The Journal of Family Practice

CASE 1

Debra P is a 62-year-old African American woman who calls your office to report that she has an upcoming routine colonoscopy planned in 2 weeks. She has been taking warfarin for the past 2 years for ischemic stroke prevention secondary to atrial fibrillation (AF), and her gastroenterologist recommended that she contact her family physician (FP) to discuss periprocedural anticoagulation plans. Ms. P is currently taking warfarin 5 mg on Mondays, Wednesdays, and Fridays, and 2.5 mg all other days of the week. Her international normalized ratio (INR) was 2.3 when it was last checked 2 weeks ago, and it has been stable and within goal range for the past 6 months. Her medical history includes AF, well-controlled hypertension, and type 2 diabetes mellitus, as well as gout and stage 3 chronic kidney disease. Ms. P denies any history of stroke or transient ischemic attack (TIA). She is requesting instructions on how to manage her warfarin before and after her upcoming colonoscopy.

CASE 2

Jerry Q is a 68-year-old Caucasian man with longstanding osteoarthritis who is scheduled to undergo a total left knee arthroplasty in one week. His orthopedic surgeon recommended that he contact his FP for instructions regarding managing apixaban perioperatively. Jerry has been taking apixaban 5 mg bid for the past 9 months due to a history of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) (both unprovoked). Mr. Q had been taking warfarin following his first DVT 4 years ago, but, after reporting that INR monitoring was a burden, he was started on apixaban. The patient has normal renal function and is relatively healthy otherwise. How should apixaban be managed before and after his upcoming surgery?

Each year, approximately 15% to 20% of patients taking an oral anticoagulant undergo a procedure that carries a heightened risk for bleeding.^1,2 Stopping oral anticoagulation is often necessary before—and sometimes briefly after—many of these procedures in order to minimize the risk of bleeding.³ This means that countless decisions must be made by health care providers each year regarding if, when, and how to pause and resume oral anticoagulation. These decisions are not always straightforward, especially when you consider the risks for thrombosis and bleeding that are unique to the procedure and to the individual patient.

With these variables in mind, the health care provider must make decisions regarding anticoagulation during the periprocedural period based on the following 5 questions:

1. Will this patient need to have his/her oral anticoagulant stopped prior to the procedure?
2. If the patient’s oral anticoagulation needs to be held, when should it be stopped and for how long?
3. Will periprocedural bridging with a parenteral anticoagulant be necessary prior to the procedure?
4. When should the patient resume his or her oral anticoagulant after the procedure, and at what dosage?
5. Will bridging with a parenteral anticoagulant be necessary after the procedure?

Before addressing these 5 questions, though, physicians must assess patients’ thrombotic and bleeding risks.^4-6

Anticoagulant regimens and the risks of discontinuing them

The 2 most common indications for long-term oral anticoagulation are venous thromboembolism (VTE), which occurs in approximately one million Americans every year,^7,8 and stroke prevention in the setting of AF (AF occurs in 3-6 million US adults per year).⁶

Countless decisions must be made by health care providers each year regarding if, when, and how to pause and resume oral anticoagulation. And these decisions are not always straightforward.

Warfarin is also often used in patients with mechanical heart valves for long-term stroke prevention; however, direct oral anticoagulants (DOACs) are not recommended for patients with mechanical heart valves because trials have not yet demonstrated their safety or efficacy in this population.^4,5,9

Who’s at highest risk for an acute thromboembolic event?

When planning for interruptions in oral anticoagulation, it is important to identify patients at highest risk for an acute thromboembolic event. Patients with 10% or higher annual risk for VTE or ischemic stroke are generally placed into this high-risk category (TABLE 1^3,5,6,9-11).³ Keep in mind that the absolute risk for thromboembolism during a brief period of oral coagulation interruption is relatively low, even in those patients considered to be at high risk. Using a mathematical approach (although simplistic), a patient with a 10% annual risk for a thromboembolic event would have <0.3% chance for developing such an event in the acute phase, even if their anticoagulation was withheld for up to 10 days ([10%/365 days] × 10 days).

Patients with mechanical heart valves. Nearly all patients with a mechanical heart valve are at moderate to high risk for ischemic stroke.³

For patients with AF, the CHADS₂ and CHA₂DS₂-VASc scoring tools can be used to estimate annual thrombosis risk based on the presence of risk factors (TABLE 2^10,11).^6,9-11 It should be noted, however, that these scoring tools have not been validated specifically for periprocedural risk estimations. Nonetheless, the latest 2017 American College of Cardiology (ACC) guidelines recommend the use of the CHA₂DS₂-VASc scoring tool for making decisions regarding perioperative bridging in patients with AF.¹¹

Patients with previous VTE. Multiple aspects of a patient’s past medical history need to be taken into account when estimating annual and acute risk for VTE. Patients at the highest risk for VTE recurrence (annual VTE risk ≥10%) include those with recent VTE (past 90 days), active malignancy, and/or severe thrombophilias (TABLE 1^3,5,6,9-11).^3,5,6 Patients without any of these features can still be at moderate risk for recurrent VTE, as a single VTE without a clear provoking factor can confer a 5% to 10% annualized risk for recurrence.^12,13 Previous proximal DVT and PE are associated with a higher risk for recurrence than a distal DVT, and males have a higher recurrence risk than females.^5,12 There are scoring tools, such as DASH (D-dimer, Age, Sex, Hormones) and the “Men Continue and HERDOO2,” that can help estimate annualized risk for VTE recurrence; however, they are not validated (nor particularly useful) when making decisions in the perioperative period.^14,15

Additional risk factors. Consider additional risk factors for thromboembolism, including estrogen/hormone replacement therapy, pregnancy, leg or hip fractures, immobility, trauma, spinal cord injury, central venous lines, congestive heart failure, thrombophilia, increased age, obesity, and varicose veins.^5,16

In addition, some surgeries have a higher inherent risk for thrombosis. Major orthopedic surgery (knee and hip arthroplasty, hip fracture surgery) and surgeries for major trauma or spinal cord injuries are associated with an exceedingly high rate of VTE.¹⁷ Similarly, coronary artery bypass surgery, heart valve replacement, and carotid endarterectomies carry the highest risk for acute ischemic stroke.³

Who’s at highest risk for bleeding?

Establishing the bleeding risk associated with a procedure is imperative prior to urgent and elective surgeries to help determine when anticoagulation therapy should be discontinued and reinitiated, as well as whether bridging therapy is appropriate. The 2012 CHEST guidelines state that bleeding risk should be assessed based on timing of anticoagulation relative to surgery and whether the anticoagulation is being used as prophylaxis for, or treatment of, thromboembolism.³ Categorizing procedures as having a minimal, low, or high risk for bleeding can be helpful in making anticoagulation decisions (TABLE 3).^3,18-21

In addition to the bleeding risk associated with procedures, patient-specific factors need to be considered. A bleeding event within the past 3 months, platelet abnormalities, a supratherapeutic INR at the time of surgery, a history of bleeding from previous bridging, a bleed history with a similar procedure, and a high HAS-BLED (Hypertension, Abnormal renal or liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol usage) score are all factors that elevate the risk for perioperative bleeding.^10,11 Although validated only in patients taking warfarin, the HAS-BLED scoring system can be utilized in patients with AF to estimate annual risk for major bleeding (TABLE 2^10,11).¹⁰

With this risk information in mind, it’s time to move on to the 5 questions you’ll need to ask.

1. Should the patient’s oral anticoagulation be stopped prior to the upcoming procedure?

The answer, of course, hinges on the patient’s risk of bleeding.

Usually, it is not necessary to withhold any doses of oral anticoagulation if your patient is scheduled for a procedure with minimal risk for bleeding (TABLE 3^3,18-21).³ However, it may be reasonable to stop anticoagulation if your patient has additional features that predispose to high bleeding risk (eg, hemophilia, Von Willebrand disease, etc). The CHEST guidelines recommend adding an oral prohemostatic agent (eg, tranexamic acid) if anticoagulation will be continued during a dental procedure.³

If your patient is undergoing any other procedure that has a low to high risk for bleeding, oral anticoagulation should be withheld prior to the procedure in most instances,^3,11 although there are exceptions. For example, cardiac procedures, such as AF catheter ablation and cardiac pacemaker placement, are often performed with uninterrupted oral anticoagulation despite their bleeding risk category.³

When in doubt, discuss the perceived bleeding and clotting risks directly with the specialist performing the procedure. In patients who have had a VTE or ischemic stroke within the past 3 months, consider postponing the invasive procedure until the patient is beyond this period of highest thrombotic risk.¹¹

Warfarin may need to be stopped anywhere from 2 to 5 days prior to the procedure, depending on a number of variables.

Previous proximal deep vein thrombosis and pulmonary embolism are associated with a higher risk for recurrence than a distal DVT, and males have a higher recurrence risk than females.

Warfarin has a half-life of approximately 36 hours, so it can take 3 to 5 days for warfarin concentrations to drop to safe levels for procedures with low to moderate bleeding risk and 5 to 7 days for procedures with high bleeding risk.²¹ The 2012 CHEST guidelines recommend that warfarin therapy be discontinued 5 days prior to surgery to minimize the risk for bleeding.³ The Anticoagulation Forum, a leading expert panel that produced a set of useful anticoagulation guidelines in 2016, recommends stopping warfarin 4 to 5 days prior to a procedure.²¹ If the provider chooses to withhold warfarin before a procedure with minimal bleeding risk, it should be stopped 2 to 3 days prior.³

Consider checking INR values the week before. A 2017 consensus statement from the ACC recommends that the timing of warfarin discontinuation be based on an INR value taken 5 to 7 days prior to the surgical procedure.¹¹ This allows for a more tailored approach to preparing the patient for surgery. If the INR is below goal range, warfarin may need to be withheld for only 3 to 4 days prior to a procedure. Conversely, INRs above goal range may require warfarin to be held 6 or more days, depending on the degree of INR elevation.

While not always feasible in clinical practice, the CHEST guidelines recommend obtaining an INR value the day prior to the procedure to determine if the INR value is low enough to proceed with surgery, or if a low dose of oral vitamin K needs to be administered to ensure that the INR is in a safe range the following day.³

DOACs

DOACs can be withheld for much shorter durations preoperatively than warfarin.

Major orthopedic surgery and surgeries for major trauma or spinal cord injuries are associated with an exceedingly high rate of venous thromboembolism.

When withholding anticoagulants, the goal is to have a low amount of anticoagulant effect (12%-25%) present during low-risk procedures and a nominal amount of anticoagulant effect (3%-6%) present for high-risk procedures.²⁰ DOACs have much shorter half-lives than warfarin (7-19 hours vs 36-48 hours, respectively), so they can be withheld for much shorter durations preoperatively.²⁰ For patients undergoing procedures that are considered to have a minimal risk for bleeding (such as minor dental and dermatologic procedures), DOACs do not generally need to be withheld; however, it may be ideal to time the procedure when the DOAC is at a trough concentration (before the next dose is due).³

Coronary artery bypass surgery, heart valve replacement, and carotid endarterectomies carry the highest risk for acute ischemic stroke.

DOACs generally need to be withheld for only 1 to 3 days prior to major surgical procedures in patients with normal renal function (creatinine clearance [CrCl] >30 mL/min using the Cockcroft-Gault formula).²⁰ The available oral direct factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban) should generally be stopped 24 hours prior to a procedure that has a low bleeding risk, and 48 hours prior to procedures with high bleeding risk (TABLE 4^11,20).²⁰ These medications may need to be withheld for an additional 1 to 2 days in patients with acute kidney injury or stage IV kidney disease.²⁰

Dabigatran. About 80% of dabigatran is excreted renally, so its elimination is much more dependent on renal function than is that of the oral direct factor Xa inhibitors.²⁰ Therefore, it generally needs to be withheld for at least 1 to 2 days longer than the oral factor Xa inhibitors unless CrCl >80 mL/min (TABLE 4^11,20).²⁰

3. Is preoperative bridging with parenteral anticoagulation necessary?

In certain instances, patients who have a high thromboembolic risk and are discontinuing warfarin therapy may require bridging therapy with a low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). If a patient’s CrCl is <30 mL/min, then UFH is the preferred agent for perioperative bridging.²¹

But before any decision is made, it’s best to have a good understanding of what the guidelines—and the literature—have to say.

Key studies and guidelines

The 2012 CHEST guidelines recommend providing bridge therapy for any patient at high risk for thromboembolism (>10% annual risk) and consideration of bridge therapy in the setting of moderate clotting risk (5%-10% annual risk), depending on specific patient and procedural risk factors (TABLE 1^3,5,6,9-11).³

In 2015, a landmark clinical trial was published that significantly shaped how patients taking warfarin are managed periprocedurally.²² The Bridge (Bridging anticoagulation in patients who require temporary interruption of warfarin therapy for an elective invasive procedure or surgery) trial was the first prospective, randomized controlled trial to assess the efficacy and safety of parenteral bridging in patients with AF taking warfarin and undergoing an elective surgery.

Patients in the trial received either dalteparin at a therapeutic dose of 100 IU/kg or a matching placebo administered subcutaneously bid from 3 days before the procedure until 24 hours before the procedure, and then for 5 to 10 days after the procedure. The incidence of thromboembolic events was not significantly lower in the dalteparin group than in the placebo group (0.3% vs 0.4%, respectively; P=.73), while major bleeding rates were nearly 3-fold higher in the dalteparin group (3.2% vs 1.3%; P=.005). The trial concluded that placebo “was noninferior to perioperative bridging with LMWH for the prevention of arterial thromboembolism and decreased the risk of major bleeding.”²²

When withholding anticoagulants, the goal is to have a low amount of anticoagulant effect (12%-25%) present during low-risk procedures and a nominal amount (3%-6%) present for high-risk procedures.

