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Hormonal Contraceptives: What if Exposed During Pregnancy?

INTRODUCTION

Hormonal contraceptives, also known as birth control pills, provide reliable contraception and several contraceptive unrelated benefits. The decrease in their estrogen and progestin contents had led to a decrease in cardiovascular side effects (1). Owing to their ease of use, these preparations are a reliable option for the vast majority of women using contraception. Their action is to suppress the secretion of gonadotropin-releasing hormone from the hypothalamus and gonadotropins from the pituitary gland. The outstanding mechanism is the prevention of ovulation through the inhibition of the midcycle luteinizing hormone surge. In addition, these agents inhibit ovarian folliculogenesis by suppressing follicle-stimulating hormone secretion from the pituitary gland (2).

Hormonal contraceptives are frequently prescribed for abnormal menstrual bleedings, hyperandrogenism, hormone replacement therapy, primary ovarian failure, and polycystic ovary syndrome on behalf of contraception. Women who learn about their pregnancies while on contraception therapy are concerned that the drug may have negative effects on the fetus due to its hormonal components. In the literature, these agents are notified not for use in pregnant women. Most products are defined as contraindicated in women who are pregnant or suspected to be pregnant. Some patterns of genital anomalies, such as hypospadias in male babies and clitoral enlargement and labial fusion in female babies who were exposed to hormones in utero during the first trimester, have been reported (3). Based on this data, treatment should be discontinued in case of pregnancy. On the other hand, these agents are not related to major fetal or maternal side effects when used inadvertently in early pregnancy (4).

The aim of the present study was to investigate the potential effects of hormonal contraceptives on the neonatal outcomes of women who had been exposed to these agents without being aware of their pregnancy. Neonatal outcomes include fetal abnormality, major and/or minor birth defects, postnatal complications, and delivery circumstances.

MATERIALS and METHODS

Twenty-five pregnant women who were admitted to the Teratology Information Service (TIS) between 2014 and 2018 for teratogenic risk analysis of hormonal contraceptives exposed inadvertently during their pregnancies were included in the study. The study was approved by the Ethics Committee of Clinical Trials of the Faculty of Medicine (approval date: 10/24/2018, approval no.: 2018/19/14).

Information about the hormonal contraceptives used by pregnant women was recorded by using a structured registration form. In addition to the active substance of hormonal contraceptives, all other agents used concomitantly (herbs and drugs exposed in the acute or chronic process), radiation exposures, and smoking and alcohol consumptions were documented. Data about contraceptive doses, administration routes, amounts, indications, start and expiry periods, women's ages, races, and education levels were collected. The gestational week was calculated based on ultrasonography or the last menstrual period. This information was obtained face-to-face at first contact with the TIS. Women were contacted by telephone to collect neonatal outcomes after their expected date of birth. The type of delivery, gestational age at delivery, birth weight, neonatal sex, and the presence of any congenital anomalies or neurobehavioral disorders were recorded.

Statistical Analysis

Data were analyzed using the SPSS 17.0 program (SPSS Inc., Chicago, IL, USA). Data were expressed as median (range) for continuous variables.

RESULTS

Data About Pregnant Women

Twenty-five cases with inadvertent exposure to hormonal contraceptives in pregnancy between 2014 and 2018 were identified. The age of pregnant women was between 23 and 35 years. All were Turkish citizens living in Kahramanmaras province, except for two women who were from Gaziantep. Their education levels were primary or elementary level. The median gestational age at the first contact with the TIS was 8 (5-23) weeks. There was no exposure to radiation, cigarette, alcohol, or herb. In the present study, the contraceptive agent subtypes used by pregnant women included medroxyprogesterone acetate 5 mg (n=9), estradiol valerate 2 mg+norgestrel 0.5 mg (n=4), ethinyl estradiol 0.03 mg+levonorgestrel 0.15 mg (n=4), ulipristal 30 mg (n=2), medroxyprogesterone acetate 150 mg/ml (n=2), ethinyl estradiol 0.02 mg+gestodene 0.075 mg (n=2), norethisterone enanthate 50 mg+estradiol valerate 5 mg (n=1), desogestrel 75 [micro]g (n=1), progesterone 50 mg/ml (n=1), dydrogesterone 10 mg (n=1), and norethindrone 5 mg (n=1), provided that one woman had used one or more types of agents. Hormonal contraceptives had been used for the following indications: abnormal uterine bleeding (n=13), contraception (n=9), emergency contraception (n=2), and secondary amenorrhea (n=1). Table 1 shows the data about pregnant women.

