**2. Oral contraceptives**

#### **2.1. Cessation**

The pathway in women using OCs to return to fertility is often straightforward. The information leaflet of the particular regime often includes clear and specific instructions for women seeking discontinuation and pregnancy (which often only consist of ceasing its use). Women are often advised to wait for their menstrual period before seeking a new pregnancy because the day of the last menstrual period is useful in pregnancy date calculations. In our center, midwifes provide preconceptional counseling, which can include contraception recommendations and assessment (this applies to contraception in general). Many health issues affecting the health of the mother and the future baby can be addressed in these visits [24] and we can only recommend this practice.

#### **2.2. Physiology**

The mechanisms of action of oral contraceptives (OCs) are derived from the effect of the estrogen and the progestin in the formulation. Estrogens act by inhibiting follicular development and inhibiting hypothalamic–pituitary ovulation trigger. Progestins increase the thickness of the cervical mucus. The effects of Oral Combined Contraceptives (COCs) on endometrium vary depending on the doses, formulation and duration of use; with current commonly used lower doses contraceptives these effects include arrest of glandular proliferation, abortive secretion, stromal hyperplasia, decidualization and atrophy [25]. Intramuscular or locally administered progestins cause endometrial atrophy [26].

There is not much information on the reversibility of these changes. For example, cervical mucus can have lower scores for the first 2 months after discontinuing OCs and decreased menstrual flow was described to last for four months [27]. Some studies have linked reduced endometrial thickness and long-term COC usage: Talukdar et al. studied the effect long-term use of combined oral contraceptives on endometrial thickness. They gathered 137 women between 30 and 45 years old subject to frozen embryo transfer cycles and determined the endometrial thickness on day 10. The group with endometrium thin than 7 mm (n = 30, a proposed threshold for successful implantation) had longer COC usage compared to the rest of the women. Authors this could be mediated by the effects of OCs on stem cells in an inactive endometrium. In particular, some authors have said this effect after long-term use of OCs is "infrequent but persistent" [28]. These results should be taken cautiously and require further confirmation in larger groups of healthy women in prospective studies; as we will discuss later infertility has not been associated to OC.

The effects of COCs on gonadotropins have also been studied: Compared to women who never used COCs, women using them showed similar or slightly lower FSH levels, whereas women who used them showed slightly higher FSH levels that seemed to wane over time. (LH showed a similar pattern, but it was only significant in one of the two study groups). The authors attributed this to a possible rebound effect of gonadotropins after withdrawing the hormonal COC and a suppression of endogenous estrogen and progesterone [29]. After withdrawal of COCs normal physiology is gradually restored: in a study with 24 women it was observed that the first cycle is longer and with lower gonadotrophin levels compared to the third cycle; ovulation changes were observed in 17/24 women in the first cycle and in 21/24 women in the third cycle [30]. Recent use of OCs and their long-term use have been associated with longer follicular phases (longer time to ovulation) by some authors, but they acknowledged there are conflicting results on this issue in the literature and many women might choose to start using OCs to help regulate their cycles, which might already be longer [31].

Estrogens are known to stimulate prolactin production. Some reports associated post-pill amenorrhea and galactorrhea and serum prolactin is elevated in OC users; this is more pronounced in women who use high-dose OCs but not significant association was found with long-term usage [32]. However prolactin levels do not seem to be altered in women who previously used COCs [33].

#### **2.3. Return to fertility**

Over the course of many decades contraceptive methods have deeply improved. Secondary effects of oral contraceptives have been detected and lower dose formulations have been developed. Many studies have assessed long-term effects of OCs on various aspects of women's health [14, 21], including their future reproductive health. In some topics conflicting evidence is available as the results and conclusions of some studies differ from others. This is not the case for contraceptive reversibility (which has consistently been observed for decades in many studies and is remarked in NICE [13] and WHO [22] guidelines, as we will discuss later), but for some rare pregnancy events (twin pregnancy, preterm birth). Obtaining contradicting results is not uncommon in clinical research and does not necessarily imply there was a flaw conducting the study [23]. Publishing these studies is not a mistake, but inadequately interpreting them could be. Conflicting and inconclusive evidence should be treated with special caution; unconfirmed results or contradictory results are not ground for evidence-based recommendations. In this chapter we will analyze the reversibility of physiological changes, the observed fertility changes and the future pregnancy complications of several contraceptive methods: OCs (including progestin only pill and emergency contraception), injectables, implants and IUDs.

The pathway in women using OCs to return to fertility is often straightforward. The information leaflet of the particular regime often includes clear and specific instructions for women seeking discontinuation and pregnancy (which often only consist of ceasing its use). Women are often advised to wait for their menstrual period before seeking a new pregnancy because the day of the last menstrual period is useful in pregnancy date calculations. In our center, midwifes provide preconceptional counseling, which can include contraception recommendations and assessment (this applies to contraception in general). Many health issues affecting the health of the mother and the future baby can be addressed in these visits [24] and we

The mechanisms of action of oral contraceptives (OCs) are derived from the effect of the estrogen and the progestin in the formulation. Estrogens act by inhibiting follicular development and inhibiting hypothalamic–pituitary ovulation trigger. Progestins increase the thickness of the cervical mucus. The effects of Oral Combined Contraceptives (COCs) on endometrium vary depending on the doses, formulation and duration of use; with current commonly used lower doses contraceptives these effects include arrest of glandular proliferation, abortive secretion, stromal hyperplasia, decidualization and atrophy [25]. Intramuscular or locally

There is not much information on the reversibility of these changes. For example, cervical mucus can have lower scores for the first 2 months after discontinuing OCs and decreased menstrual flow was described to last for four months [27]. Some studies have linked reduced

**2. Oral contraceptives**

can only recommend this practice.

administered progestins cause endometrial atrophy [26].

