for 
146  establishing a causal association for a human teratogenic exposure, such as with isotretinoin 
147  (Centers for Disease Control and Prevention (CDC) 1984; Rosa 1983), or a serious adverse 
148  event, such as oligohydramnios with trastuzumab (Zagouri et al. 2013).  In general, such 
149  evidence has been evaluated on a case-by-case basis.  Case reports have been most useful and 
150  influential in situations where the adverse pregnancy outcome rarely occurs as a background 
                                                 
10 See the guidance for industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment 
(March 2005).   
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151  event, and the adverse outcome is well-documented.  A suspected safety signal arising from case 
152  reports and case series that is not initially confirmed should be viewed as the start of an iterative 
153  process, and not necessarily conclusive evidence of absence of risk.  
154   
155  Known limitations of spontaneous postmarketing reports (such as under-reporting, lack of a 
156  denominator, and incomplete information) pose considerable challenges in analyzing cases and 
157  determining whether a causal relationship exists between a product exposure and an adverse 
158  pregnancy outcome.11  Thus, routine pharmacovigilance usually will be insufficient for a 
159  conclusive assessment regarding the potential risk of an exposure during pregnancy because of 
160  the inability to quantify risk.  Observational studies such as pregnancy registries and other 
161  pharmacoepidemiological studies usually are needed to provide additional information including 
162  a control group to derive and compare rates on safety outcomes of drugs and biological products 
163  used during pregnancy.  A sponsor should have a structured approach for pregnancy surveillance 
164  with targeted questionnaires to obtain follow-up information on all potentially exposed 
165  pregnancies of which the sponsor becomes aware, regardless of whether the pregnant woman 
166  chooses to enroll in a registry.  Pregnant women should be able to decline participation or 
167  additional follow-up at any time at their discretion. 
168   
169   
170  IV.  PREGNANCY REGISTRIES 
171   
172  A.  Overview 
173   
174  A pregnancy registry actively collects information on drug or biological product exposure during 
175  pregnancy and associated pregnancy outcomes, which can be used to conduct a prospective 
176  observational study (women are enrolled before the pregnancy outcome).  Pregnancy registries 
177  depend on the voluntary participation of women who have been exposed to a specific drug or 
178  biological product during pregnancy and unexposed women who enroll into the comparator 
179  cohort.  Pregnancy registry data are prospectively collected by maternal interview and medical 
180  record documentation and may include results of the clinical examination of the newborn.  
181  Because of the prospective design of pregnancy registries, they may support assessment of 
182  multiple maternal, obstetrical, fetal, and infant outcomes, including pregnancies that do not result 
183  in a live birth.  
184   
185  A pregnancy registry may be U.S.-based or international in its scope.  When submitting interim 
186  and final pregnancy registry study reports, sponsors should include cumulative analyses of 
187  worldwide pregnancy surveillance data to provide perspective on registry feasibility and updates 
188  on available safety data in pregnant women that may not be included in the registry.  
189    
190  Pregnancy registries have the following strengths:   
191   
192    By enrolling women exposed to the product of interest, pregnancy registries can be an 
193  efficient way to collect data on the effects of rare exposures during pregnancy. 
194   
                                                 