Patterns of Contraceptive Exposure

All pregnancies were treated at standard doses. The administration routes were oral and intramuscular. The median start time of exposures was 3.5 weeks, and the median expiry week was 5 weeks. The gestational age at the beginning of contraception exposure ranged between <0 and 8 weeks, and expiry week ranged between <0 and 11 weeks. We found that 22 women were exposed to contraceptives in the first trimester, and 3 women in the preconception period. Table 2 presents the patterns of contraceptive exposure.

Data About Delivery and Neonatal Outcomes

We reached 16 women after the expected date of delivery. Among the infants of 16 women, all infants were born healthy, except for 1 infant who died at the first postnatal week. She was a premature female baby born at gestational week 32. Among the living 15 infants, 9 had been delivered by cesarean, and the other 6 infants were by vaginal delivery. The median gestational age at birth was 38 (32-41) weeks. The median weight at birth was 3200 (2000-4000) g. Gender of the newborns was 75% female. Among the living 15 babies, 3 were preterm (gestational age <37 weeks), and 2 were small for gestational age (SGA, birth weight <2500 g). Table 3 presents the data about delivery and neonatal outcomes.

DISCUSSION

In the present study, we evaluated pregnant women who were inadvertently exposed to hormonal contraceptives for the prevention of pregnancy or other underlying obstetric disorders. A total of 25 pregnant women who were admitted to our TIS for inadvertent exposure to hormonal contraception during pregnancy were included in the study. We analyzed their medications and evaluated the drugs for the risk of teratogenic effects. Among the 16 women that we could reach after delivery, we found that 1 female baby had died postnatally in the first week of life, 3 infants were born preterm, and 2 infants were SGA. In the present study, the most common contraceptives used by pregnant women were medroxyprogesterone acetate, pharmaceutical combination form of estradiol valerate+norgestrel, and pharmaceutical combination form of ethinyl estradiol+levonorgestrel.

Medroxyprogesterone acetate suppresses gonadotropin release and inhibits ovulation (5). It has oral and intramuscular depot forms. In our study, nine women had used medroxyprogesterone acetate 5 mg oral tablet, and two women were treated with medroxyprogesterone acetate 150 mg/ml intramuscular formula. Male and female pseudohermaphroditism, clitoral hypertrophy, and epispadias in infants with maternal exposure to medroxyprogesterone acetate were reported in previous studies (6). It was reported that progesterone receptor mRNA expression, increased in male fetuses and decreased in female fetuses due to medroxyprogesterone acetate exposure in utero, interacts with the androgen receptor in the development of a possible abnormal genital tubercle (6).

A controlled human study did not find an association between maternal exposure to medroxyprogesterone acetate treatment and an increase in congenital malformations (7). In an evaluation of depot medroxyprogesterone acetate-exposed births, an increase in the number of infants with low birth weight (<2500 g) was identified compared with controls (8). On the other hand, progesterone is known to inhibit basal and tumor necrosis factor-alpha-induced apoptosis in fetal membranes to prevent preterm labor (9). In our study, we found that 11 women used medroxyprogesterone acetate in the first trimester. Among the outcomes of 11 women, 1 infant was born preterm (36 weeks of gestation) with low birth weight (2000 g), and 1 female baby born preterm (32 weeks) had died postnatally in the first week of life. These women were both concomitantly exposed to diclofenac during the first 6 weeks of their pregnancies. The use of nonsteroidal anti-inflammatory drugs close to conception, including diclofenac, is reported to be related with increased abortion risk (10).