**2.1. Cessation**

216 Family Planning

**2.2. Physiology**

Despite these described biochemical or histological findings, the reversibility of OCs has been clinically observed for decades and across many different ethnic groups (**Table 1**); many studies have reported 1 year pregnancy rates between 70 and 90% and 2 years pregnancy rates of 80–90% [1, 34].

In the 1960s, the "postpill amenorrhea syndrome" was described as amenorrhea, anovulation and reduced reproductive fecundity for more than 1 year following discontinuation of OCs in some women who previously had regular menstruation. Some authors noted that many women with this syndrome exhibited oligomenorrhea before starting oral contraceptive usage [35]. It was thought that the exogenous administration of hormonal therapy with OCs delayed the return to normal function of the hypothalamic-pituitary-ovary axis [36]. Some authors advocated "watchful waiting" in women not seeking pregnancy, mentioning that regular menses tend to reappear after 12–18 months, and emphasized the importance of ruling


**Study design**

> Randic et al.

Prospective,

748 parous (planned

Mean age: 27.1

82.9%

89.5%

(first group)

pregnancy) 2713

(complications)

209 IUD users (71

Mean 27 y

Median 21

71.2 vs. 79.1%

79.7 vs.

86.6%

months (range

6–53)

Nova-T vs. 138 IUD

– LNG)

[115]

Andersson

Prospective

IUD

> et al. [116]

Tadesse [117]

Buckshee

Prospective

Subdermal

627 India

Implant

(Norplant II)

et al. [118] Bahamondes

Prospective

Injectable

70 users Brazil, Chile,

Mean age

Mean number

82.9%

Not

Return of fertility was not

related to the woman's

age at the time of

discontinuation, her weight,

or the number of Cyclofem

injections.

reported

of injections:

7.1 ± 4.6

~25.6

Colombia and Peru

(Cyclofem)

et al. [95] Zimmerman

Prospective

OC

348 users of 30 mcg EE

Mean age:

Median 4–6

95%

Not

reported

months

/ 2

mg DNG (Valette)

26.8 y

Mean age

104.6 ± 93.5

88%

99%

No statistical differences in

Contraceptive Methods and the Subsequent Search for a Pregnancy

pregnancy rates were found

for age and duration of use

of the IUD

http://dx.doi.org/10.5772/intechopen.72525

weeks

30.5 y

observational

et al. [119] Delbarge

Prospective

IUD Gynefix

128 users

> et al. [120]

Farrow et al.

Retrospective

OC

8497 users who

Mean age 28

From 1 to more

According to

Mean

The article includes many

analysis categories, such

as woman's alcohol

consumption or cigarettes

smoked

219

96.6%

years of use:

>5: 89.5%,

3–4: 88%, 1–2:

of 5 years: >5:

56.8% of the

participant

3–4: 20.3%, 1–2:

85.2%, <1:

11%, <1: 7%,

83.5%

never: 4.9%

conceived intentionally

South-west England

[42]

Prospective

Copper T200

780 users. Ethiopia

Mean age 29

Mean 3.5 years

86.6%

No data

Nulligravid:

3.2% multip.

93.5% grand

multip: 3.3 %

18–35 years

Mean 55.8 ±

80.3%

88.3%

17.7 m

**Method**

**Participants**

**Subjects**

**Exposure** 

**1-year** 

**2-year** 

**Comments**

**pregnancy rate**

**pregnancy** 

**rate**

**(months)**


**Study design**

Pardthaisong

Retrospective

Depo provera

796 DMPA vs. 125 IUD

vs. 27.7

Mean age:24.5

Not reported

78.2 vs. 79%

92.1 vs.

Median delay to conception:

DMPA: 5.5 months. IUD 4.5

months

The proportion of pill users who conceived in the first

month was 30% less than the others, but by the third

month this difference had disappeared

>90%

Median time to planned

pregnancy was 3 months

for the TCu 380 Ag group

and 4 months for the

Levonorgestrel 20 group

93.3%

(DMPA) vs.

[34]

and

Prospective: 2

IUD

arms

Harlap and

Retrospective

1403 OC

4477 other

contraceptives

Baras [109]

Belhadj et al.

Randomized,

Mirena IUD

110 females

20mcg/d vs.

CuT380Ag

prospective

[110]

Skjeldestad

Prospective

Copper IUDs

101 IUDs users (Nova

Mean age 28.3

56% <24m

85%

93%

T, MLCu 250 vs. MLCu

375) Norway

observational

et al. [111] Affandi et al.

Prospective

Implant

80 Implanon vs. 80

Mean age

35.3 ± 13.1 vs.

48.8 vs. 37.5%

60.0 vs.

