Ectopic pregnancy: Methotrexate therapy

INTRODUCTION — An ectopic pregnancy is a pregnancy outside of the uterine cavity. The majority of ectopic pregnancies occur in the fallopian tube, but other possible sites include interstitial (a pregnancy located in the proximal segment of the fallopian tube that is embedded within the muscular wall of the uterus), cervical, intramural, ovarian, or abdominal. Other abnormally implanted pregnancies, including hysterotomy (ie, cesarean, myomectomy) scar pregnancies can also occur. In rare cases, a multiple gestation may be heterotopic (includes both a uterine and extrauterine pregnancy).

Ectopic pregnancy is a potentially life-threatening condition. While surgical approaches are the gold-standard treatment, because of advances in early diagnosis, many patients are candidates for medical therapy with methotrexate (MTX), and the overall success rate of medical treatment in properly selected patients is high.

Treatment of ectopic pregnancy with MTX will be reviewed here. Related topics regarding ectopic pregnancy are discussed in detail separately, including:

●Epidemiology, risk factors, and pathology (see "Ectopic pregnancy: Epidemiology, risk factors, and anatomic sites")

●Clinical manifestations and diagnosis (see "Ectopic pregnancy: Clinical manifestations and diagnosis")

●Choosing a treatment (see "Ectopic pregnancy: Choosing a treatment")

●Surgical management (see "Tubal ectopic pregnancy: Surgical treatment")

●Expectant management (see "Ectopic pregnancy: Expectant management of tubal pregnancy")

●Diagnosis and management of uncommon sites of ectopic and abnormally implanted intrauterine pregnancies (see "Abdominal pregnancy" and "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Heterotopic pregnancy' and "Ectopic pregnancy: Choosing a treatment", section on 'Heterotopic pregnancy' and "Cesarean scar pregnancy")

●Patients with pregnancy of unknown location (see "Approach to the patient with pregnancy of unknown location")

INDICATIONS AND ALTERNATIVES — The indication for pharmacologic management of ectopic pregnancy is a clinical diagnosis of ectopic pregnancy in a patient who meets the selection criteria for MTX therapy and who is able and willing to comply with the close follow-up that is necessary after pharmacologic management (algorithm 1).

How to choose between MTX and surgery (or expectant management in a small proportion of patients) and contraindications to MTX (eg, hemodynamic instability, heterotopic pregnancy with a coexisting viable intrauterine pregnancy, breastfeeding, hypersensitivity to MTX) are also illustrated in the algorithm and are discussed in detail separately. (See "Ectopic pregnancy: Choosing a treatment" and "Ectopic pregnancy: Choosing a treatment", section on 'Choosing between methotrexate and surgery'.)

CLINICAL PHARMACOLOGY

Mechanism of action — MTX is a folic acid antagonist widely used for treatment of neoplasia, severe psoriasis, and rheumatoid arthritis. It inhibits deoxynucleic acid (DNA) synthesis and cell reproduction, primarily in actively proliferating cells such as malignant cells, trophoblasts, and fetal cells. MTX is rapidly cleared by the kidneys, with 90 percent of an intravenous dose excreted unchanged within 24 hours of administration [1].

In some protocols, reduced folates (leucovorin, also called folinic acid, N5-formyl-tetrahydrofolate, citrovorum factor) are given in combination with MTX to bypass the metabolic block induced by MTX and thus rescue normal cells from toxicity. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Rationale for leucovorin rescue'.)

Dosing and administration — Treatment of ectopic pregnancy uses an intermediate MTX dose (50 mg/m² body surface area [BSA] or 1 mg/kg body weight) with a maximum dose (based on the author's clinical experience) of 100 mg in patients with normal renal function. However, no studies have evaluated the maximum dose of MTX in patients with ectopic pregnancy.

By contrast, low doses (7.5 to 25 mg weekly) are typically used to treat rheumatologic disorders, and high-dose MTX (≥500 mg/m²) is used to treat some malignancies. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration' and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Definition of high-dose methotrexate'.)

