OBSTETRICS

Maternal treatment with

analgesics
and risk for birth defects

opioid

Cheryl S. Broussard, PhD; Sonja A. Rasmussen, MD, MS; Jennita Reefhuis,

PhD; Jan M. Friedman, MD, PhD; Michael W. Jann, PharmD; Tiffany RiehleColarusso, MD, MSE; Margaret A. Honein, PhD, MPH; for the National Birth
Defects Prevention Study
OBJECTIVE: We examined whether maternal opioid treatment between 1 month

before pregnancy and the first trimester was associated with

birth defects.

STUDY DESIGN: The National Birth Defects Prevention Study (1997 through 2005) is

an ongoing population-based case-control study. We estimated adjusted odds ratios

(ORs) and 95% confidence intervals (CIS) for birth defects categories with at least
200 case infants or at least 4 exposed case infants.
RESULTS: Therapeutic opioid use was reported by 2.6% of 17,449 case mothers and

2.0% of 6701 control mothers. Treatment was statistically significantly associated

with conoventricular septal defects (OR, 2.7; 95% CI, 1.1 6.3), atrioventricular septal
defects (OR, 2.0; 95% CI, 1.23.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI,
1.44.1), spina bifida (OR, 2.0; 95% CI, 1.33.2), or gastroschisis (OR, 1.8; 95% CI,
1.12.9) in infants.
CONCLUSION: Consistent with some previous investigations, our study shows an

association between early pregnancy maternal opioid analgesic treatment and

certain birth defects. This information should be considered by women and their
physicians who are making treatment decisions during pregnancy.
Key words: analgesic, birth defect, medication, opioid, pregnancy
Cite this article as: Broussard CS, Rasmussen SA, Reefhuis J, et al. Maternal treatment with opioid
analgesics and risk for birth defects. Am J Obstet Gynecol
2011;204:314.e1-11.

ajor birth defects affect about3%of the 4 million US live births each year 1-3 and

are a leading cause of infant mortality. 1,4 Congenitalheart defects(CHD) are among
the most common birth defects, affecting nearly 1% of US births, 5,6 and are the main
contributor to infant mortality attributable to birth defects.7,8
Opioid medications are potent prescription analgesics that are the mainstay for
treatment of severe pain.9 Opioids are often used in combination with nonopioid
analgesics, such as acetaminophen, and lower doses are also a component of some
cough suppressants.10 Previous studies have shown that opioid analgesic use and
abuse have been increasing in recentyears,11-13 but the effects of opioid use on the
developing fetus during pregnancy are poorly understood. Associations between
maternal firsttrimester use of the opioid analgesic codeine and CHD in infants were
found in 3 of 4 previous case-control studies,14-17 with case counts ranging from 141
390 (and control counts of 176 3002). Most previous studies considered CHD of any
type as a single group and had insufficient sample sizes to examine individual heart
defects. Other studies have shown associations between first-trimester codeine use
and other birth defects such as orofacial clefts,18,19 but these findings have been

inconsistent across studies. Effects of maternal use of opioids other than codeine
have not been thoroughly studied, but previous reports have shown no increase in
risks for birth defects following prenatal exposures to oxycodone, propoxyphene, or
meperidine.18,20 Neural tube defects have not been associated with maternal opioid
treatment in human pregnancy, 21-23 but experimental studies showed increased
frequencies of neural tube defects in the offspring after treatment of pregnant
hamsters with high doses of morphine, meperidine, pentazocine, hydromorphone, or
propoxyphene.24,25 Despite evidence of adverse fetal effects with maternal codeine
use and the paucity of data on the effects of maternal use of other opioids, such
treatment is often assumed to be safe during pregnancy. 26 Our study objective was to
examine whether maternal therapeutic use of opioid analgesics in early pregnancy is
associated with CHD or other birth defects.