73.8%

~28.0 y. Mean

55,8 ± 17.7

parity ~ 2.3

375 nulligravid

Not reported

Not reported

91.5 vs.

Removal because of

complications: No reduction

in fertility or increase

in ectopic gestation,

miscarriage, or preterm

delivery rates in 12 months

95.7%

676 gravid

women

Norplant Indonesian

women

[112]

Wilson et al.

Prospective

IUD

1051 IUD. New

Zealand

[106]

Gupta et al.

Prospective

IUD (8 types:

91 users India.

Mean age

22.9

m

92.3%

96.7%

~27.6

6 Cu-bearing,

progestasert

IPCS 52 and

Lippes Loop)

Silvin et al.

Prospective,

Norplant vs.

178 users (62 vs. 116)

Mean age ~

Mean 31, 35

83 vs. 84%

87 vs. 92%

months

27.45

Norplant II

multicenter

[114]

[113]

**Method**

**Participants**

**Subjects**

**Exposure** 

**1-year** 

**2-year** 

**Comments**

218 Family Planning

**pregnancy rate**

**pregnancy** 

**rate**

**(months)**


**Table 1.** Studies evaluating return to fertility. out other causes of amenorrhea [37]. Some women with amenorrhea after discontinuing OCs could have preexistent menstrual irregularities masked by OC. In the 1980s more reliable studies showed no association between oral contraceptive use and secondary amenorrhea and lack of specific findings in this syndrome [38]. Current practice holds that women who do not menstruate 3 months after discontinuing COC usage should be evaluated like any woman

Contraceptive Methods and the Subsequent Search for a Pregnancy

http://dx.doi.org/10.5772/intechopen.72525

Diana Mansour published in 2010 an interesting comprehensive review of the literature assessing pregnancy rates following discontinuation of several contraceptive methods; 17 prospective studies were included. One year pregnancy rate following cessation of OCs (3 studies) ranged from 79.4 to 95% and median time to pregnancy, estimated from available

The Oxford-FPA study, published in 1978, was one of the first studies that investigated this issue. In this prospective cohort study 12 months after contraception cessation 70.1 of women who used OCs remained undelivered, which is significantly higher than 46.4% for the dia

phragm group or 47.6% for the other methods group. After 36 months the differences became

Doll et al [41] performed a study in nulliparous women from 17 family planning clinics in England and Scotland; they found that duration of oral contraceptive use was linearly associ

ated with decreased fertility and that return to fertility is slower in users ceasing OC (32% delivery after 1 year) compared versus users ceasing IUD (39%) or users abandoning barrier methods (54%); 18 months after ceasing using contraceptives these values were 70% delivery for previous OCs group, 67% delivery for previous IUD group and 76% delivery for the bar

rier method group. Authors observed significantly faster return to fertility for users of barrier

studies usually report around 1-year conception rates (>80%) [42]. Temporary (a few months) delays in fertility have been observed in other studies in women using OCs [43, 44] and reflect physiological changes: some women return to fertility faster than others. In this study dura

tion of OC use had no significant effect on fertility and women who interrupted OCs and used barrier methods for 3 months had faster return to fertility than those who tried to conceive immediately after stopping using OCs [41]. After 42 months of ceasing OCs 11% of women

A recent Danish prospective cohort study also observed a temporary reduced fertility in the 3 months after OCs discontinuation compared to barrier methods, but pregnancy probabilities became similar thereafter [45]. From the Kaplan–Meier curves time to pregnancy (TTP) percentiles were obtained, the 25th, 50th (median) and 75th percentiles were 2, 3 and 7 cycles for women who had discontinued barrier methods and 2, 4 and 9 cycles for women whose last method were OCs. A dose–response relationship between time using OCs and increased fecundability was observed, with confidence intervals becoming significant after 10 years of use. High-dose OCs was associated with shorter TTP. This study has some limitations, but the conclusion is very reasonable: there is no evidence that using OCs for years impairs fecund

ability. Other studies have also showed that long-term OC use is not associated with reduced

fertility [46], but not all studies agree on this matter [47].

= 0.002) without statistical differences between OCs and IUDs. Other


221





with amenorrhea [39].

data, was 2.5–3 cycles) [

non-significant [40].

methods (log rank test, p

had not delivered a baby.

1].

out other causes of amenorrhea [37]. Some women with amenorrhea after discontinuing OCs could have preexistent menstrual irregularities masked by OC. In the 1980s more reliable studies showed no association between oral contraceptive use and secondary amenorrhea and lack of specific findings in this syndrome [38]. Current practice holds that women who do not menstruate 3 months after discontinuing COC usage should be evaluated like any woman with amenorrhea [39].

Diana Mansour published in 2010 an interesting comprehensive review of the literature assessing pregnancy rates following discontinuation of several contraceptive methods; 17 prospective studies were included. One year pregnancy rate following cessation of OCs (3 studies) ranged from 79.4 to 95% and median time to pregnancy, estimated from available data, was 2.5–3 cycles) [1].

The Oxford-FPA study, published in 1978, was one of the first studies that investigated this issue. In this prospective cohort study 12 months after contraception cessation 70.1 of women who used OCs remained undelivered, which is significantly higher than 46.4% for the diaphragm group or 47.6% for the other methods group. After 36 months the differences became non-significant [40].