MTX can be given systemically (ie, intravenously, intramuscularly [IM], or orally) or by direct local injection into the ectopic pregnancy sac with either a transvaginal or transabdominal (eg, laparoscopic) approach. IM administration is the most common route for treatment of tubal pregnancy [2]. Local injection is not generally used for tubal pregnancy, as it has been found to be less effective than salpingostomy [3], requires administration by an experienced physician, and is highly operator dependent. In addition, patients bearing the risks of laparoscopic surgery should have definitive treatment (ie, removal of the ectopic gestation via salpingectomy or salpingostomy). Local injection is used in some cases of rare ectopic gestation locations (eg, cervical). (See "Cervical pregnancy: Diagnosis and management", section on 'Treatment'.)

When leucovorin is administered as part of the multiple-dose MTX protocol, it is typically administered by IM injection; it can also be given orally. Leucovorin calcium is the preparation used for this indication. (See 'Patients with an interstitial pregnancy: Multiple-dose' below.)

Adverse reactions — Adverse reactions to MTX are usually mild and self-limited. The most common are stomatitis and conjunctivitis. Rare side effects include gastritis, enteritis, dermatitis, pneumonitis, alopecia, elevated liver enzymes, and bone marrow suppression. Approximately 30 percent of patients in the single-dose protocol will have side effects; this rate is lower than with multiple-dose regimens (40 percent) [4]. (See 'Preferred approach for most patients: Single-dose' below and "Major side effects of low-dose methotrexate".)

Toxicities of high-dose MTX are discussed in detail separately. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Overview of adverse effects'.)

Comparing single- versus multi-dose therapy — For most patients, we prefer an initial approach with single-dose therapy rather two-dose or multiple-dose therapy for tubal ectopic pregnancy (see 'Clinical protocol' below). While the overall rate of resolution of ectopic pregnancy reported in the literature is approximately 90 percent for both single- and multi-dose protocols [3-5], multi-dose protocols appear to cause more adverse effects [4]. A single-dose approach is also less expensive, requires less intensive monitoring, and does not require leucovorin rescue. In clinical use, however, protocols may overlap. Fourteen percent of patients on single-dose regimens ultimately receive two or more doses, and 10 percent of patients on multi-dose regimens receive just a single dose [4].

Data from systematic reviews and a meta-analysis evaluating the various regimens show mixed results:

●In a systematic review of two randomized trials including 159 patients comparing single-dose with fixed multiple-dose regimens, treatment success was similar between groups (89 to 91 and 86 to 93 percent, respectively) [3]. There were no consistent findings regarding rates of complications between the two regimens.

●By contrast, in another systematic review of 26 observational studies including 1300 patients with ectopic pregnancy, overall success rates were lower for single- compared with multi-dose regimens [4]. This difference was even larger after adjustment for factors such as human chorionic gonadotropin (hCG) level and presence of embryonic cardiac activity (odds ratio [OR] 4.7, 95% CI 1.8-12.6). However, fewer side effects were noted after single-dose compared with multi-dose treatment (31 versus 41 percent).

●In a meta-analysis evaluating seven randomized trials that compared patients treated for ectopic pregnancy with a single-dose, two-dose, or multiple-dose MTX, the two-dose protocol was associated with higher treatment success compared with the single-dose protocol (OR 1.8, 95% CI 1.1-3) [6]. In addition, the two-dose protocol was more successful than single-dose protocol in patients with high hCG levels (defined as hCG levels >3000 milli-international units/mL; OR 3.2, 95% CI 1.5-6.8), and in patients with a large adnexal mass (defined as >2 cm; OR 2.9, 95% CI 1.2-6.9). Compared with the single-dose protocol, the multi-dose protocol was associated with a nonsignificant reduction in treatment failure (OR 0.6, 95% CI 0.3-1.1) and a higher chance of side effects (OR 2.1, 95% CI 1.2-3.5).

For patients with interstitial pregnancy, there are no high-quality data comparing single-dose versus multi-dose MTX therapy. In one prospective study including 17 patients with interstitial pregnancy treated with single-dose MTX, 16 patients (94 percent) experienced pregnancy resolution; a second dose was required in six patients [7]. One patient experienced rupture of the ectopic pregnancy following two doses of MTX and was managed surgically.