MATERIALS AND METHODS

We analyzed data from the National Birth Defects Prevention Study(NBDPS)for infants
born Oct. 1, 1997, through Dec. 31, 2005. NBDPS is an ongoing multisite populationbased case-control study of _30 types of major structural birth defects that focuses
on exposures immediately before and during pregnancy. Each
of the study sites (Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey,
New York, North Carolina, Texas, and Utah) ascertains deliveries with birth defects
through birth defects surveillance systems using standard, detailed case definitions.
The study was approved by institutional review boards of
the Centers for Disease Control and Prevention and all other participating centers.
NBDPS focuses on birth defects with unknown etiologies; therefore, infants with
recognized chromosomal abnormalities or single-gene disorders are excluded. Some
cardiac anomalies that are usually physiological rather than pathological
were also excluded, eg, patent ductus arteriosus or patent foramen ovale in
premature infants. In addition,
some cardiovascular anomalies were excluded from NBDPS either because of their
rarity, poor ascertainment in infancy, unclear significance (eg, insufficiency of the
tricuspid, mitral, or pulmonary valves), or because they were vascular (noncardiac)
defects or arrhythmias (nonstructural defects). All CHD cases were confirmed by
echocardiography, cardiac catheterization, surgery, or autopsy. 27 Classification of
NBDPS cases has previously been described.6,28 Briefly, the process for NBDPS-eligible
defects involves confirmation of the diagnosis from medical record abstracts and
determining whether each case is an isolated defect, 1 of multiple unrelated major
defects, or a component of a syndrome or other complex pattern. 28 For CHD,
classification is also performed on a second axis to describe the complexity
of cardiac involvement, by clinicians with expertise in pediatric cardiology. Simple
heart defects are anatomically discrete or well-recognized single entities;
associations are common, uncomplicated
combinations of heart defects; and heart defects that do not fall into either category
are considered complex. Cardiac classification and subsequent grouping into larger
categories are based on clinical and presumed developmental mechanisms that may
have relevance in considering the teratogenic effect of exposures. 6 An annual
random sample of approximately 1200 liveborn infants without birth defects (control
infants) is selected from the same geographic regions and time period as the cases,
either from
birth certificates or birth hospitals. Mothers are invited to participate in an hour-long
computer-assisted telephone interview, conducted by interviewers in English or
Spanish, between 6 weeks and 2 years after the mothers estimated date of delivery
(EDD) (average is 11 months post-EDD for cases and 9 months for controls). The
interview assesses various maternal health factors, pregnancy history information,
dietary

and other drug exposures, and sociodemographic characteristics. Exposures are

assessed for the period from 3 months before conception through the end of the
pregnancy. Pregnancy was defined as the time period from conception (ie, 2 weeks
after the last menstrual period) to delivery, and pregnancy months for this analysis
were consecutive 30-day periods. Mothers are asked about medications used for each
specific illness (eg, influenza) or indication (eg, surgery) mentioned within the
maternal health section of the questionnaire, and are also encouraged to report any
other medications not already mentioned. Respondents are asked to report the start
and stop dates, duration, and frequency of medication use using calendar dates or
pregnancy months. All medications reported in each section of the interview are
compiled and coded using the Slone Drug Dictionary, 29 which NBDPS licenses from
Boston Universitys Slone Epidemiology Center. This dictionary links products to their
active ingredients. We defined opioid exposure as maternal report of use of _1
products with any of the following components taken for therapeutic reasons in any
dose, duration, or frequency: codeine, hydrocodone, meperidine, oxycodone,
propoxyphene, morphine, tramadol, methadone, hydromorphone, fentanyl, or
pentazocine. We included
individual and combination products. The exposure window of interest was the period
from 1 month before to 3 months after conception. We conducted multivariable
logistic regression analyses to calculate adjusted odds ratios (ORs). We examined
birth defect categories that had _200 cases or _4 exposed cases to limit analyses to
defect categories that would likely have adequate statistical power and to enable us
to identify potentially elevated risks among rarer defect groups. All models were
adjusted for maternal age (continuous), race/ethnicity (non-Hispanic white, nonHispanic black, Hispanic, other), education (_12 years, _12 years), prepregnancy
obesity (body mass index _30, body mass index _30, using prepregnancy weight and
height self-reported by the mother during the telephone interview), periconceptional
smoking status (no smoking from 1 month before to 1 month after conception,
smoking at least once in the same
period), and study center (10 sites previously listed). These variables were chosen
based on the strength of their relation in univariate analyses with all NBDPS birth
defects. There were maternal interviews from
19,059 cases and 6807 controls who met the inclusion dates. The participation rate
was 70% for cases and 67% for controls. We excluded participants with missing data
on whether they were treated with an opioid analgesic in early pregnancy, due either
to an incomplete medication history from the interview or an unknown medication
start or stop date. We excluded mothers with preexisting diabetes, which has been
found to be a strong independent risk factor for birth defects. 30,31 To focus our
investigation on therapeutic opioid analgesic use, we also excluded mothers who
reported opioid exposure in the form of illicit drugs such as heroin any time during
pregnancy. Our final sample for analysis included 17,449 cases with the included
defects and 6701 controls (Figure). Although the total number of cases included was
greater than the total number of controls, controls substantially outnumbered cases
in most analyses, each of which involved comparisons of infants with 1 particular
category or subcategory of birth defects to all controls. Of note, infants with _1 defect
were included in multiple birth defect categories. Our primary analysis tested the
hypothesis that maternal therapeutic use of opioid analgesics in early pregnancy was
associated with the occurrence of CHD, cleft lip and/or palate, or neural tube defects
in infants. Secondary, exploratory analyses were also performed in other birth defect
groups. Weconducted subanalyses limiting either the exposure or birth defect groups.
First, using the same case groups and exposure definition as the main analysis, we
restricted the exposure time period to only the first 2 months after conception. Next,
using the original case groups and the original exposure time period (1 month before
to 3 months after conception),

we estimated the effects of exposure to particular opioid analgesics. Because of the

decreased sample size, we estimated crude ORs only for the most commonly
reported components. Finally, using the same exposure definition as the main
analysis, we examined cases with isolated birth defects or simple, isolated heart
defects separately.

