znjke.com 2016; 352 doi: https://doi.org/10.1136/znjke.com.h6712 (Published 06 January 2016) mention this as: znjke.com 2016;352:h6712
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Abstract

Study question Is dental contraceptive use roughly the time of pregnant onset linked with an boosted risk of major birth defects?

Methods In a prospective observational cohort study, data on dental contraceptive use and major birth defects were gathered among 880 694 live births native Danish registries in between 1997 and also 2011. We conservatively suspect that dental contraceptive exposure lasted approximately the many recently filled prescription. The key outcome measure was the number of significant birth defects transparent one year follow-up (defined follow to the European surveillance of Congenital Anomalies classification). Logistic regression estimated prevalence odds ratios of any major birth defect as well as categories of birth defect subgroups.

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Study answer and limitations Prevalence of significant birth defects (per 1000 births) to be consistent across each oral contraceptive exposure team (25.1, never users; 25.0, usage >3 months before pregnancy beginning (reference group); 24.9, usage 0-3 months prior to pregnancy onset (that is, current use); 24.8, use after pregnancy onset). No increase in prevalence of significant birth defects was checked out with dental contraceptive exposure amongst women with current use prior to pregnancy (prevalence odds ratio 0.98 (95% trust interval 0.93 come 1.03)) or usage after pregnant onset (0.95 (0.84 come 1.08)), compared with the recommendation group. Over there was likewise no boost in pervasiveness of any kind of birth defect subgroup (for example, limb defects). It is unknown whether females took oral contraceptives up to the date of their most recently fill prescription. Also, the rarity of bear defects made disaggregation the the outcomes difficult. Residual confounding was possible, and also the evaluation lacked information on folate, among the proposed mechanisms.

What this examine adds Oral contraceptive exposure just prior to or throughout pregnancy walk not appear to be associated with an boosted risk of significant birth defects.

Funding, competing interests, data sharing BMC to be funded through the Harvard T H Chan college of publicly Health’s Maternal health and wellness Task Force and also Department of epidemiology Rose travel Fellowship; training grant T32HD060454 in reproductive, perinatal, and also paediatric epidemiology and also award F32HD084000 from the Eunice Kennedy Shriver nationwide Institute of kid Health and Human Development; and grant T32CA09001 indigenous the national Cancer Institute. The authors have no contending interests or added data to share.


Oral contraceptive drugs are the most renowned contraceptive method in many parts that the world.1 2 Although dental contraceptives are over 99% reliable with perfect use, an approximated 9% of oral contraceptive users come to be pregnant in their an initial year that use,3 fan to let go or delay doses, drug interactions, or illness4 in what is well-known as a breakthrough pregnancy. Many more women will protect against using dental contraceptives when planning a pregnancy and conceive in ~ a couple of menstrual cycles. In both this instances, a woman might inadvertently disclose her fetus come exogenous sex hormones (such as progestins).5 6

Yet, despite years of research on the safety of oral contraceptive use, tiny is known around the combination of oral contraceptive use just prior to or throughout pregnancy v the offspring’s health. In particular, it is uncertain whether this circulating exogenous sex hormone can damage the fetus and how lengthy potential results of turn around exogenous sex hormones can last. The literature has actually primarily concentrated on bear defects, however findings conflict and also their translate is complicated owing to methodological limitations. For example, most of these studies were conducted over 30 years ago; relied on me reported, retreat exposure evaluate in small case-control samples; and examined a single outcome (for example, body defects).7 several of these findings indicate that dental contraceptive use is linked with details birth defects—including hypoplastic left heart syndrome,8 gastroschisis,8 limb defects,9 and also urinary tract anomalies10—while others discovered no together association.11 12 13 14 15 16 17 18 19

With regard come mechanisms, exogenous sex hormones have actually been shown to boost plasma concentration of vitamin A,20 which deserve to be teratogenic.21 Studies also suggest the serum folate concentrations decrease after dental contraceptive use and remain decreased for increase to 3 months ~ discontinuation; this could lead to a variety of birth defects.5 6

Using lot of Danish registries, we conducted a nationwide cohort examine to investigate even if it is recent oral contraceptive use (less than 3 months prior to pregnancy) or use throughout early pregnancy was associated with an enhanced risk of significant birth defects.