Doll et al [41] performed a study in nulliparous women from 17 family planning clinics in England and Scotland; they found that duration of oral contraceptive use was linearly associated with decreased fertility and that return to fertility is slower in users ceasing OC (32% delivery after 1 year) compared versus users ceasing IUD (39%) or users abandoning barrier methods (54%); 18 months after ceasing using contraceptives these values were 70% delivery for previous OCs group, 67% delivery for previous IUD group and 76% delivery for the barrier method group. Authors observed significantly faster return to fertility for users of barrier methods (log rank test, p = 0.002) without statistical differences between OCs and IUDs. Other studies usually report around 1-year conception rates (>80%) [42]. Temporary (a few months) delays in fertility have been observed in other studies in women using OCs [43, 44] and reflect physiological changes: some women return to fertility faster than others. In this study duration of OC use had no significant effect on fertility and women who interrupted OCs and used barrier methods for 3 months had faster return to fertility than those who tried to conceive immediately after stopping using OCs [41]. After 42 months of ceasing OCs 11% of women had not delivered a baby.

A recent Danish prospective cohort study also observed a temporary reduced fertility in the 3 months after OCs discontinuation compared to barrier methods, but pregnancy probabilities became similar thereafter [45]. From the Kaplan–Meier curves time to pregnancy (TTP) percentiles were obtained, the 25th, 50th (median) and 75th percentiles were 2, 3 and 7 cycles for women who had discontinued barrier methods and 2, 4 and 9 cycles for women whose last method were OCs. A dose–response relationship between time using OCs and increased fecundability was observed, with confidence intervals becoming significant after 10 years of use. High-dose OCs was associated with shorter TTP. This study has some limitations, but the conclusion is very reasonable: there is no evidence that using OCs for years impairs fecundability. Other studies have also showed that long-term OC use is not associated with reduced fertility [46], but not all studies agree on this matter [47].

**Study design**

> Hov et al.

2 branches. A:

Copper IUD

205 users Norway (A:

109 IUD removed due

to wish to be pregnant

vs. B: 96 IUD removed

due to complication)

Prospective

[121]

Wiegratz

Prospective

OC: 30 microg

706 users Germany

Mean age: 26.8

21.5m ± 16.8m

86.6% (more

not

reported

than 15.5%

in the first

3 cycles)

Meantime 3.5

cycles

(median 16m)

ethinyl E2

and 2 mg dienogest

(Valette)

Cronin et al.

Prospective

OC

2064 users

Mean age 28.1

2.8 ±

0.8 years

21.1 % after first

88.3%

circle. 79.4%

1-year

years

(drospirenone

and other

progestins)

cohort

[46]

Stoddard

Prospective

IUD

69 IUD (50 Cu, 19

Mean age: 27.6

81 vs. 70%

(p=0.18)

vs. 29.5

LNG) vs. 42 non

IUD.

St Louis, USA.

et al. [122] Abdinasab

Retrospective

Cu IUD

750 non-nulliparous

Mean age: 34.8

57.46 ± 47.74

m

Mean length from Cu

T-380A IUD removal to

pregnancy was 14.87 ± 5.18

months

vs. 33.9

Iranian women 375

Cases: history of using

Cu T-380A IUD > 5

months. 375 Controls:

history of other

contraceptives: OCP,

withdrawal method,

male condom.

**Table 1.**

Studies evaluating return to fertility.

cohort study

(T-380)

et al. [123]

observational

et al. [44]

**Method**

**Participants**

**Subjects**

**Exposure** 

**1-year** 

**2-year** 

**Comments**

220 Family Planning

**pregnancy rate**

**pregnancy** 

**rate**

90% (group A).

98%

93.6 vs.

No difference in cumulative

probability to become

pregnant by parity, duration

of IUD use and age upon

removal of IUD

**(months)**

The effect of other variables (weight, smoking …) on time to fertility after OC discontinuation has been evaluated in many studies, but small sample sizes limit the interpretation of these results [1].

The relationship between OCs and **birth weight** has been controversial in the literature. A study with 260 Boston women found previous OC use increased birthweight and placental weight compared to non-users [62] with more pronounced effects in women with longer use and with stronger hormonal contraceptives. The authors suggested this effect might be medi-

Contraceptive Methods and the Subsequent Search for a Pregnancy

http://dx.doi.org/10.5772/intechopen.72525

223

A 2015 Danish prospective cohort study evaluated the effect of oral contraceptives usage before pregnancy on birth weight [63]. The authors used data from online questionnaires and from the Danish Medical Birth Registry; 5921 women were followed for 12 months and 4046 live births took place. After adjustment for several confounding variables women who had discontinued OCs less than a month before conception exhibited higher mean birth weight (97 g, 95% CI: 26–80 g) compared to those who discontinued more than 12 months before conception; and lower mean birth weight was observed in women with previous >12 years of

Previous use of OCs has not been consistently associated with **birth defects** on the offspring. Some studies old studies found this link [55] but other studies did not. In a cohort (n = 732) from the Jerusalem Perinatal Study children were tested up to 3 years age. Although some dim trend in IQ values was suggested, those whose mothers were OCs users did not exhibit statistically significant differences in weight, height, development quotient or intellectual quotient [64].