RESULTS
Of the 17,449 mothers of case infants with various included birth defects, 454 (2.6%)
reported opioid analgesic treatment between 1 month before and 3 months after
conception. Among 6701 control mothers, 134 (2.0%) reported treatment in this time
period. The most commonly reported opioids were codeine
(34.5%), hydrocodone (34.5%), oxycodone (14.4%), and meperidine (12.9%), with
codeine and hydrocodone exposure being slightly more common among cases, and
oxycodone and meperidine exposure slightly more common among controls. Lower
maternal education level, prepregnancy obesity, and periconceptional smoking were
all slightly more frequent among cases than controls (Table 1). The reasons for opioid
use were based on the questionnaire topic under which the medication was reported.
For the
66%of exposedwomenwhose treatment could be linked to a specific reason, opioids
were most commonly reported within the surgical procedures (41%), infections
(34%), chronic diseases (20%), and injuries (18%) sections of the questionnaire. The
primary analysis included a total of 7724 infants with _1 of 15 different kinds of CHD.
Some of these defects were grouped into 1 of 4 larger phenotypic categories
(conotruncal defects, left ventricular outflow tract obstruction defects, right
ventricular outflow tract obstruction defects, or septal defects) or into 1 of
2CHDassociations (ventricular septal defect _ atrial septal defect, ventricular septal
defect _ pulmonary valve stenosis), and ORs were estimated for each case group and
higher level classification in comparison to the same set of 6701 control infants.
Effect estimates were statistically significantly elevated for all eligible CHD combined
(OR, 1.4; 95% confidence interval
[CI], 1.11.7). Statistically significant associations with maternal opioid use were
found among infants with
conoventricular septal defect, atrioventricular septal defect, atrial septal defect (not
otherwise specified), hypoplastic left heart syndrome, tetralogy of Fallot, or
pulmonary valve stenosis (Table 2). We also found a significant association between
maternal opioid use between 1 month before and 3 months after conception
with spina bifida (OR, 2.0; 95% CI, 1.33.2), as hypothesized, but not with the other
neural tube defects (anencephaly or craniorachischisis) studied (Table 2). The
exploratory analyses of maternal opioid use for infants with _1 of 18 other categories
of birth defects found statistically significant associations for hydrocephaly (OR, 2.0;
95% CI, 1.0 3.7), glaucoma or anterior chamber eye defects (OR, 2.6; 95% CI, 1.0
6.6), and gastroschisis (OR, 1.8; 95% CI, 1.12.9). Limiting the exposure definition to
the first 2 months after conception produced results very similar to the main
estimates using exposure during the period from 1 month before to 3 months after
conception (results not shown). Point estimates using the tighter exposure period
definition were generally greater in magnitude; we saw the highest OR for
hypoplastic left heart syndrome (OR, 3.7; 95% CI, 2.1 6.6). Codeine and/or
hydrocodone accounted for the majority of statistically significant findings from the
main analysis, and oxycodone was only significantly associated with pulmonary valve
stenosis (Table 3). However, given that the CIs for the effect estimates for each
specific birth defect overlap, we cannot conclude whether one medication would be
preferable to another in terms of risk for birth defects. Most birth defects found to be
statistically significantly associated with early pregnancy opioid treatment in the
main analysis were also associated in the subanalysis limited to isolated cases for
noncardiac defects or simple, isolated cases for heart defects (Table 4). Ors from

the subanalysis were generally similar to those from the main analysis. When
reviewing the nonisolated cases, we did not observe any pattern or common
combinations of birth defects.