Ethinyl estradiol is a synthetic estrogen that is widely used to treat menopausal symptoms and menstrual disorders and can be used in combination with progestin for contraception. The frequency of congenital anomalies was not significantly increased among the infants of women who used ethinyl estradiol in combination with progestin during pregnancy (4). In our study, women with exposure to estradiol components gave birth to six term healthy and two preterm infants (35 weeks).

Levonorgestrel is a frequently used progestin for emergency contraception (11). It can prevent or delay ovulation, increase the thickness of the cervical mucus, and disrupt the corpus luteum formation (12). Recent studies showed that preovulatory levonorgestrel administration can lead to post-fertilization luteal effects and may explain its clinical effects when used before ovulation (13). In a follow-up study, children exposed to levonorgestrel were compared with a control group of children over a period of 2 years. There were no differences observed in physical growth, mental development, or birth defects between these two groups (14). In addition, an increase in nongenital anomalies was not found after norgestrel nor levonorgestrel exposure in pregnancy (15). In our study, a combination of ethinyl estradiol+levonorgestrel was used by four women in the first trimester, and they gave birth to healthy infants.

Body weight should be considered in the clinical effectiveness, as body weight alters the effectiveness of emergency contraception with levonorgestrel. Previous studies showed a significant decrease in the effectiveness of levonorgestrel emergency contraception in women with high body weight (16, 17).

We found that 75% of the infants delivered subsequently were female. Hormonal contraception used before and in early pregnancy may have increased the rate of the female gender; this is consistent with the results of a previous study (18). However, in some studies, no significant differences were reported between the sex ratios of the infants whose mothers had been exposed to hormonal contraceptives compared with those of controls. In addition, no correlation was found between the sex of the fetus and the total duration of oral contraceptive used (19).

Our study has limitations. First, the congenital abnormality rate was calculated using live newborns and terminated pregnancies due to congenital malformations, and therefore, the data may not represent all birth defects, such as those associated with miscarriages and stillbirths. We could not perform genetic analysis for the possible chromosomal abnormalities in living babies or autopsy for the possible congenital malformation patterns of the case in postnatal exitus. Thus, the real teratogenic effect rate might be higher than our data imply. Second, neonatal outcomes were obtained from patient telephone questionnaires rather than direct access to the medical record and neonatal examination. Physical examination of the infants and the first 2 years of follow-up should be critical, since mothers may not have detailed medical information about the health of their babies. Finally, the sample size in our study was too small. Further large scale studies should be conducted in the future.

CONCLUSION

In conclusion, hormonal contraceptives taken during pregnancy did not cause an increased risk of congenital malformations. In the future, we will expand our patient population and extend the postnatal follow-up time for advanced monitoring of the health status of infants and their neurobehavioral development. Thus, we will be able to obtain more remarkable results and counsel pregnant women accordingly.

Ethics Committee Approval: The study was approved by the Ethics Committee of Clinical Trials of the Faculty of Medicine (approval date: 24/10/2018, approval no.: 2018/19/14).

Peer-review: Externally peer-reviewed.

Author Contributions: Conceived and designed the study: DAA. Performed the cases: DAA, YE. Analyzed the data: DAA, YE. Wrote the paper: DAA, YE. All authors have read and approved the final manuscript.