Methods

We used data from the Danish clinical Birth register that consisted of all singleton live births ceded from 1 January 1997 to 31 march 2011. We excluded births v a lacking or implausible gestational age. After excluding infants with birth defects with known causes (such together fetal alcohol syndrome) or chromosomal aberrations (n=2714), the final cohort had 880 694 liveborn infants. Individual level data were linked between registries by use of the Danish polite Registration System’s unique personal identification number assigned to all Danish residents.


Data sources

The clinical Birth register was created in 1968 and contains info on all Danish births, including date of birth, many births, gestational age, and also various newborn characteristics, as well as maternal qualities such as parity and smoking status.22 The Danish nationwide Patient Register consists of information on outpatient and emergency room visits and also inpatient admissions to every Danish hospitals.23 indigenous this register, we acquired diagnostic details on birth defects and also maternal clinical conditions. Details on age, ar of residence, and place of bear of the females was acquired from the main administrative register (known together the main Person Register).24 Statistics Denmark listed data ~ above maternal education and learning level, gross family members income, and also civil status.

In the clinical Birth Register, gestational period is calculated by the an initial day that the last menstrual period and consequently corrected in most pregnancies by ultrasonographic measurements. Because that this study, we estimated pregnancy start by individually the gestational age from the day of birth.


Oral contraceptive exposure

The Danish national Prescription Register has information on medicine prescriptions filled in ~ Danish pharmacies because 1995, such together the anatomical therapeutic chemical code (G03A because that all dental contraceptives, consisting of less common forms such as progestin just pills and also emergency contraception) and the date the prescription was filled.25 we conservatively assumed that a mrs was exposed approximately the day of her many recently to fill prescription. Each mrs was categorised follow to her oral contraceptive use regardless of other hormonal contraceptive usage (for example, progestin intrauterine device).

We defined never users as those who never ever filled an dental contraceptive prescription since the development of the prescription register. Offered the high prevalence of dental contraceptive use, never ever users are most likely a highly selected group of individuals and also therefore might not be the best reference group. Based upon the previous literature, an especially on the proposed mechanism of lessened folate increase to three months after stopping use,5 6 we modelled dental contraceptive exposure into unique categories (>3 months before pregnancy onset (reference group), 0-3 months prior to pregnancy beginning (that is, recent use), and after pregnant onset). The two main exposures of attention were use after pregnant onset and also recent use before pregnancy onset.


Major birth defects outcome

Major bear defects were established from the nationwide Patient Register, permitting for a one year follow-up ~ birth. Validation studies of this registry verified that 88% of birth defect diagnoses26 to be correct when evidenced by medical record review. Major birth defects were characterized according come the European security of Congenital Anomalies classification, excluding minor defects (web table S1).27

The major outcome was any major birth defect, and secondary outcomes were subgroups of significant birth defects categorised by organ system. Ahead studies have actually observed associations in between oral contraceptive exposure and hypoplastic left heart syndrome,8 gastroschisis,8 body defects,9 and urinary street anomalies.10 We consisted of analyses of limb and urinary street defects in our secondary outcomes; we also added analyses of specific birth defects including gastroschisis and also hypoplastic left heart syndrome.


Statistical analyses

We used logistic regression come estimate prevalence odds ratios the any major birth defect and also categories of birth defect subgroups. Because that these classification analyses, an infant could add to number of analyses. Because that instance, if a child had actually one defect categorised together “nervous system” and also another categorised together “eye,” that pregnancy was contained in both analyses.