COMMENT
Using data from a large populationbased case-control study, we found associations
between maternal therapeutic use of opioid medications in early pregnancy and
several types of CHD, consistent with some previous findings for first-trimester use of
the opioid codeine. 14-16 Previous reports considered associations with CHD as a single
group; we also found a statistically significant association with an aggregate group
that includes infants with any 1 of the 15 NBDPS-eligible diagnostic categories of
heart defects (OR, 1.4; 95% CI, 1.11.7), but this risk is not directly comparable to
those reported in previous studies because of differences in the CHD inclusion
criteria. The ORs of greatest magnitude were observed for conoventricular septal
defects, atrioventricular septal defects, atrial septal defects (not otherwise specified),
and hypoplastic left heart syndrome, a defect that accounts for much of the infant
mortality burden attributable to CHD.32 Even though our data set is the largest used
to date to study opioid exposure andCHDand includes the most recently available
data from this ongoing study, sample sizes for some individual CHD categories are at
the borderline for what is required to observe these effects. Upon subanalysis,
codeine and hydrocodone accounted for the majority of statistically significant
findings from our main analysis, but these drugs were also the most frequently used,
representing 69% of all reported exposures. Most estimated effect measures for
opioid-associated birth defects were higher when using a tighter early pregnancy
exposure period definition than those seen with exposures at any time during the
first trimester or in the month before conception. A stronger relationship with
treatment confined to the critical window for embryologic development (3-8 weeks
postfertilization) is consistent with what would be expected if the associations were
causal. We also found statistically significant associations of early pregnancy opioid
treatment among infants with spina bifida, which concurs with experimental studies
performed in hamsters.24,25 Maternal opioid treatment has not been associated with
an increased risk of neural tube defects in previous epidemiologic studies of human
pregnancy,21-23 and additional evaluation of this observation is necessary. Similarly,
the significant associations we observed in exploratory analyses with maternal opioid
treatment among infants with hydrocephaly, glaucoma, or gastroschisis have not
been previously reported. Given the probability that some findings may be due to
chance, our results should be treated with caution and deserve further investigation.
The prevalence of opioid treatment in early pregnancy among control and case
mothers was observed to be 2-2.6%. According to the National Health and Nutrition
Examination Survey, the percentage of women aged 18-44 years who reported
prescription narcotic drug use in the month prior to interview from 1999 through
2002 was approximately 5%. In this same time period, women of all ages reported
more use than men, and use among women increased by nearly one-half from that
reported in 1988 through 1994.11 The activity of opioids and their receptors as growth
regulators during embryologic development may provide a mechanism that explains
our findings.
One native opioid peptide, opioid growth factor, acts as a negative growth
regulator.33 In addition, endogenous opioids can inhibit DNA synthesis and decrease
cellular proliferation, and blockade of opioid growth factor receptors with opioid
antagonists increases DNA synthesis in multiple fetal tissues, including neural and
cardiac tissues, consistent with our study results. 34 Exogenous opioids might also act
on opioid
growth factor receptors during embryogenesis, resulting in delayed cell growth and
migration at critical times in development and consequent increased risk for certain
birth defects. Our study has several strengths. We used data from the largest

collaborative population-based study of birth defects in the United States. Whereas

many previous studies of birth defects have not adequately characterized birth
defects
phenotypes, our cases were reviewed by clinical geneticists with expertise in birth
defects, and heart defects were also reviewed by clinicians with expertise in pediatric
cardiology. Furthermore, grouping of CHD based on presumed developmental
mechanisms may aid in understanding the potential effects of exposures.
6 The study used multiple questions to ascertain medication use, and we were able to
classify reported products into their component ingredients. Our findings are also
subject to several limitations. Nonresponse is one of those limitations; however, the
rates of nonresponse of 30% among case mothers and 33% among control mothers
were similar. Exposure information was obtained through retrospective maternal selfreport, which might result in recall bias and/or exposure misclassification, particularly
given the variable time to interview. While the average time lag between delivery
and interview was 9-11 months, some women who were interviewed 2 years after the
EDD were asked to recall exposures up to 3 years in the past. Postpregnancy
reporting of prescription medications has been shown to be relatively complete when
very specific recall prompts are used, including questions on both medical conditions
necessitating treatment and the treatment itself.35 This study included medication
recall questions based on medical conditions, illnesses, or events but did not
specifically ask about opioid medications by name, which could have negatively
impacted recall. Whereas case mothers are generally more likely to have reflected on
pregnancy exposures than control mothers in case-control studies, control infants in
this study were not required to be healthy, but instead were live births without
major birth defects. In addition, previous analyses of the issue of recall bias have
found that even in studies of reproductive outcomes, exposure misclassification is
likely to be nondifferential and result in estimates biased toward the null. 36,37
Misclassification of prepregnancy body mass index was also possible, with likely
underestimation of the proportion of obese mothers among both case and control
infants.38-40 The study does not collect information on medication dose, so we were
unable to assess dose-response relationships. Because many of the medication
products included in our analysis were multiple-component products, one must
consider the influence of other ingredients. Also, because the most commonly
reported reason for opioid use was surgical procedures, other medications (eg,
anesthesia) could have been used concomitantly for this or other indications.
Confounding by indication is unlikely for opioid medications because of the wide
range of conditions they are used to treat. In conclusion, we found that maternal
opioid analgesic treatment early in pregnancy was associated with certain types of
birth defects in infants, including some types ofCHD,which are important contributors
to infant morbidity and mortality.8 Identification of a biologically plausible mechanism
supports this finding, although better pathogenetic understanding is needed to
explain why opioid analgesic treatment is associated with some defects but not
others. It is important to emphasize that an increased relative risk for any rare birth
defect with an exposure usually translates into only a modest absolute increase in
risk above the baseline birth defects risk. For example, the estimated birth
prevalence of hypoplastic left heart syndrome in the United States is 2.4/10,000 live
births.2 Our findings suggest a potentially 2.4-fold increased risk for a hypoplastic left
heart syndrome-affected pregnancy in a woman taking opioid analgesics
periconceptionally; this would suggest up to a 5.8 in 10,000 (0.06%) chance of that
woman having an infant with hypoplastic left heart syndrome. It is critical that health
care providers weigh the benefits of these medications along with their potential risks
when discussing analgesic treatment options with patients who are or may become
pregnant, including reproductive-aged women who
are not planning a pregnancy but might be at risk of an unintended pregnancy.

