Most pregnancies in women with rheumatologic disease will result in the delivery of a healthy baby. Pregnancy can be particularly risky in women with active disease or on teratogenic medications, making contraception an important issue for these women. All women with rheumatologic disease have contraceptive options, including barrier methods, the intra-uterine device and progesterone-only medications. Active inflammatory disease, whether in the form of lupus, systemic vasculitis or myositis, places the pregnancy at increased risk. Pre-eclampsia is a particular risk for women with lupus or antiphospholipid syndrome and may be decreased by daily low-dose aspirin. Rheumatoid arthritis typically improves and does not have a major impact on pregnancy outcomes. The expected post-partum arthritis flare may be avoided by restarting medications soon after delivery. Judicious use of medication and close observation may be the keys to successful pregnancy in women with rheumatologic disease.
Contraception
Fertility is maintained despite rheumatologic disease in most women. It is particularly important to discuss contraception with patients early and often for several reasons. Women with rheumatologic diseases do not have a higher rate of infertility than the healthy population. They do, however, often take medications that may be harmful for a foetus. In addition, timing a pregnancy to coincide with a period of disease quiescence increases the chances for a healthy and uneventful pregnancy for both mother and baby.
Despite often debilitating disease, young women with rheumatologic disease are sexually active, and often doing so without effective contraception. In a recent study of 199 non-pregnant women with systemic lupus erythematosus (SLE), 27% reported having had unprotected intercourse within the past 3 months and 11% reported that they did not use contraception ‘most of the time’ . Some of the most commonly used contraceptive methods are the most unreliable (see Table 1 ).
| Method | Percent using this method | Unintended pregnancy rate a |
|---|---|---|
| Condoms | 47% | 17% |
| Estrogen-progestin method | 24% | 9% |
| Withdrawal | 23% | 18% |
| Progestin-only method | 7% | 5% |
| Rhythm Method | 6% | 25% |
| Intrauterine Device (IUD) | 4% | 2% |
a The unintended pregnancy rate is the percentage of women expected to be pregnant at the end of 1 year of regular intercourse with typical use of the method.
Another reason that contraceptive counselling is essential in the rheumatologic practice is that young women are not provided comprehensive reproductive health education in schools in much of the United States . This means that a woman in her teens and 20s is likely to be poorly equipped to choose an effective method of contraception without physician guidance. When a young woman starting on methotrexate is told “don’t get pregnant,” she may not have a clear idea how to put this instruction into action.
A common misconception among young women with lupus is that they ‘cannot take birth control’. Although physicians typically mean that oestrogen-containing birth control may be contraindicated, this message is often misinterpreted to apply to all forms of effective contraception. It is important to stress that there are several excellent, reliable options available to women with rheumatologic disease.
Contraceptive Options
The three main types of contraceptives available to all women with rheumatologic disease are barrier methods, progestin-only methods and the intrauterine device (IUD).
Barrier methods
Barrier methods are an effective method to prevent pregnancy and the only method to protect against sexually transmitted disease. With typical use, the unintended pregnancy rate, however, remains high: 17% for condoms and 16% for diaphragm. The use of spermicide without a barrier will result in a 29% failure rate; however, when spermicide is combined with condoms or a diaphragm, the failure rate falls to 2.5% . The combination of condoms plus spermicide has the distinct advantage of being inexpensive and available without a prescription. It is frequently recommended that patients without an effective contraception plan stop at the drug store on the way home to purchase condoms and spermicide to ensure it is available to her. For women concerned about hormonal contraception, having a diaphragm or cervical cap fit and prescribed by their gynaecologist is another good option. These, too, should be used in combination with spermicide to improve efficacy.