Patients excluded from the trial included those with a mechanical heart valve, or a recent (within 3 months) embolism, stroke, or TIA, and only 3% of enrolled patients would have been classified as having a high bleeding risk according to CHEST guidelines.^3,22

A prospective observational registry study produced similar findings and found that those patients who received bridging had more bleeding events and a higher incidence of myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days than those who did not receive bridging.²³ Other retrospective cohort studies comparing bridging to no bridging strategies in patients taking warfarin for VTE, mechanical heart valves, or AF have also failed to show a reduction in the incidence of thrombotic events with LMWH bridging.^24,25

In 2016, the European Society of Cardiology suggested that “bridging does not seem to be beneficial, except in patients with mechanical heart valves.”²⁶ Similarly, the 2016 Anticoagulation Forum guidelines state that “most patients with VTE can safely interrupt warfarin for invasive procedures without bridge therapy,” and that bridge therapy should be “reserved for those at highest recurrent VTE risk (eg, VTE within the previous month; prior history of recurrent VTE during anticoagulation therapy interruption; undergoing a procedure with high inherent risk for VTE, such as joint replacement surgery or major abdominal cancer resection).”²¹ They go on to state that even in these high-risk groups, the clinical decision to use bridging therapy needs to carefully weigh the benefits against the potential risks of bleeding.²¹

Controversy also surrounds the intensity of LMWH bridging. The Anticoagulation Forum guidelines state that the use of prophylactic rather than therapeutic dose LMWH may be considered, while the CHEST guidelines do not make a firm recommendation regarding LMWH dose while bridging.^3,21 Ultimately, in patients who receive perioperative bridging with LMWH, the CHEST guidelines recommend that it should be stopped 24 hours prior to the procedure and resumed in accordance with the bleeding risk of the procedure (ie, prophylactic doses may be appropriate within 24 hours postprocedure, while full treatment doses may need to be delayed for 48 to 72 hours if surgical bleeding risk is high).³ UFH bridge therapy may be stopped 4 to 6 hours prior to surgery.³

DOACs. Given the rapid onset and relatively short half-lives of DOACs, use of a parenteral bridging agent is generally not necessary or recommended before or after an invasive procedure in patients taking a DOAC.²⁰

4. When should oral anticoagulation be resumed postoperatively, and at what intensity?

Warfarin can generally be resumed the same day as the procedure (in the evening), assuming there are no active bleeding complications.^3,11 Once fully reversed, it generally takes around 5 days for warfarin to become fully therapeutic, so it can be started soon after surgery without increasing the risk for early postoperative bleeding.²⁰

DOACs. Consider the patient’s individual and procedural risks for bleeding when determining when to resume a DOAC postoperatively. That’s because unlike warfarin, which takes several days to take full effect, DOACs provide a nearly immediate anticoagulation effect.^20,21 For procedures that have a low bleeding risk, it is recommended to resume therapeutic anticoagulation 24 hours after the procedure has ended.^3,11,20 For procedures that have a high risk for bleeding, resumption of therapeutic anticoagulation should be delayed until 48 to 72 hours after the procedure has ended.^3,11,20

5. Is postoperative bridging with parenteral anticoagulation necessary?

Warfarin. If a patient was deemed to be at sufficient VTE risk to be bridged preoperatively, then that patient likely also should be bridged postoperatively, particularly if the surgery itself is associated with a heightened thrombotic risk. While warfarin can generally be resumed postoperatively the same day as the procedure, full therapeutic doses of a LMWH should not be initiated sooner than 24 hours postoperatively, and initiation should be delayed for 48 to 72 hours for procedures with the highest bleeding risk (such as neurosurgery).^3,11,21 Prophylactic doses of LMWH can generally be resumed as early as 12 hours postoperatively for procedures with high VTE risk (such as major orthopedic surgery).¹⁷

DOACs. In patients undergoing a procedure that carries both a high thromboembolic and high bleeding risk (such as major orthopedic surgery), initiation of a full-dose DOAC may need to be delayed for 2 to 3 days; however, more immediate VTE prophylaxis is usually necessary.^3,17 Prophylaxis after such procedures can begin 12 hours after the procedure with a low-intensity LMWH, which should be continued until it is deemed safe to resume full-intensity DOAC therapy.^3,17,18 If the patient is undergoing major orthopedic surgery, an FDA-approved prophylactic dose of a DOAC could be a temporary alternative to LMWH.²⁷

CASE 1

Ms. P’s upcoming colonoscopy may require a biopsy and would be classified as a procedure with low bleeding risk (per TABLE 3), so warfarin should be withheld prior to her procedure. You could check her INR 5 to 7 days before her colonoscopy to guide how many doses need to be withheld; however, given the patient’s tight INR control over the previous 6 months, you can assume her INR will be in goal range at that check. As a result, you recommend that she avoid an extra INR check and stop taking her warfarin 5 days prior to the colonoscopy.

Cohort studies involving patients taking warfarin for VTE, mechanical heart valves, or atrial fibrillation have failed to show a reduction in the incidence of thrombotic events with LMWH bridging.

Ms. P has a CHA₂DS₂VASc score of 3, which puts her at a relatively low risk for acute ischemic stroke over the next 1 to 2 weeks. Given the results of the BRIDGE trial, you recommend no parenteral bridging agent before or after her procedure. You also recommend that the patient resume her usual dose of warfarin the same day as her procedure (in the evening) unless her gastroenterologist recommends otherwise. You schedule her for a follow-up INR 5 to 7 days after her colonoscopy.

CASE 2

Mr. Q’s total knee arthroplasty (TKA)—a procedure associated with a high risk of bleeding—requires an interruption in his apixaban therapy. Additionally, he is at high risk for recurrent thromboembolism, given his history of recurrent, unprovoked DVTs; however, he is past the highest risk period (VTE within the past 3 months; his last one was 9 months ago). He is otherwise healthy and has normal renal function, so his apixaban should be withheld for a total of 4 doses (48 hours) prior to his procedure. He should resume his full dose of apixaban 48 to 72 hours after his procedure to minimize the risk for bleeding.

However, given that a TKA is a procedure associated with a high rate of postoperative VTE, initiate prophylactic anticoagulation (such as enoxaparin 40 mg subcutaneously daily or apixaban 2.5 mg PO bid) about 12 hours after the procedure and continue it until full-dose apixaban is resumed.

CORRESPONDENCE
Jeremy Vandiver, PharmD, BCPS, University of Wyoming School of Pharmacy, 1000 E. University Ave., Dept. 3375, Laramie, WY 82071; [email protected].

CASE 1

Debra P is a 62-year-old African American woman who calls your office to report that she has an upcoming routine colonoscopy planned in 2 weeks. She has been taking warfarin for the past 2 years for ischemic stroke prevention secondary to atrial fibrillation (AF), and her gastroenterologist recommended that she contact her family physician (FP) to discuss periprocedural anticoagulation plans. Ms. P is currently taking warfarin 5 mg on Mondays, Wednesdays, and Fridays, and 2.5 mg all other days of the week. Her international normalized ratio (INR) was 2.3 when it was last checked 2 weeks ago, and it has been stable and within goal range for the past 6 months. Her medical history includes AF, well-controlled hypertension, and type 2 diabetes mellitus, as well as gout and stage 3 chronic kidney disease. Ms. P denies any history of stroke or transient ischemic attack (TIA). She is requesting instructions on how to manage her warfarin before and after her upcoming colonoscopy.

CASE 2

Jerry Q is a 68-year-old Caucasian man with longstanding osteoarthritis who is scheduled to undergo a total left knee arthroplasty in one week. His orthopedic surgeon recommended that he contact his FP for instructions regarding managing apixaban perioperatively. Jerry has been taking apixaban 5 mg bid for the past 9 months due to a history of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) (both unprovoked). Mr. Q had been taking warfarin following his first DVT 4 years ago, but, after reporting that INR monitoring was a burden, he was started on apixaban. The patient has normal renal function and is relatively healthy otherwise. How should apixaban be managed before and after his upcoming surgery?

Each year, approximately 15% to 20% of patients taking an oral anticoagulant undergo a procedure that carries a heightened risk for bleeding.^1,2 Stopping oral anticoagulation is often necessary before—and sometimes briefly after—many of these procedures in order to minimize the risk of bleeding.³ This means that countless decisions must be made by health care providers each year regarding if, when, and how to pause and resume oral anticoagulation. These decisions are not always straightforward, especially when you consider the risks for thrombosis and bleeding that are unique to the procedure and to the individual patient.

With these variables in mind, the health care provider must make decisions regarding anticoagulation during the periprocedural period based on the following 5 questions:

1. Will this patient need to have his/her oral anticoagulant stopped prior to the procedure?
2. If the patient’s oral anticoagulation needs to be held, when should it be stopped and for how long?
3. Will periprocedural bridging with a parenteral anticoagulant be necessary prior to the procedure?
4. When should the patient resume his or her oral anticoagulant after the procedure, and at what dosage?
5. Will bridging with a parenteral anticoagulant be necessary after the procedure?

Before addressing these 5 questions, though, physicians must assess patients’ thrombotic and bleeding risks.^4-6

Anticoagulant regimens and the risks of discontinuing them

The 2 most common indications for long-term oral anticoagulation are venous thromboembolism (VTE), which occurs in approximately one million Americans every year,^7,8 and stroke prevention in the setting of AF (AF occurs in 3-6 million US adults per year).⁶

Countless decisions must be made by health care providers each year regarding if, when, and how to pause and resume oral anticoagulation. And these decisions are not always straightforward.

Warfarin is also often used in patients with mechanical heart valves for long-term stroke prevention; however, direct oral anticoagulants (DOACs) are not recommended for patients with mechanical heart valves because trials have not yet demonstrated their safety or efficacy in this population.^4,5,9

Who’s at highest risk for an acute thromboembolic event?

When planning for interruptions in oral anticoagulation, it is important to identify patients at highest risk for an acute thromboembolic event. Patients with 10% or higher annual risk for VTE or ischemic stroke are generally placed into this high-risk category (TABLE 1^3,5,6,9-11).³ Keep in mind that the absolute risk for thromboembolism during a brief period of oral coagulation interruption is relatively low, even in those patients considered to be at high risk. Using a mathematical approach (although simplistic), a patient with a 10% annual risk for a thromboembolic event would have <0.3% chance for developing such an event in the acute phase, even if their anticoagulation was withheld for up to 10 days ([10%/365 days] × 10 days).

Patients with mechanical heart valves. Nearly all patients with a mechanical heart valve are at moderate to high risk for ischemic stroke.³

For patients with AF, the CHADS₂ and CHA₂DS₂-VASc scoring tools can be used to estimate annual thrombosis risk based on the presence of risk factors (TABLE 2^10,11).^6,9-11 It should be noted, however, that these scoring tools have not been validated specifically for periprocedural risk estimations. Nonetheless, the latest 2017 American College of Cardiology (ACC) guidelines recommend the use of the CHA₂DS₂-VASc scoring tool for making decisions regarding perioperative bridging in patients with AF.¹¹

Patients with previous VTE. Multiple aspects of a patient’s past medical history need to be taken into account when estimating annual and acute risk for VTE. Patients at the highest risk for VTE recurrence (annual VTE risk ≥10%) include those with recent VTE (past 90 days), active malignancy, and/or severe thrombophilias (TABLE 1^3,5,6,9-11).^3,5,6 Patients without any of these features can still be at moderate risk for recurrent VTE, as a single VTE without a clear provoking factor can confer a 5% to 10% annualized risk for recurrence.^12,13 Previous proximal DVT and PE are associated with a higher risk for recurrence than a distal DVT, and males have a higher recurrence risk than females.^5,12 There are scoring tools, such as DASH (D-dimer, Age, Sex, Hormones) and the “Men Continue and HERDOO2,” that can help estimate annualized risk for VTE recurrence; however, they are not validated (nor particularly useful) when making decisions in the perioperative period.^14,15

Additional risk factors. Consider additional risk factors for thromboembolism, including estrogen/hormone replacement therapy, pregnancy, leg or hip fractures, immobility, trauma, spinal cord injury, central venous lines, congestive heart failure, thrombophilia, increased age, obesity, and varicose veins.^5,16

In addition, some surgeries have a higher inherent risk for thrombosis. Major orthopedic surgery (knee and hip arthroplasty, hip fracture surgery) and surgeries for major trauma or spinal cord injuries are associated with an exceedingly high rate of VTE.¹⁷ Similarly, coronary artery bypass surgery, heart valve replacement, and carotid endarterectomies carry the highest risk for acute ischemic stroke.³

Who’s at highest risk for bleeding?

Establishing the bleeding risk associated with a procedure is imperative prior to urgent and elective surgeries to help determine when anticoagulation therapy should be discontinued and reinitiated, as well as whether bridging therapy is appropriate. The 2012 CHEST guidelines state that bleeding risk should be assessed based on timing of anticoagulation relative to surgery and whether the anticoagulation is being used as prophylaxis for, or treatment of, thromboembolism.³ Categorizing procedures as having a minimal, low, or high risk for bleeding can be helpful in making anticoagulation decisions (TABLE 3).^3,18-21

In addition to the bleeding risk associated with procedures, patient-specific factors need to be considered. A bleeding event within the past 3 months, platelet abnormalities, a supratherapeutic INR at the time of surgery, a history of bleeding from previous bridging, a bleed history with a similar procedure, and a high HAS-BLED (Hypertension, Abnormal renal or liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol usage) score are all factors that elevate the risk for perioperative bleeding.^10,11 Although validated only in patients taking warfarin, the HAS-BLED scoring system can be utilized in patients with AF to estimate annual risk for major bleeding (TABLE 2^10,11).¹⁰

With this risk information in mind, it’s time to move on to the 5 questions you’ll need to ask.

1. Should the patient’s oral anticoagulation be stopped prior to the upcoming procedure?

The answer, of course, hinges on the patient’s risk of bleeding.

Usually, it is not necessary to withhold any doses of oral anticoagulation if your patient is scheduled for a procedure with minimal risk for bleeding (TABLE 3^3,18-21).³ However, it may be reasonable to stop anticoagulation if your patient has additional features that predispose to high bleeding risk (eg, hemophilia, Von Willebrand disease, etc). The CHEST guidelines recommend adding an oral prohemostatic agent (eg, tranexamic acid) if anticoagulation will be continued during a dental procedure.³

If your patient is undergoing any other procedure that has a low to high risk for bleeding, oral anticoagulation should be withheld prior to the procedure in most instances,^3,11 although there are exceptions. For example, cardiac procedures, such as AF catheter ablation and cardiac pacemaker placement, are often performed with uninterrupted oral anticoagulation despite their bleeding risk category.³

When in doubt, discuss the perceived bleeding and clotting risks directly with the specialist performing the procedure. In patients who have had a VTE or ischemic stroke within the past 3 months, consider postponing the invasive procedure until the patient is beyond this period of highest thrombotic risk.¹¹

Warfarin may need to be stopped anywhere from 2 to 5 days prior to the procedure, depending on a number of variables.

Previous proximal deep vein thrombosis and pulmonary embolism are associated with a higher risk for recurrence than a distal DVT, and males have a higher recurrence risk than females.

Warfarin has a half-life of approximately 36 hours, so it can take 3 to 5 days for warfarin concentrations to drop to safe levels for procedures with low to moderate bleeding risk and 5 to 7 days for procedures with high bleeding risk.²¹ The 2012 CHEST guidelines recommend that warfarin therapy be discontinued 5 days prior to surgery to minimize the risk for bleeding.³ The Anticoagulation Forum, a leading expert panel that produced a set of useful anticoagulation guidelines in 2016, recommends stopping warfarin 4 to 5 days prior to a procedure.²¹ If the provider chooses to withhold warfarin before a procedure with minimal bleeding risk, it should be stopped 2 to 3 days prior.³

Consider checking INR values the week before. A 2017 consensus statement from the ACC recommends that the timing of warfarin discontinuation be based on an INR value taken 5 to 7 days prior to the surgical procedure.¹¹ This allows for a more tailored approach to preparing the patient for surgery. If the INR is below goal range, warfarin may need to be withheld for only 3 to 4 days prior to a procedure. Conversely, INRs above goal range may require warfarin to be held 6 or more days, depending on the degree of INR elevation.

While not always feasible in clinical practice, the CHEST guidelines recommend obtaining an INR value the day prior to the procedure to determine if the INR value is low enough to proceed with surgery, or if a low dose of oral vitamin K needs to be administered to ensure that the INR is in a safe range the following day.³

DOACs

DOACs can be withheld for much shorter durations preoperatively than warfarin.

Major orthopedic surgery and surgeries for major trauma or spinal cord injuries are associated with an exceedingly high rate of venous thromboembolism.

When withholding anticoagulants, the goal is to have a low amount of anticoagulant effect (12%-25%) present during low-risk procedures and a nominal amount of anticoagulant effect (3%-6%) present for high-risk procedures.²⁰ DOACs have much shorter half-lives than warfarin (7-19 hours vs 36-48 hours, respectively), so they can be withheld for much shorter durations preoperatively.²⁰ For patients undergoing procedures that are considered to have a minimal risk for bleeding (such as minor dental and dermatologic procedures), DOACs do not generally need to be withheld; however, it may be ideal to time the procedure when the DOAC is at a trough concentration (before the next dose is due).³

Coronary artery bypass surgery, heart valve replacement, and carotid endarterectomies carry the highest risk for acute ischemic stroke.