TABEL 1
Karakteristik populasi penelitian, Lahir Cacat Nasional Pencegahan studi, 1997 sampai
2005
Variabel Kasus n (%) Kontrol n (%) OR (95% CI)
Studi situs 17.449 6.701
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Arkansas 2328 (13.3) 832 (12.4) (rujukan)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
California 2262 (13.0) 845 (12,6) 1,0 (0,9-1,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Georgia 2.082 (11,9) 728 (10,9) 1,0 (0,9-1,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Iowa 1731 (9,9) 756 (11,3) 0,8 (0,7-0,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Massachusetts 2386 (13,7) 851 (12,7) 1,0 (0,9-1,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
New Jersey 1513 (8,7) 573 (8,6) 0,9 (0,8-1,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
New York 1258 (7,2) 592 (8,8) 0,8 (0,7-0,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
North Carolina 667 (3,8) 395 (5,9) 0,6 (0,5-0,7)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Texas 2176 (12,5) 762 (11,4) 1,0 (0,9-1,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Utah 1046 (6.0) 367 (5,5) 1,0 (0,9-1,2)
.................................................. .................................................. ..........................................

........ .................................................. .................................................. .................................

................. .................................................. ................
Usia ibu melahirkan, y 17449 6701
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
20 1898? (10.9) 711 (10,6) 1,1 (1,0-1,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
20-24 4111 (23,9) 1531 (22,9) 1,1 (1.0-1.2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
25-29 4478 (25,7) 1.777 (26,5) (rujukan)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
30-34 4313 (24,7) 1743 (26,0) 1,0 (0.9-1.1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
35-39 2139 (12,3) 803 (12,0) 1,1 (1.0-1.2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
40 509? (2,9) 136 (2,0) 1,5 (1,2-1,8)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
Ibu ras / etnis 17397 6672
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Non-Hispanic putih 10.472 (60,2) 3.993 (59,9) (rujukan)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Non-Hispanik hitam 1706 (9,8) 761 (11,4) 0,9 (0,8-0,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Hispanik 4033 (23,2) 1.486 (22,3) 1,0 (1,0-1,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......

Lainnya 1.186 (6,8) 432 (6,5) 1,0 (0,9-1,2)

.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
Ibu pendidikan, y 17326 6649
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
12 3092? (17.9) 1.121 (16,9) 1,1 (1,0-1,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
12 14234? (82,2) 5.528 (83,1) (rujukan)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
Ibu hamil obesitas 16722 6432
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Indeks massa tubuh? 30 13658 (81,7) 5.399 (83,9) (rujukan)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Indeks massa tubuh? 30 3064 (18,3) 1.033 (16,1) 1,2 (1,1-1,3)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
Asam folat suplemen usea 17446 6701
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Tidak menggunakan / digunakan di lain waktu 8.608 (49,3) 3.293 (49,1) (rujukan)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Setiap penggunaan 8838 (50,7) 3.408 (50,9) 1,0 (0,9-1,0)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
Smokinga 17358 6666
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Tidak ada 13.728 (79,1) 5.407 (81,1) (rujukan)
.................................................. .................................................. ..........................................

........ .................................................. .................................................. .................................

................. .................................................. .......
Setiap 3.630 (20,9) 1.259 (18,9) 1,1 (1,1-1,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
Kelompok kasus mencakup semua bayi dengan 1 cacat? berhak lahir. Subyek dengan
informasi yang kurang untuk variabel telah dikecualikan dari tallies untuk itu variabel
saja.
CI, confidence interval; OR, odds ratio.
penggunaan Dilaporkan dari 1 bulan sebelum sampai 1 bulan setelah pembuahan
kehamilan.
Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011.
www.AJOG.org Obstetri Penelitian
April

TABEL 2
Asosiasi antara pengobatan analgesik opioid ibu dan spesifik cacat lahir utama
Lahir cacat Jumlah no.a No terkena AOR (95% CI)
Hipotesis-pengujian analisis
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Kontrol 6701 134 Referensi
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Anencephaly / craniorachischisis 340 9 1.7 (0,84-3,4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Spina bifida 718 26 2,0 (1,3-3,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Setiap cacat jantung termasuk 7724 211 1,4 (1,1-1,7)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Laterality cacat dengan CHD 198 4 1.2 (0,42-3,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Atrioventrikular cacat septum 175 9 2.4 (1,2-4,8)

.................................................. .................................................. ..........................................