Intrauterine device
The most commonly used IUD in the United States contains progesterone, which is released locally to atrophy the uterine lining, impair the transport of sperm and egg and decrease the frequency of ovulation. With typical use, 2% of couples will become pregnant over a year using this form of birth control. The continuation rate of the IUD is 80% at 1 year, far greater than birth control pills or injectables. The key benefits of the IUD are that it can remain in place for 5 years, it often decreases or completely halts menstrual bleeding and fertility is promptly restored following removal. Placement of an IUD is generally done in the gynaecology office. There is, unfortunately, a risk of expulsion, with 5% falling out over the 5-year life span of the device. Following placement, some women will have several months of irregular bleeding that can cause a certain degree of dissatisfaction. In the first 20 days after insertion, there is an estimated 1% risk of intrauterine infection. A high degree of immunosuppression should not be considered a contraindication to IUD placement; the risk of unplanned pregnancy in this population far outweighs the risk for infection. Prophylactic antibiotics are not typically prescribed, but may be considered if a woman is significantly immunosuppressed.
Progestin-only methods
Women with rheumatologic diseases are able to safely use progestin-only methods to avoid pregnancy. These come in several forms: daily pills (the ‘mini-pill’), every 3-month injections (Depo-provera®), a 3-year implant (Implanon®), an IUD (Mirena®) and emergency contraception (Plan B®). Progestin does not appear to increase immune activity and is not associated with increased disease flares . In addition, the dose of progestin used in contraceptives does not increase the risk for thrombosis .
Emergency contraception
Marketed under the name ‘Plan B’, emergency contraception consists of progesterone-only pills (levonorgestrel) taken following unprotected intercourse to prevent conception. These pills contain no oestrogen, so should be considered safe for women with rheumatologic disease. The pills work by inhibiting ovulation, altering the tubal flow of sperm and egg to prevent fertilisation and changing the endometrium to prevent implantation. They will not expel an implanted embryo, so will not adversely affect an established pregnancy. When taken within 72 h of unprotected intercourse, the pills will decrease the chances of getting pregnant from 8% to 1% . The sooner the pills are taken following intercourse, the higher likelihood that they will prevent pregnancy. The most common side effects include nausea in up to a quarter of users, abdominal pain, fatigue, headache and dizziness. The risk of ectopic pregnancy is higher than usual for conceptions exposed to emergency contraception, presumably because it slows the passage of the egg through the fallopian tube. If the next menses is missed, a pregnancy test should be performed and, if positive, an intrauterine pregnancy should be confirmed. In the United States, anyone over the age of 17 is able to purchase emergency contraception from a pharmacist without a prescription. Younger patients require a prescription. For patients with unreliable contraceptive use, purchasing a pack of emergency contraception to have on hand is often recommended.
Oestrogen-based contraceptives
Oestrogen is included in the most popular birth control pills, not for contraceptive purposes but to diminish some of the side effects of progesterone. The vaginal hormone ring and the patch also contain a combination of oestrogen and progesterone. With actual use, these typically have a 5% failure rate. These contraceptives keep the serum oestradiol level at about 200 pg ml −1 throughout the month, compared with the typical fluctuation in oestradiol from 50 pg ml −1 up to 200 pg ml −1 at the oestrogen surge prior to ovulation. This higher oestradiol level can promote thrombosis in susceptible women, making these drugs contraindicated in women with antiphospholipid antibodies. Women with SLE are at a threefold higher risk for thrombosis than the general population, making oestrogen-based contraception risky.
Two randomised, placebo controlled trials found that birth control pills containing oestrogen did not significantly increase the risk for lupus flare among women with mild, stable lupus (see Table 2 ) . These studies did not include women with active disease, precluding the assessment that these pills are safe during periods of high disease activity. The SELENA study excluded women with positive antiphospholipid antibodies; the Sanchez-Guerero study allowed women with these antibodies but not the clinical syndrome of antiphospholipid syndrome (APS).
| SELENA-OCP | Sanchez-Guerrero, et. al. | ||||
|---|---|---|---|---|---|
| Placebo | OCP | Copper IUD | Progestin-only | OCP | |
| N | 92 | 91 | 54 | 54 | 54 |
| Severe flare | 7.6% | 7.7% | 3.7% | 7.4% | 3.7% |
| Any flare | 69% | 76% | 74% | 74% | 67% |
| Thrombosis | 3 | 2 | 0 | 2 | 2 |
There are conflicting data about the association of SLE onset and the oral contraceptive pills (OCP). An analysis of the Nurses’ Health Study found an increased risk (odds ratio (OR) 1.9) for SLE with prior OCP use . A large study of 786 women with SLE and 7814 controls found an increased risk for SLE with OCP use (relative risk (RR) 1.19 for any use, 1.54 for current use and 2.52 for recently started OCP) . However, a study of almost 200 women with SLE and their friends did not find a risk from OCP use . In addition, the Carolina Lupus Study, which followed up women from the time of SLE diagnosis, did not find an association with OCP use . Several epidemiologic studies have found no association between birth control pills and rheumatoid arthritis .