DOACs generally need to be withheld for only 1 to 3 days prior to major surgical procedures in patients with normal renal function (creatinine clearance [CrCl] >30 mL/min using the Cockcroft-Gault formula).²⁰ The available oral direct factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban) should generally be stopped 24 hours prior to a procedure that has a low bleeding risk, and 48 hours prior to procedures with high bleeding risk (TABLE 4^11,20).²⁰ These medications may need to be withheld for an additional 1 to 2 days in patients with acute kidney injury or stage IV kidney disease.²⁰

Dabigatran. About 80% of dabigatran is excreted renally, so its elimination is much more dependent on renal function than is that of the oral direct factor Xa inhibitors.²⁰ Therefore, it generally needs to be withheld for at least 1 to 2 days longer than the oral factor Xa inhibitors unless CrCl >80 mL/min (TABLE 4^11,20).²⁰

3. Is preoperative bridging with parenteral anticoagulation necessary?

In certain instances, patients who have a high thromboembolic risk and are discontinuing warfarin therapy may require bridging therapy with a low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). If a patient’s CrCl is <30 mL/min, then UFH is the preferred agent for perioperative bridging.²¹

But before any decision is made, it’s best to have a good understanding of what the guidelines—and the literature—have to say.

Key studies and guidelines

The 2012 CHEST guidelines recommend providing bridge therapy for any patient at high risk for thromboembolism (>10% annual risk) and consideration of bridge therapy in the setting of moderate clotting risk (5%-10% annual risk), depending on specific patient and procedural risk factors (TABLE 1^3,5,6,9-11).³

In 2015, a landmark clinical trial was published that significantly shaped how patients taking warfarin are managed periprocedurally.²² The Bridge (Bridging anticoagulation in patients who require temporary interruption of warfarin therapy for an elective invasive procedure or surgery) trial was the first prospective, randomized controlled trial to assess the efficacy and safety of parenteral bridging in patients with AF taking warfarin and undergoing an elective surgery.

Patients in the trial received either dalteparin at a therapeutic dose of 100 IU/kg or a matching placebo administered subcutaneously bid from 3 days before the procedure until 24 hours before the procedure, and then for 5 to 10 days after the procedure. The incidence of thromboembolic events was not significantly lower in the dalteparin group than in the placebo group (0.3% vs 0.4%, respectively; P=.73), while major bleeding rates were nearly 3-fold higher in the dalteparin group (3.2% vs 1.3%; P=.005). The trial concluded that placebo “was noninferior to perioperative bridging with LMWH for the prevention of arterial thromboembolism and decreased the risk of major bleeding.”²²

When withholding anticoagulants, the goal is to have a low amount of anticoagulant effect (12%-25%) present during low-risk procedures and a nominal amount (3%-6%) present for high-risk procedures.

Patients excluded from the trial included those with a mechanical heart valve, or a recent (within 3 months) embolism, stroke, or TIA, and only 3% of enrolled patients would have been classified as having a high bleeding risk according to CHEST guidelines.^3,22

A prospective observational registry study produced similar findings and found that those patients who received bridging had more bleeding events and a higher incidence of myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days than those who did not receive bridging.²³ Other retrospective cohort studies comparing bridging to no bridging strategies in patients taking warfarin for VTE, mechanical heart valves, or AF have also failed to show a reduction in the incidence of thrombotic events with LMWH bridging.^24,25

In 2016, the European Society of Cardiology suggested that “bridging does not seem to be beneficial, except in patients with mechanical heart valves.”²⁶ Similarly, the 2016 Anticoagulation Forum guidelines state that “most patients with VTE can safely interrupt warfarin for invasive procedures without bridge therapy,” and that bridge therapy should be “reserved for those at highest recurrent VTE risk (eg, VTE within the previous month; prior history of recurrent VTE during anticoagulation therapy interruption; undergoing a procedure with high inherent risk for VTE, such as joint replacement surgery or major abdominal cancer resection).”²¹ They go on to state that even in these high-risk groups, the clinical decision to use bridging therapy needs to carefully weigh the benefits against the potential risks of bleeding.²¹

Controversy also surrounds the intensity of LMWH bridging. The Anticoagulation Forum guidelines state that the use of prophylactic rather than therapeutic dose LMWH may be considered, while the CHEST guidelines do not make a firm recommendation regarding LMWH dose while bridging.^3,21 Ultimately, in patients who receive perioperative bridging with LMWH, the CHEST guidelines recommend that it should be stopped 24 hours prior to the procedure and resumed in accordance with the bleeding risk of the procedure (ie, prophylactic doses may be appropriate within 24 hours postprocedure, while full treatment doses may need to be delayed for 48 to 72 hours if surgical bleeding risk is high).³ UFH bridge therapy may be stopped 4 to 6 hours prior to surgery.³

DOACs. Given the rapid onset and relatively short half-lives of DOACs, use of a parenteral bridging agent is generally not necessary or recommended before or after an invasive procedure in patients taking a DOAC.²⁰

4. When should oral anticoagulation be resumed postoperatively, and at what intensity?

Warfarin can generally be resumed the same day as the procedure (in the evening), assuming there are no active bleeding complications.^3,11 Once fully reversed, it generally takes around 5 days for warfarin to become fully therapeutic, so it can be started soon after surgery without increasing the risk for early postoperative bleeding.²⁰

DOACs. Consider the patient’s individual and procedural risks for bleeding when determining when to resume a DOAC postoperatively. That’s because unlike warfarin, which takes several days to take full effect, DOACs provide a nearly immediate anticoagulation effect.^20,21 For procedures that have a low bleeding risk, it is recommended to resume therapeutic anticoagulation 24 hours after the procedure has ended.^3,11,20 For procedures that have a high risk for bleeding, resumption of therapeutic anticoagulation should be delayed until 48 to 72 hours after the procedure has ended.^3,11,20

5. Is postoperative bridging with parenteral anticoagulation necessary?

Warfarin. If a patient was deemed to be at sufficient VTE risk to be bridged preoperatively, then that patient likely also should be bridged postoperatively, particularly if the surgery itself is associated with a heightened thrombotic risk. While warfarin can generally be resumed postoperatively the same day as the procedure, full therapeutic doses of a LMWH should not be initiated sooner than 24 hours postoperatively, and initiation should be delayed for 48 to 72 hours for procedures with the highest bleeding risk (such as neurosurgery).^3,11,21 Prophylactic doses of LMWH can generally be resumed as early as 12 hours postoperatively for procedures with high VTE risk (such as major orthopedic surgery).¹⁷

DOACs. In patients undergoing a procedure that carries both a high thromboembolic and high bleeding risk (such as major orthopedic surgery), initiation of a full-dose DOAC may need to be delayed for 2 to 3 days; however, more immediate VTE prophylaxis is usually necessary.^3,17 Prophylaxis after such procedures can begin 12 hours after the procedure with a low-intensity LMWH, which should be continued until it is deemed safe to resume full-intensity DOAC therapy.^3,17,18 If the patient is undergoing major orthopedic surgery, an FDA-approved prophylactic dose of a DOAC could be a temporary alternative to LMWH.²⁷

CASE 1

Ms. P’s upcoming colonoscopy may require a biopsy and would be classified as a procedure with low bleeding risk (per TABLE 3), so warfarin should be withheld prior to her procedure. You could check her INR 5 to 7 days before her colonoscopy to guide how many doses need to be withheld; however, given the patient’s tight INR control over the previous 6 months, you can assume her INR will be in goal range at that check. As a result, you recommend that she avoid an extra INR check and stop taking her warfarin 5 days prior to the colonoscopy.

Cohort studies involving patients taking warfarin for VTE, mechanical heart valves, or atrial fibrillation have failed to show a reduction in the incidence of thrombotic events with LMWH bridging.

Ms. P has a CHA₂DS₂VASc score of 3, which puts her at a relatively low risk for acute ischemic stroke over the next 1 to 2 weeks. Given the results of the BRIDGE trial, you recommend no parenteral bridging agent before or after her procedure. You also recommend that the patient resume her usual dose of warfarin the same day as her procedure (in the evening) unless her gastroenterologist recommends otherwise. You schedule her for a follow-up INR 5 to 7 days after her colonoscopy.

CASE 2

Mr. Q’s total knee arthroplasty (TKA)—a procedure associated with a high risk of bleeding—requires an interruption in his apixaban therapy. Additionally, he is at high risk for recurrent thromboembolism, given his history of recurrent, unprovoked DVTs; however, he is past the highest risk period (VTE within the past 3 months; his last one was 9 months ago). He is otherwise healthy and has normal renal function, so his apixaban should be withheld for a total of 4 doses (48 hours) prior to his procedure. He should resume his full dose of apixaban 48 to 72 hours after his procedure to minimize the risk for bleeding.

However, given that a TKA is a procedure associated with a high rate of postoperative VTE, initiate prophylactic anticoagulation (such as enoxaparin 40 mg subcutaneously daily or apixaban 2.5 mg PO bid) about 12 hours after the procedure and continue it until full-dose apixaban is resumed.

CORRESPONDENCE
Jeremy Vandiver, PharmD, BCPS, University of Wyoming School of Pharmacy, 1000 E. University Ave., Dept. 3375, Laramie, WY 82071; [email protected].

CASE 1

Debra P is a 62-year-old African American woman who calls your office to report that she has an upcoming routine colonoscopy planned in 2 weeks. She has been taking warfarin for the past 2 years for ischemic stroke prevention secondary to atrial fibrillation (AF), and her gastroenterologist recommended that she contact her family physician (FP) to discuss periprocedural anticoagulation plans. Ms. P is currently taking warfarin 5 mg on Mondays, Wednesdays, and Fridays, and 2.5 mg all other days of the week. Her international normalized ratio (INR) was 2.3 when it was last checked 2 weeks ago, and it has been stable and within goal range for the past 6 months. Her medical history includes AF, well-controlled hypertension, and type 2 diabetes mellitus, as well as gout and stage 3 chronic kidney disease. Ms. P denies any history of stroke or transient ischemic attack (TIA). She is requesting instructions on how to manage her warfarin before and after her upcoming colonoscopy.

CASE 2

Jerry Q is a 68-year-old Caucasian man with longstanding osteoarthritis who is scheduled to undergo a total left knee arthroplasty in one week. His orthopedic surgeon recommended that he contact his FP for instructions regarding managing apixaban perioperatively. Jerry has been taking apixaban 5 mg bid for the past 9 months due to a history of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) (both unprovoked). Mr. Q had been taking warfarin following his first DVT 4 years ago, but, after reporting that INR monitoring was a burden, he was started on apixaban. The patient has normal renal function and is relatively healthy otherwise. How should apixaban be managed before and after his upcoming surgery?

Each year, approximately 15% to 20% of patients taking an oral anticoagulant undergo a procedure that carries a heightened risk for bleeding.^1,2 Stopping oral anticoagulation is often necessary before—and sometimes briefly after—many of these procedures in order to minimize the risk of bleeding.³ This means that countless decisions must be made by health care providers each year regarding if, when, and how to pause and resume oral anticoagulation. These decisions are not always straightforward, especially when you consider the risks for thrombosis and bleeding that are unique to the procedure and to the individual patient.

With these variables in mind, the health care provider must make decisions regarding anticoagulation during the periprocedural period based on the following 5 questions:

1. Will this patient need to have his/her oral anticoagulant stopped prior to the procedure?
2. If the patient’s oral anticoagulation needs to be held, when should it be stopped and for how long?
3. Will periprocedural bridging with a parenteral anticoagulant be necessary prior to the procedure?
4. When should the patient resume his or her oral anticoagulant after the procedure, and at what dosage?
5. Will bridging with a parenteral anticoagulant be necessary after the procedure?

Before addressing these 5 questions, though, physicians must assess patients’ thrombotic and bleeding risks.^4-6

Anticoagulant regimens and the risks of discontinuing them

The 2 most common indications for long-term oral anticoagulation are venous thromboembolism (VTE), which occurs in approximately one million Americans every year,^7,8 and stroke prevention in the setting of AF (AF occurs in 3-6 million US adults per year).⁶

Countless decisions must be made by health care providers each year regarding if, when, and how to pause and resume oral anticoagulation. And these decisions are not always straightforward.

Warfarin is also often used in patients with mechanical heart valves for long-term stroke prevention; however, direct oral anticoagulants (DOACs) are not recommended for patients with mechanical heart valves because trials have not yet demonstrated their safety or efficacy in this population.^4,5,9

Who’s at highest risk for an acute thromboembolic event?

When planning for interruptions in oral anticoagulation, it is important to identify patients at highest risk for an acute thromboembolic event. Patients with 10% or higher annual risk for VTE or ischemic stroke are generally placed into this high-risk category (TABLE 1^3,5,6,9-11).³ Keep in mind that the absolute risk for thromboembolism during a brief period of oral coagulation interruption is relatively low, even in those patients considered to be at high risk. Using a mathematical approach (although simplistic), a patient with a 10% annual risk for a thromboembolic event would have <0.3% chance for developing such an event in the acute phase, even if their anticoagulation was withheld for up to 10 days ([10%/365 days] × 10 days).

Patients with mechanical heart valves. Nearly all patients with a mechanical heart valve are at moderate to high risk for ischemic stroke.³

For patients with AF, the CHADS₂ and CHA₂DS₂-VASc scoring tools can be used to estimate annual thrombosis risk based on the presence of risk factors (TABLE 2^10,11).^6,9-11 It should be noted, however, that these scoring tools have not been validated specifically for periprocedural risk estimations. Nonetheless, the latest 2017 American College of Cardiology (ACC) guidelines recommend the use of the CHA₂DS₂-VASc scoring tool for making decisions regarding perioperative bridging in patients with AF.¹¹

Patients with previous VTE. Multiple aspects of a patient’s past medical history need to be taken into account when estimating annual and acute risk for VTE. Patients at the highest risk for VTE recurrence (annual VTE risk ≥10%) include those with recent VTE (past 90 days), active malignancy, and/or severe thrombophilias (TABLE 1^3,5,6,9-11).^3,5,6 Patients without any of these features can still be at moderate risk for recurrent VTE, as a single VTE without a clear provoking factor can confer a 5% to 10% annualized risk for recurrence.^12,13 Previous proximal DVT and PE are associated with a higher risk for recurrence than a distal DVT, and males have a higher recurrence risk than females.^5,12 There are scoring tools, such as DASH (D-dimer, Age, Sex, Hormones) and the “Men Continue and HERDOO2,” that can help estimate annualized risk for VTE recurrence; however, they are not validated (nor particularly useful) when making decisions in the perioperative period.^14,15

Additional risk factors. Consider additional risk factors for thromboembolism, including estrogen/hormone replacement therapy, pregnancy, leg or hip fractures, immobility, trauma, spinal cord injury, central venous lines, congestive heart failure, thrombophilia, increased age, obesity, and varicose veins.^5,16

In addition, some surgeries have a higher inherent risk for thrombosis. Major orthopedic surgery (knee and hip arthroplasty, hip fracture surgery) and surgeries for major trauma or spinal cord injuries are associated with an exceedingly high rate of VTE.¹⁷ Similarly, coronary artery bypass surgery, heart valve replacement, and carotid endarterectomies carry the highest risk for acute ischemic stroke.³

Who’s at highest risk for bleeding?

Establishing the bleeding risk associated with a procedure is imperative prior to urgent and elective surgeries to help determine when anticoagulation therapy should be discontinued and reinitiated, as well as whether bridging therapy is appropriate. The 2012 CHEST guidelines state that bleeding risk should be assessed based on timing of anticoagulation relative to surgery and whether the anticoagulation is being used as prophylaxis for, or treatment of, thromboembolism.³ Categorizing procedures as having a minimal, low, or high risk for bleeding can be helpful in making anticoagulation decisions (TABLE 3).^3,18-21

In addition to the bleeding risk associated with procedures, patient-specific factors need to be considered. A bleeding event within the past 3 months, platelet abnormalities, a supratherapeutic INR at the time of surgery, a history of bleeding from previous bridging, a bleed history with a similar procedure, and a high HAS-BLED (Hypertension, Abnormal renal or liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol usage) score are all factors that elevate the risk for perioperative bleeding.^10,11 Although validated only in patients taking warfarin, the HAS-BLED scoring system can be utilized in patients with AF to estimate annual risk for major bleeding (TABLE 2^10,11).¹⁰

With this risk information in mind, it’s time to move on to the 5 questions you’ll need to ask.