11 Ibid. 
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195    A pregnancy registry can be initiated and start to accrue real-time data as soon as a 
196  product becomes commercially available, in contrast to the use of claims data and 
197  electronic health records where there will be a lag time in data availability.  
198   
199    Prospective enrollment facilitates ascertainment of an exposure of interest close to the 
200  time it occurs and before information about the pregnancy outcome is known.   
201   
202    Pregnancy registries have the potential to obtain accurate information about whether 
203  exposure occurred and the timing of the exposure in relation to gestational age, dose, 
204  frequency, and duration of the exposure, as well as covariates, and may therefore reduce 
205  exposure misclassification, recall bias, and confounding.   
206   
207    A pregnancy registry can potentially collect data on a variety of pregnancy and infant 
208  outcomes, including postnatal outcomes.  
209   
210    A pregnancy registry can be designed to include data from physical examination of the 
211  newborn, and periodic clinical assessment of the offspring of exposed mothers, enabling 
212  access to detailed clinical information about outcomes of interest, without relying on 
213  International Classification of Diseases (ICD) codes.  
214   
215  Pregnancy registries have the following limitations:  
216   
217    Analyses of collected data may have minimal statistical power to detect associations for 
218  rare pregnancy outcomes.  
219   
220    Most pregnancy registries are designed primarily to collect data used to assess the overall 
221  risk of MCMs.  Effects on less common, specific MCMs may be missed for all but the 
222  most potent teratogens.    
223   
224    Patient recruitment and retention are often challenging, and identification of an 
225  appropriate comparator group may not always be feasible. 
226   
227    Data from pregnancy registries generally are not sufficient by themselves to assess the 
228  safety of products during pregnancy, and other study methods such as retrospective 
229  cohort studies or case control studies may be needed to corroborate registry findings.   
230   
231  The ability of a pregnancy registry to provide safety data that can be used to inform product 
232  labeling depends on factors such as the availability and quality of key clinical data and the 
233  number of patients enrolled into the registry.  Sponsors should address registry design 
234  considerations (discussed below) in a written protocol and statistical analysis plan that include 
235  considerations of study feasibility.   
236   
237  B.  Registry Design Considerations 
238   
239  A well-written protocol for a pregnancy registry should describe its objectives, which may range 
240  from open-ended safety surveillance to testing a specific hypothesis.  The following issues 
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241  should be addressed in the protocol to ensure consistency of data collection and analysis that will 
242  provide scientifically valid results.  
243   
244  1.  Objectives 
245   
246  The protocol should state the objectives of the registry for all study outcomes.  An effective 
247  pregnancy registry has the potential to serve as an early warning system to identify a previously 
248  unrecognized major teratogen soon after market introduction by identifying MCMs in infants of 
249  exposed mothers.  For less potent teratogens or for drugs and biological products that cause other 
250  adverse pregnancy outcomes, a pregnancy registry can function as a signal detection study and 
251  generate hypotheses that can be tested using other methods that may be better powered to assess 
252  specific birth defects or other abnormalities.   
253   
254  2.  Study Population for Inclusion  
255   
256  Ideally, women in the exposed and unexposed cohort should be enrolled in a pregnancy registry 
257  prospectively (i.e., before the conduct of any prenatal tests that could provide knowledge of the 
258  outcome of pregnancy).  If the condition of the fetus has already been assessed through prenatal 
259  testing (e.g., targeted ultrasound, amniocentesis), such reports traditionally have been considered 
260  retrospective.  However, because it may be difficult to obtain enrollment before prenatal testing 
261  on a consistent basis, the study population should include all women, including those who have 
262  had early prenatal testing, and the protocol should address how pregnancies with prenatal testing 
263  before enrollment will be evaluated in statistical analyses to avoid potential bias.  
264   
265  3.  Outcome Definition(s) and Ascertainment 
266   
267  A pregnancy can result in live birth, miscarriage (loss before 20 weeks), elective termination, or 
268  fetal death/stillbirth (loss after 20 weeks).  Within each of these categories the fetus or infant can 
269  be evaluated for the presence or absence of the primary outcome.  As part of the study design, 
270  the protocol should state a priori criteria for defining study outcomes.  Criteria for defining birth 
271  defects as major should be clearly stated.  For example, MCMs might be defined as 
272  abnormalities in structural development that are medically or cosmetically significant, are 
273  present at birth, and persist in postnatal life unless or until repaired.  Similarly, criteria should 
274  be established for abnormalities that will be excluded from the definition of outcome (e.g., those 
275  that are minor, transient, chromosomal abnormalities, genetic syndromes, positional defects, 
276  prematurity related) (Holmes and Westgate 2011).  A standardized classification system should 
277  be used, as appropriate.  An expert clinical geneticist or dysmorphologist should review and 
278  classify medical records and reports of all MCMs.  The clinical expert reviewer and method of 
279  assessment should be the same for both the exposed and comparator group(s) and the reviewer 
280  should be blinded to the exposure status. 
281   
282  Some examples of other outcomes that may be primary or secondary on a case-by-case basis 
283  include:  
284   
285    Measures of fetal growth deficiency (small for gestational age)  
286    Preterm delivery  
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287    Other pregnancy complications  
288    Developmental milestones or neurologic abnormalities in offspring of exposed mothers 
289    Abnormalities of immune system development in offspring of exposed mothers 
290   
291  4.  Sample Size and Statistical Power 
292   
293  A written protocol for a pregnancy registry should include a statistical analysis plan with a 
294  description of target sample size based on power calculations, and assessment of feasibility of 
295  the study in the patient population of interest.  When estimating the target sample size, it is 
296  important to take into consideration the expected background rate of pregnancy loss, and cases 
297  that may be lost to follow-up or otherwise unevaluable.  Estimated rates based on the general 
298  population may not apply to specific disease groups (e.g., diabetes).   
299   
300  Determination of an adequate sample size depends on the objective(s) and design of the registry 
301  and the background rate of the outcome in the study population.  If more than one pregnancy 
302  outcome is considered, sample size determination should be based on the outcome with the 
303  lowest background rate (e.g., MCMs).  Consideration should be given to the prevalence of the 
304  disease in females of reproductive potential and pregnant women and anticipated frequency of 
305  product exposure in pregnant women.  
306   
307  No known teratogen increases the risk of all MCMs.  Typically, a specific defect or pattern of 
308  defects is associated with a specific teratogenic exposure during a critical period.  Specific 
309  MCMs occur rarely in the general population (i.e., fewer than 1 in 1,000 live births).  
310  Historically, pregnancy registries have not had sufficient sample size or power to evaluate 
311  increased risks for specific MCMs unless the relative risks are large (Gelperin 2017; Bird et al. 
312  2018).  Therefore, most registries compare the overall proportion of the total combined number 
313  of various MCMs observed in the exposed group to the overall proportion in the comparator 
314  group(s).  Sponsors should include justification for the choice of expected background rates for 
315  outcomes of interest in their proposed sample size and power calculations.   
316   
317  5.  Safety Evaluation When a Pregnancy Registry Is Not Feasible 
318   
319  In some situations, a pregnancy registry may never have adequate power to allow statistical 
320  inference.  Achievement of an adequate sample size may not occur when the likelihood of 
321  exposure in pregnancy is low, or use of a product is not recommended during pregnancy.  
322  Anticipated issues with registry study feasibility should be stated in the protocol and 
323  appropriately addressed, for example by expanding the inclusion criteria to include all reports of 
324  exposed pregnancies (both prospective and retrospective).  For products that are anticipated to be 
325  used rarely during pregnancy (e.g., treatment of advanced cancer), sponsors can consider a 
326  pregnancy surveillance program (a structured approach for data collection with targeted 
327  questionnaires to obtain follow-up information on all exposed pregnancies of which sponsors 
328  become aware).  This type of case series of exposed pregnancies can inform clinical and 
329  regulatory decision-making.  Worldwide safety data collection is usually needed to identify a 
330  sufficient number of exposed pregnancies for clinical safety assessment. 
331   
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332  6.  Comparator Selection  Reference Group(s) 
333   
334  The strategy for selection of an appropriate comparison group(s) should be made when designing 
335  the pregnancy registry and should be included in the protocol.  Ideally, the registry should enroll 
336  a concurrent internal comparison group of pregnant women unexposed to the evaluated 
337  treatment.  In addition, patients with the same disease (and disease severity, if feasible) should be 
338  compared, because confounding due to the underlying condition may arise.  Cohorts exposed to 
339  different treatment regimens, when available, can serve as additional internal comparator groups 
340  when evaluating a specific drug or biological product used as one treatment in a multiproduct or 
341  disease-based registry study (for example, autoimmune diseases).   
342   
343  A background rate or the prevalence of congenital anomalies in a population-based surveillance 
344  system (e.g., Metropolitan Atlanta Congenital Defects Program (MACDP))12 or from another 
345  pregnancy registry may be the only available comparator in certain situations.  However, if 
346  background rates or information from the external population-based surveillance system are 
347  chosen as a comparison group, it is important to be aware of the limitations of whatever existing 
348  system is used so that appropriate analyses can be designed, and results interpreted correctly.  
349  For example, while MACDP prevalence data are well-documented and stable over time, they 
350  have several characteristics that limit their validity as a comparator group for a pregnancy 
351  registry.  Limitations include the small geographic region from which the data are drawn 
352  (metropolitan Atlanta); inclusion and exclusion criteria for outcomes of interest that differ from 
353  the registries (particularly with regard to chromosome abnormalities); and the duration of 
354  postnatal follow-up.  Importantly, because external comparators typically estimate risk in the 
355  general, mostly healthy, population, they may not be helpful to discern effects of the exposure of 
356  interest and the underlying disease of the pregnant woman undergoing treatment, such as 
357  diabetes or asthma.   
358   
359  When available and feasible, sponsors can consider use of external databases with data on 
360  background rates in the disease population of interest to ensure comparability of groups.  
361  Selection of an appropriate comparator is important because comparing dissimilar populations 
362  could bias the study results, indicate a risk when none exists, or mask an increased risk that 
363  exists.  When feasible, selection of multiple comparator groups may be informative.   
364   
365  7.  Exposure Definition and Ascertainment 
366   
367  Sponsors should collect detailed information on start and stop dates for all products taken during 
368  pregnancy, as well as dose, frequency, duration, and indication.  Exposure information in the 
369  time period just before pregnancy is also often important, especially for products with a long 
370  half-life.  Accurate information about specific gestational timing of exposure(s) can help identify 
371  critical exposure periods during gestation and biological plausibility for specific effects.  
372   
373  8.  Covariates  Potential Confounders 
374   
375  Sponsors should consider the potential for confounding by indication, which makes it difficult to 
376  determine whether any observed effects are caused by the drug or biological product or the 
                                                 