A priori understanding of the risk components for birth defects and also determinants of oral contraceptive usage were supplied to pick potential confounders because that adjustment. Us imputed any missing covariate values v each variable’s respective setting (web table S2) and also most covariates had actually less 보다 0.01% missing values. Covariates included:

• Demographics (maternal period at pregnancy onset, calendar year of pregnant onset, location of birth, ar of residence, married or living with partner, level of education, and household income)

• Parity

• background of bear defects in a vault pregnancy

• smoking cigarettes in pregnancy

• healthcare use (prescription drug usage in the past six months, hospital admissions in the past five years, and outpatient contact in the past five years).

We conducted sensitivity analyses with propensity score matching. Utilizing logistic regression, we approximated propensity scores as the probability of exposure to oral contraceptives after pregnant onset provided baseline characteristics at pregnancy onset. The propensity score likewise included every two way interactions in between demographic variables in the regression. Exposed ladies (defined together those who offered oral contraceptives after pregnant onset) were climate matched in a 1:4 proportion to unexposed females (defined as those that stopped oral contraceptive use more than three months before pregnancy onset). Corresponding was done by use of the nearest neighbour equivalent algorithm (a caliper width equal to 0.1 of the typical deviation that the logit score).28 29

We likewise ran further sensitivity analyses by including birth defects identified amongst induced abortions ~ 12 gestational main (ICD-10 (international group of diseases, 10th revision) password O05.3 and also O05.4) and stillbirths, as explained in information previously.30 However, the it is registered of bear defects among induced abortions and stillbirths was no validated. Data because that this sensitivity analysis were obtainable for the duration from 1 January 2004 to 31 in march 2011 (n=429 940, net fig). We offered SAS software (version 9.2) for all analyses.


Patient involvement

No patient were affiliated in setting the research inquiry or the outcome measures, no one were they involved in emerging plans because that recruitment, design, or implementation the the study. No patients to be asked to recommend on interpretation or creating up of results. There space no plans come disseminate the outcomes of the study to examine participants or the appropriate patient community.


Results

Of 880 694 liveborn babies in our study cohort, 2.5% (n=22 013) were diagnosed v a major birth defect in ~ the an initial year of life. Over 2 thirds that the cohort mothers (69%, n=611 007) had actually used dental contraceptives yet stopped an ext than three months before pregnancy onset, when 21% (n=183 963) never used dental contraceptives. However, 8% (n=74 542) had actually recently quit using dental contraceptives (0-3 months before pregnancy onset), and 1% (n=11 182) provided oral contraceptives past pregnancy onset, both categories us had thought about as exposed.

Table 1⇓ reflects the features of cohort mother according to oral contraceptive exposure timing. Contrasted with females who had stopped using dental contraceptives an ext than three months prior to pregnancy beginning (reference group), both groups of exposed women were normally younger, less likely to it is in married or living through a partner, much less educated, had actually a lower income, were much less likely to be parous, and smoked more often throughout pregnancy.

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Table 1

Characteristics of pregnancies according to maternal dental contraceptive usage before and also after pregnancy onset in 1997-2011 (n=880 694). Data room no (%) the pregnancies


The prevalence of significant birth defects (per 1000 births) to be consistent throughout each of the oral contraceptive exposure groups: 25.1 for never users, 25.0 for dental contraceptive use much more than three months prior to pregnancy beginning (reference), 24.9 for dental contraceptive use 0 to three months before pregnancy onset (recent), and also 24.8 for oral contraceptive use after pregnant onset.

Our major analyses proved no enhanced risk of any major birth defect linked with oral contraceptive exposure (table 2⇓); this contained women who had actually recently stopped using oral contraceptives (prevalence odds proportion 0.98 (95% trust interval 0.93 come 1.03)) and also women who used oral contraceptives after pregnant onset (0.95 (0.84 come 1.08)). Equivalent results in sensitivity analyses, which consisted of the addition of pregnancies finishing as stillbirths and induced abortions to the cohort, were consistent (0.95 (0.89 to 1.02) and also 0.99 (0.84 come 1.16), respectively; table 3⇓). The an outcome for mothers using oral contraceptives after pregnancy onset was also consistent in a sensitivity analysis using propensity score corresponding (0.95 (0.83 to 1.09), table 4⇓).