1. Should the patient’s oral anticoagulation be stopped prior to the upcoming procedure?

The answer, of course, hinges on the patient’s risk of bleeding.

Usually, it is not necessary to withhold any doses of oral anticoagulation if your patient is scheduled for a procedure with minimal risk for bleeding (TABLE 3^3,18-21).³ However, it may be reasonable to stop anticoagulation if your patient has additional features that predispose to high bleeding risk (eg, hemophilia, Von Willebrand disease, etc). The CHEST guidelines recommend adding an oral prohemostatic agent (eg, tranexamic acid) if anticoagulation will be continued during a dental procedure.³

If your patient is undergoing any other procedure that has a low to high risk for bleeding, oral anticoagulation should be withheld prior to the procedure in most instances,^3,11 although there are exceptions. For example, cardiac procedures, such as AF catheter ablation and cardiac pacemaker placement, are often performed with uninterrupted oral anticoagulation despite their bleeding risk category.³

When in doubt, discuss the perceived bleeding and clotting risks directly with the specialist performing the procedure. In patients who have had a VTE or ischemic stroke within the past 3 months, consider postponing the invasive procedure until the patient is beyond this period of highest thrombotic risk.¹¹

Warfarin may need to be stopped anywhere from 2 to 5 days prior to the procedure, depending on a number of variables.

Previous proximal deep vein thrombosis and pulmonary embolism are associated with a higher risk for recurrence than a distal DVT, and males have a higher recurrence risk than females.

Warfarin has a half-life of approximately 36 hours, so it can take 3 to 5 days for warfarin concentrations to drop to safe levels for procedures with low to moderate bleeding risk and 5 to 7 days for procedures with high bleeding risk.²¹ The 2012 CHEST guidelines recommend that warfarin therapy be discontinued 5 days prior to surgery to minimize the risk for bleeding.³ The Anticoagulation Forum, a leading expert panel that produced a set of useful anticoagulation guidelines in 2016, recommends stopping warfarin 4 to 5 days prior to a procedure.²¹ If the provider chooses to withhold warfarin before a procedure with minimal bleeding risk, it should be stopped 2 to 3 days prior.³

Consider checking INR values the week before. A 2017 consensus statement from the ACC recommends that the timing of warfarin discontinuation be based on an INR value taken 5 to 7 days prior to the surgical procedure.¹¹ This allows for a more tailored approach to preparing the patient for surgery. If the INR is below goal range, warfarin may need to be withheld for only 3 to 4 days prior to a procedure. Conversely, INRs above goal range may require warfarin to be held 6 or more days, depending on the degree of INR elevation.

While not always feasible in clinical practice, the CHEST guidelines recommend obtaining an INR value the day prior to the procedure to determine if the INR value is low enough to proceed with surgery, or if a low dose of oral vitamin K needs to be administered to ensure that the INR is in a safe range the following day.³

DOACs

DOACs can be withheld for much shorter durations preoperatively than warfarin.

Major orthopedic surgery and surgeries for major trauma or spinal cord injuries are associated with an exceedingly high rate of venous thromboembolism.

When withholding anticoagulants, the goal is to have a low amount of anticoagulant effect (12%-25%) present during low-risk procedures and a nominal amount of anticoagulant effect (3%-6%) present for high-risk procedures.²⁰ DOACs have much shorter half-lives than warfarin (7-19 hours vs 36-48 hours, respectively), so they can be withheld for much shorter durations preoperatively.²⁰ For patients undergoing procedures that are considered to have a minimal risk for bleeding (such as minor dental and dermatologic procedures), DOACs do not generally need to be withheld; however, it may be ideal to time the procedure when the DOAC is at a trough concentration (before the next dose is due).³

Coronary artery bypass surgery, heart valve replacement, and carotid endarterectomies carry the highest risk for acute ischemic stroke.

DOACs generally need to be withheld for only 1 to 3 days prior to major surgical procedures in patients with normal renal function (creatinine clearance [CrCl] >30 mL/min using the Cockcroft-Gault formula).²⁰ The available oral direct factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban) should generally be stopped 24 hours prior to a procedure that has a low bleeding risk, and 48 hours prior to procedures with high bleeding risk (TABLE 4^11,20).²⁰ These medications may need to be withheld for an additional 1 to 2 days in patients with acute kidney injury or stage IV kidney disease.²⁰

Dabigatran. About 80% of dabigatran is excreted renally, so its elimination is much more dependent on renal function than is that of the oral direct factor Xa inhibitors.²⁰ Therefore, it generally needs to be withheld for at least 1 to 2 days longer than the oral factor Xa inhibitors unless CrCl >80 mL/min (TABLE 4^11,20).²⁰

3. Is preoperative bridging with parenteral anticoagulation necessary?

In certain instances, patients who have a high thromboembolic risk and are discontinuing warfarin therapy may require bridging therapy with a low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). If a patient’s CrCl is <30 mL/min, then UFH is the preferred agent for perioperative bridging.²¹

But before any decision is made, it’s best to have a good understanding of what the guidelines—and the literature—have to say.

Key studies and guidelines

The 2012 CHEST guidelines recommend providing bridge therapy for any patient at high risk for thromboembolism (>10% annual risk) and consideration of bridge therapy in the setting of moderate clotting risk (5%-10% annual risk), depending on specific patient and procedural risk factors (TABLE 1^3,5,6,9-11).³

In 2015, a landmark clinical trial was published that significantly shaped how patients taking warfarin are managed periprocedurally.²² The Bridge (Bridging anticoagulation in patients who require temporary interruption of warfarin therapy for an elective invasive procedure or surgery) trial was the first prospective, randomized controlled trial to assess the efficacy and safety of parenteral bridging in patients with AF taking warfarin and undergoing an elective surgery.

Patients in the trial received either dalteparin at a therapeutic dose of 100 IU/kg or a matching placebo administered subcutaneously bid from 3 days before the procedure until 24 hours before the procedure, and then for 5 to 10 days after the procedure. The incidence of thromboembolic events was not significantly lower in the dalteparin group than in the placebo group (0.3% vs 0.4%, respectively; P=.73), while major bleeding rates were nearly 3-fold higher in the dalteparin group (3.2% vs 1.3%; P=.005). The trial concluded that placebo “was noninferior to perioperative bridging with LMWH for the prevention of arterial thromboembolism and decreased the risk of major bleeding.”²²

When withholding anticoagulants, the goal is to have a low amount of anticoagulant effect (12%-25%) present during low-risk procedures and a nominal amount (3%-6%) present for high-risk procedures.

Patients excluded from the trial included those with a mechanical heart valve, or a recent (within 3 months) embolism, stroke, or TIA, and only 3% of enrolled patients would have been classified as having a high bleeding risk according to CHEST guidelines.^3,22

A prospective observational registry study produced similar findings and found that those patients who received bridging had more bleeding events and a higher incidence of myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days than those who did not receive bridging.²³ Other retrospective cohort studies comparing bridging to no bridging strategies in patients taking warfarin for VTE, mechanical heart valves, or AF have also failed to show a reduction in the incidence of thrombotic events with LMWH bridging.^24,25

In 2016, the European Society of Cardiology suggested that “bridging does not seem to be beneficial, except in patients with mechanical heart valves.”²⁶ Similarly, the 2016 Anticoagulation Forum guidelines state that “most patients with VTE can safely interrupt warfarin for invasive procedures without bridge therapy,” and that bridge therapy should be “reserved for those at highest recurrent VTE risk (eg, VTE within the previous month; prior history of recurrent VTE during anticoagulation therapy interruption; undergoing a procedure with high inherent risk for VTE, such as joint replacement surgery or major abdominal cancer resection).”²¹ They go on to state that even in these high-risk groups, the clinical decision to use bridging therapy needs to carefully weigh the benefits against the potential risks of bleeding.²¹

Controversy also surrounds the intensity of LMWH bridging. The Anticoagulation Forum guidelines state that the use of prophylactic rather than therapeutic dose LMWH may be considered, while the CHEST guidelines do not make a firm recommendation regarding LMWH dose while bridging.^3,21 Ultimately, in patients who receive perioperative bridging with LMWH, the CHEST guidelines recommend that it should be stopped 24 hours prior to the procedure and resumed in accordance with the bleeding risk of the procedure (ie, prophylactic doses may be appropriate within 24 hours postprocedure, while full treatment doses may need to be delayed for 48 to 72 hours if surgical bleeding risk is high).³ UFH bridge therapy may be stopped 4 to 6 hours prior to surgery.³

DOACs. Given the rapid onset and relatively short half-lives of DOACs, use of a parenteral bridging agent is generally not necessary or recommended before or after an invasive procedure in patients taking a DOAC.²⁰

4. When should oral anticoagulation be resumed postoperatively, and at what intensity?

Warfarin can generally be resumed the same day as the procedure (in the evening), assuming there are no active bleeding complications.^3,11 Once fully reversed, it generally takes around 5 days for warfarin to become fully therapeutic, so it can be started soon after surgery without increasing the risk for early postoperative bleeding.²⁰

DOACs. Consider the patient’s individual and procedural risks for bleeding when determining when to resume a DOAC postoperatively. That’s because unlike warfarin, which takes several days to take full effect, DOACs provide a nearly immediate anticoagulation effect.^20,21 For procedures that have a low bleeding risk, it is recommended to resume therapeutic anticoagulation 24 hours after the procedure has ended.^3,11,20 For procedures that have a high risk for bleeding, resumption of therapeutic anticoagulation should be delayed until 48 to 72 hours after the procedure has ended.^3,11,20

5. Is postoperative bridging with parenteral anticoagulation necessary?

Warfarin. If a patient was deemed to be at sufficient VTE risk to be bridged preoperatively, then that patient likely also should be bridged postoperatively, particularly if the surgery itself is associated with a heightened thrombotic risk. While warfarin can generally be resumed postoperatively the same day as the procedure, full therapeutic doses of a LMWH should not be initiated sooner than 24 hours postoperatively, and initiation should be delayed for 48 to 72 hours for procedures with the highest bleeding risk (such as neurosurgery).^3,11,21 Prophylactic doses of LMWH can generally be resumed as early as 12 hours postoperatively for procedures with high VTE risk (such as major orthopedic surgery).¹⁷

DOACs. In patients undergoing a procedure that carries both a high thromboembolic and high bleeding risk (such as major orthopedic surgery), initiation of a full-dose DOAC may need to be delayed for 2 to 3 days; however, more immediate VTE prophylaxis is usually necessary.^3,17 Prophylaxis after such procedures can begin 12 hours after the procedure with a low-intensity LMWH, which should be continued until it is deemed safe to resume full-intensity DOAC therapy.^3,17,18 If the patient is undergoing major orthopedic surgery, an FDA-approved prophylactic dose of a DOAC could be a temporary alternative to LMWH.²⁷

CASE 1

Ms. P’s upcoming colonoscopy may require a biopsy and would be classified as a procedure with low bleeding risk (per TABLE 3), so warfarin should be withheld prior to her procedure. You could check her INR 5 to 7 days before her colonoscopy to guide how many doses need to be withheld; however, given the patient’s tight INR control over the previous 6 months, you can assume her INR will be in goal range at that check. As a result, you recommend that she avoid an extra INR check and stop taking her warfarin 5 days prior to the colonoscopy.

Cohort studies involving patients taking warfarin for VTE, mechanical heart valves, or atrial fibrillation have failed to show a reduction in the incidence of thrombotic events with LMWH bridging.

Ms. P has a CHA₂DS₂VASc score of 3, which puts her at a relatively low risk for acute ischemic stroke over the next 1 to 2 weeks. Given the results of the BRIDGE trial, you recommend no parenteral bridging agent before or after her procedure. You also recommend that the patient resume her usual dose of warfarin the same day as her procedure (in the evening) unless her gastroenterologist recommends otherwise. You schedule her for a follow-up INR 5 to 7 days after her colonoscopy.

CASE 2

Mr. Q’s total knee arthroplasty (TKA)—a procedure associated with a high risk of bleeding—requires an interruption in his apixaban therapy. Additionally, he is at high risk for recurrent thromboembolism, given his history of recurrent, unprovoked DVTs; however, he is past the highest risk period (VTE within the past 3 months; his last one was 9 months ago). He is otherwise healthy and has normal renal function, so his apixaban should be withheld for a total of 4 doses (48 hours) prior to his procedure. He should resume his full dose of apixaban 48 to 72 hours after his procedure to minimize the risk for bleeding.

However, given that a TKA is a procedure associated with a high rate of postoperative VTE, initiate prophylactic anticoagulation (such as enoxaparin 40 mg subcutaneously daily or apixaban 2.5 mg PO bid) about 12 hours after the procedure and continue it until full-dose apixaban is resumed.

CORRESPONDENCE
Jeremy Vandiver, PharmD, BCPS, University of Wyoming School of Pharmacy, 1000 E. University Ave., Dept. 3375, Laramie, WY 82071; [email protected].

Caring for a newborn can be a source of joy for family physicians (FPs). In this article, we examine care provided in the first month of life, including a thorough physical examination, safe hospital discharge procedures, assessment of neonatal feeding, evaluation of jaundice and fever, and prevention of sudden infant death syndrome (SIDS). In addition, we describe how FPs can support women of childbearing age between pregnancies, with the goal of reducing the risk of adverse outcomes in future pregnancies. (See “Your role in risk assessment and interventions during the interconception period.”)

Before parents leave the hospital with their newborn, it is essential that they receive written and verbal counseling on important issues in neonatal care. A discharge checklist can help make sure all topics have been covered.¹ A hearing screen and pulse oximetry before discharge are required for all newborns in most states, in addition to important preventive counseling for parents. TABLE 1² and TABLE 2² summarize important newborn physical exam findings and common skin conditions. Parents should be given additional written information regarding prevention of SIDS and proper use of car seats.

Hospital physicians should assess maternal medical and psychosocial readiness for discharge. Through shared decision-making with the newborn’s parents, physicians should create a plan for outpatient follow-up. Assessment through a physician home visit can provide safe and effective care similar to what is provided at a visit to an office medical practice.^3-7 A follow-up appointment should be made 2 to 5 days before discharge, preferably connecting the newborn to a medical home where comprehensive health care services are offered.^1,5,6,8

Age, gestational age, risk factors for hyperbilirubinemia, and the timing and level of bilirubin testing should be considered when establishing a follow-up interval. Most newborns who are discharged before 72 hours of age should have a follow-up visit in 2 days; a newborn who has a recognized risk factor for a health problem should be seen sooner. Newborns in the “low-risk zone” (ie, no recognized risk factors) should be seen based on age at discharge or need for breastfeeding support.⁹

Tracking baby’s weight, ensuring proper feeding

A newborn who is discharged at 24 hours of life, or sooner, should be seen in the office within 2 days of discharge to 1) ensure that he (she) is getting proper nutrition and 2) monitor his weight^1,3,5 (TABLE 3^10-13). All newborns should be seen again at 2 weeks of life, with additional visits more frequently if there are concerns about nutrition.¹

Recording an accurate weight is critical; the newborn should be weighed completely undressed and without a diaper. Healthy newborns can safely lose up to 10% of birth weight within the first week of life; they should be back to their birth weight by approximately 2 weeks of life.^10,11 A healthy newborn loses approximately 0.5 to 1 oz a day;¹¹ greater than 10% loss of birth weight should trigger a thorough medical work-up and feeding assessment.