Conflict of Interest: The authors have no conflicts of interest to declare.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES

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(2.) Choi J, Smitz J. Luteinizing hormone and human chorionic gonadotropin: distinguishing unique physiologic roles. Gynecol Endocrinol 2014; 30(3): 174-81. [CrossRef]

(3.) Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS, Lammer EJ. Maternal progestin intake and risk of hypospadias. Arch PediatrAdolesc Med 2005; 159(10): 957-62. [CrossRef]

(4.) Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016; 65(3): 1-103. [CrossRef]

(5.) Barnhart KT, Schreiber CA. Return to fertility following discontinuation of oral contraceptives. FertilSteril 2009; 91(3): 659-63. [CrossRef]

(6.) Willingham E, Agras K, de Souza AE Jr, Konijeti R, Yucel S, Rickie W, et al. Steroid receptors and mammalian penile development: an unexpected role for progesterone receptor? J Urol 2006; 176(2): 728-33. [CrossRef]

(7.) Zhang J, Mao X, Wang Y, Chen Q, Lu X, Hong Q, et al. Neonatal outcomes and congenital malformations in children born after human menopausal gonadotropin and medroxyprogesterone acetate treatment cycles. Arch Gynecol Obstet 2017; 296(6): 1207-17. [CrossRef]

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(9.) Luo G, Abrahams VM, Tadesse S, Funai EF, Hodgson EJ, Gao J, et al. Progesterone inhibits basal and TNF-alpha-induced apoptosis in fetal membranes: a novel mechanism to explain progesterone-mediated prevention of preterm birth. Reprod Sci 2010; 17(6): 532-9. [CrossRef]

(10.) Bloor M, Paech M. Nonsteroidal anti-inflammatory drugs during pregnancy and the initiation of lactation. Anesth Analg 2013; 116(5): 1063-75. [CrossRef]

(11.) Cheng L, Giilmezoglu AM, Piaggio G, Ezcurra E, Van Look PF. Interventions for emergency contraception. Cochrane Database Syst Rev 2008; (2): CD001324. [CrossRef]

(12.) Gemzell-Danielsson K, Berger C, Lalitkumar PG. Mechanisms of action of oral emergency contraception. Gynecol Endocrinol 2014; 30(10): 685-7. [CrossRef]

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(14.) Zhang L, Ye W, Yu W, Cheng L, Shen L, Yang Z. Physical and mental development of children after levonorgestrel emergency contraception exposure: a follow-up prospective cohort study. Biol Reprod 2014; 91(1): 27. [CrossRef]

(15.) Zhang L, Chen J, Wang Y, Ren F, Yu W, Cheng L. Pregnancy outcome after levonorgestrel-only emergency contraception failure: a prospective cohort study. Hum Reprod 2009; 24(7): 1605-11. [CrossRef]

(16.) Haeger KO, Lamme J, Cleland K. State of emergency contraception in the U.S., 2018. Contracept Reprod Med 2018; 3: 20. [CrossRef]

(17.) Kapp N, Abitbol JL, Mathe H, Scherrer B, Guillard H, Gainer E, et al. Effect of body weight and BMI on the efficacy of levonorgestrel emergency contraception. Contraception 2015; 91(2): 97-104. [CrossRef]

(18.) Pejtsik B, Hadnagy J, Rappai G, Kobor J. Effect of oral contraceptives on developmental anomalies and on the sex ratio of newborn infants. [Article in Hungarian]. OrvHetil 1990; 131(22): 1187-90.

(19.) Klinger HP, Glasser M. Contraceptives and the conceptus. II. Sex of the fetus and neonate after oral contraceptive use. Contraception 1981; 23(4): 367-74. [CrossRef]

Duygun Altintas Aykan [iD], Yusuf Ergun [iD]

Cite this article as: Altintas Aykan D, Ergun Y. Hormonal Contraceptives: What if Exposed During Pregnancy? Erciyes Med J 2019; 41(1): 50-5.