Role of combined drug therapy — While combined use of MTX with other medications (eg, mifepristone, gefitinib) has been studied, we do not use combination therapy in our practice; combination therapy adds cost and potential complications to an already effective therapy.

●Mifepristone – Mifepristone is a progesterone receptor antagonist used for the management of patients with pregnancy loss or undergoing pregnancy termination. In a meta-analysis of three randomized trials including 442 patients with tubal ectopic pregnancy, single-dose MTX alone or in combination with oral mifepristone (600 mg) had similar rates of success; side effects, need for a second injection of methotrexate, and operative rates were also similar between groups [8].

●Gefitinib – Gefitinib is a selective inhibitor of epidermal growth factor receptor and is used in the treatment of non-small cell lung cancer and breast cancer [9,10]. As the placenta has the highest expression of epidermal growth factor of all nonmalignant tissues, its use (in combination with MTX) has been investigated for the treatment of patients with ectopic pregnancy.

In a small case series including 12 patients with an ectopic pregnancy, combination therapy with MTX plus gefitinib resulted in a faster decline of serum hCG than treatment of historical controls with MTX alone [10]. However, a subsequent randomized trial did not support these findings. In this trial including 325 patients with tubal ectopic pregnancy (median hCG level 1994 milli-international units/mL), those receiving MTX plus seven days of either gefitinib (250 mg daily) or placebo had similar rates of surgical intervention, time to resolution, and subsequent doses of MTX [11]. While serious complications occurred in 4 to 5 percent of patients and were similar between groups, more patients in the gefitinib group experienced diarrhea (47 versus 24 percent) and rash (61 versus 23 percent).

Gefitinib may result in interstitial lung disease, particularly in patients of Japanese ancestry.

PRETREATMENT EVALUATION — Prior to treatment with MTX, the following evaluation is performed:

●Physical examination and patient history

●Serum beta-human chorionic gonadotropin (hCG)

●Transvaginal ultrasound

●Blood type and screen

●Complete blood count and renal (creatinine) and liver (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) function tests

These are discussed in detail separately. (See "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Diagnostic evaluation'.)

CLINICAL PROTOCOL — The regimens below are named for the intended number of methotrexate doses and not the actual number of doses needed.

Protocols may vary and the choice of protocol depends on provider and institutional preference.

Preferred approach for most patients: Single-dose — For most patients with tubal pregnancy, we suggest a single intramuscular (IM) dose of MTX. Approximately 15 to 20 percent of such patients will require a second dose of MTX, and patients should be made aware of this before starting the protocol [4,12]. Less than 1 percent of patients need more than two doses [4].

In the single-dose protocol (table 1), day 1 is the day that MTX is administered; a human chorionic gonadotropin (hCG) is also measured on day 1 [2,13,14]. The dose used is 50 mg/m² body surface area (BSA; maximum dose 100 mg in patients with normal renal function). BSA may be calculated based on height and weight on the day of treatment using a BSA calculator (calculator 1) or the following formula:

●In a commonly used protocol, on days 4 and 7, a serum hCG concentration is drawn [15-17]. If the decrease in hCG between days 4 and 7 is <15 percent, a second dose of MTX 50 mg/m² IM is administered. It is common to observe an increase in hCG levels from day 1 through day 4, and this should not cause concern [18]. This is due to continued hCG production by syncytiotrophoblast despite cessation of production by cytotrophoblast.

●If an additional dose of MTX is indicated, we do not repeat pretreatment laboratory testing (complete blood count, renal and liver function tests (see 'Pretreatment evaluation' above); there are no data suggesting that one dose of MTX changes the results of these tests.

Follow-up includes:

●After day 7, hCG testing is repeated weekly. On day 14:

•If there is a ≥15 percent hCG decline from days 7 to 14, check hCG weekly until the level is undetectable (this level varies by laboratory). The hCG concentration usually declines to <15 milli-international units/mL by 35 days postinjection, but some patients have a slow clearance of serum hCG and it may take as long as 109 days to become undetectable [12,19]. The risk of gestational trophoblastic disease is low.