Breastfeeding. For breastfeeding mothers, physicians should recommend on-demand feeding or a feeding at least every 2 or 3 hours. Adequate intake in breastfed infants can be intimidating for new parents to monitor, but they can use a written chart or any of several available smartphone applications to document length and timing of feeds and frequency of urination and bowel movements. By the fifth day of life, a newborn should be having at least 6 voids and 3 or 4 stools a day.^10-12

In addition, physicians can counsel parents on what to look for—in the mother and the newborn—to confirm that breastfeeding is successful, with adequate nutritional intake (TABLE 3^10-13). Physicians should recommend against providing a pacifier to breastfeeding infants during the first several weeks of life—or until breastfeeding is well established (usually at 3 or 4 weeks of age). The World Health Organization (WHO) recommends against providing bottles, pacifiers, and artificial nipples to breastfeeding newborns.¹⁴ Liquids other than colostrum or breast milk should not be given unless there is a documented medical need, such as inadequate weight gain or feeding difficulty.¹⁵ If the newborn experiences early latch difficulties, supplementation with expressed breast milk is preferable to supplementation with formula. Assistance from a trained lactation consultant is a key element in the support of the breastfeeding dyad.^11,12,16

Breastfeeding optimizes development of the newborn’s immune system, thus bolstering disease prevention; it also assists with maternal postpartum weight loss and psychological well-being. Exclusively or primarily formula-fed newborns are at increased risk of gastrointestinal, ear, and respiratory infections throughout infancy and childhood; type 1 diabetes mellitus; asthma; childhood and adult obesity; and leukemia.^17,18 Mothers who feed their newborn primarily formula increase their own risk of obesity, type 2 diabetes mellitus, ovarian and breast cancer, and depression.^17-22

Infant feeding is a personal and family choice but, in the absence of medical contraindications—such as maternal human immunodeficiency virus infection and galactosemia—exclusive breastfeeding should be recommended.^17,18 FPs are well suited to support the mother–infant breastfeeding dyad in the neonatal period, based on expert recommendations. Specifically, the American Academy of Family Physicians (AAFP) and American Academy of Pediatrics (AAP) recommend that all infants be exclusively breastfed for the first 6 months of life and continue some breastfeeding through the first year or longer.^17,18 WHO recommends breastfeeding until 24 months of age—longer if mother and infant want to, unless breastfeeding is contraindicated.^14,17,18

Physicians should provide up-to-date information to parents regarding the risks and benefits of feeding choices. Support for breastfeeding mothers postnatally has been shown to be helpful in lengthening the time of exclusive breastfeeding.¹² Certain medications pass through breast milk, and updated guides to medication cautions can be found at the National Institutes of Health’s LACTMED Web site (https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm).¹³ In many cases, when a maternal medication is incompatible with breastfeeding, the family physician can consider substituting another appropriate medication that is compatible.

Physician recommendation and support improves the rate of breastfeeding, but many mother–infant dyads require additional support to maintain breastfeeding for the recommended duration; such support can take the form of a certified lactation consultant or counselor, doula, or peer counselor.^23-25 Although structured breastfeeding education in the antenatal period has been demonstrated to be effective in improving breastfeeding initiation and duration, recent research shows that support groups and assistance from the professionals previously mentioned also improve the breastfeeding rate.^26-28

Adequate intake in breastfed infants can be intimidating for new parents to monitor, but they can use a written chart or any of several available smartphone applications.

The AAFP recommends that FPs’ offices adopt specific, evidence-based practices that can have an impact on breastfeeding initiation and duration. Such practices include phone and in-person breastfeeding support from nursing staff and removing any formula advertisements from the office.¹⁷

Formula feeding. When parents choose formula feeding, most infants tolerate cow’s milk-based formula.²⁹ For healthy term infants, differences between brands of formula are generally insignificant. Soy-protein formulas are of value only if lactose intolerance is strongly suspected, such as after prolonged episodes of loose stools. Even then, intolerance is usually transient and cow’s milk-based formula can be tried again in 2 to 4 weeks.

Physicians should recommend 20 kcal/oz of iron-fortified formula for infants who are fed formula—except in special circumstances, such as premature newborns, who may require a more calorie-dense formula. Parents should pay special attention to the manufacturer’s instructions for mixing formula with water because overdilution can cause hyponatremia. Typical volume for newborns should be at least 15 to 30 mL/feed for the first few days; newborns should not go more than 4 hours between feedings. Within the first week, newborns will start taking 60 to 90 mL/feed and increase that gradually to approximately 120 mL/feed by the end of the first month of life. On average, infants need a little more than 100 kcal/kg of body weight a day; for a 3.5-kg infant, that is at least 500 mL of formula over the course of a day.^17,22

Because formula does not contain fluoride, physicians should recommend that parents mix formula that is provided as a powder with fluoridated water. Low-iron formula offers no advantage; feeding with it will cause iron-deficiency anemia in most infants.

When tongue-tie interferes with feeding

Tongue-tie—or ankyloglossia, an atypically short or thick lingual frenulum—is present in 3% to 16% of all births. The condition can make breastfeeding difficult; result in poor neonatal weight gain; and cause sore nipples in 25% to 44% of cases.³⁰ Once tongue-tie is noted, the physician should talk to the mother about the history of feeding success, including whether her nipples are sore and whether the newborn is having difficulty feeding (ie, transferring milk). The Hazelbaker Assessment Tool for Lingual Frenulum Function and the simpler Bristol Tongue Assessment Tool can be used to assess the severity of tongue-tie.^30-35

When tongue-tie interferes with feeding, a physician who is not trained in treatment can refer the mother and infant to a specialist in the community. Frenotomy has been used for many years as a treatment for tongue-tie; improvement in nipple pain and the mother-reported breastfeeding score have been reported postoperatively in several studies.^30-33

Ensure proper vitamin D intake through supplementation

Newborns should consume 400 IU/d of supplemental vitamin D to prevent deficiency and its clinical manifestation, rickets, or other associated abnormalities of calcium metabolism. Deficiency of vitamin D has also been linked to a number of other conditions, including developmental delay and, possibly, type 1 diabetes mellitus in childhood and cardiovascular disease later in life.³⁶

Newborns should consume 400 IU/d of supplemental vitamin D to prevent deficiency and its clinical manifestation, rickets, or other associated abnormalities of calcium metabolism.

In the first months of life, few infants who are solely formula-fed will consume a full liter daily; for them, supplementation of vitamin D for at least one month should be prescribed.³⁵ For breastfed infants, high-dosage maternal vitamin D supplementation may be effective, precluding infant oral vitamin D supplementation³⁶; however, neither the AAFP nor the AAP has issued guidance promoting maternal supplementation in lieu of direct oral infant supplementation.³⁷

Jaundice prevention—and recognition

An elevated bilirubin level is seen in most newborns in the first days of life because of increased production and decreased clearance of bilirubin—a condition known as physiologic jaundice. Conditions that aggravate physiologic hyperbilirubinemia include inborn errors of metabolism, ABO blood-group incompatibility, hemoglobin variants, and inflammatory states such as sepsis. It is important to distinguish physiologic jaundice from exaggerated physiologic and pathologic forms of hyperbilirubinemia; the latter is a medical emergency. Before we get to that, a word about prevention.

Prevention. Because poor caloric intake and dehydration are associated with hyperbilirubinemia, physicians should advise breastfeeding mothers to feed their newborn at least 8 to 12 times daily during the first week of life. However, routine supplementation of liquids other than breast milk should be discouraged in newborns who are not dehydrated.³⁸

The total serum bilirubin level should be tested in every newborn who has clinical jaundice in the first 24 hours of life.

All pregnant women should be tested for ABO and Rh (D) blood types and undergo serum screening for isoimmune antibodies. Randomized trials have demonstrated that the incidence of significant hyperbilirubinemia can be reduced if, for Rh-negative mothers and those who did not undergo prenatal blood-group testing, infant cord blood is tested for 1) ABO and Rh (D) types and 2) direct antibody (Coombs’ test).^38,39

Screening and assessment. It is recommended that all newborns be screened for jaundice before discharge by 1) assessment of clinical risk factors or 2) testing of transcutaneous bilirubin (TcB) or total serum bilirubin (TSB). Furthermore, because evidence shows that treating clinical jaundice can improve outcomes and rehospitalization, TSB should be measured in every newborn who has clinical jaundice in the first 24 hours of life. Measurement of TcB or TSB should also be performed on all infants in whom there appears to be clinical jaundice that is excessive for age.^38,39

During routine clinical care, TcB measurement provides a reasonable estimate of the TSB level in healthy newborns at levels less than 15 mg/dL,⁴⁰ although TcB testing might not be available in the outpatient office. An AAP management algorithm can help determine when a newborn should be seen for outpatient follow-up based on risk of hyperbilirubinemia; higher-risk newborns should be reevaluated in 24 hours.⁹ Outpatient visual assessment of jaundice for cephalocaudal progression—in a well-lit room, with a fully undressed newborn—correlates well with TSB test results. However, visual assessment should not be used alone to screen for hyperbilirubinemia; recent studies have demonstrated that such assessment lacks clinical reliability.⁴⁰

Laboratory assessment. All bilirubin levels should be interpreted based on the newborn’s age in hours. The need for phototherapy should be based on the zone (low, low-intermediate, high-intermediate, or high, as categorized in the AAP nomogram³⁸ in which the TSB level falls. TABLE 4^38-40 provides recommendations for laboratory studies based on risk factors. Standard curves for risk stratification have been developed by the AAP.^37,38

Treatment. Decisions to initiate treatment should be based on the AAP algorithm.³⁸ When initiating phototherapy, precautions include ensuring adequate fluid intake, patching eyes, and monitoring temperature. Phototherapy can generally be stopped when the TSB level falls by 5 mg/dL or below 14 mg/dL. Home phototherapy, using a fiberoptic blanket, for uncomplicated jaundice (in carefully selected newborns with reliable parents) allows continued breastfeeding and bonding with the family, and can significantly decrease the rate of rehospitalization for infants older than 34 weeks.⁴¹

Breastfeeding is often associated with a higher bilirubin level than is seen in infants fed formula exclusively; increasing the frequency of feeding usually reduces the bilirubin level. So-called breast-milk jaundice is a delayed, but common, form of jaundice that is usually diagnosed in the second week of life and peaks by the end of the second week, resolving gradually over one to 4 months. If evaluation reveals no pathologic source, breastfeeding can generally be continued. Temporary discontinuation of breastfeeding to consider a diagnosis of breast-milk jaundice or other reasons for an elevated bilirubin level increases the risk of breastfeeding failure and is usually unnecessary.^12,37,39

Fever—a full work-up, thorough history are key

Concern about serious bacterial illness (SBI) makes the evaluation of fever critical for those who care for newborns. Many studies have attempted to identify which newborns might be able to be cared for safely as outpatients to prevent unnecessary testing and antibiotics.^5,42 Regrettably, SBI in infants remains difficult to predict, and protocols that have been developed may miss as many as 1 of every 10 newborns who has SBI.⁴³ Initial management of all infants 28 days old or younger with fever must therefore include a full work-up, including lumbar puncture and empiric antibiotics.⁴⁴

Evaluation. When an infant younger than 28 days has a fever, the physician should first verify that the temperature was taken rectally and how it was documented. In an infant who has a history of prematurity, it is crucial to correct for chronological age when deciding on proper evaluation.

Additional important findings in the history include a significant change in behavior, associated symptoms, and exposure to sick contacts. The maternal and birth history, including prolonged rupture of membranes, colonization with group B Streptococcus, administration of antibiotics at delivery, and genital herpes simplex virus (HSV) infection may suggest a cause for fever.⁴⁵

The evaluation of fever might include the white blood cell (WBC) count, blood culture, measurement of markers of inflammation, urine studies, lumbar puncture, stool culture, and chest radiograph. Traditionally, the WBC count has been utilized as a standard marker for sepsis, although it has a low sensitivity and specificity for SBI, especially in newborns.⁴⁶ Blood cultures should be obtained routinely in the newborn with fever, and before antibiotics are administered in older infants.

Procalcitonin (PCT; a calcitonin precursor) and the inflammatory marker C-reactive protein (CRP) have been shown, in several large studies, to have relatively high sensitivity and specificity for SBI; measurement of these constituents may enhance detection of serious illness.^46-49 In a large study of 2047 febrile infants older than 30 months, the PCT level was determined to be more accurate than the CRP level, the WBC count, and the absolute neutrophil count in predicting SBI.^48,49 PCT shows the most promise for preventing a full fever work-up and empiric antibiotics. It has not yet been widely translated into practice, however, because of a lack of clear guidance on how to combine PCT levels with other laboratory markers and clinical decision-making.^48-50

Urinalysis (UA) should be obtained for all newborns who present with fever. Traditionally, it was recommended that urine should be cultured for all newborns with fever; however, more recent data show that the initial urinalysis is much more sensitive than once thought. In a study, UA was positive (defined as pyuria or a positive leukocyte esterase test, or both) in all but 1 of 203 infants who had bacteremic UTI (sensitivity, 99.5%).⁵¹

The procalcitonin level was determined to be more accurate than the C-reactive protein level, the white blood cell count, and the absolute neutrophil count in predicting serious bacterial illness.

Stool culture is necessary in newborns only when they present with blood or mucus in diarrhea. Lumbar puncture should be performed in all febrile newborns and all newborns for whom empiric antibiotics have been prescribed.^43,44 A chest radiograph may be useful in diagnosis when a newborn has any other sign of pulmonary disease: respiratory rate >50/min, retractions, wheezing, grunting, stridor, nasal flaring, cough, and positive findings on lung examination.^43,44

Treatment. Management for all newborns who have a rectal temperature ≥38° C includes admission to the hospital and empiric antibiotics; guidance is based primarily on expert consensus. Common pathogens for SBI include group B Strep, Escherichia coli, Enterococcus spp., and Listeria monocytogenes.^43,44 Empiric antibiotics, including ampicillin (to cover L monocytogenes) and cefotaxime or gentamicin should be started immediately after sending for blood, urine, and cerebrospinal fluid (CSF) cultures.^43-45

Management for all newborns who have rectal temperature ≥38° C includes admission to the hospital and empiric antibiotics.

All infants who are ill-appearing or have vesicles, seizures, or a maternal history of genital HSV infection should also be started on empiric acyclovir. Vesicles should be cultured and CSF should be sent for HSV DNA polymerase chain reaction before acyclovir is administered.^43-45

Sudden infant death syndrome: Steps to take to minimize risk

SIDS is defined as the sudden death of a child younger than 1 year that remains unexplained after a thorough case investigation and comprehensive review of the clinical history. The risk of SIDS in the United States is less than 1 for every 1000 live births; incidence peaks between 2 and 4 months of age.⁵² In the United States, SIDS and other sleep-related infant deaths, such as strangulation in bed or accidental suffocation, account for more than 4000 deaths a year.⁵³ The incidence of SIDS declined markedly after the “Back to Sleep” campaign was launched in 2003, but has leveled off since 2005.^53-55

Numerous risk factors for SIDS have been identified, including maternal factors (young maternal age, maternal smoking during pregnancy, late or no prenatal care) and infant and environmental factors (prematurity, low birth weight, male gender, prone sleeping position, sleeping on a soft surface or with bedding accessories, bed-sharing (ie, sleeping in the parents’ bed), and overheating. In many cases, the risk factors are modifiable; sleeping in the prone position is the most meaningful modifiable risk factor.

Home monitors have not been proven to reduce the incidence of SIDS and are not recommended for that purpose.

To minimize the risk for SIDS, parents should be educated on the risk factors—prenatally as well as at each infant well visit. Home monitors have not been proven to reduce the incidence of SIDS and are not recommended for that purpose.^54-57 Although evidence is strongest for supine positioning as a preventive intervention for SIDS, other evidence-based recommendations include use of a firm sleep surface; breastfeeding; use of a pacifier; room-sharing with parents without bed-sharing; routine immunization; avoidance of overheating; avoiding falling asleep with the infant on a chair or couch; and avoiding exposure to tobacco smoke, alcohol, and drugs of abuse.^55,56 A recent systematic review showed that large-scale community interventions and education campaigns can play a significant role in parental and community adoption of safe sleep recommendations; however, families and communities rarely exhibit complete adherence to safe sleep practices.⁵⁷

Other concerns in the first month of life and immediately beyond

In TABLE 5,² we list additional common newborn problems not reviewed in the text of this article and summarize evidence-based treatment strategies.