........ .................................................. .................................................. .................................
................. ................................................
Kembali anomali vena pulmonal 206 4 0,71 (0,22-2,3)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Single ventrikel / kompleks 201 4 1.1 (0,42-3,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Conotruncal cacat 1481 41 1,5 (1.0-2.1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Tetralogi Fallot 672 21 1,7 (1,1-2,8)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
D-Transposisi arteri besar 461 10 1.1 (0,56-2,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Defek septum ventrikel conoventricular 110 6 2,7 (1,1-6,3)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Waktu cacat saluran obstruksi outflow ventrikel 1195 36 1,5 (1.0-2.2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Sindrom hipoplasia jantung kiri 357 17 2,4 (1,4-4,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Coarctation dari aorta 630 11 0,88 (0,47-1,6)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Stenosis aorta 253 7 1.3 (0,61-2,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Hak cacat saluran obstruksi outflow ventrikel 1175 40 1,6 (1.1-2.3)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................

................. ................................................
Pulmonary stenosis katup 867 34 1,7 (1,2-2,6)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Cacat septum 3482 87 1.2 (0,93-1,6)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Defek septum ventrikel perimembranous 1402 29 0,99 (0.65-1.5)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Atrial cacat septum secundum 1507 43 1,3 (0.94-1.9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
defek septum atrium tidak disebutkan secara spesifik 511 17 2,0 (1.2-3.6)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
PJK asosiasi: defek septum ventrikel? cacat septum atrium 528 17 1,7 (1,0-2,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
PJK asosiasi: stenosis katup pulmonal? cacat septum ventrikel 131 4 1.3 (0,46-3,7)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Celah langit-langit 936 25 1,3 (0,84-2,0)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Celah bibir sumbing langit-langit dengan 1162 33 1,4 (0.96-2.1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Celah bibir sumbing tanpa langit-langit 614 9 0,68 (0,34-1,3)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
TABEL 2
Asosiasi antara pengobatan analgesik opioid ibu dan spesifik cacat lahir utama (lanjutan)
Lahir cacat Jumlah no.a No terkena AOR (95% CI)

Analisa
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Kontrol 6701 134 Referensi
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Amniotic band syndrome / ekstremitas tubuh dinding kompleks 203 5 1.0 (0,37-2,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Hidrosefali 301 11 2,0 (1,0-3,7)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Katarak 217 7 1.6 (0,72-3,5)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Glaukoma / cacat anterior chamber 103 5 2,6 (1,0-6,6)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Anotia / microtia 403 4 0,77 (0,28-2,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Atresia esophagus 434 12 1.4 (0,76-2,5)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Usus atresia / stenosis 266 4 0,88 (0,32-2,4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Anorectal atresia / stenosis 623 18 1,5 (0,87-2,4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Hipospadia kedua derajat / ketiga 1.313 29 0,92 (0,59-1,4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Bilateral ginjal agenesis atau hipoplasia 112 4 1.3 (0,40-4,2)
.................................................. .................................................. ..........................................

........ .................................................. .................................................. .................................

................. .................................................. .......
Longitudinal tungkai defisiensi 269 6 1.1 (0,49-2,6)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Longitudinal tungkai defisiensi preaxial 157 4 1.3 (0,48-3,6)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Transverse ekstremitas defisiensi 415 7 1.0 (0,46-2,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Craniosynostosis 806 16 0,82 (0,48-1,4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Hernia diafragma 507 12 1.2 (0,66-2,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Omphalocele 267 7 1.3 (0,60-2,8)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Gastroschisis 726 26 1,8 (1,1-2,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
Odds rasio yang disesuaikan untuk ibu, usia ras / etnis, pendidikan, ada atau tidak adanya
hamil, kehadiran obesitas atau tidak adanya periconceptional merokok, dan pusat studi.
AOR, rasio odds yang disesuaikan; PJK, cacat jantung kongenital, CI, selang
kepercayaan.
sebuah Beberapa perbandingan yang digunakan kurang dari jumlah kontrol (misalnya,
hipospadia hanya digunakan kontrol laki-laki); sejumlah kasus termasuk orang dengan
data eksposur nonmissing dan tidak termasuk hamil
penderita diabetes (tipe 1 atau 2) dan ibu pelaporan paparan opioid narkoba.
Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011.
TABEL 3
Asosiasi antara komponen opioid umum dan spesifik cacat lahir utama
Hydrocodone oxycodone codeine meperidin
Lahir cacat
No terkena

casesa
crOR
(95% CI)
No terkena
casesa
crOR
(95% CI)
No terkena
casesa
crOR
(95% CI)
No terkena
casesa
crOR
(95% CI)
Hipotesis-pengujian analisis
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Anencephaly /
craniorachischisis
3 4 1,9 (0.67-5.3)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Spina bifida 7 1.5 (0,68-3,4) 11 2,5 (1,3-4,8)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Setiap cacat jantung termasuk 71 1.4 (0,98-2,1) 70 1.4 (0,99-2,1) 28 1.0 (0,59-1,7) 30 1,2
(0,68-2,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Atrioventrikular septal
cacat
4 3,6 (1.3-10.2) 4 3,7 (1.3-10.4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Conotruncal cacat 14 1,5 (0,81-2,7) 16 1.7 (0,97-3,1) 4 0,75 (0,26-2,2) 5 1.0 (0,39-2,7)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Tetralogi Fallot 6 1.4 (0,59-3,3) 10 2,4 (1,2-4,8) 4 1.7 (0,58-4,8)
.................................................. .................................................. ..........................................