-If hCG does not become undetectable, a new pregnancy should be excluded.

-In our practice, if three weekly values are similar, we give an additional dose of MTX (50 mg/m²). This typically accelerates the decline of serum hCG.

•If there is a <15 percent hCG decline from days 7 to 14, an additional dose of MTX 50 mg/m² IM is given.

•If the hCG is rising, a transvaginal ultrasound should be performed.

We give a maximum of three doses of MTX. In rare cases in which the hCG falls <15 percent between weekly measurements after a third dose, we perform a laparoscopic salpingostomy or salpingectomy. (See "Tubal ectopic pregnancy: Surgical treatment".)

Leucovorin rescue is not required for patients treated with the single-dose protocol, even if multiple doses are ultimately given.

There appears to be no clinical benefit from routine serial ultrasound examinations [20]. After treatment, the ectopic pregnancy is often noted to increase in size and may persist for weeks on serial ultrasound examinations. This probably represents hematoma rather than persistent trophoblastic tissue and is not predictive of treatment failure. However, ultrasound evaluation for peritoneal fluid is indicated for patients with severe abdominal pain. (See 'Posttreatment instructions and counseling' below.)

Role of two-dose protocol — Administration of a two-dose protocol has been described for selected patients with tubal ectopic pregnancy in whom human chorionic hCG levels are high (>3000 milli-international units/mL) or with an adnexal mass measuring >2 cm (table 1); however, we do not use the two-dose protocol in our practice. (See 'Comparing single- versus multi-dose therapy' above.)

In this protocol, MTX 50 mg/m² BSA (maximum dose 100 mg in patients with normal renal function) is administered on day 1 and a second dose of MTX 50 mg/m² on day 4. Serum hCG levels are obtained on days 1, 4, and 7. If on day 7:

●Serum hCG declines >15 percent from the previous measurement, treatment is stopped, and the surveillance phase (which consists of weekly measurement of hCG until it is undetectable) begins.

●Serum hCG measurement declines <15 percent, a third dose of MTX may be administered on day 7, and hCG is reassessed on day 11. A fourth dose of MTX may be administered on day 11 for insufficient decline in hCG, with subsequent reassessment on day 14. If there continues to be an insufficient hCG decline at that point, surgery should be considered.

Patients with an interstitial pregnancy: Multiple-dose — Successful medical management of interstitial pregnancy (located at the junction of the fallopian tube and uterine cavity) was first reported with a multiple-dose protocol (figure 1 and table 1). The most common regimen is the administration of MTX (1 mg/kg body weight per day IM or intravenously; maximum dose 100 mg in patients with normal renal function) on days 1, 3, 5, and 7 and IM leucovorin (0.1 mg/kg) on days 2, 4, 6, and 8 [21]. Serum hCG levels are drawn on days 1, 3, 5, and 7. If the serum hCG declines >15 percent from the previous measurement, treatment is stopped, and a surveillance phase begins.

The surveillance phase consists of weekly hCG measurements. If the hCG declines <15 percent from the previous level, the patient is given an additional dose of MTX 1 mg/kg IM followed the next day with a dose of IM leucovorin 0.1 mg/kg. The hCG is followed until the level is undetectable. In one study, the mean duration to achieve an undetectable serum hCG concentration was 43±64 days [22]. A residual interstitial mass or heterogeneous area with persistent vascularity on ultrasound has been reported despite complete hCG resolution [23,24].

Interstitial pregnancies managed with selective arterial embolization, local injection of MTX, or local injection of potassium chloride, with or without systemic MTX have also been described, and local injection of MTX may be associated with improved success rates [25-28]. In one retrospective study including 38 patients with interstitial pregnancy treated medically, those treated with systemic compared with local MTX had lower rates of pregnancy resolution (46.7 versus 87.5 percent, respectively); the regimens of MTX treatment varied [28].