Department of Pharmacology, Kahramanmaras Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey

Submitted 15.11.2018

Accepted 25.12.2018

Available Online Date 08.01.2019

Correspondence Duygun Altintas Aykan, Department of Pharmacology, Kahramanmaras Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey

Phone: +90 344 300 34 34

e.mail: altintasduygun_dr@yahoo.com

DOI: 10.14744/etd.2018.18176
Table 1. Data about pregnant women

Age   Nationality   Indication                  Education level   USG
                                                                  (week)

         TR         Secondary amenorrhea        --                 9
23       TR         Abnormal uterine bleeding   Elementary
34       TR         Abnormal uterine bleeding   Elementary        12
         TR         Abnormal uterine bleeding   --                 5
34       TR         Contraception               Primary           12
         TR         Abnormal uterine bleeding   --                 6
         TR         Abnormal uterine bleeding   --                12
         TR         Abnormal uterine bleeding   --                 6
35       TR         Abnormal uterine bleeding   Primary            5
         TR         Abnormal uterine bleeding   --                12
         TR         Abnormal uterine bleeding   --                 6
         TR         Emergency contraception     --                 7
         TR         Abnormal uterine bleeding   --                 8
31       TR         Contraception               None               8
         TR         Abnormal uterine bleeding   --                 8
25       TR         Contraception               Primary           10
26       TR         Contraception               Primary            8
         TR         Contraception               --                 7
29       TR         Contraception               Primary           23
31       TR         Contraception               --                 6
34       TR         Abnormal uterine bleeding   Primary            7
23       TR         Contraception               Elementary         7
26       TR         Emergency contraception     --                 6
28       TR         Contraception               Primary            8
         TR         Abnormal uterine bleeding   Elementary         7

Age   Contraceptive

      MPA Progesterone
23    Estradiol valerate+norgestrel
34    Dydrogesterone
      Estradiol valerate
      +norgestrel
      MPA
34    Ethinyl estradiol+levonorgestrel
      MPA
      MPA
      MPA
35    Norethindrone
      MPA
      Estradiol valerate+norgestrel
      Ulipristal
      MPA
31    MPA
      MPA
25    Ethinyl estradiol+levonorgestrel
      Ethinyl estradiol+gestodene
26    Norethisterone
      enanthate+estradiol valerate
      Desogestrel
29    Ethinyl estradiol
      +gestodene
31    Ethinyl estradiol+levonorgestrel
34    Estradiol valerate+norgestrel
23    Ethinyl estradiol+levonorgestrel
26    Ulipristal
28    MPA
      MPA

USG: Ultrasonography; TR: Turkish; MPA: Medroxyprogesterone acetate


Table 2. Patterns of contraceptive exposure

Exposed to contraceptive      Dose  Route   Start  Expiry  Exposed
                                            week   week    period