CORRESPONDENCE
Scott Hartman, MD, Associate Professor, Department of Family Medicine, University of Rochester Medical Center, 777 South Clinton Avenue, Rochester, NY 14620; [email protected].

Acknowledgement
We thank Nancy Phillips for her assistance in the preparation of this article.

Caring for a newborn can be a source of joy for family physicians (FPs). In this article, we examine care provided in the first month of life, including a thorough physical examination, safe hospital discharge procedures, assessment of neonatal feeding, evaluation of jaundice and fever, and prevention of sudden infant death syndrome (SIDS). In addition, we describe how FPs can support women of childbearing age between pregnancies, with the goal of reducing the risk of adverse outcomes in future pregnancies. (See “Your role in risk assessment and interventions during the interconception period.”)

Before parents leave the hospital with their newborn, it is essential that they receive written and verbal counseling on important issues in neonatal care. A discharge checklist can help make sure all topics have been covered.¹ A hearing screen and pulse oximetry before discharge are required for all newborns in most states, in addition to important preventive counseling for parents. TABLE 1² and TABLE 2² summarize important newborn physical exam findings and common skin conditions. Parents should be given additional written information regarding prevention of SIDS and proper use of car seats.

Hospital physicians should assess maternal medical and psychosocial readiness for discharge. Through shared decision-making with the newborn’s parents, physicians should create a plan for outpatient follow-up. Assessment through a physician home visit can provide safe and effective care similar to what is provided at a visit to an office medical practice.^3-7 A follow-up appointment should be made 2 to 5 days before discharge, preferably connecting the newborn to a medical home where comprehensive health care services are offered.^1,5,6,8

Age, gestational age, risk factors for hyperbilirubinemia, and the timing and level of bilirubin testing should be considered when establishing a follow-up interval. Most newborns who are discharged before 72 hours of age should have a follow-up visit in 2 days; a newborn who has a recognized risk factor for a health problem should be seen sooner. Newborns in the “low-risk zone” (ie, no recognized risk factors) should be seen based on age at discharge or need for breastfeeding support.⁹

Tracking baby’s weight, ensuring proper feeding

A newborn who is discharged at 24 hours of life, or sooner, should be seen in the office within 2 days of discharge to 1) ensure that he (she) is getting proper nutrition and 2) monitor his weight^1,3,5 (TABLE 3^10-13). All newborns should be seen again at 2 weeks of life, with additional visits more frequently if there are concerns about nutrition.¹

Recording an accurate weight is critical; the newborn should be weighed completely undressed and without a diaper. Healthy newborns can safely lose up to 10% of birth weight within the first week of life; they should be back to their birth weight by approximately 2 weeks of life.^10,11 A healthy newborn loses approximately 0.5 to 1 oz a day;¹¹ greater than 10% loss of birth weight should trigger a thorough medical work-up and feeding assessment.

Breastfeeding. For breastfeeding mothers, physicians should recommend on-demand feeding or a feeding at least every 2 or 3 hours. Adequate intake in breastfed infants can be intimidating for new parents to monitor, but they can use a written chart or any of several available smartphone applications to document length and timing of feeds and frequency of urination and bowel movements. By the fifth day of life, a newborn should be having at least 6 voids and 3 or 4 stools a day.^10-12

In addition, physicians can counsel parents on what to look for—in the mother and the newborn—to confirm that breastfeeding is successful, with adequate nutritional intake (TABLE 3^10-13). Physicians should recommend against providing a pacifier to breastfeeding infants during the first several weeks of life—or until breastfeeding is well established (usually at 3 or 4 weeks of age). The World Health Organization (WHO) recommends against providing bottles, pacifiers, and artificial nipples to breastfeeding newborns.¹⁴ Liquids other than colostrum or breast milk should not be given unless there is a documented medical need, such as inadequate weight gain or feeding difficulty.¹⁵ If the newborn experiences early latch difficulties, supplementation with expressed breast milk is preferable to supplementation with formula. Assistance from a trained lactation consultant is a key element in the support of the breastfeeding dyad.^11,12,16

Breastfeeding optimizes development of the newborn’s immune system, thus bolstering disease prevention; it also assists with maternal postpartum weight loss and psychological well-being. Exclusively or primarily formula-fed newborns are at increased risk of gastrointestinal, ear, and respiratory infections throughout infancy and childhood; type 1 diabetes mellitus; asthma; childhood and adult obesity; and leukemia.^17,18 Mothers who feed their newborn primarily formula increase their own risk of obesity, type 2 diabetes mellitus, ovarian and breast cancer, and depression.^17-22

Infant feeding is a personal and family choice but, in the absence of medical contraindications—such as maternal human immunodeficiency virus infection and galactosemia—exclusive breastfeeding should be recommended.^17,18 FPs are well suited to support the mother–infant breastfeeding dyad in the neonatal period, based on expert recommendations. Specifically, the American Academy of Family Physicians (AAFP) and American Academy of Pediatrics (AAP) recommend that all infants be exclusively breastfed for the first 6 months of life and continue some breastfeeding through the first year or longer.^17,18 WHO recommends breastfeeding until 24 months of age—longer if mother and infant want to, unless breastfeeding is contraindicated.^14,17,18

Physicians should provide up-to-date information to parents regarding the risks and benefits of feeding choices. Support for breastfeeding mothers postnatally has been shown to be helpful in lengthening the time of exclusive breastfeeding.¹² Certain medications pass through breast milk, and updated guides to medication cautions can be found at the National Institutes of Health’s LACTMED Web site (https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm).¹³ In many cases, when a maternal medication is incompatible with breastfeeding, the family physician can consider substituting another appropriate medication that is compatible.

Physician recommendation and support improves the rate of breastfeeding, but many mother–infant dyads require additional support to maintain breastfeeding for the recommended duration; such support can take the form of a certified lactation consultant or counselor, doula, or peer counselor.^23-25 Although structured breastfeeding education in the antenatal period has been demonstrated to be effective in improving breastfeeding initiation and duration, recent research shows that support groups and assistance from the professionals previously mentioned also improve the breastfeeding rate.^26-28

Adequate intake in breastfed infants can be intimidating for new parents to monitor, but they can use a written chart or any of several available smartphone applications.

The AAFP recommends that FPs’ offices adopt specific, evidence-based practices that can have an impact on breastfeeding initiation and duration. Such practices include phone and in-person breastfeeding support from nursing staff and removing any formula advertisements from the office.¹⁷

Formula feeding. When parents choose formula feeding, most infants tolerate cow’s milk-based formula.²⁹ For healthy term infants, differences between brands of formula are generally insignificant. Soy-protein formulas are of value only if lactose intolerance is strongly suspected, such as after prolonged episodes of loose stools. Even then, intolerance is usually transient and cow’s milk-based formula can be tried again in 2 to 4 weeks.

Physicians should recommend 20 kcal/oz of iron-fortified formula for infants who are fed formula—except in special circumstances, such as premature newborns, who may require a more calorie-dense formula. Parents should pay special attention to the manufacturer’s instructions for mixing formula with water because overdilution can cause hyponatremia. Typical volume for newborns should be at least 15 to 30 mL/feed for the first few days; newborns should not go more than 4 hours between feedings. Within the first week, newborns will start taking 60 to 90 mL/feed and increase that gradually to approximately 120 mL/feed by the end of the first month of life. On average, infants need a little more than 100 kcal/kg of body weight a day; for a 3.5-kg infant, that is at least 500 mL of formula over the course of a day.^17,22

Because formula does not contain fluoride, physicians should recommend that parents mix formula that is provided as a powder with fluoridated water. Low-iron formula offers no advantage; feeding with it will cause iron-deficiency anemia in most infants.

When tongue-tie interferes with feeding

Tongue-tie—or ankyloglossia, an atypically short or thick lingual frenulum—is present in 3% to 16% of all births. The condition can make breastfeeding difficult; result in poor neonatal weight gain; and cause sore nipples in 25% to 44% of cases.³⁰ Once tongue-tie is noted, the physician should talk to the mother about the history of feeding success, including whether her nipples are sore and whether the newborn is having difficulty feeding (ie, transferring milk). The Hazelbaker Assessment Tool for Lingual Frenulum Function and the simpler Bristol Tongue Assessment Tool can be used to assess the severity of tongue-tie.^30-35

When tongue-tie interferes with feeding, a physician who is not trained in treatment can refer the mother and infant to a specialist in the community. Frenotomy has been used for many years as a treatment for tongue-tie; improvement in nipple pain and the mother-reported breastfeeding score have been reported postoperatively in several studies.^30-33

Ensure proper vitamin D intake through supplementation

Newborns should consume 400 IU/d of supplemental vitamin D to prevent deficiency and its clinical manifestation, rickets, or other associated abnormalities of calcium metabolism. Deficiency of vitamin D has also been linked to a number of other conditions, including developmental delay and, possibly, type 1 diabetes mellitus in childhood and cardiovascular disease later in life.³⁶

Newborns should consume 400 IU/d of supplemental vitamin D to prevent deficiency and its clinical manifestation, rickets, or other associated abnormalities of calcium metabolism.

In the first months of life, few infants who are solely formula-fed will consume a full liter daily; for them, supplementation of vitamin D for at least one month should be prescribed.³⁵ For breastfed infants, high-dosage maternal vitamin D supplementation may be effective, precluding infant oral vitamin D supplementation³⁶; however, neither the AAFP nor the AAP has issued guidance promoting maternal supplementation in lieu of direct oral infant supplementation.³⁷

Jaundice prevention—and recognition

An elevated bilirubin level is seen in most newborns in the first days of life because of increased production and decreased clearance of bilirubin—a condition known as physiologic jaundice. Conditions that aggravate physiologic hyperbilirubinemia include inborn errors of metabolism, ABO blood-group incompatibility, hemoglobin variants, and inflammatory states such as sepsis. It is important to distinguish physiologic jaundice from exaggerated physiologic and pathologic forms of hyperbilirubinemia; the latter is a medical emergency. Before we get to that, a word about prevention.

Prevention. Because poor caloric intake and dehydration are associated with hyperbilirubinemia, physicians should advise breastfeeding mothers to feed their newborn at least 8 to 12 times daily during the first week of life. However, routine supplementation of liquids other than breast milk should be discouraged in newborns who are not dehydrated.³⁸

The total serum bilirubin level should be tested in every newborn who has clinical jaundice in the first 24 hours of life.

All pregnant women should be tested for ABO and Rh (D) blood types and undergo serum screening for isoimmune antibodies. Randomized trials have demonstrated that the incidence of significant hyperbilirubinemia can be reduced if, for Rh-negative mothers and those who did not undergo prenatal blood-group testing, infant cord blood is tested for 1) ABO and Rh (D) types and 2) direct antibody (Coombs’ test).^38,39

Screening and assessment. It is recommended that all newborns be screened for jaundice before discharge by 1) assessment of clinical risk factors or 2) testing of transcutaneous bilirubin (TcB) or total serum bilirubin (TSB). Furthermore, because evidence shows that treating clinical jaundice can improve outcomes and rehospitalization, TSB should be measured in every newborn who has clinical jaundice in the first 24 hours of life. Measurement of TcB or TSB should also be performed on all infants in whom there appears to be clinical jaundice that is excessive for age.^38,39

During routine clinical care, TcB measurement provides a reasonable estimate of the TSB level in healthy newborns at levels less than 15 mg/dL,⁴⁰ although TcB testing might not be available in the outpatient office. An AAP management algorithm can help determine when a newborn should be seen for outpatient follow-up based on risk of hyperbilirubinemia; higher-risk newborns should be reevaluated in 24 hours.⁹ Outpatient visual assessment of jaundice for cephalocaudal progression—in a well-lit room, with a fully undressed newborn—correlates well with TSB test results. However, visual assessment should not be used alone to screen for hyperbilirubinemia; recent studies have demonstrated that such assessment lacks clinical reliability.⁴⁰

Laboratory assessment. All bilirubin levels should be interpreted based on the newborn’s age in hours. The need for phototherapy should be based on the zone (low, low-intermediate, high-intermediate, or high, as categorized in the AAP nomogram³⁸ in which the TSB level falls. TABLE 4^38-40 provides recommendations for laboratory studies based on risk factors. Standard curves for risk stratification have been developed by the AAP.^37,38

Treatment. Decisions to initiate treatment should be based on the AAP algorithm.³⁸ When initiating phototherapy, precautions include ensuring adequate fluid intake, patching eyes, and monitoring temperature. Phototherapy can generally be stopped when the TSB level falls by 5 mg/dL or below 14 mg/dL. Home phototherapy, using a fiberoptic blanket, for uncomplicated jaundice (in carefully selected newborns with reliable parents) allows continued breastfeeding and bonding with the family, and can significantly decrease the rate of rehospitalization for infants older than 34 weeks.⁴¹

Breastfeeding is often associated with a higher bilirubin level than is seen in infants fed formula exclusively; increasing the frequency of feeding usually reduces the bilirubin level. So-called breast-milk jaundice is a delayed, but common, form of jaundice that is usually diagnosed in the second week of life and peaks by the end of the second week, resolving gradually over one to 4 months. If evaluation reveals no pathologic source, breastfeeding can generally be continued. Temporary discontinuation of breastfeeding to consider a diagnosis of breast-milk jaundice or other reasons for an elevated bilirubin level increases the risk of breastfeeding failure and is usually unnecessary.^12,37,39

Fever—a full work-up, thorough history are key

Concern about serious bacterial illness (SBI) makes the evaluation of fever critical for those who care for newborns. Many studies have attempted to identify which newborns might be able to be cared for safely as outpatients to prevent unnecessary testing and antibiotics.^5,42 Regrettably, SBI in infants remains difficult to predict, and protocols that have been developed may miss as many as 1 of every 10 newborns who has SBI.⁴³ Initial management of all infants 28 days old or younger with fever must therefore include a full work-up, including lumbar puncture and empiric antibiotics.⁴⁴

Evaluation. When an infant younger than 28 days has a fever, the physician should first verify that the temperature was taken rectally and how it was documented. In an infant who has a history of prematurity, it is crucial to correct for chronological age when deciding on proper evaluation.

Additional important findings in the history include a significant change in behavior, associated symptoms, and exposure to sick contacts. The maternal and birth history, including prolonged rupture of membranes, colonization with group B Streptococcus, administration of antibiotics at delivery, and genital herpes simplex virus (HSV) infection may suggest a cause for fever.⁴⁵

The evaluation of fever might include the white blood cell (WBC) count, blood culture, measurement of markers of inflammation, urine studies, lumbar puncture, stool culture, and chest radiograph. Traditionally, the WBC count has been utilized as a standard marker for sepsis, although it has a low sensitivity and specificity for SBI, especially in newborns.⁴⁶ Blood cultures should be obtained routinely in the newborn with fever, and before antibiotics are administered in older infants.

Procalcitonin (PCT; a calcitonin precursor) and the inflammatory marker C-reactive protein (CRP) have been shown, in several large studies, to have relatively high sensitivity and specificity for SBI; measurement of these constituents may enhance detection of serious illness.^46-49 In a large study of 2047 febrile infants older than 30 months, the PCT level was determined to be more accurate than the CRP level, the WBC count, and the absolute neutrophil count in predicting SBI.^48,49 PCT shows the most promise for preventing a full fever work-up and empiric antibiotics. It has not yet been widely translated into practice, however, because of a lack of clear guidance on how to combine PCT levels with other laboratory markers and clinical decision-making.^48-50

Urinalysis (UA) should be obtained for all newborns who present with fever. Traditionally, it was recommended that urine should be cultured for all newborns with fever; however, more recent data show that the initial urinalysis is much more sensitive than once thought. In a study, UA was positive (defined as pyuria or a positive leukocyte esterase test, or both) in all but 1 of 203 infants who had bacteremic UTI (sensitivity, 99.5%).⁵¹

The procalcitonin level was determined to be more accurate than the C-reactive protein level, the white blood cell count, and the absolute neutrophil count in predicting serious bacterial illness.