Surgical treatment of interstitial pregnancy is discussed separately. (See "Tubal ectopic pregnancy: Surgical treatment", section on 'Interstitial pregnancy'.)

Patients with other sites of ectopic pregnancy — Medical and surgical management of other sites of ectopic pregnancy (ie, heterotopic, cervical, abdominal), and abnormally implanted intrauterine pregnancies (ie, cesarean scar pregnancy) are discussed separately. (See "Ectopic pregnancy: Choosing a treatment", section on 'Heterotopic pregnancy' and "Cervical pregnancy: Diagnosis and management" and "Abdominal pregnancy" and "Cesarean scar pregnancy".)

POSTTREATMENT INSTRUCTIONS AND COUNSELING

●Instructions – Patients should adhere to the following instructions during MTX treatment [16]:

•Avoid vaginal intercourse and new conception until human chorionic gonadotropin (hCG) is undetectable.

•Avoid pelvic examinations during surveillance of MTX therapy due to theoretical risk of tubal rupture.

•Avoid sun exposure to limit risk of MTX dermatitis.

•Avoid vitamins containing folic acid.

•It is common advice to avoid nonsteroidal antiinflammatory drugs (NSAIDs), as the interaction with MTX may decrease renal excretion of MTX and increase the risk of toxicity. However, for rheumatologic disease, low-dose MTX is sometimes given concurrently with NSAIDs along with close monitoring; the dose given for ectopic pregnancy is considered an intermediate dose. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Pharmacology' and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Potential drug-drug-interactions'.)

●Counseling about pain after treatment – Mild to moderate abdominal pain of short duration (one to two days) at six to seven days after receiving the MTX is common. The pain may be due to tubal abortion or tubal distention from hematoma formation and can usually be controlled with acetaminophen.

By contrast, severe abdominal pain is concerning for tubal rupture. Such patients should be further evaluated with transvaginal ultrasonography; findings suggestive of hemoperitoneum raise clinical suspicion of tubal rupture. In one study, three parameters predicted hemoperitoneum ≥300 mL in patients with ectopic pregnancy: moderate to severe pelvic pain, fluid above the uterine fundus or around the ovary, and hemoglobin concentration <10 g/dL [29]. A patient with none of these three criteria had a probability of 5.3 percent of hemoperitoneum ≥300 mL. When two or more criteria were present, the probability for hemoperitoneum ≥300 mL reached 92.6 percent.

If hemoperitoneum is not found on ultrasound, patients with severe pain should be closely observed for hemodynamic changes which may accompany tubal rupture. Falling hCG levels do not preclude the possibility of tubal rupture. If tubal rupture is suspected, immediate surgery is required. (See "Tubal ectopic pregnancy: Surgical treatment".)

Severe pain alone in a hemodynamically stable patient is not an indication for surgery. As an example, in a review including 56 patients with ectopic pregnancy and managed with ectopic pregnancy, presenting with abdominal pain severe enough to be evaluated in the clinic or emergency department or requiring hospitalization, only eight patients subsequently required surgery [30].

SUBSEQUENT PREGNANCY — The safe interval from MTX treatment to conception is unclear and there are no studies addressing the earliest time to conceive after MTX treatment of ectopic pregnancy. In our practice, we advise patients not to conceive for three months [16]. However, there is no evidence of teratogenic risk to those who conceive sooner [31]. All patients trying to conceive should take folate daily, according to routine preconception recommendations. (See "Preconception and prenatal folic acid supplementation".)

Toxicology literature recommends a four- to six-month washout period before attempting to become pregnant [32], and residual MTX may be stored in the liver and kidney for months. However, in a retrospective study including patients who conceive after MTX treatment for ectopic pregnancy, those who conceived within <6 compared with ≥6 months, rates of fetal malformation and adverse outcome were similar between groups [33].

MTX treatment does not seem to affect future fertility rates. In a meta-analysis of seven observational studies involving 327 patients with a history of ectopic pregnancy, the mean number of retrieved oocytes from in vitro fertilization cycles before and after MTX therapy was similar [34]. Baseline follicle-stimulating hormone level, duration of stimulation, total gonadotrophin dose used for stimulation, and estradiol level on ovulation trigger before and after MTX treatment were also comparable.