It might occur that a woman accidentally and unknowingly takes oral contraceptives for some period after conception, a situation sometimes called **breakthrough pregnancy**, thereby exposing the fetus to doses of estrogens or progestins. This situation is especially worrying and distressing for affected women. In the past a frequent case of fetal exposure to potent oestrogens was that of women prescribed diethylstilbestrol (DES) in pregnancy to prevent abortions; after a study [65] linked this to vaginal clear-cell carcinoma in 1971 the FDA banned this drug in pregnant women. The daughters of women treated with DES in pregnancy have shown increased risk of cervical and vaginal precancerous states, a possible slight increase in breast cancer in women older than 40 years old, reproductive tract structural anomalies, infertility and pregnancy complications. The sons of treated women may be at increased risk for epididymal cysts and maybe other genital abnormalities. The NIH and the CDC provide information for healthcare providers and patients on this public healthcare issue [66, 67].

Several studies have evaluated how the use of oral contraceptives with way less estrogenic potency compared to DES after conception could influence male hypospadias and urinary tract anomalies, but the results have been inconclusive and contradictory: In some studies the association was clear [68], but others did not observe this association [69]. A recent 2009 large Danish case–control study evaluated the relationship between use oral contraceptives after conception and male hypospadias. This study used prescription data rather than selfreported maternal exposure data in order to prevent the recall bias, a relevant cause of spurious associations in retrospective case–control studies. The adjusted prevalence ratios were close to one and none of them was significant: for example 0.85 (95% CI: 0.65–1.28) for exposure to COC in early pregnancy and hypospadias detected within 6 months postpartum [70]. Women with **breakthrough pregnancies** or conception close to OCs cessation should also be assured large studies have not identified increased prevalence of **birth defects**. A meta-analysis published in 1990 found no association for OC exposure early in pregnancy and heart defects or

ated by the higher levels of estradiol and progesterone observed in former users.

OCs use vs. <4 years (−85 g, 95% CI: −158, −11).

Many studies do not evaluate COCs and POP separately or focus only on the former. POPs have not exhibited delays in the return of fertility [48]. With Norgestrel pills conception can occur within once cycle of stopping the medication [49]. In a randomized open-label study with 103 women after discontinuing a desogestrel-only pill ovulation appeared as early as 7 days, with an average of 17.2 days; [50] (with traditional POP ovulation occurs in 30–40% of users, but this pill has a remarkable anovulatory effect shared with combined formulations).

Emergency oral contraception (mifepristone) does not harm future fertility [51] and woman should be informed that emergency oral contraceptives do not protect from future pregnancies. In women who had successful abortive expulsion of the gestational sac the mean times to ovulation after mifepristone administration was 20.6 days (±5.1; range 8–36) [52].

#### **2.4. Pregnancy complications and outcomes**

Some studies have linked previous OCs usage with **twin conception** [53, 54, 55], whereas others have not observed this association or limited its findings to OCs with high doses of estrogen [56]. Increased levels of FSH are observed in mothers of twin pregnancies; the "endocrine hypothesis" of dizygotic twin pregnancies holds that high FSH is responsible for multiple ovulation [57]; it has been suggested this mechanism might be the link between OC usage and dizygotic twin conceptions. However many of the studies reported increased monozygotic twins rates. More recent evidence is lacking on this matter.

The effect of OCs on **fetal loss** has been studied for many decades. The first studies did not find any link or described the effect of OCs as protective [53]. Some studies have shown consumption of oral contraceptives for more than 9 years could protect against miscarriage [58]. On the other hand a Spanish retrospective [59] case–control study (N = 300) did actually identify taking oral contraceptives for more than 2 years before pregnancy as a risk factor of miscarriage (OR: 2.56, 95% CI: 1.16–5.67); the statistical methods included a step-wise regression, a controverted statistical procedure known for its risk of spurious associations. The authors hypothesized that the endometrial atrophy associated to taking (modern) low-dose oral contraceptives for extended periods of time could cause miscarriage or that acquired activated protein C resistance could be the link between oral contraceptives use and miscarriage.

A Danish prospective cohort study published in 2016 did not confirm these findings; 4500 women participated in this study. The hazard ratios were all non-significant and smaller than 1; the study did not find association between spontaneous abortion and discontinuing oral anticonceptives closer to conception (categories: discontinuing 0–1 months before conception, 2–6 months or 7–12 vs. discontinuing more than a year (reference) before conception); or between spontaneous abortion and longer use of oral contraceptives (comparing less than 4 years COC usage (reference) vs. 4–7 years, 8–11 years and equal or more than 12 years) [60].

The Jerusalem Perinatal Study is a cohort study that recorded several variables on 92,408 live neonates and stillbirths from the 1964–1976 period and on their families; these data were linked to several registries and many epidemiological studies were carried out [14]. For instance, in this study former COC usage conferred no risk of obstetric complications [61].

The relationship between OCs and **birth weight** has been controversial in the literature. A study with 260 Boston women found previous OC use increased birthweight and placental weight compared to non-users [62] with more pronounced effects in women with longer use and with stronger hormonal contraceptives. The authors suggested this effect might be mediated by the higher levels of estradiol and progesterone observed in former users.