12 https://www.cdc.gov/ncbddd/birthdefects/macdp.html  
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377  underlying disease.  Data should be collected on the pregnant womans pertinent medical history, 
378  current disease status, and overall management.  Other potential confounders for which data 
379  should be collected include, for example:  socioeconomic status, maternal age, tobacco and 
380  alcohol use, illegal drug use, maternal body mass index, folic acid and vitamin use during the 
381  pregnancy, obstetrical history, medical history, family history of adverse pregnancy outcomes 
382  including MCMs, and other relevant confounders (Caton 2012). 
383   
384  9.  Data Collection 
385   
386  The value of the pregnancy registry depends on the accuracy and comprehensiveness of its data.  
387  All data collection efforts should be identical among exposed and comparator study groups to 
388  minimize bias.   
389   
390  The objective(s) of the registry should determine the type, extent, and length of patient follow-
391  up.  The feasibility of obtaining reliable pregnancy and infant outcome information is a critical 
392  consideration in pregnancy registry design.  Although prenatal health care providers are a good 
393  source of information on outcomes, such as miscarriage, elective terminations, live births, and 
394  pregnancy complications, they are not a good resource for information on infant conditions not 
395  readily diagnosed at or soon after birth.  The infants health care provider is the best resource for 
396  full information on the health status of the infant after birth.  The protocol should also specify 
397  inclusion of pertinent findings from postmortem examination of pregnancies with nonlive birth 
398  outcomes to avoid bias due to under-ascertainment of major malformations (Holmes and 
399  Westgate 2011).  
400   
401  The protocol should include a plan and rationale for follow-up contacts during and/or after 
402  pregnancy.  The follow-up contact should obtain details on the pregnancy course, outcome, 
403  status of the infant, and any evidence of abnormalities. 
404   
405  See Appendix A for a list of recommended data elements to include when designing a pregnancy 
406  registry. 
407   
408  10.  Data Analysis and Presentation 
409   
410  Validation of cases should be performed through medical record review and adjudication of 
411  outcomes by a clinical dysmorphologist or appropriate specialist for both the exposed and 
412  comparator group(s). 
413   
414  Inferential statistics should be applied to test prespecified hypotheses regarding the potential 
415  association between the exposure and the outcome(s) of interest.  
416   
417  Potential biases should be discussed, as well as possible methods for mitigation, if applicable.  
418  Descriptive statistics are the primary approach for summarizing patient characteristics and 
419  additional data from a pregnancy registry.  Given the heterogeneous nature of data obtained in 
420  pregnancy registries, there is no one format for data presentation that is applicable for all studies.  
421  The choice of a final format depends on outcomes identified in the registry protocol, 
422  unanticipated findings, and expert advice.  We encourage sponsors to develop forms of data 
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423  presentation and analysis that fully capture outcomes of concern within their particular registry.  
424  Separate analyses should be performed for each pregnancy outcome (miscarriage, elective 
425  termination, fetal death/stillbirth, live birth) and stratified by gestational timing of exposure (with 
426  a separate analysis of first trimester exposures for MCMs).  Additional analytical approaches 
427  should be used to assess covariates and factors that may affect the study findings, such as 
428  gestational timing of enrollment (Margulis et al. 2015).  
429   
430  11.  Privacy and Human Subject Protection Issues 
431   
432  Sponsors should consider privacy (including data protection) and human subject protection 
433  (including obtaining informed consent and institutional review board (IRB) oversight) when 
434  designing a pregnancy registry and developing protocols for the subsequent use of the data from 
435  the registry.  FDA recommends that an IRB be consulted when developing a pregnancy registry 
436  to ensure that the collection of data and all other procedures associated with the registry will 
437  withstand scientific and ethical scrutiny. 
438   
439  Because pregnancy registries typically do not involve the administration of an investigational 
440  product, there is not likely to be any foreseeable risk or harm to the pregnant woman, fetus, or 
441  resulting child from participating in the registry other than risk associated with inappropriate 
442  disclosure of identifiable private information.  The patient should be requested to sign medical 
443  record release forms to allow collection of the records from the health care provider(s) of the 
444  mother and infant.  Investigators are responsible for ensuring that any data releases are compliant 
445  with the Health Insurance Portability and Accountability Act and that all research performed 
446  complies with standards of privacy of individually identifiable health information. 
447   
448  If the registry involves the collection of information on the child after birth, either through a 
449  physical examination or specimen collection, considerations should be given to 21 CFR part 50, 
450  subpart D, Additional Safeguards for Children in Clinical Investigations (for FDA-regulated 
451  human subjects research). 
452   
453  12.  Independent Data Monitoring Committee/Scientific Advisory Board 
454   
455  To ensure scientific integrity and appropriate patient protection, we encourage each registry to 
456  have an independent data monitoring committee (or scientific advisory board) similar to those 
457  used for clinical studies.  Members of the committee could include experts in obstetrics, 
458  embryology, teratology, pharmacology, epidemiology, pediatrics, clinical genetics, and any 
459  relevant therapeutic areas.  The committee could assist in the review of data, classification of 
460  specific pregnancy outcomes including MCMs when relevant, and the dissemination of 
461  information to ensure that results are interpreted and reported accurately.  We recommend that 
462  the role and duties of the committee or scientific advisory board be specified in the protocol. 
463   
464  13.  Recruitment and Retention Plans 
465   
466  Successful recruitment and retention strategies are critical to the success of pregnancy studies 
467  such as registries or other studies requiring enrollment of study subjects.  We recommend a 
468  robust recruitment and retention plan that includes a multipronged approach to ensure 
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469  widespread coverage of the eligible population.  Early enrollment also may improve detection of 
470  pregnancy outcomes such as miscarriage.  These plans should be flexible and continuously 
471  reassessed throughout the study to ensure the registry maintains an adequate number of eligible 
472  pregnant women in both the exposure and comparator groups.   
473   
474  a.  Recruitment 
475   
476  Engaging health care providers and patients before the initiation of recruitment increases 
477  awareness of the study and provides an opportunity to seek feedback from these stakeholders 
478  regarding the study plan.  We encourage sponsors to collaborate with entities such as existing 
479  registries, patient advocacy groups, medical societies, and other relevant organizations to engage 
480  in awareness activities.  
481   
482  Under the Pregnancy and Lactation Labeling Rule requirements, if there is a pregnancy registry 
483  for the product, relevant contact information must be included in product labeling under the 
484  subheading Pregnancy Exposure Registry.13  Suggested modes of contact information include a 
485  toll-free telephone number or a websites uniform resource locator (URL).  
486   
487  The FDAs Office of Womens Health (OWH) maintains an online list of pregnancy registries 
488  that are actively enrolling women to raise awareness about pregnancy registries and connect 
489  consumers and health professionals to registries.  The registries are posted to the FDAs OWH 
490  web page based on a sponsors or investigators request to list its registry.  FDA encourages 
491  sponsors and investigators to submit a pregnancy registry listing to OWH at 
492  Registries@fda.hhs.gov.  FDA does not endorse any registry and is not responsible for the 
493  content of registries listed on the web page.14    
494   
495  Recruitment strategies can be described as facility-based, health care provider-initiated, or 
496  patient-initiated.  
497   
498    Facility-based recruitment can occur at the level of a practice or health system.  
499  Electronic health records can be used to identify drug or biological product users to 
500  facilitate the enrollment process for providers.  For example, an automated alert of a 
501  pregnancy registry can be generated in response to positive pregnancy test results and/or 
502  specific drug or biological product prescriptions.   
503   
504    Health care provider-initiated recruitment of patients is an important deciding factor for 
505  many pregnant women.  Provider recruitment approaches include: 
506   
507    Announcement of the registry study and contact information in the product labeling  
508    Promotional materials and product Internet pages  
                                                 
13 21 CFR 201.57(c)(9)(i)(A). 
 