........ .................................................. .................................................. .................................

................. ................................................
Waktu keluar ventrikel
obstruksi saluran cacat
15 2,0 (1.1-3.5) 14 1,9 (1.0-3.4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Hipoplasia jantung kiri
sindroma
7 3,1 (1.4-6.9) 7 3,2 (1.4-7.1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Coarctation dari aorta 4 0,99 (0,35-2,8) 4 1.0 (0,36-2,8)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Stenosis aorta 4 2.5 (0,89-7,0) 2
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Keluar ventrikel kanan
obstruksi saluran cacat
10 1,3 (0.66-2.6) 13 1,8 (0.95-3.3) 9 2,1 (0.99-4.6) 5 1,3 (0.49-3.4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Pulmonary stenosis katup 8 1.3 (0,62-2,9) 12 2,2 (1,2-4,3) 8 2.4 (1,1-5,4) 4 1.4 (0,47-4,0)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Cacat septum 24 1.1 (0,65-1,8) 26 1,2 (0,73-1,9) 11 0,88 (0,43-1,8) 19 1.7 (0,90-3,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Ventricular septal defect
perimembranous
13 1,4 (0.78-2.7) 8 0,91 (0.43-1.9) 4 0,79 (0.28-2.3)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Atrial septal defect
secundum
8 0,83 (0.39-1.8) 16 1,7 (0.95-3.0) 7 1,3 (0.56-3.0) 10 2,0 (0.96-4.3)

.................................................. .................................................. ..........................................

........ .................................................. .................................................. .................................
................. ................................................
Atrial septal tidak cacat
dinyatakan khusus
4 1,2 (0.44-3.4) 5 1,6 (0.62-4.0)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
PJK asosiasi:
ventrikel septal cacat
? atrial septal defect
2 8 2,4 (1.1-5.2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Celah langit-langit 6 0,98 (0,41-2,3) 12 2,1 (1,1-3,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Celah bibir sumbing langit-langit dengan 11 1.4 (0,75-2,8) 11 1,5 (0,78-3,0) 7 1.7 (0,713,8)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
Analisa
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Hidrosefali 5 2.6 (1,0-6,7) 4 2.1 (0,76-6,0)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Katarak 3 4 2.4 (0,86-6,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Esophageal atresia 5 1,8 (0,71-4,6) 3
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Anorectal atresia / stenosis 5 1.3 (0,50-3,2) 7 1.8 (0,81-4,0)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Hipospadia kedua / ketiga

gelar
11 0,89 (0.45-1.8) 4 0,47 (0.16-1.4) 6 1,4 (0.52-3.8) 9 1,8 (0.76-4.2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Craniosynostosis 6 1.2 (0,49-2,7) 5 0,99 (0,39-2,5)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
6 hernia diafragma 1.9 (0,79-4,4) 5 1.6 (0,62-4,0)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Gastroschisis 9 1.9 (0,94-4,0) 15 3,3 (1,8-6,1) 5 1.9 (0,73-5,1)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
crORs disajikan untuk kategori cacat lahir dengan setidaknya 4 kasus terkena? 1 dari
bahan-bahan dipertimbangkan dalam subanalysis ini.
PJK, cacat jantung kongenital, CI, confidence interval; crOR, kasar odds ratio.
sebuah Termasuk mereka dengan data eksposur nonmissing dan tidak termasuk hamil
penderita diabetes (tipe 1 atau 2) dan ibu pelaporan paparan opioid narkoba.
Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011.
Penelitian Obstetri www.AJOG.org
TABEL 4
Asosiasi antara pengobatan analgesik opioid ibu dan "terisolasi" dan nonisolateda cacat
lahir utama
Terisolasi / terpencil kasus sederhana
Nonisolated / nonsimple
terisolasi kasus
Lahir cacat
No terkena
casesb aORc (95% CI)
No terkena
casesb aORc (95% CI)
Hipotesis-pengujian analisis
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Anencephaly / craniorachischisis 8 1.6 (0,78-3,4) 1
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Spina bifida 21 1,8 (1,1-3,0) 5 3,7 (1,4-9,6)

.................................................. .................................................. ..........................................

........ .................................................. .................................................. .................................
................. .................................................. .......
Setiap cacat jantung termasuk 137 1,3 (1,0-1,7) 74 1,4 (1,1-1,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Atrioventrikular cacat septum 3 6 3.9 (1,6-9,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Conotruncal cacat 24 1.2 (0,77-1,9) 17 2,1 (1,2-3,5)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Tetralogi Fallot 16 1.6 (0,95-2,8) 5 2.2 (0,87-5,5)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
D-Transposisi arteri besar 7 0,97 (0,45-2,1) 3
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Defek septum ventrikel conoventricular 0 6 5.1 (2,1-12,4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Waktu ventrikel keluar cacat obstruksi saluran 27 1.6 (1,1-2,5) 9 1.3 (0,63-2,5)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Sindrom hipoplasia jantung kiri 16 2,5 (1,5-4,3) 1
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Coarctation dari aorta 5 0,80 (0,32-2,0) 6 0,97 (0,42-2,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Stenosis aorta 5 1.3 (0,52-3,2) 2
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Keluar ventrikel kanan cacat obstruksi saluran 33 1,9 (1,3-2,9) 7 0,89 (0,41-1,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................