The effect of other variables (weight, smoking …) on time to fertility after OC discontinuation has been evaluated in many studies, but small sample sizes limit the interpretation of these

Many studies do not evaluate COCs and POP separately or focus only on the former. POPs have not exhibited delays in the return of fertility [48]. With Norgestrel pills conception can occur within once cycle of stopping the medication [49]. In a randomized open-label study with 103 women after discontinuing a desogestrel-only pill ovulation appeared as early as 7 days, with an average of 17.2 days; [50] (with traditional POP ovulation occurs in 30–40% of users, but this pill has a remarkable anovulatory effect shared with combined formulations). Emergency oral contraception (mifepristone) does not harm future fertility [51] and woman should be informed that emergency oral contraceptives do not protect from future pregnancies. In women who had successful abortive expulsion of the gestational sac the mean times to

ovulation after mifepristone administration was 20.6 days (±5.1; range 8–36) [52].

Some studies have linked previous OCs usage with **twin conception** [53, 54, 55], whereas others have not observed this association or limited its findings to OCs with high doses of estrogen [56]. Increased levels of FSH are observed in mothers of twin pregnancies; the "endocrine hypothesis" of dizygotic twin pregnancies holds that high FSH is responsible for multiple ovulation [57]; it has been suggested this mechanism might be the link between OC usage and dizygotic twin conceptions. However many of the studies reported increased monozygotic

The effect of OCs on **fetal loss** has been studied for many decades. The first studies did not find any link or described the effect of OCs as protective [53]. Some studies have shown consumption of oral contraceptives for more than 9 years could protect against miscarriage [58]. On the other hand a Spanish retrospective [59] case–control study (N = 300) did actually identify taking oral contraceptives for more than 2 years before pregnancy as a risk factor of miscarriage (OR: 2.56, 95% CI: 1.16–5.67); the statistical methods included a step-wise regression, a controverted statistical procedure known for its risk of spurious associations. The authors hypothesized that the endometrial atrophy associated to taking (modern) low-dose oral contraceptives for extended periods of time could cause miscarriage or that acquired activated protein C resistance could be the link between oral contraceptives use and miscarriage.

A Danish prospective cohort study published in 2016 did not confirm these findings; 4500 women participated in this study. The hazard ratios were all non-significant and smaller than 1; the study did not find association between spontaneous abortion and discontinuing oral anticonceptives closer to conception (categories: discontinuing 0–1 months before conception, 2–6 months or 7–12 vs. discontinuing more than a year (reference) before conception); or between spontaneous abortion and longer use of oral contraceptives (comparing less than 4 years COC usage (reference) vs. 4–7 years, 8–11 years and equal or more than 12 years) [60]. The Jerusalem Perinatal Study is a cohort study that recorded several variables on 92,408 live neonates and stillbirths from the 1964–1976 period and on their families; these data were linked to several registries and many epidemiological studies were carried out [14]. For instance, in this study former COC usage conferred no risk of obstetric complications [61].

**2.4. Pregnancy complications and outcomes**

twins rates. More recent evidence is lacking on this matter.

results [1].

222 Family Planning

A 2015 Danish prospective cohort study evaluated the effect of oral contraceptives usage before pregnancy on birth weight [63]. The authors used data from online questionnaires and from the Danish Medical Birth Registry; 5921 women were followed for 12 months and 4046 live births took place. After adjustment for several confounding variables women who had discontinued OCs less than a month before conception exhibited higher mean birth weight (97 g, 95% CI: 26–80 g) compared to those who discontinued more than 12 months before conception; and lower mean birth weight was observed in women with previous >12 years of OCs use vs. <4 years (−85 g, 95% CI: −158, −11).

Previous use of OCs has not been consistently associated with **birth defects** on the offspring. Some studies old studies found this link [55] but other studies did not. In a cohort (n = 732) from the Jerusalem Perinatal Study children were tested up to 3 years age. Although some dim trend in IQ values was suggested, those whose mothers were OCs users did not exhibit statistically significant differences in weight, height, development quotient or intellectual quotient [64].

It might occur that a woman accidentally and unknowingly takes oral contraceptives for some period after conception, a situation sometimes called **breakthrough pregnancy**, thereby exposing the fetus to doses of estrogens or progestins. This situation is especially worrying and distressing for affected women. In the past a frequent case of fetal exposure to potent oestrogens was that of women prescribed diethylstilbestrol (DES) in pregnancy to prevent abortions; after a study [65] linked this to vaginal clear-cell carcinoma in 1971 the FDA banned this drug in pregnant women. The daughters of women treated with DES in pregnancy have shown increased risk of cervical and vaginal precancerous states, a possible slight increase in breast cancer in women older than 40 years old, reproductive tract structural anomalies, infertility and pregnancy complications. The sons of treated women may be at increased risk for epididymal cysts and maybe other genital abnormalities. The NIH and the CDC provide information for healthcare providers and patients on this public healthcare issue [66, 67].