- •
Contraceptives should be available to all women with rheumatologic disease.
- •
The IUD is an effective, safe, long-term method of birth control.
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Spermicide significantly improves the effectiveness of barrier methods, such as condoms and diaphragms.
- •
Progestin-only contraceptives, available in pills, shots and implants, do not worsen rheumatologic disease nor increase the risk for thrombosis.
- •
Emergency contraception is progestin-only and should be safe for women with rheumatologic disease.
Systemic lupus erythematosis
SLE is the most studied condition during pregnancy due to the young age and female predominance of the disease. We know that the risk for pregnancy loss is increased for women with SLE; the risk for early loss (<20 weeks’ gestation) is only modestly increased, but the risk for late loss (>20 weeks’ gestation) is about eightfold higher than the general population (see Fig. 1 ). Women with lupus are also at increased risk for preterm birth, with active SLE during pregnancy as the primary risk factor for this complication . Pre-eclampsia and lupus activity may lead to a medically induced preterm delivery, but women with lupus are also at increased risk for premature rupture of membranes .
Though unexpected complications can happen in any pregnancy, poor pregnancy outcomes can be largely predicted by the level of lupus activity at conception and during pregnancy, a history of lupus nephritis, the presence of maternal SSA/Ro and SSB/La antibodies, APS and maternal hypertension .
Lupus activity at the time of conception and in the first trimester increases the risk of pregnancy loss, particularly stillbirth, by up to threefold . First trimester thrombocytopaenia and proteinuria are two objective markers of SLE activity that increase the risk for pregnancy loss to 36–43% .
A history of lupus nephritis, and particularly currently active lupus nephritis, increases the risks for pregnancy loss, preterm birth and pre-eclampsia. Two recent studies demonstrated this finding by comparing the pregnancy outcomes for women with prior and current lupus nephritis with women without prior nephritis. For women with quiescent lupus nephritis at the time of conception, the risks of preterm birth and pregnancy loss were only modestly elevated. However, for women with currently active lupus nephritis, the risks of these complications increased two- to threefold. Only 10–15% of pregnancies complicated by active lupus nephritis resulted in a full-term live birth .
Having increased lupus activity in the prior 6 months greatly increases the risk for flare during pregnancy. In the Hopkins Lupus Cohort, of women with inactive lupus in the 6 months prior to conception, only 8% had moderate-to-severe lupus activity in pregnancy. By contrast, 58% of women with moderate-to-severe disease prior to conception had similarly (or more dramatically) active disease in pregnancy . In a retrospective questionnaire of women with lupus, 18% reported that their lupus had flared during pregnancy and 18% reported that it had improved . Clinically, some women will report significant improvement in symptoms, particularly joint pains and rash, during pregnancy in a manner similar to women with rheumatoid arthritis. What clinical, physiologic and perhaps genetic factors differentiate these women from those who flare during pregnancy is not currently understood.
Pre-eclampsia in lupus pregnancy
Pre-eclampsia is defined as hypertension (>140/90) and proteinuria (>300 mg per 24 h) that develops in a woman past 20 weeks’ gestation and resolves post-partum. In the general population, an estimated 2–8% of women will develop pre-eclampsia, typically close to term. Risk factors include prior pre-eclampsia, hypertension and renal insufficiency. The physiologic aetiology of pre-eclampsia is poorly understood, but it is thought to begin with poor implantation and diminished trophoblast invasion of the uterine spiral arteries . As the placenta grows, the blood flow through these deficient arteries leads to areas of placental ischaemia and damage. In addition, the placenta may produce too little prostacycline, a vasodilator, and too much thromboxane, a vasoconstrictor and platelet activator. This leads to further placental damage, as well as vascular changes in the mother, leading to hypertension and renal dysfunction.