After medical treatment of an interstitial pregnancy (see 'Patients with an interstitial pregnancy: Multiple-dose' above), there is an unknown risk of uterine rupture in a subsequent pregnancy [35].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ectopic pregnancy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Ectopic pregnancy (The Basics)")

●Beyond the Basics topics (see "Patient education: Ectopic (tubal) pregnancy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Indication – Methotrexate (MTX) is used to treat selected patients with a tubal ectopic pregnancy who are able and willing to comply with close follow-up (algorithm 1). How to choose between MTX and surgery and contraindications to MTX are also illustrated in the algorithm and are discussed in detail separately. (See 'Indications and alternatives' above and "Ectopic pregnancy: Choosing a treatment", section on 'Choosing between methotrexate and surgery'.)

●Pretreatment testing – Pretreatment testing includes serum human chorionic gonadotropin (hCG), transvaginal ultrasound, complete blood count, blood type and screen, and renal and liver function tests. (See 'Pretreatment evaluation' above.)

●Clinical protocol (table 1)

•Most patients: Single-dose protocol – For most patients with a tubal pregnancy treated with MTX, we suggest a single-dose rather than a multi-dose regimen (Grade 2C). While the overall rate of resolution of ectopic pregnancy is similar, the single-dose protocol appears to cause fewer adverse effects. As an alternative, some physicians plan for a two-dose protocol for selected patients (eg, hCG >3000 milli-international units/mL, adnexal masses >2 cm), however, we do not use this protocol in our practice. (See 'Preferred approach for most patients: Single-dose' above and 'Comparing single- versus multi-dose therapy' above and 'Role of two-dose protocol' above.)

In single-dose protocols, intramuscular (IM) MTX 50 mg/m² (maximum dose 100 mg in patients with normal renal function) is given followed by an hCG level on treatment days 4 and 7 and then weekly. If the decrease in hCG between days 4 and 7 is <15 percent, a second dose of MTX is administered. Additional doses of MTX are given if the hCG level does not decline sufficiently. Serum hCG is then followed until the level is undetectable. (See 'Preferred approach for most patients: Single-dose' above.)

•Patients with interstitial pregnancy: Multiple-dose protocol – For patients with an interstitial pregnancy, we suggest a multiple-dose protocol (Grade 2C). However, reasonable alternatives include selective arterial embolization or local injection of MTX or potassium chloride, with or without systemic MTX. Limited data suggest local injection of MTX may be associated with improved success rates, however, it requires administration by an experienced physician and is highly operator dependent. (See 'Patients with an interstitial pregnancy: Multiple-dose' above and 'Dosing and administration' above.)

In multiple-dose protocols, MTX is given on days 1, 3, 5, and 7 and leucovorin on days 2, 4, 6, and 8. If the serum hCG concentration plateaus or increases in two consecutive measurements, a second course may be given seven days after the previous dose. HCG is followed weekly until undetectable. (See 'Patients with an interstitial pregnancy: Multiple-dose' above.)

•Other patients – Management of patients with other sites of ectopic pregnancy (eg, heterotopic, cervical, abdominal) or abnormally implanted intrauterine pregnancy (ie, cesarean scar) are discussed in detail separately. (See 'Patients with other sites of ectopic pregnancy' above.)

●Posttreatment counseling – Mild abdominal pain of short duration (one to two days) that occurs six to seven days after receiving the medication is common. Patients with severe pain should be observed closely for hemodynamic changes which may accompany a tubal rupture. Clinical suspicion of a tubal rupture is an indication for immediate surgery. (See 'Posttreatment instructions and counseling' above.)

●Subsequent pregnancy – In our practice, we advise patients not to conceive for three months, however, there is no evidence of teratogenic risk to those who conceive sooner. All patients trying to conceive should take folate daily, according to routine preconception recommendations. (See 'Subsequent pregnancy' above.)