14 The Pregnancy Registries web page is located at 
https://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm251314.htm.  The OWH mailbox 
address and the web page URL may change.  See the FDA website for the most recent information 
(https://www.fda.gov/). 
 
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509    Announcements in professional journals and newsletters  
510    Personal mailings to specialists  
511    Presentations and exhibits at professional meetings  
512   
513    Patient-initiated recruitment efforts rely on patients to contact the registry study staff and 
514  self-enroll.  Because pregnancy is often recognized by the patient first, registries that 
515  enroll patients directly can allow for recruitment of patients earlier in pregnancy.  Useful 
516  avenues to notify pregnant women of pregnancy registries include:  
517   
518    Print media including publications, press releases, and articles in newspapers and 
519  magazines with pregnant women among their readership  
520   
521    Distribution of flyers and posters in locations such as hospitals, ultrasound clinics, 
522  laboratories, prenatal classes, community centers, stores, and coffee shops (Webster 
523  et al. 2012) 
524   
525    Social media 
526   
527    Downloadable applications for mobile devices or personal computers could enable 
528  broader participation through ease of providing information15   
529   
530  Successful strategies to encourage the participation of pregnant women in medical research that 
531  may be applicable to postapproval safety studies include: 
532   
533    Incentives that facilitate study participation (Webb et al. 2010)  
534   
535    Employing empathetic, culturally sensitive, and personable study staff (El-Khorazaty et 
536  al. 2007).  
537   
538  b.  Retention 
539   
540  Even though recruitment materials may yield strong initial recruitment results, we recommend 
541  implementing a robust retention plan to ensure that an adequate number of pregnant women 
542  remain in the registry.  The retention plan should address specifics of patient retention strategies, 
543  contingency plans to obtain follow-up information, methods to track follow-up rates over time, 
544  and implementation steps to improve follow-up if expected follow-up rates are not met.   
545   
546  FDA also recommends that retention efforts focus on participating health care providers to 
547  improve retention rates and reduce the burden of data collection (e.g., implementing streamlined 
548  processes and succinct forms).  Access to pregnancy registry results provides a strong incentive 
549  for the participation of health care providers, particularly obstetric care providers, and the 
550  provision of interim data reports to participating health care providers may bolster retention.  
551  Additionally, high levels of retention have been achieved by pregnancy registries that 
552  communicate directly with patients.  Emphasizing the mission of the pregnancy registry may 
                                                 
15 See the FDAs MyStudies Application (App) web page at 
https://www.fda.gov/Drugs/ScienceResearch/ucm624785.htm. 
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553  reinforce participants motivation to remain in the study.  Sharing study results through a 
554  newsletter or website has been found to be effective in reinforcing patients altruistic reasons for 
555  participation.  Establishing and maintaining a longitudinal relationship between participant and 
556  interviewer can reduce loss to follow-up.  As with other longitudinal studies, collecting contact 
557  information of family members or friends in case the patient cannot be reached can aid in 
558  retention.  Recruitment and retention of pregnant women may be aided by a flexible follow-up 
559  schedule (e.g., conducting follow-up interviews by telephone, during evening and weekend hours 
560  or over a secure online platform), because participants may be balancing work and childcare 
561  responsibilities.  
562   
563  14.  Multiproduct Pregnancy Registries 
564   
565  To prevent overburdening patients, physicians, and health delivery systems with multiple 
566  requests to participate in individual studies, we encourage sponsors to work together directly or 
567  through consortiums to develop or support multiproduct registries.  A multiproduct pregnancy 
568  registry actively collects information on exposure to various product therapies in specific 
569  diseases, such as human immunodeficiency virus or epilepsy (Hernandez-Diaz et al. 2012).  In 
570  some cases, a general multiproduct registry, such as that conducted by a teratogen information 
571  service, collects information on products for unrelated indications.16  Multiproduct registries 
572  have advantages over single-product registries with respect to efficiency and economy.  They 
573  also have the advantage of having comparison groups of pregnant women unexposed to the drug 
574  or biological product of interest readily available (see section IV.B.6., Comparator Selection  
575  Reference Group(s)).  
576   
577  15.  Pregnancy Registry Discontinuation 
578   
579  We recommend that a pregnancy registry be continued until one or more of the following occurs: 
580   
581    Sufficient information has accumulated to meet the scientific objectives of the registry  
582   
583    The feasibility of collecting sufficient information diminishes to unacceptable levels 
584  because of low exposure rates, poor enrollment, or loss to follow-up 
585   
586    Other methods of gathering appropriate information become achievable or are deemed 
587  preferable 
588   
589  16.  Lactation Study Added on to a Pregnancy Registry 
590   
591  There is also often a need to collect lactation data to provide information on the safety of drugs 
592  and biological products during breast-feeding.  Pregnancy registries can be used to recruit and 
593  enroll breast-feeding women in lactation studies.  Some women enrolled in a pregnancy registry 
594  are already taking a drug or biological product during pregnancy, and because they may be likely 
595  to continue treatment after delivery, these women are an ideal population in which to study 
                                                 
16 See the MotherToBaby pregnancy studies conducted by the Organization of Teratology Information Specialists 
available at https://mothertobaby.org/pregnancy-studies/.  
 