Stool culture is necessary in newborns only when they present with blood or mucus in diarrhea. Lumbar puncture should be performed in all febrile newborns and all newborns for whom empiric antibiotics have been prescribed.^43,44 A chest radiograph may be useful in diagnosis when a newborn has any other sign of pulmonary disease: respiratory rate >50/min, retractions, wheezing, grunting, stridor, nasal flaring, cough, and positive findings on lung examination.^43,44

Treatment. Management for all newborns who have a rectal temperature ≥38° C includes admission to the hospital and empiric antibiotics; guidance is based primarily on expert consensus. Common pathogens for SBI include group B Strep, Escherichia coli, Enterococcus spp., and Listeria monocytogenes.^43,44 Empiric antibiotics, including ampicillin (to cover L monocytogenes) and cefotaxime or gentamicin should be started immediately after sending for blood, urine, and cerebrospinal fluid (CSF) cultures.^43-45

Management for all newborns who have rectal temperature ≥38° C includes admission to the hospital and empiric antibiotics.

All infants who are ill-appearing or have vesicles, seizures, or a maternal history of genital HSV infection should also be started on empiric acyclovir. Vesicles should be cultured and CSF should be sent for HSV DNA polymerase chain reaction before acyclovir is administered.^43-45

Sudden infant death syndrome: Steps to take to minimize risk

SIDS is defined as the sudden death of a child younger than 1 year that remains unexplained after a thorough case investigation and comprehensive review of the clinical history. The risk of SIDS in the United States is less than 1 for every 1000 live births; incidence peaks between 2 and 4 months of age.⁵² In the United States, SIDS and other sleep-related infant deaths, such as strangulation in bed or accidental suffocation, account for more than 4000 deaths a year.⁵³ The incidence of SIDS declined markedly after the “Back to Sleep” campaign was launched in 2003, but has leveled off since 2005.^53-55

Numerous risk factors for SIDS have been identified, including maternal factors (young maternal age, maternal smoking during pregnancy, late or no prenatal care) and infant and environmental factors (prematurity, low birth weight, male gender, prone sleeping position, sleeping on a soft surface or with bedding accessories, bed-sharing (ie, sleeping in the parents’ bed), and overheating. In many cases, the risk factors are modifiable; sleeping in the prone position is the most meaningful modifiable risk factor.

Home monitors have not been proven to reduce the incidence of SIDS and are not recommended for that purpose.

To minimize the risk for SIDS, parents should be educated on the risk factors—prenatally as well as at each infant well visit. Home monitors have not been proven to reduce the incidence of SIDS and are not recommended for that purpose.^54-57 Although evidence is strongest for supine positioning as a preventive intervention for SIDS, other evidence-based recommendations include use of a firm sleep surface; breastfeeding; use of a pacifier; room-sharing with parents without bed-sharing; routine immunization; avoidance of overheating; avoiding falling asleep with the infant on a chair or couch; and avoiding exposure to tobacco smoke, alcohol, and drugs of abuse.^55,56 A recent systematic review showed that large-scale community interventions and education campaigns can play a significant role in parental and community adoption of safe sleep recommendations; however, families and communities rarely exhibit complete adherence to safe sleep practices.⁵⁷

Other concerns in the first month of life and immediately beyond

In TABLE 5,² we list additional common newborn problems not reviewed in the text of this article and summarize evidence-based treatment strategies.

CORRESPONDENCE
Scott Hartman, MD, Associate Professor, Department of Family Medicine, University of Rochester Medical Center, 777 South Clinton Avenue, Rochester, NY 14620; [email protected].

Acknowledgement
We thank Nancy Phillips for her assistance in the preparation of this article.

Caring for a newborn can be a source of joy for family physicians (FPs). In this article, we examine care provided in the first month of life, including a thorough physical examination, safe hospital discharge procedures, assessment of neonatal feeding, evaluation of jaundice and fever, and prevention of sudden infant death syndrome (SIDS). In addition, we describe how FPs can support women of childbearing age between pregnancies, with the goal of reducing the risk of adverse outcomes in future pregnancies. (See “Your role in risk assessment and interventions during the interconception period.”)

Before parents leave the hospital with their newborn, it is essential that they receive written and verbal counseling on important issues in neonatal care. A discharge checklist can help make sure all topics have been covered.¹ A hearing screen and pulse oximetry before discharge are required for all newborns in most states, in addition to important preventive counseling for parents. TABLE 1² and TABLE 2² summarize important newborn physical exam findings and common skin conditions. Parents should be given additional written information regarding prevention of SIDS and proper use of car seats.

Hospital physicians should assess maternal medical and psychosocial readiness for discharge. Through shared decision-making with the newborn’s parents, physicians should create a plan for outpatient follow-up. Assessment through a physician home visit can provide safe and effective care similar to what is provided at a visit to an office medical practice.^3-7 A follow-up appointment should be made 2 to 5 days before discharge, preferably connecting the newborn to a medical home where comprehensive health care services are offered.^1,5,6,8

Age, gestational age, risk factors for hyperbilirubinemia, and the timing and level of bilirubin testing should be considered when establishing a follow-up interval. Most newborns who are discharged before 72 hours of age should have a follow-up visit in 2 days; a newborn who has a recognized risk factor for a health problem should be seen sooner. Newborns in the “low-risk zone” (ie, no recognized risk factors) should be seen based on age at discharge or need for breastfeeding support.⁹

Tracking baby’s weight, ensuring proper feeding

A newborn who is discharged at 24 hours of life, or sooner, should be seen in the office within 2 days of discharge to 1) ensure that he (she) is getting proper nutrition and 2) monitor his weight^1,3,5 (TABLE 3^10-13). All newborns should be seen again at 2 weeks of life, with additional visits more frequently if there are concerns about nutrition.¹

Recording an accurate weight is critical; the newborn should be weighed completely undressed and without a diaper. Healthy newborns can safely lose up to 10% of birth weight within the first week of life; they should be back to their birth weight by approximately 2 weeks of life.^10,11 A healthy newborn loses approximately 0.5 to 1 oz a day;¹¹ greater than 10% loss of birth weight should trigger a thorough medical work-up and feeding assessment.

Breastfeeding. For breastfeeding mothers, physicians should recommend on-demand feeding or a feeding at least every 2 or 3 hours. Adequate intake in breastfed infants can be intimidating for new parents to monitor, but they can use a written chart or any of several available smartphone applications to document length and timing of feeds and frequency of urination and bowel movements. By the fifth day of life, a newborn should be having at least 6 voids and 3 or 4 stools a day.^10-12

In addition, physicians can counsel parents on what to look for—in the mother and the newborn—to confirm that breastfeeding is successful, with adequate nutritional intake (TABLE 3^10-13). Physicians should recommend against providing a pacifier to breastfeeding infants during the first several weeks of life—or until breastfeeding is well established (usually at 3 or 4 weeks of age). The World Health Organization (WHO) recommends against providing bottles, pacifiers, and artificial nipples to breastfeeding newborns.¹⁴ Liquids other than colostrum or breast milk should not be given unless there is a documented medical need, such as inadequate weight gain or feeding difficulty.¹⁵ If the newborn experiences early latch difficulties, supplementation with expressed breast milk is preferable to supplementation with formula. Assistance from a trained lactation consultant is a key element in the support of the breastfeeding dyad.^11,12,16

Breastfeeding optimizes development of the newborn’s immune system, thus bolstering disease prevention; it also assists with maternal postpartum weight loss and psychological well-being. Exclusively or primarily formula-fed newborns are at increased risk of gastrointestinal, ear, and respiratory infections throughout infancy and childhood; type 1 diabetes mellitus; asthma; childhood and adult obesity; and leukemia.^17,18 Mothers who feed their newborn primarily formula increase their own risk of obesity, type 2 diabetes mellitus, ovarian and breast cancer, and depression.^17-22

Infant feeding is a personal and family choice but, in the absence of medical contraindications—such as maternal human immunodeficiency virus infection and galactosemia—exclusive breastfeeding should be recommended.^17,18 FPs are well suited to support the mother–infant breastfeeding dyad in the neonatal period, based on expert recommendations. Specifically, the American Academy of Family Physicians (AAFP) and American Academy of Pediatrics (AAP) recommend that all infants be exclusively breastfed for the first 6 months of life and continue some breastfeeding through the first year or longer.^17,18 WHO recommends breastfeeding until 24 months of age—longer if mother and infant want to, unless breastfeeding is contraindicated.^14,17,18

Physicians should provide up-to-date information to parents regarding the risks and benefits of feeding choices. Support for breastfeeding mothers postnatally has been shown to be helpful in lengthening the time of exclusive breastfeeding.¹² Certain medications pass through breast milk, and updated guides to medication cautions can be found at the National Institutes of Health’s LACTMED Web site (https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm).¹³ In many cases, when a maternal medication is incompatible with breastfeeding, the family physician can consider substituting another appropriate medication that is compatible.

Physician recommendation and support improves the rate of breastfeeding, but many mother–infant dyads require additional support to maintain breastfeeding for the recommended duration; such support can take the form of a certified lactation consultant or counselor, doula, or peer counselor.^23-25 Although structured breastfeeding education in the antenatal period has been demonstrated to be effective in improving breastfeeding initiation and duration, recent research shows that support groups and assistance from the professionals previously mentioned also improve the breastfeeding rate.^26-28

Adequate intake in breastfed infants can be intimidating for new parents to monitor, but they can use a written chart or any of several available smartphone applications.

The AAFP recommends that FPs’ offices adopt specific, evidence-based practices that can have an impact on breastfeeding initiation and duration. Such practices include phone and in-person breastfeeding support from nursing staff and removing any formula advertisements from the office.¹⁷

Formula feeding. When parents choose formula feeding, most infants tolerate cow’s milk-based formula.²⁹ For healthy term infants, differences between brands of formula are generally insignificant. Soy-protein formulas are of value only if lactose intolerance is strongly suspected, such as after prolonged episodes of loose stools. Even then, intolerance is usually transient and cow’s milk-based formula can be tried again in 2 to 4 weeks.

Physicians should recommend 20 kcal/oz of iron-fortified formula for infants who are fed formula—except in special circumstances, such as premature newborns, who may require a more calorie-dense formula. Parents should pay special attention to the manufacturer’s instructions for mixing formula with water because overdilution can cause hyponatremia. Typical volume for newborns should be at least 15 to 30 mL/feed for the first few days; newborns should not go more than 4 hours between feedings. Within the first week, newborns will start taking 60 to 90 mL/feed and increase that gradually to approximately 120 mL/feed by the end of the first month of life. On average, infants need a little more than 100 kcal/kg of body weight a day; for a 3.5-kg infant, that is at least 500 mL of formula over the course of a day.^17,22

Because formula does not contain fluoride, physicians should recommend that parents mix formula that is provided as a powder with fluoridated water. Low-iron formula offers no advantage; feeding with it will cause iron-deficiency anemia in most infants.

When tongue-tie interferes with feeding

Tongue-tie—or ankyloglossia, an atypically short or thick lingual frenulum—is present in 3% to 16% of all births. The condition can make breastfeeding difficult; result in poor neonatal weight gain; and cause sore nipples in 25% to 44% of cases.³⁰ Once tongue-tie is noted, the physician should talk to the mother about the history of feeding success, including whether her nipples are sore and whether the newborn is having difficulty feeding (ie, transferring milk). The Hazelbaker Assessment Tool for Lingual Frenulum Function and the simpler Bristol Tongue Assessment Tool can be used to assess the severity of tongue-tie.^30-35

When tongue-tie interferes with feeding, a physician who is not trained in treatment can refer the mother and infant to a specialist in the community. Frenotomy has been used for many years as a treatment for tongue-tie; improvement in nipple pain and the mother-reported breastfeeding score have been reported postoperatively in several studies.^30-33

Ensure proper vitamin D intake through supplementation

Newborns should consume 400 IU/d of supplemental vitamin D to prevent deficiency and its clinical manifestation, rickets, or other associated abnormalities of calcium metabolism. Deficiency of vitamin D has also been linked to a number of other conditions, including developmental delay and, possibly, type 1 diabetes mellitus in childhood and cardiovascular disease later in life.³⁶

Newborns should consume 400 IU/d of supplemental vitamin D to prevent deficiency and its clinical manifestation, rickets, or other associated abnormalities of calcium metabolism.

In the first months of life, few infants who are solely formula-fed will consume a full liter daily; for them, supplementation of vitamin D for at least one month should be prescribed.³⁵ For breastfed infants, high-dosage maternal vitamin D supplementation may be effective, precluding infant oral vitamin D supplementation³⁶; however, neither the AAFP nor the AAP has issued guidance promoting maternal supplementation in lieu of direct oral infant supplementation.³⁷

Jaundice prevention—and recognition

An elevated bilirubin level is seen in most newborns in the first days of life because of increased production and decreased clearance of bilirubin—a condition known as physiologic jaundice. Conditions that aggravate physiologic hyperbilirubinemia include inborn errors of metabolism, ABO blood-group incompatibility, hemoglobin variants, and inflammatory states such as sepsis. It is important to distinguish physiologic jaundice from exaggerated physiologic and pathologic forms of hyperbilirubinemia; the latter is a medical emergency. Before we get to that, a word about prevention.

Prevention. Because poor caloric intake and dehydration are associated with hyperbilirubinemia, physicians should advise breastfeeding mothers to feed their newborn at least 8 to 12 times daily during the first week of life. However, routine supplementation of liquids other than breast milk should be discouraged in newborns who are not dehydrated.³⁸

The total serum bilirubin level should be tested in every newborn who has clinical jaundice in the first 24 hours of life.