................. ................................................
Pulmonary stenosis katup 27 2.0 (1,3-3,1) 7 1.1 (0,52-2,5)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
48 cacat septum 1.1 (0,78-1,6) 39 1.4 (0,96-2,0)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
cacat septum ventrikel perimembranous 19 1.0 (0,62-1,7) 10 0,91 (0,46-1,8)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
Atrial cacat septum secundum 19 1.1 (0,70-1,9) 24 1,5 (0,97-2,4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. ................................................
defek septum atrium tidak dinyatakan khusus 8 1.8 (0,81-4,1) 9 2,4 (1,2-4,8)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Celah langit-langit 19 1.2 (0,74-2,0) 6 1.7 (0,72-3,9)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Celah bibir sumbing langit-langit dengan 26 1.3 (0,84-2,0) 7 2,8 (1,3-6,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Celah bibir sumbing tanpa langit-langit 9 0,72 (0,36-1,4) 0
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. ................
Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011. (Lanjutan)
TABEL 4
Asosiasi antara pengobatan analgesik opioid ibu dan "terisolasi" dan nonisolateda cacat
lahir utama
(Lanjutan)
Terisolasi / terpencil kasus sederhana
Nonisolated / nonsimple
terisolasi kasus
Lahir cacat
No terkena
casesb aORc (95% CI)
No terkena

casesb aORc (95% CI)

Analisa
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Hidrosefali 8 2.0 (0,96-4,2) 3
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Katarak 7 2.0 (0,89-4,3) 0
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Glaukoma / cacat bilik anterior 5 3.2 (1,2-8,2) 0
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Atresia esofagus 1 11 2.2 (1,2-4,2)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Usus atresia / stenosis 4 1.0 (0,38-2,9) 0
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Anorectal atresia / stenosis 10 1.9 (0,96-3,6) 8 1.1 (0,52-2,4)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Hipospadia kedua derajat / ketiga 26 0,91 (0,57-1,5) 3
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
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Longitudinal tungkai defisiensi 2 4 2.0 (0,71-5,5)
.................................................. .................................................. ..........................................
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Longitudinal defisiensi preaxial ekstremitas 0 4 2.4 (0,84-6,6)
.................................................. .................................................. ..........................................
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Transverse ekstremitas defisiensi 5 0,84 (0,34-2,1) 2
.................................................. .................................................. ..........................................
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Craniosynostosis 16 0,92 (0,53-1,6) 0

.................................................. .................................................. ..........................................

........ .................................................. .................................................. .................................
................. .................................................. .......
11 hernia diafragma 1.4 (0,73-2,6) 1
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
................. .................................................. .......
Omphalocele 3 4 1.8 (0,64-5,0)
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
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Gastroschisis 25 1,9 (1,2-3,1) 1
.................................................. .................................................. ..........................................
........ .................................................. .................................................. .................................
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aORs disajikan untuk kategori cacat lahir dengan setidaknya 4 kasus terpapar
dipertimbangkan dalam subanalysis ini.
AOR, rasio odds yang disesuaikan; CI, selang kepercayaan.
sebuah Cacat yang tidak pernah terjadi "terisolasi" (misalnya, urutan band ketuban) tidak
dimasukkan dalam analisis ini. Kedua cacat jantung bawaan dan cacat noncardiac dapat
terjadi sebagai cacat "terisolasi", sebagai salah satu
beberapa cacat utama yang tidak berhubungan, atau sebagai komponen dari sindrom atau
pola kompleks lainnya (baik dari terakhir menjadi "nonisolated") .28 Untuk cacat jantung
bawaan, klasifikasi juga terjadi pada sumbu kedua
berfokus pada jantung untuk menggambarkan kompleksitas keterlibatan jantung.
"Sederhana" cacat jantung secara anatomi diskrit baik yang diakui atau entitas tunggal;
"asosiasi" didefinisikan sebagai umum, tidak rumit
kombinasi cacat jantung, dan cacat jantung yang tidak masuk dalam kategori baik
dianggap "kompleks" (2 terakhir dianggap "nonsimple" untuk analisis ini); b Jumlah
kasus termasuk orang
dengan nonmissing data eksposur dan tidak termasuk hamil penderita diabetes (tipe 1
atau 2) dan ibu pelaporan paparan opioid narkoba; c Odds rasio yang disesuaikan untuk
ibu, usia ras / etnis,
pendidikan, ada atau tidak adanya hamil, kehadiran obesitas atau tidak adanya
periconceptional merokok, dan pusat studi.
Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011.