Several studies have evaluated how the use of oral contraceptives with way less estrogenic potency compared to DES after conception could influence male hypospadias and urinary tract anomalies, but the results have been inconclusive and contradictory: In some studies the association was clear [68], but others did not observe this association [69]. A recent 2009 large Danish case–control study evaluated the relationship between use oral contraceptives after conception and male hypospadias. This study used prescription data rather than selfreported maternal exposure data in order to prevent the recall bias, a relevant cause of spurious associations in retrospective case–control studies. The adjusted prevalence ratios were close to one and none of them was significant: for example 0.85 (95% CI: 0.65–1.28) for exposure to COC in early pregnancy and hypospadias detected within 6 months postpartum [70].

Women with **breakthrough pregnancies** or conception close to OCs cessation should also be assured large studies have not identified increased prevalence of **birth defects**. A meta-analysis published in 1990 found no association for OC exposure early in pregnancy and heart defects or limb reduction defects [71]. Charlton et al. collected data on OCs use and major birth defects on 880,694 live births from Danish registries; the prevalence of major birth defects (per 1000 births) was 25.1 for never users of OCs, 25.0 for OCs used more than 3 months before conception, 24.9 for OCs used less than 3 months before conception and 24.8 for OCs used after conception; the confidence intervals were not significant, and association was not found either for prevalences by defect subgroup [72]. Older studies (with older contraceptive formulations) arrived to more or less similar results: No significant association was observed between congenital malformations and conceiving within 1 month of stopping OC, and in breakthrough pregnancies the ratio of observed to expected major malformations was only significant in mothers one pack or more of cigarettes daily [73]. A recent study in 2010 (with 4000 healthy controls and 9986 infants with birth defects) did not find association for 32 anomalies when OCs usage took place before conception and only found association for gastroschisis (OR 1.82, 95% CI 1.25–1.67) and hypoplastic left heart syndrome (OR 2.33, 1.28–4.25) when OCs usage took place afterwards [74].

Some authors have noted in the last years we have observed increasing rates of OCs use as well as increasing rates of Autism Spectrum Disorder diagnoses and have raised hypotheses regarding specific consequences in the offspring; this remains to be elucidated in future clini-

Contraceptive Methods and the Subsequent Search for a Pregnancy

http://dx.doi.org/10.5772/intechopen.72525

225

It seems clear that fertility returns promptly with OCs and that any delay to return to normal physiology does not remarkably influence 1 year or longer fertility rates. There's no consistent evidence to conclude OCs are associated with future miscarriage, preterm birth, low birth

Removing the implant is often an easy and uncomplicated procedure. In a clinical trial performed by Bahamondes et al., women perceived the pain of the as none (444, 86%), mild (65, 13%), moderate (8, 2%) or severe (0) for the ENG (etonorgestrel) implant; and none (252, 81%), mild (49, 16%), moderate (6, 2%) or severe (1%) for the LNG (levonorgestrel) implant [82]. The ease of removal was reported as easy (492, 94%), slightly difficult (22, 4%) or difficult (8, 2%) for the ENG implant and easy (254, 81%), slightly difficult (47, 15%) or difficult (12, 4%). In this study, two (0.4%) ENG removals were complicated (the implant broke) and seven (2.2%)

The ACOG has published some recommendations regarding the clinical challenges posed by LARC, including the implants [83]. Ultrasonography can be helpful if the implant is impalpable when removal is attempted [84]; in rare cases magnetic resonance might be required to

There is no evidence fertility is delayed after removal of contraceptive implants [13]. In a study Etonogestrel became not detectable within 1 week of removal of Implanon® implant [85]. Pregnancies have been observed to occur as early as 7–14 days after removal [86]. Within 1 month of Implanon removal ovulation has been observed to return in 40% (16/40) women; and 12 months conception rate was 96% (23/24) in women who had the implant removed and

NuvaRing® is the only ring available to the United States; it releases 15 μg ethinyl estradiol +120 μg etonogestrel per day (which are rapidly absorbed through the vaginal epithelium [88]) and lasts 3 weeks. Ovulation returns after removal of the vaginal ring (in a mean time of 19 days [89]). In the majority of women who discontinue NovaRing ovulation and spontane-

Many other contraceptive preparations are being developed, and prompt return of fertility is usually the rule. After discontinuation of a transdermal patch ovulation has been described to

The considerations on pregnancy outcomes for OCs can be extrapolated to those methods in

LNG removals were complicated (in seven cases the implant broke).

did not implement other contraceptive methods [87].

ous menstrual cycles return within a month [90].

return in the first cycle in 86% of women [91].

which estrogens and progestogens are administered non-orally.

cal studies [81].

**2.5. Conclusion**

locate it.

weight or hypospadias.

**3. Implants and rings**

**POPs** have some particular characteristics regarding pregnancy outcomes. If the contraception fails a higher incidence of ectopic pregnancy versus other contraceptive methods has been described, but the incidences were similar to those in women not using contraceptives [12]. A proposed explanation is a reduction in the activity of fallopian tube cilia and tubal motility alteration [75]. Fetal male hypospadias was more likely to occur among women who took progestogens to prevent pregnancy complications or to help with becoming pregnant between a month before conception and 3 months after this point (reaching adjusted OR > 3, and stratified OR > 2). However the association was non-significant for those women who took progestogen as a contraceptive [76].