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596  product levels in milk.  For information on how to conduct a lactation study, see the draft 
597  guidance for industry Clinical Lactation Studies:  Considerations for Study Design.17 
598   
599   
600  V.  COMPLEMENTARY STUDIES 
601   
602  Use of complementary studies with different study designs may help address the limitations 
603  inherent to a pregnancy registry.  Additionally, as more postmarketing safety information 
604  becomes available from interim registry reports, spontaneous reports, or case series, a more 
605  specific safety signal may become apparent.  Thus, additional studies that complement data 
606  obtained from pregnancy registries and other sources, referred to as complementary studies in 
607  this guidance, can be implemented as the need arises to better understand the specific effects of 
608  using a drug or biological product during pregnancy, and to more precisely quantify the 
609  magnitude of an association between a pregnancy exposure and a specific outcome.   
610   
611  Complementary studies can be retrospective in design, using secondary data (i.e., data collected 
612  for purposes other than to assess the safety of one specific drug or biological product).18  
613  Common retrospective data sources and study designs used for complementary studies for 
614  purposes of pregnancy-related research can include the following: 
615   
616    Electronic data sources (e.g., insurance claims and electronic health record databases)  
617    Population-based surveillance and national registries or registers 
618    Population-based case control studies 
619   
620  These data sources and designs are discussed in the following subsections.19 
621   
622  A.  Electronic Data Sources 
623   
624  Electronic data sources often contain a large number of records available for research.  At the 
625  time of publication of this guidance, electronic data sources readily available for pregnancy 
626  research include electronic administrative claims databases and/or electronic health record 
627  (EHR) databases, referred to collectively as electronic health care data (EHD) in this guidance.  
628  Best practices for studies using these data sources have been described in guidance20 and also 
629  apply to pregnancy studies using EHDs. 
630   
                                                 
17 When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.   
 
18 As the need arises, secondary data can be supplemented with additional data collection (e.g., maternal interview). 
 
19 Methods used to identify and evaluate pregnancy outcomes in a pregnancy registry study described in section IV., 
Pregnancy Registries (e.g., study objective(s), outcome(s), comparators, exposure, confounders, statistical analysis 
plan) also apply when considering complementary studies and will not be repeated in this section.  This section 
addresses concerns specific to the data sources selected for complementary studies. 
 
20 See the guidance for industry and FDA staff Best Practices for Conducting and Reporting 
Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data (May 2013). 
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631  Regardless of the specific type of electronic data sources and study design used, investigators 
632  should fully understand and describe the strengths and limitations of the data source proposed 
633  (including the population(s) covered, data elements captured and their validity, system(s) of care, 
634  and system-specific clinical and pharmacy data) to evaluate whether the data source is 
635  appropriate to address specific pregnancy-related hypotheses.  
636   
637  Pregnancy and/or live birth data from EHD sources have been developed and used in a variety of 
638  ways to evaluate product exposure and/or safety during pregnancy (Devine et al. 2010; Andrade 
639  et al. 2012; Taylor et al. 2015; Huybrechts et al. 2014).  Despite its successful and growing use, 
640  selection of an EHD source to evaluate drug or biological product safety in pregnancy should 
641  reflect consideration of methods used to identify pregnancies, estimates of conception and 
642  gestational age, linkage to offspring records, and ascertainment and validation of pregnancy and 
643  birth outcomes.  Each of these considerations is discussed below. 
644   
645  1.  Methods to Identify Pregnancies 
646   
647  The ability to identify clinically recognized pregnancies and births using EHD is central to use of 
648  any database capable of assessing product safety during pregnancy.  Identifying live births in an 
649  EHD is relatively straightforward because delivery codes are available and relatively reliable.   
650   
651  Sponsors should consider the implications of limiting a study population to that of only live 
652  births, because birth defects likely to result in non-live birth outcomes would not be captured.  
653  Failure to include non-live births in a study population primarily affects study generalizability; 
654  however, it also may result in a biased relative risk estimate if the rate of pregnancy loss or 
655  termination caused by the defect is higher in one group than the other.  
656   
657  Use of EHD to identify non-live birth pregnancy outcomes for assessment of safety signals is 
658  challenging.  Non-live birth outcomes may be identified in EHD by the presence of diagnostic 
659  and/or procedure codes specific to the outcome.  However, gestational age at the time of the 
660  outcome may be difficult to estimate if gestational age-specific codes accompanying the outcome 
661  codes are unavailable or unreliable.  Without a reasonable estimate of gestational age, a reliable 
662  assessment of pregnancy exposure is difficult unless the investigator has access to ultrasound or 
663  laboratory data.   
664   
665  2.  Estimates of Conception and Gestational Age 
666   
667  A valid estimate of gestational age, from which a conception date may be estimated, is critical 
668  for determining the timing of an exposure during pregnancy.  For studies assessing pregnancy 
669  outcomes among live births only, several methods exist for identifying gestational age.  These 
670  include: 
671   
672    U.S. birth certificates (when available)  
673    Diagnostic ICD codes found in EHD databases21 and algorithms using these codes 
674    EHR or ultrasound report   
                                                 
21 Given the potential variability in code validity by data source and outcome type (e.g., live birth versus stillbirth), 
codes to identify gestational age should be validated in each database. 
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675   
676  3.  Linkages to Offspring 
677   
678  Common methods for mother-infant linkages in the United States include linkages using birth 
679  certificates and linkages using unique data elements within the same EHD source (Andrade et al. 
680  2012).  Linkages of pregnancies identified in EHD to offspring using birth or fetal death 
681  certificates or other sources (e.g., medical records, national or state birth defect surveillance 
682  registries) can provide the investigator access to several important variables that are not captured, 
683  poorly captured, or captured with inadequate detail in EHD sources (e.g., maternal/paternal 
684  race/ethnicity, maternal smoking status, parity, birth defects, some drug exposure, and precise 
685  estimates of gestational age and birthweight of the newborn).  
686   
687  Even when only EHD sources are available, study data can be enhanced by linking those from 
688  the mother to the offspring.  Many EHD sources contain unique identifiers assigned to both the 
689  mother and infant that may reflect the relationship to the primary health insurance policyholder.  
690  Matching this number, as well as the mothers delivery date, to the newborns date of birth often 
691  successfully links the mothers pregnancy to the infants health records.  However, if the 
692  newborn is covered under a different insurance policy than the mother, the linkage may be 
693  impossible or at least limited to the clinical information available on the birth certificate or other 
694  data sources.  
695   
696  In the United States, linkages of non-live birth outcomes identified in EHD sources to other data 
697  sources are limited.  Some states require reporting of fetal deaths (after 20 weeks), and this 
698  information may be available to investigators on a case-by-case basis via the states vital records 
699  department.  Information collected by the state is often similar to that collected on a birth 
700  certificate, but specific data elements vary by state.   
701   
702  4.  Study Outcome Ascertainment and Validation 
703   
704  Diagnostic and procedure codes contained in EHD sources can be used to identify and study 
705  product-associated MCMs.  However, the presence of any single diagnostic code does not 
706  necessarily imply a correct diagnosis.  Diagnostic codes may reflect coding errors, rule-out 
707  diagnoses, actual diagnoses, or the presence of an abnormality that has not yet been validated or 
708  characterized.  The validity of diagnostic codes for specific birth defects varies greatly by 
709  specific defect and data source (Cooper et al. 2008; Palmsten et al. 2014).  Outcome validation is 
710  still needed for all outcomes unless a high-performing algorithm has been previously validated 
711  for the specific outcome in the same (or similar) database under consideration.  Some outcomes 
712  can be ascertained in multiple ways.  For instance, preterm birth and small for gestational age 
713  may be identified through the presence of diagnostic codes or may be calculated using 
714  gestational age and birth weight data found on the birth certificate and/or medical record.  
715  Investigators should validate these outcomes in the specific database of interest if considering 
716  their use as endpoints in EHD studies. 
717   
718  For all birth outcomes identified using EHD, sponsors should use a gold standard method of 
719  validation such as a medical chart for the development of a testable algorithm.  For MCMs, 
720  sponsors should use reviews by clinical experts (geneticists or dysmorphologists) and/or linkage 
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721  to birth defect registries and/or birth certificate data.  The use of only EHD without access to 
722  such gold standard sources or, at a minimum, a high-performing validated algorithm measuring 
723  the same outcome in the specific database being considered may result in inaccuracy.  
724   
725  B.  Population-Based Surveillance and National Registries or Registers22 
726   
727  Population-based birth defect data sources are part of surveillance networks that extend to an 
728  entire group of people having similar demographics (e.g., the entire nation in some European 
729  countries), or to similar groups of people (e.g., state or regional births in the United States).  The 
730  advantage of using birth defect surveillance registries for MCM identification or validation is 
731  that the identified MCM cases have already been adjudicated.  Many of these registries capture 
732  and adjudicate birth defect information for live births, stillbirths/fetal deaths, and elective 
733  terminations.  Some international birth defect registries follow guidelines developed by the 
734  World Health Organization, in collaboration with the CDC and the International Clearinghouse 
735  for Birth Defects Surveillance and Research (ICBDSR).  Birth defect definitions in these 
736  registries include MCMs associated with chromosomal abnormalities, which may not be 
737  applicable to outcomes associated with drug or biological product exposures.   
738   
739  If maternal exposure information is collected, much of it is obtained from obstetrical records.  If 
740  sponsors consider population-based birth defect registries for exposure-based complementary 
741  studies, they may need to supplement the registries with drug or biological product exposure 
742  information from targeted maternal interviews and/or link to prescription information when 
743  personal interviews are not possible.23 
744   
745  Population-based birth defect registries have the substantial advantage of having large sample 
746  sizes that allow the study of relatively rare MCMs.   
747   
748  Examples of population-based birth defect surveillance networks include: 
749   
750    State-based Surveillance (United States) 
751   
752    Vaccine and Medications in Pregnancy Surveillance System (VAMPSS) (United  
753  States)24 
754   
755    The ICBDSR25 
756   
                                                 