Women with lupus are at particularly high risk for pre-eclampsia. There are estimates that 10–25% of women with lupus develop this complication, sometimes early in the third trimester . Risk factors for pre-eclampsia in women with lupus include prior lupus nephritis, hypertension and APS.
Distinguishing lupus nephritis from pre-eclampsia can be a challenge, and at times, impossible. Pre-eclampsia is often accompanied by an increase in serum uric acid or a decline in urine calcium. Lupus nephritis may be suggested by falling complement, rising anti-dsDNA titres and other signs or symptoms of active lupus, such as arthritis, fevers and rash. Both severe pre-eclampsia and lupus can both present with thrombocytopaenia, haemolysis and elevated liver tests, preventing these from being clear distinguishing factors between the two. The treatment for pre-eclampsia is delivery. When is it unclear whether pre-eclampsia or lupus activity is the cause for illness and the pregnancy is near term, then delivery may be the best option. If the constellation of symptoms does not begin to resolve within 48 h of delivery, then aggressive treatment for active SLE is indicated. If the patient is far from term, however, treatment with high-dose steroids and, in some cases, renal biopsy, may be able to improve the medical situation to allow further time in utero for foetal development.
The risk for pre-eclampsia, as well as preterm birth and pregnancy loss, may be decreased by daily low-dose aspirin, particularly in women at high risk for these complications (see Table 3 ). Aspirin decreases the vasoconstrictor thromboxane and platelet activation, both factors contributing to pre-eclampsia. A Cochrane Review of aspirin in pregnancy included 57 trials and over 37 000 women; none of these studies specifically included autoimmune diseases . Low-dose aspirin was found to be safe for the mother and baby, as well as potentially beneficial (see Table 3 ). For women at high risk for pre-eclampsia, daily low-dose aspirin can decrease the risk for pre-eclampsia by 25% and the risk for pregnancy loss by 31%. As women with lupus are at particularly high risk for pre-eclampsia, we recommend starting all women with lupus on 81 mg of aspirin per day.
| All pregnancies RR (CI) | High risk pregnancies a RR (CI) | |
|---|---|---|
| Preeclampsia | 0.83 (0.77−0.89) | 0.75 (0.66−0.85) |
| Preterm birth | 0.92 (0.88−0.97) | 0.93 (0.88-0.99) |
| Fetal or neonatal death | 0.86 (0.76-0.98) | 0.69 (0.53-0.90) |
a High risk pregnancies included women with a history of severe preeclampsia, diabetes, chronic hypertension, renal disease, or autoimmune disease.
Systemic lupus erythematosis
SLE is the most studied condition during pregnancy due to the young age and female predominance of the disease. We know that the risk for pregnancy loss is increased for women with SLE; the risk for early loss (<20 weeks’ gestation) is only modestly increased, but the risk for late loss (>20 weeks’ gestation) is about eightfold higher than the general population (see Fig. 1 ). Women with lupus are also at increased risk for preterm birth, with active SLE during pregnancy as the primary risk factor for this complication . Pre-eclampsia and lupus activity may lead to a medically induced preterm delivery, but women with lupus are also at increased risk for premature rupture of membranes .
Though unexpected complications can happen in any pregnancy, poor pregnancy outcomes can be largely predicted by the level of lupus activity at conception and during pregnancy, a history of lupus nephritis, the presence of maternal SSA/Ro and SSB/La antibodies, APS and maternal hypertension .
Lupus activity at the time of conception and in the first trimester increases the risk of pregnancy loss, particularly stillbirth, by up to threefold . First trimester thrombocytopaenia and proteinuria are two objective markers of SLE activity that increase the risk for pregnancy loss to 36–43% .