A Norwegian study published in 2015 evaluated the risk of preterm birth and found this risk varied depending on the moment of exposure and the progestin used. COCs with Norethisterone were particularly associated with preterm birth in some exposure periods (with adjusted OR reaching 3.33 (95% CI: 1.69–6.57 for the period 0–12 weeks after conception, a period that seemed particularly critical in some subgroups); for COCs with Drospirenone or Levonogestrel or POPs the association seemed weaker or absent. Authors noted the association for preterm birth seemed consistent across all exposure periods, but they also acknowledged other confounding factors could explain this association. Authors pondered a weakly estrogenic environment could be deleterious for fetal growth. The study also evaluated birth weight using z-scores (a more precise and current definition) and found no association with OCs [77]. A cohort study in China agrees with this association (OR for OCs usage in multiple logistic regression: 8.162, 95% CI: 1.622–41.072) [78]. Other studies found that exposure to OCs in the 6 months before conception was associated with higher birth weight compared to longer duration exposures [63].

There is no evidence that Emergency Contraception is associated with worse outcomes in future pregnancies. The pregnancy outcomes of women undergoing mifepristone-induced abortion were studied in nearly 15,000 pregnant women in China. There were no statistically significant differences in preterm delivery, frequency of low birth weight or mean infant birth weight when comparing these women with those with surgically induced abortion. When comparing mifepristone-induced abortion and women without previous abortion the former had higher mean birth weight and no significant differences in pregnancy length [79]. Other studies have found the outcome of medically terminated pregnancies is similar to those of mothers without them and better than those of mothers with surgically terminated pregnancies [80].

Some authors have noted in the last years we have observed increasing rates of OCs use as well as increasing rates of Autism Spectrum Disorder diagnoses and have raised hypotheses regarding specific consequences in the offspring; this remains to be elucidated in future clinical studies [81].

#### **2.5. Conclusion**

limb reduction defects [71]. Charlton et al. collected data on OCs use and major birth defects on 880,694 live births from Danish registries; the prevalence of major birth defects (per 1000 births) was 25.1 for never users of OCs, 25.0 for OCs used more than 3 months before conception, 24.9 for OCs used less than 3 months before conception and 24.8 for OCs used after conception; the confidence intervals were not significant, and association was not found either for prevalences by defect subgroup [72]. Older studies (with older contraceptive formulations) arrived to more or less similar results: No significant association was observed between congenital malformations and conceiving within 1 month of stopping OC, and in breakthrough pregnancies the ratio of observed to expected major malformations was only significant in mothers one pack or more of cigarettes daily [73]. A recent study in 2010 (with 4000 healthy controls and 9986 infants with birth defects) did not find association for 32 anomalies when OCs usage took place before conception and only found association for gastroschisis (OR 1.82, 95% CI 1.25–1.67) and hypoplastic left heart syndrome (OR 2.33, 1.28–4.25) when OCs usage took place afterwards [74].

**POPs** have some particular characteristics regarding pregnancy outcomes. If the contraception fails a higher incidence of ectopic pregnancy versus other contraceptive methods has been described, but the incidences were similar to those in women not using contraceptives [12]. A proposed explanation is a reduction in the activity of fallopian tube cilia and tubal motility alteration [75]. Fetal male hypospadias was more likely to occur among women who took progestogens to prevent pregnancy complications or to help with becoming pregnant between a month before conception and 3 months after this point (reaching adjusted OR > 3, and stratified OR > 2). However the association was non-significant for those women who

A Norwegian study published in 2015 evaluated the risk of preterm birth and found this risk varied depending on the moment of exposure and the progestin used. COCs with Norethisterone were particularly associated with preterm birth in some exposure periods (with adjusted OR reaching 3.33 (95% CI: 1.69–6.57 for the period 0–12 weeks after conception, a period that seemed particularly critical in some subgroups); for COCs with Drospirenone or Levonogestrel or POPs the association seemed weaker or absent. Authors noted the association for preterm birth seemed consistent across all exposure periods, but they also acknowledged other confounding factors could explain this association. Authors pondered a weakly estrogenic environment could be deleterious for fetal growth. The study also evaluated birth weight using z-scores (a more precise and current definition) and found no association with OCs [77]. A cohort study in China agrees with this association (OR for OCs usage in multiple logistic regression: 8.162, 95% CI: 1.622–41.072) [78]. Other studies found that exposure to OCs in the 6 months before conception was associated with higher birth weight compared to longer duration exposures [63].

There is no evidence that Emergency Contraception is associated with worse outcomes in future pregnancies. The pregnancy outcomes of women undergoing mifepristone-induced abortion were studied in nearly 15,000 pregnant women in China. There were no statistically significant differences in preterm delivery, frequency of low birth weight or mean infant birth weight when comparing these women with those with surgically induced abortion. When comparing mifepristone-induced abortion and women without previous abortion the former had higher mean birth weight and no significant differences in pregnancy length [79]. Other studies have found the outcome of medically terminated pregnancies is similar to those of mothers without

them and better than those of mothers with surgically terminated pregnancies [80].

took progestogen as a contraceptive [76].

224 Family Planning

It seems clear that fertility returns promptly with OCs and that any delay to return to normal physiology does not remarkably influence 1 year or longer fertility rates. There's no consistent evidence to conclude OCs are associated with future miscarriage, preterm birth, low birth weight or hypospadias.