22 For the purposes of this section, the term registry is used interchangeably with register (a term more commonly 
used in Europe). 
 
23 International population-based birth defect registries, usually European, can link to other databases to obtain drug 
or biological product exposure and outcome information. 
 
24 http://www.bu.edu/slone/research/studies/vampss/  
 
25 http://www.icbdsr.org/resources/annual-report/  
 
 
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757    The European Registration of Congenital Anomalies and Twins, registries26 
758   
759  Those that capture MCMs as a result of mandatory reporting allow for an accurate estimate of 
760  incident birth defects in the network, especially when the numerator can be easily linked to the 
761  number of pregnant women in the country or the region as the denominator during the study 
762  period.    
763   
764  Regardless of the type of surveillance or registry selected for analysis, limiting observation only 
765  to MCMs increases the risk of missing important toxic product effects that may be incompatible 
766  with life or that may occur at different times during the pregnancy.  Some registries, however, do 
767  include stillbirths and elective terminations.  Therefore, it is important to thoroughly understand 
768  and describe what information is and is not available in the population-based registries 
769  considered for a study, including what information is available on maternal drug or biological 
770  product exposures. 
771   
772  C.  Population-Based Case Control Studies 
773   
774  Case-control study designs (including nested designs) are frequently considered when there is a 
775  need to collect additional information from the mothers through personal interviews, to obtain 
776  additional information on infants, to request permission to review medical records, or to perform 
777  long-term follow-up of the offspring.  Case-control studies also may be needed if the registry is 
778  unable to collect sufficient data to assess a safety signal previously identified from another data 
779  source.  
780   
781  1.  Selection of Pregnancy-Related Cases and Controls  
782   
783  Cases with pregnancy or infant outcomes of interest can be identified from EHD, or regional, 
784  national, or international birth defect registries.  The same concerns identified earlier in this 
785  guidance for selection of controls or comparators for pregnancy registry studies (internal or 
786  external controls) also apply to selection of controls or comparators for complementary case-
787  control studies (see section IV.B.6., Comparator Selection  Reference Group(s)).  For any 
788  study, it is most important to ensure that comparators or controls are selected from the same 
789  disease population (internal controls) when possible.  Controls can be identified from the same 
790  EHD or vital statistics departments or from general (state, regional, or national) birth records 
791  giving rise to the cases; alternatively, birth outcomes (cases and controls) can be identified from 
792  exposure- or disease-based registries.  
793   
794  When a case-control design is considered to evaluate a pregnancy outcome, regardless of the 
795  source from which cases and controls were identified, sponsors should validate case or control 
796  status using medical records or other reliable sources such as birth defect registries or review by 
797  clinical experts.  Documentation of validation should be provided when selecting cases from 
798  these data sources.  Case status identified from national or international networks are usually 
799  already validated. 
800   
                                                 
26 http://www.eurocat-network.eu/aboutus/datacollection/guidelinesforregistration/malformationcodingguides  
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801  2.  Exposure Assessment  
802   
803  The advantages of obtaining additional information by interviewing the mother as part of a case-
804  control study include the ability to collect data on all types of drug or biological product 
805  exposures, including those not covered by insurance (e.g., over-the-counter, supplements).  An 
806  additional strength is the ability to extend or adapt the interview to capture information not 
807  available from other databases:  personal or family history; race and other demographics; dose, 
808  timing, and duration of product use; history of maternal disease or indication for medication; 
809  comorbidities; and potential confounders such as body mass index, tobacco and alcohol use, 
810  reproductive history, occupation (maternal and paternal), and the occurrence of breast-feeding.  
811  At the interview, investigators can obtain informed consent to review medical records to confirm 
812  diagnoses or to identify brand or lot, among others.  If relevant, investigators can request 
813  biological specimens (e.g., breast milk samples, buccal swabs for DNA testing) to test for 
814  product penetrance or assess hereditary effects.  Direct access to the mothers allows specialized 
815  physical examinations and developmental follow-up of the offspring.  
816   
817  Exposure recall bias is always a concern for information obtained from maternal interviews, 
818  because such self-reported data are collected after the pregnancy outcome (i.e., case status) is 
819  known.  Recall bias could be introduced if the accuracy of reported exposure is different between 
820  cases and controls, for example mothers of birth defect cases may more accurately recall 
821  exposures during pregnancy versus mothers of unaffected infants.  Attempts to minimize this 
822  bias could include selecting as controls mothers with other adverse pregnancy outcomes (e.g., 
823  malformed infants with chromosomal defects or with malformations other than the one(s) of 
824  interest) or other serious medical problems.  Another approach to minimize recall bias is the use 
825  of pharmacy records among cases and controls to confirm reported drug or biological product 
826  exposures, when available, although pharmacy data only provide information on prescription 
827  fills and not necessarily on quantity consumed and may not include over-the-counter products.   
828   
829  3.  Examples of Pregnancy Case-Control Studies in the United States 
830   
831  Examples of case-control studies are listed below and can be used as a starting point for 
832  designing a study.  Note, however, that data from these studies, although population-based, are 
833  only specific to the populations studied and may not be relevant to the study population under 
834  consideration.  If comparisons are to be made to these studies, every effort should be made to 
835  understand and explain the similarities and differences and to identify resulting confounding and 
836  biases. 
837   
838    The National Birth Defects Prevention Study27  
839   
840    Birth Defects Study to Evaluate Pregnancy exposures28  
841   
                                                 