Medroxyprogesterone           2x1   p.o     4        5     1st trim
acetate 5 mg
Progesterone 50 mg/ml         1x1   i.m     5        6     1st trim
Estradiol valerate 2          1x1   p.o     6        9     1st trim
mg+norgestrel 0.5 mg
Dydrogesterone 10 mg          2x1   p.o     4        6     1st trim
Estradiol valerate            1x1   p.o     3        4     1st trim
2 mg+norgestrel 0.5 mg
Medroxyprogesterone           3x1   p.o     5        6     1st trim
acetate 5 mg
Ethinyl estradiol 0.03        1x1   p.o     8       11     1st trim
mg+levonorgestrel 0.15 mg
Medroxyprogesterone           1x1   p.o     0        1     Before
acetate 5 mg                                               conception
Medroxyprogesterone           1x1   p.o     4        6     1st trim
acetate 5 mg
Medroxyprogesterone           2x1   p.o     0        1     Before
acetate 5 mg                                               conception
Norethindrone 5 mg            3x1   p.o     2        3     1st trim
Medroxyprogesterone           2x1   p.o     4        5     1st trim
acetate 5 mg
Estradiol valerate 2          1x1   p.o     0        5     1st trim
mg+norgestrel 0.5 mg
Ulipristal 30 mg              1x1   p.o     5        6     1st trim
Medroxyprogesterone           1x1   p.o     4        5     1st trim
acetate 5 mg
Medroxyprogesterone           1x1   i.m    <0       <0     Before
acetate 150 mg/ml                                          conception
Medroxyprogesterone           2x1   p.o     5        7     1st trim
acetate 5 mg
Ethinyl estradiol 0.03 mg+    1x1   p.o     0        5     1st trim
levonorgestrel 0.15 mg
Ethinyl estradiol 0.02        1x1   p.o     5        6     1st trim
mg+gestodene 0.075 mg
Norethisterone enanthate 50   1x1   i.m     2        3     1st trim
mg+estradiol valerate 5 mg
Desogestrel 75 [micro]g       1x4   p.o     3        4     1st trim
Ethinyl estradiol 0.02        1x1   p.o     0        3     1st trim
mg+gestodene 0.075 mg
Ethinyl estradiol 0.03        1x1   p.o     0        5     1st trim
mg+levonorgestrel 0.15 mg
Estradiol valerate 2          1x1   p.o     0        5     1st trim
mg+norgestrel 0.5 mg
Ethinyl estradiol 0.03        1x1   p.o     0        6     1st trim
mg+levonorgestrel 0.15 mg
Ulipristal 30 mg              1x1   p.o     2        3     1st trim
Medroxyprogesterone           1x1   i.m     7        8     1st trim
acetate 150 mg/ml
Medroxyprogesterone           2x1   p.o     4        6     1st trim
acetate 5 mg

p.o: Per oral; i.m: Intramuscular; trim: Trimester

Table 3. Data about delivery and neonatal outcome

Exposed to                 Results    Delivery  Gestational  Weight
contraceptive                          route     age (week)  (gram)

MPA                        Healthy    Cesarean      38        3600
Progesterone
Estradiol                  Healthy    Cesarean      38        3850
valerate+norgestrel
Dydrogesterone             Healthy    Cesarean      35        2700
Estradiol
valerate+norgestrel
Ethinyl                    Healthy    Cesarean      38        3000
estradiol+levonorgestrel
MPA                        Healthy    Cesarean      40        3200
Norethindrone              Healthy    Vaginal       41        3300
MPA                        Healthy    Cesarean      36        2000
Ethinyl                    Healthy    Vaginal       39        3500
estradiol+levonorgestrel
Ethinyl
estradiol+gestodene
Norethisterone             Healthy    Vaginal       40        2800
enanthate+estradiol
valerate
Desogestrel                Healthy    Vaginal       40        3300
Ethinyl                    Healthy    Vaginal       35        2300
estradiol+gestodene
Ethinyl                    Healthy    Cesarean      39        4000
estradiol+levonorgestrel
Ethinyl                    Healthy    Cesarean      37        2800
estradiol+levonorgestrel
Ulipristal                 Healthy    Cesarean      38        3400
MPA                        Postnatal  Cesarean      32        --
                           exitus
MPA                        Healthy    Vaginal       40        3200

Exposed to                  Sex
contraceptive

MPA
Progesterone
Estradiol                  Female
valerate+norgestrel
Dydrogesterone             Male
Estradiol
valerate+norgestrel
Ethinyl                    Female
estradiol+levonorgestrel
MPA
Norethindrone              Female
MPA                        Female
Ethinyl                    Female
estradiol+levonorgestrel
Ethinyl
estradiol+gestodene
Norethisterone             Female
enanthate+estradiol
valerate
Desogestrel                Female
Ethinyl                    Male
estradiol+gestodene
Ethinyl
estradiol+levonorgestrel
Ethinyl                    Male
estradiol+levonorgestrel
Ulipristal
MPA                        Female
MPA                        Female

MPA: Medroxyprogesterone acetate
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Title Annotation:ORIGINAL ARTICLE
Author:Aykan, Duygun Altintas; Ergun, Yusuf
Publication:Erciyes Medical Journal
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Date:Mar 1, 2019
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