A history of lupus nephritis, and particularly currently active lupus nephritis, increases the risks for pregnancy loss, preterm birth and pre-eclampsia. Two recent studies demonstrated this finding by comparing the pregnancy outcomes for women with prior and current lupus nephritis with women without prior nephritis. For women with quiescent lupus nephritis at the time of conception, the risks of preterm birth and pregnancy loss were only modestly elevated. However, for women with currently active lupus nephritis, the risks of these complications increased two- to threefold. Only 10–15% of pregnancies complicated by active lupus nephritis resulted in a full-term live birth .
Having increased lupus activity in the prior 6 months greatly increases the risk for flare during pregnancy. In the Hopkins Lupus Cohort, of women with inactive lupus in the 6 months prior to conception, only 8% had moderate-to-severe lupus activity in pregnancy. By contrast, 58% of women with moderate-to-severe disease prior to conception had similarly (or more dramatically) active disease in pregnancy . In a retrospective questionnaire of women with lupus, 18% reported that their lupus had flared during pregnancy and 18% reported that it had improved . Clinically, some women will report significant improvement in symptoms, particularly joint pains and rash, during pregnancy in a manner similar to women with rheumatoid arthritis. What clinical, physiologic and perhaps genetic factors differentiate these women from those who flare during pregnancy is not currently understood.
Pre-eclampsia in lupus pregnancy
Pre-eclampsia is defined as hypertension (>140/90) and proteinuria (>300 mg per 24 h) that develops in a woman past 20 weeks’ gestation and resolves post-partum. In the general population, an estimated 2–8% of women will develop pre-eclampsia, typically close to term. Risk factors include prior pre-eclampsia, hypertension and renal insufficiency. The physiologic aetiology of pre-eclampsia is poorly understood, but it is thought to begin with poor implantation and diminished trophoblast invasion of the uterine spiral arteries . As the placenta grows, the blood flow through these deficient arteries leads to areas of placental ischaemia and damage. In addition, the placenta may produce too little prostacycline, a vasodilator, and too much thromboxane, a vasoconstrictor and platelet activator. This leads to further placental damage, as well as vascular changes in the mother, leading to hypertension and renal dysfunction.
Women with lupus are at particularly high risk for pre-eclampsia. There are estimates that 10–25% of women with lupus develop this complication, sometimes early in the third trimester . Risk factors for pre-eclampsia in women with lupus include prior lupus nephritis, hypertension and APS.
Distinguishing lupus nephritis from pre-eclampsia can be a challenge, and at times, impossible. Pre-eclampsia is often accompanied by an increase in serum uric acid or a decline in urine calcium. Lupus nephritis may be suggested by falling complement, rising anti-dsDNA titres and other signs or symptoms of active lupus, such as arthritis, fevers and rash. Both severe pre-eclampsia and lupus can both present with thrombocytopaenia, haemolysis and elevated liver tests, preventing these from being clear distinguishing factors between the two. The treatment for pre-eclampsia is delivery. When is it unclear whether pre-eclampsia or lupus activity is the cause for illness and the pregnancy is near term, then delivery may be the best option. If the constellation of symptoms does not begin to resolve within 48 h of delivery, then aggressive treatment for active SLE is indicated. If the patient is far from term, however, treatment with high-dose steroids and, in some cases, renal biopsy, may be able to improve the medical situation to allow further time in utero for foetal development.
The risk for pre-eclampsia, as well as preterm birth and pregnancy loss, may be decreased by daily low-dose aspirin, particularly in women at high risk for these complications (see Table 3 ). Aspirin decreases the vasoconstrictor thromboxane and platelet activation, both factors contributing to pre-eclampsia. A Cochrane Review of aspirin in pregnancy included 57 trials and over 37 000 women; none of these studies specifically included autoimmune diseases . Low-dose aspirin was found to be safe for the mother and baby, as well as potentially beneficial (see Table 3 ). For women at high risk for pre-eclampsia, daily low-dose aspirin can decrease the risk for pre-eclampsia by 25% and the risk for pregnancy loss by 31%. As women with lupus are at particularly high risk for pre-eclampsia, we recommend starting all women with lupus on 81 mg of aspirin per day.
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