27 http://nbdps.org/  
 
28 http://www.bdsteps.org/  
 
 
20 
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842    Pregnancy Health Interview Study (Birth Defects Study), a multicenter case-control study 
843  based at the Slone Epidemiology Center at Boston University, a collaborator of the 
844  VAMPSS29  
845   
                                                 
29 http://www.bu.edu/slone/research/studies/phis/  
21 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
846  REFERENCES 
847   
848  Literature 
849   
850  Andrade, SE, Davis RL, Cheetham TC, Cooper WO, Li DK, Amini T, Beaton SJ, Dublin S, 
851  Hammad TA, Pawloski PA, Raebel MA, Smith DH, Staffa JA, Toh S, Dashevsky I, Haffenreffer 
852  K, Lane K, Platt R, and Scott PE, 2012, Medication Exposure in Pregnancy Risk Evaluation 
853  Program, Matern Child Health J, 16(7):13491354. 
854   
855  Andrade, SE, Scott PE, Davis RL, Li DK, Getahun D, Cheetham TC, Raebel MA, Toh S, Dublin 
856  S, Pawloski PA, Hammad TA, Beaton SJ, Smith DH, Dashevsky I, Haffenreffer K, and Cooper 
857  WO, 2013, Validity of Health Plan and Birth Certificate Data for Pregnancy Research, 
858  Pharmacoepidemiol Drug Saf, 22(1):715. 
859   
860  Bird, S, Gelperin K, Taylor L, Sahin L, Hammad H, Andrade SE, Mohamoud MA, Toh S, and 
861  Hampp C, 2018, Enrollment and Retention in 34 United States Pregnancy Registries Contrasted 
862  With the Manufacturers Capture of Spontaneous Reports for Exposed Pregnancies, Drug Safety, 
863  41:8794. 
864   
865  Caton, AR, 2012, Exploring the Seasonality of Birth Defects in the New York State Congenital 
866  Malformations Registry, Birth Defects Research (Part A), 94(6):424437. 
867   
868  CDC, 1984, Isotretinoin  A Newly Recognized Human Teratogen, Morb Mortal Wkly Rep., 
869  Apr 6, 33(13):171173. 
870   
871  Cooper, WO, Hernandez-Diaz S, Gideon P, Dyer SM, Hall K, Dudley J, Cevasco M, Thompson 
872  AB, and Ray WA, 2008, Positive Predictive Value of Computerized Records for Major 
873  Congenital Malformations, Pharmacoepidemiol Drug Saf, 17(5):455460. 
874   
875  Council for International Organizations of Medical Sciences, 2010, Practical Aspects of Signal 
876  Detection in Pharmacovigilance:  Report of CIOMS Working Group VIII. 
877   
878  Curtin, SC, Abma JC, and Kost K, 2015, 2010 Pregnancy Rates Among U.S. Women, NCHS 
879  health e-stat.  
880   
881  Devine, S, West S, Andrews E, Tennis P, Hammad TA, Eaton S, Thorp J, and Olshan A, 2010, 
882  The Identification of Pregnancies Within the General Practice Research Database, 
883  Pharmacoepidemiol Drug Saf, 19(1):4550. 
884   
885  El-Khorazaty, MN, Johnson AA, Kiely M, El-Mohandes AA, Subramanian S, Laryea HA, 
886  Murray KB, Thornberry JS, and Joseph JG, 2007, Recruitment and Retention of Low-Income 
887  Minority Women in a Behavioral Intervention to Reduce Smoking, Depression, and Intimate 
888  Partner Violence During Pregnancy, BMC Public Health, 7:233. 
889   
890  Finer, Zolna, 2016, Declines in Unintended Pregnancy in the United States, 2008-2011, N Engl J 
891  Med, 374(9):843852. 
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  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
892   
893  Frew, PM, Saint-Victor DS, Brewinski Isaacs M, Kim S, Swamy GK, Sheffield JS, Edwards 
894  KM, Villafana T, Kamagate O, and Ault K, 2014, Recruitment and Retention of Pregnant 
895  Women Into Clinical Research Trials:  An Overview of Challenges, Facilitators, and Best 
896  Practices, Clin Infect Dis, 59 Suppl 7:S400S407. 
897   
898  Gelperin, K, Hammad H, Leishear K, Bird ST, Taylor L, Hampp C, and Sahin L, 2017, A 
899  Systematic Review of Pregnancy Exposure Registries:  Examination of Protocol-Specified 
900  Pregnancy Outcomes, Target Sample Size, and Comparator Selection, Pharmacoepidemiol Drug 
901  Saf, 26:208214. 
902   
903  Gliklich, R, Dreyer N, and Leavy M, editors, 2014, Registries for Evaluating Patient Outcomes:  
904  A Users Guide, third edition, two volumes.  (Prepared by the Outcome DEcIDE Center 
905  (Outcome Sciences, Inc., a Quintiles company) under Contract No. 290 2005 00351 TO7.)  
906  AHRQ Publication No. 13(14)-EHC111, Rockville, MD:  Agency for Healthcare Research and 
907  Quality, April 2014. 
908   
909  Hernandez-Diaz, S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby M, and Holmes LB, 
910  2012, Comparative Safety of Antiepileptic Drugs During Pregnancy, Neurology, May 22, 
911  78(21):16921699. 
912   
913  Holmes, LB, Mittendorf R, Shen A, Smith CR, and Hernandez-Diaz S, 2011, Fetal Effects of 
914  Anticonvulsant Polytherapies:  Different Risks From Different Drug Combinations, Arch Neurol, 
915  68(10):12751281. 
916   
917  Holmes, LB and Westgate MN, 2011, Inclusion and Exclusion Criteria for Malformations in 
918  Newborn Infants Exposed to Potential Teratogens, Birth Defects Research (Part A), 91:807812. 
919   
920  Huybrechts, K, Bateman BT, Palmsten K, Desai RJ, Patorno E, Gopalakrishnan C, Levin R, 
921  Mogun H, and Hernandez-Diaz S, 2015, Antidepressant Use Late in Pregnancy and Risk of 
922  Persistent Pulmonary Hypertension of the Newborn, JAMA, Jun 2, 313(21):21422151.  
923   
924  Huybrechts, KF, Palmsten K, Avorn J, Cohen LS, Holmes LB, Franklin JM, Mogun H, Levin R, 
925  Kowal M, Setoguchi S, and Hernandez-Diaz S, 2014, Antidepressant Use in Pregnancy and the 
926  Risk of Cardiac Defects, N Engl J Med, 370(25):23972407. 
927   
928  Margulis, AV, Mittleman MA, Glynn RJ, Holmes LB, and Hernandez-Diaz S, 2015, Effects of 
929  Gestational Age at Enrollment in Pregnancy Exposure Registries, Pharmacoepidemiol Drug Saf, 
930  Apr, 24(4):343352. 
931   
932  National Birth Defects Prevention Network, 2004, Guidelines for Conducting Birth Defects 
933  Surveillance, Sever LE editor. 
934   
935  Obican, S and Scialli AR, 2011, Teratogenic Exposures, American Journal of Medical Genetics 
936  Part C (Seminars in Medical Genetics), 157:15169. 
937   
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  Contains Nonbinding Recommendations 
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938  Palmsten, K, Huybrechts KF, Kowal MK, Mogun H, and Hernandez-Diaz S, 2014, Validity of 
939  Maternal and Infant Outcomes Within Nationwide Medicaid Data, Pharmacoepidemiol Drug Saf, 
940  23(6):646655. 
941   
942  Rosa, FW, 1983, Teratogenicity of Isotretinoin, Lancet, 2(8348):513. 
943   
944  Shephard, T, 1994, Proof of Teratogenicity, Teratology, 50:9798. 
945   
946  Taylor, LG, Thelus Jean R, Gordon G, Fram D, and Coster T, 2015, Development of a Mother-
947  Child Database for Drug Exposure and Adverse Event Detection in the Military Health System, 
948  Pharmacoepidemiol Drug Saf, 24(5):510517. 
949   
950  Webb, DA, Coyne JC, Goldenberg RL, Hogan VK, Elo IT, Bloch JR, Mathew L, Bennett IM, 
951  Dennis EF, and Culhane JF, 2010, Recruitment and Retention of Women in a Large Randomized 
952  Control Trial to Reduce Repeat Preterm Births:  The Philadelphia Collaborative Preterm 
953  Prevention Project, BMC Med Res Methodol, 10:88. 
954   
955  Webster, GM, Teschke K, and Janssen PA, 2012, Recruitment of Healthy First-Trimester 
956  Pregnant Women:  Lessons From the Chemicals, Health & Pregnancy Study (CHirP), Matern 
957  Child Health J, 16(2):430438. 
958   
959  WHO, CDC, and ICBDSR, 2014, Birth Defects Surveillance:  A Manual for Programme 
960  Managers, Geneva, World Health Organization. 
961   
962  Zagouri, F, Sergentanis TN, Chrysikos D, Papadimitriou CA, Dimopoulos MA, and Bartsch R, 
963  2013, Trastuzumab Administration During Pregnancy:  A Systematic Review and Meta-
964  Analysis, Breast Cancer Res Treat, 137(2):349357. 
965   
966  Guidances1 
967   
968  Draft guidance for industry Clinical Lactation Studies:  Considerations for Study Design2 
969   
970  Draft guidance for industry Postmarketing Safety Reporting for Human Drug and Biological 
971  Products Including Vaccines3 
972   
973  Guidance for industry Good Pharmacovigilance Practices and Pharmacoepidemiologic 
974  Assessment  
975   
976  Guidance for industry Postmarketing Studies and Clinical Trials  Implementation of Section 
977  505(o)(3) of the Federal Food, Drug, and Cosmetic Act 
                                                 
1 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
 
2 When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
 
3 When final, this guidance will represent the FDAs current thinking on this topic. 
24 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
978   
979  Guidance for industry and FDA staff Best Practices for Conducting and Reporting 
980  Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data 
981   
25 
  Contains Nonbinding Recommendations 
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982  APPENDIX A:  
983  LIST OF DATA COLLECTION ELEMENTS 
984   
985  The following data elements should be included when designing a pregnancy registry.  
986   
987  General 
988   
989  Patient identifier 
990  Name of reporter at initial contact with the registry 
991  Date of initial contact with the registry 
992  Dates of any follow-up contacts 
993  Telephone number and email address of reporter 
994  Additional contact names, telephone numbers, and email addresses (if reporter is the patient) 
995   
996  Maternal Information 
997   
998  Source of information (e.g., obstetrician, pregnant woman) 
999  Birth date 
1000  Race 
1001  Occupation  
1002  Height, weight, body mass index 
1003  Maternal medical history (e.g., hypertension, diabetes, seizure disorder, autoimmune 
1004  disease, known risk factors for adverse pregnancy outcomes including environmental or 
1005  occupational exposures) 
1006  Obstetrical history:  
1007  Number of pregnancies and outcome of each (live birth, miscarriage, pregnancy 
1008  termination (elective or therapeutic), ectopic pregnancy)  
1009  Previous maternal pregnancy complications 
1010  Previous fetal/neonatal abnormalities and type  
1011  Current pregnancy: 
1012  Date of last menstrual period 
1013  Ultrasound results for gestational dating 
1014  Prenatal test results (including dates) 
1015  Pregnancy weight gain of mother 
1016  Obstetric complications (e.g., preeclampsia, premature delivery) 
1017  Complications during pregnancy (including any adverse product reactions) and dates  
1018  Number of fetuses 
1019  Disease course(s) during pregnancy and any complications 
1020  Drug or biological product exposures (prescription drugs, over-the-counter products, and 
1021  dietary supplements): 
1022  Name 
1023  Dosage and route 
1024  Date of first use and duration 
1025  Indication 
1026  Recreational drug use (e.g., tobacco, alcohol, illicit drugs) and amount 
26 
  Contains Nonbinding Recommendations 
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1027    Family history (specify type, maternal or paternal, among others): 
1028  Malformations 
1029  Genetic disorders 
1030  Multiple fetuses/births 
1031   
1032  Neonatal Information 
1033   
1034  Initial: 
1035  Source of information (e.g., obstetrician, pediatrician, mother)     
1036  Date of receipt of information 
1037  Date of birth or termination 
1038  Gestational age at birth or termination 
1039  Gestational outcome (live born, fetal death/stillborn, miscarriage, elective termination, and 
1040  termination for a fetal anomaly) 
1041  Sex 
1042  Obstetric complications (e.g., preeclampsia, premature delivery) 
1043  Pregnancy order (singleton, twin, triplet) 
1044  Results of neonatal physical examination including 
1045  Anomalies diagnosed at birth or termination (including autopsy results) 
1046  Anomalies diagnosed after birth 
1047  Weight at birth indicating whether small, appropriate, or large for gestational age 
1048  Length at birth 
1049  Head circumference at birth indicating whether small, appropriate, or large for gestational 
1050  age 
1051  Condition at birth (including, when available, Apgar scores at 1 and 5 minutes, umbilical 
1052  cord vessels and gases, need for resuscitation, admission to intensive care nursery) 
1053  Neonatal illnesses, hospitalizations, drug therapies 
1054   
1055  Follow-up: 
1056  Source of information (e.g., pediatrician, mother)     
1057  Date of receipt of information 
1058  Anomalies diagnosed since initial report 
1059  Developmental assessment 
1060  Infant illnesses, hospitalizations, drug therapies 
1061   
27