All pregnant women should be tested for ABO and Rh (D) blood types and undergo serum screening for isoimmune antibodies. Randomized trials have demonstrated that the incidence of significant hyperbilirubinemia can be reduced if, for Rh-negative mothers and those who did not undergo prenatal blood-group testing, infant cord blood is tested for 1) ABO and Rh (D) types and 2) direct antibody (Coombs’ test).^38,39

Screening and assessment. It is recommended that all newborns be screened for jaundice before discharge by 1) assessment of clinical risk factors or 2) testing of transcutaneous bilirubin (TcB) or total serum bilirubin (TSB). Furthermore, because evidence shows that treating clinical jaundice can improve outcomes and rehospitalization, TSB should be measured in every newborn who has clinical jaundice in the first 24 hours of life. Measurement of TcB or TSB should also be performed on all infants in whom there appears to be clinical jaundice that is excessive for age.^38,39

During routine clinical care, TcB measurement provides a reasonable estimate of the TSB level in healthy newborns at levels less than 15 mg/dL,⁴⁰ although TcB testing might not be available in the outpatient office. An AAP management algorithm can help determine when a newborn should be seen for outpatient follow-up based on risk of hyperbilirubinemia; higher-risk newborns should be reevaluated in 24 hours.⁹ Outpatient visual assessment of jaundice for cephalocaudal progression—in a well-lit room, with a fully undressed newborn—correlates well with TSB test results. However, visual assessment should not be used alone to screen for hyperbilirubinemia; recent studies have demonstrated that such assessment lacks clinical reliability.⁴⁰

Laboratory assessment. All bilirubin levels should be interpreted based on the newborn’s age in hours. The need for phototherapy should be based on the zone (low, low-intermediate, high-intermediate, or high, as categorized in the AAP nomogram³⁸ in which the TSB level falls. TABLE 4^38-40 provides recommendations for laboratory studies based on risk factors. Standard curves for risk stratification have been developed by the AAP.^37,38

Treatment. Decisions to initiate treatment should be based on the AAP algorithm.³⁸ When initiating phototherapy, precautions include ensuring adequate fluid intake, patching eyes, and monitoring temperature. Phototherapy can generally be stopped when the TSB level falls by 5 mg/dL or below 14 mg/dL. Home phototherapy, using a fiberoptic blanket, for uncomplicated jaundice (in carefully selected newborns with reliable parents) allows continued breastfeeding and bonding with the family, and can significantly decrease the rate of rehospitalization for infants older than 34 weeks.⁴¹

Breastfeeding is often associated with a higher bilirubin level than is seen in infants fed formula exclusively; increasing the frequency of feeding usually reduces the bilirubin level. So-called breast-milk jaundice is a delayed, but common, form of jaundice that is usually diagnosed in the second week of life and peaks by the end of the second week, resolving gradually over one to 4 months. If evaluation reveals no pathologic source, breastfeeding can generally be continued. Temporary discontinuation of breastfeeding to consider a diagnosis of breast-milk jaundice or other reasons for an elevated bilirubin level increases the risk of breastfeeding failure and is usually unnecessary.^12,37,39

Fever—a full work-up, thorough history are key

Concern about serious bacterial illness (SBI) makes the evaluation of fever critical for those who care for newborns. Many studies have attempted to identify which newborns might be able to be cared for safely as outpatients to prevent unnecessary testing and antibiotics.^5,42 Regrettably, SBI in infants remains difficult to predict, and protocols that have been developed may miss as many as 1 of every 10 newborns who has SBI.⁴³ Initial management of all infants 28 days old or younger with fever must therefore include a full work-up, including lumbar puncture and empiric antibiotics.⁴⁴

Evaluation. When an infant younger than 28 days has a fever, the physician should first verify that the temperature was taken rectally and how it was documented. In an infant who has a history of prematurity, it is crucial to correct for chronological age when deciding on proper evaluation.

Additional important findings in the history include a significant change in behavior, associated symptoms, and exposure to sick contacts. The maternal and birth history, including prolonged rupture of membranes, colonization with group B Streptococcus, administration of antibiotics at delivery, and genital herpes simplex virus (HSV) infection may suggest a cause for fever.⁴⁵

The evaluation of fever might include the white blood cell (WBC) count, blood culture, measurement of markers of inflammation, urine studies, lumbar puncture, stool culture, and chest radiograph. Traditionally, the WBC count has been utilized as a standard marker for sepsis, although it has a low sensitivity and specificity for SBI, especially in newborns.⁴⁶ Blood cultures should be obtained routinely in the newborn with fever, and before antibiotics are administered in older infants.

Procalcitonin (PCT; a calcitonin precursor) and the inflammatory marker C-reactive protein (CRP) have been shown, in several large studies, to have relatively high sensitivity and specificity for SBI; measurement of these constituents may enhance detection of serious illness.^46-49 In a large study of 2047 febrile infants older than 30 months, the PCT level was determined to be more accurate than the CRP level, the WBC count, and the absolute neutrophil count in predicting SBI.^48,49 PCT shows the most promise for preventing a full fever work-up and empiric antibiotics. It has not yet been widely translated into practice, however, because of a lack of clear guidance on how to combine PCT levels with other laboratory markers and clinical decision-making.^48-50

Urinalysis (UA) should be obtained for all newborns who present with fever. Traditionally, it was recommended that urine should be cultured for all newborns with fever; however, more recent data show that the initial urinalysis is much more sensitive than once thought. In a study, UA was positive (defined as pyuria or a positive leukocyte esterase test, or both) in all but 1 of 203 infants who had bacteremic UTI (sensitivity, 99.5%).⁵¹

The procalcitonin level was determined to be more accurate than the C-reactive protein level, the white blood cell count, and the absolute neutrophil count in predicting serious bacterial illness.

Stool culture is necessary in newborns only when they present with blood or mucus in diarrhea. Lumbar puncture should be performed in all febrile newborns and all newborns for whom empiric antibiotics have been prescribed.^43,44 A chest radiograph may be useful in diagnosis when a newborn has any other sign of pulmonary disease: respiratory rate >50/min, retractions, wheezing, grunting, stridor, nasal flaring, cough, and positive findings on lung examination.^43,44

Treatment. Management for all newborns who have a rectal temperature ≥38° C includes admission to the hospital and empiric antibiotics; guidance is based primarily on expert consensus. Common pathogens for SBI include group B Strep, Escherichia coli, Enterococcus spp., and Listeria monocytogenes.^43,44 Empiric antibiotics, including ampicillin (to cover L monocytogenes) and cefotaxime or gentamicin should be started immediately after sending for blood, urine, and cerebrospinal fluid (CSF) cultures.^43-45

Management for all newborns who have rectal temperature ≥38° C includes admission to the hospital and empiric antibiotics.

All infants who are ill-appearing or have vesicles, seizures, or a maternal history of genital HSV infection should also be started on empiric acyclovir. Vesicles should be cultured and CSF should be sent for HSV DNA polymerase chain reaction before acyclovir is administered.^43-45

Sudden infant death syndrome: Steps to take to minimize risk

SIDS is defined as the sudden death of a child younger than 1 year that remains unexplained after a thorough case investigation and comprehensive review of the clinical history. The risk of SIDS in the United States is less than 1 for every 1000 live births; incidence peaks between 2 and 4 months of age.⁵² In the United States, SIDS and other sleep-related infant deaths, such as strangulation in bed or accidental suffocation, account for more than 4000 deaths a year.⁵³ The incidence of SIDS declined markedly after the “Back to Sleep” campaign was launched in 2003, but has leveled off since 2005.^53-55

Numerous risk factors for SIDS have been identified, including maternal factors (young maternal age, maternal smoking during pregnancy, late or no prenatal care) and infant and environmental factors (prematurity, low birth weight, male gender, prone sleeping position, sleeping on a soft surface or with bedding accessories, bed-sharing (ie, sleeping in the parents’ bed), and overheating. In many cases, the risk factors are modifiable; sleeping in the prone position is the most meaningful modifiable risk factor.

Home monitors have not been proven to reduce the incidence of SIDS and are not recommended for that purpose.

To minimize the risk for SIDS, parents should be educated on the risk factors—prenatally as well as at each infant well visit. Home monitors have not been proven to reduce the incidence of SIDS and are not recommended for that purpose.^54-57 Although evidence is strongest for supine positioning as a preventive intervention for SIDS, other evidence-based recommendations include use of a firm sleep surface; breastfeeding; use of a pacifier; room-sharing with parents without bed-sharing; routine immunization; avoidance of overheating; avoiding falling asleep with the infant on a chair or couch; and avoiding exposure to tobacco smoke, alcohol, and drugs of abuse.^55,56 A recent systematic review showed that large-scale community interventions and education campaigns can play a significant role in parental and community adoption of safe sleep recommendations; however, families and communities rarely exhibit complete adherence to safe sleep practices.⁵⁷

Other concerns in the first month of life and immediately beyond

In TABLE 5,² we list additional common newborn problems not reviewed in the text of this article and summarize evidence-based treatment strategies.

CORRESPONDENCE
Scott Hartman, MD, Associate Professor, Department of Family Medicine, University of Rochester Medical Center, 777 South Clinton Avenue, Rochester, NY 14620; [email protected].

Acknowledgement
We thank Nancy Phillips for her assistance in the preparation of this article.

THE CASE

A 67-year-old woman presented to our orthopaedic clinic with a 2-year history of bilateral thigh and knee pain and weakness of her legs. She had no history of trauma, and the pain, which was localized to the distal anterior thighs and patellofemoral area, was 7/10 at rest and worse with standing and walking.

Her medical history was significant for osteoporosis (diagnosed in 2004), hypertension, hypothyroidism, gastroesophageal reflux disease, and menopause (age 54). Her original dual-energy x-ray absorptiometry (DEXA) scan did not reveal the presence of any previous fractures. She was started on calcium and vitamin D supplementation and oral alendronate (70 mg once a week). She took alendronate for 4 years until 2008, when it was stopped due to nausea. She was then started on zoledronic acid (5 mg IV annually). She received 5 infusions of zoledronic acid between 2008 and 2013; she did not have an infusion in 2012. Her medication list also included lisinopril, omeprazole, naproxen, cyclobenzaprine, and a multivitamin. She had normal renal function (estimated glomerular filtration rate >60 mL/min/1.73 m²) and she did not drink alcohol or use tobacco.

In the 2 years prior to her visit to our clinic, she had been evaluated by her primary care provider, an orthopedic sports medicine specialist, 2 spinal surgeons, and a physiatrist. She had also undergone 30 physical therapy sessions. Bilateral femur radiographs (FIGURE 1) ordered by her orthopedist 6 months earlier demonstrated no evidence of fracture, but did show an incidental enchondroma in the right distal diaphysis and bilateral thickening of the lateral femoral cortices.

Finally, with no relief in sight, her obstetrician suggested that she might be experiencing myalgias attributable to her zoledronic acid infusions. She was subsequently referred to us.

The physical exam revealed a thin female with a body mass index of 21. She had mild tenderness on palpation of the bilateral anterior thighs and knees. There was no pain with hip or knee range of motion and minimal pain in the bilateral lower extremities with axial loading. The patient had normal sensation, did not have an antalgic gait, and exhibited 5/5 strength bilaterally in all distributions of the lower extremities.

THE DIAGNOSIS

Due to continued pain despite negative x-rays, we obtained a 3-phase bone scan of the pelvis and bilateral femurs. Delayed images showed moderately increased activity in the mid-right and mid-left lateral femoral diaphyses at the cortex and confirmed stress fractures (FIGURE 2).

DISCUSSION

Bisphosphonates are considered first-line therapy for osteoporosis, according to current evidence-based guidelines.¹ These medications inhibit osteoclast activity and can bind to the bone for more than 10 years.^2,3 (In women with bone mineral density scores ≤ –2.5, the number needed to treat is 21.^1,4)

If radiographs are negative, but suspicion remains, an MRI or a bone scan should be ordered.

Patients taking bisphosphonates, however, are susceptible to atypical femoral fractures (AFFs), which are stress or insufficiency fractures associated with minimal or no trauma.⁵ The pathophysiology remains unknown at this time, but AFFs may result from changes in bone remodeling that occur when a bone experiences repetitive microtrauma, leading to lateral cortical thickening of the femur.^6,7 Incidence of AFFs in patients taking bisphosphonates is estimated to be between 3.2 and 50 cases per 100,000 person-years; however, this risk increases to approximately 100 per 100,000 person-years with long-term use.⁵ Other risk factors include low body weight, advancing age, rheumatoid arthritis, long-term glucocorticoid therapy, and excessive alcohol and cigarette use.⁸

Symptoms typically include unilateral or bilateral prodromal pain with a sharp or achy character that is localized to the mid-thigh, upper thigh, or groin.⁹ If an AFF is suspected, we recommend performing a bilateral exam and obtaining radiographs.

If characteristic features are found (eg, signs of focal cortical thickening or beaking) and pain arises in the opposite limb, obtain a radiograph of the contralateral femur. If radiographs are negative but suspicion remains, order magnetic resonance imaging or a bone scan, to identify a cortical fracture line, bone and marrow edema, or hyperemia.⁵

Begin treatment by discontinuing bisphosphonates

Upon identification of an AFF, discontinue bisphosphonates and initiate calcium and vitamin D supplementation.⁵ Prophylactic surgical fixation may also be necessary to accelerate healing and prevent fracture propagation and further pain.

Our patient. Due to the longevity of the symptoms and the bilateral stress fractures noted on the bone scan, our patient chose to proceed with intramedullary nailing of the bilateral femurs (FIGURES 3 and 4). On postop Day 1, she was able to ambulate using a walker and to participate in bilateral weight-bearing (as tolerated). She was discharged to a skilled nursing facility, where she progressed to full weight-bearing without aid. On follow-up (one year postop), the patient reported no residual leg pain and was able to work out 5 days per week. Radiographs of her femurs demonstrated healed fractures and stable position of the intramedullary nails.

THE TAKEAWAY

An increased suspicion for AFFs due to bisphosphonate use can lead to earlier diagnosis and decreased morbidity for patients. Use of femoral imaging can promote detection and reduce financial burden.

To help prevent AFFs from occurring, we recommend reevaluating the need for continued bisphosphonate therapy after 2 to 5 years of treatment. Continued surveillance is also advisable throughout the duration of their use.

ACKNOWLEDGMENT
The authors wish to acknowledge Dr. Maurice Manring for his help in preparing this manuscript.

THE CASE

A 67-year-old woman presented to our orthopaedic clinic with a 2-year history of bilateral thigh and knee pain and weakness of her legs. She had no history of trauma, and the pain, which was localized to the distal anterior thighs and patellofemoral area, was 7/10 at rest and worse with standing and walking.

Her medical history was significant for osteoporosis (diagnosed in 2004), hypertension, hypothyroidism, gastroesophageal reflux disease, and menopause (age 54). Her original dual-energy x-ray absorptiometry (DEXA) scan did not reveal the presence of any previous fractures. She was started on calcium and vitamin D supplementation and oral alendronate (70 mg once a week). She took alendronate for 4 years until 2008, when it was stopped due to nausea. She was then started on zoledronic acid (5 mg IV annually). She received 5 infusions of zoledronic acid between 2008 and 2013; she did not have an infusion in 2012. Her medication list also included lisinopril, omeprazole, naproxen, cyclobenzaprine, and a multivitamin. She had normal renal function (estimated glomerular filtration rate >60 mL/min/1.73 m²) and she did not drink alcohol or use tobacco.

In the 2 years prior to her visit to our clinic, she had been evaluated by her primary care provider, an orthopedic sports medicine specialist, 2 spinal surgeons, and a physiatrist. She had also undergone 30 physical therapy sessions. Bilateral femur radiographs (FIGURE 1) ordered by her orthopedist 6 months earlier demonstrated no evidence of fracture, but did show an incidental enchondroma in the right distal diaphysis and bilateral thickening of the lateral femoral cortices.

Finally, with no relief in sight, her obstetrician suggested that she might be experiencing myalgias attributable to her zoledronic acid infusions. She was subsequently referred to us.

The physical exam revealed a thin female with a body mass index of 21. She had mild tenderness on palpation of the bilateral anterior thighs and knees. There was no pain with hip or knee range of motion and minimal pain in the bilateral lower extremities with axial loading. The patient had normal sensation, did not have an antalgic gait, and exhibited 5/5 strength bilaterally in all distributions of the lower extremities.

THE DIAGNOSIS

Due to continued pain despite negative x-rays, we obtained a 3-phase bone scan of the pelvis and bilateral femurs. Delayed images showed moderately increased activity in the mid-right and mid-left lateral femoral diaphyses at the cortex and confirmed stress fractures (FIGURE 2).

DISCUSSION

Bisphosphonates are considered first-line therapy for osteoporosis, according to current evidence-based guidelines.¹ These medications inhibit osteoclast activity and can bind to the bone for more than 10 years.^2,3 (In women with bone mineral density scores ≤ –2.5, the number needed to treat is 21.^1,4)

If radiographs are negative, but suspicion remains, an MRI or a bone scan should be ordered.

Patients taking bisphosphonates, however, are susceptible to atypical femoral fractures (AFFs), which are stress or insufficiency fractures associated with minimal or no trauma.⁵ The pathophysiology remains unknown at this time, but AFFs may result from changes in bone remodeling that occur when a bone experiences repetitive microtrauma, leading to lateral cortical thickening of the femur.^6,7 Incidence of AFFs in patients taking bisphosphonates is estimated to be between 3.2 and 50 cases per 100,000 person-years; however, this risk increases to approximately 100 per 100,000 person-years with long-term use.⁵ Other risk factors include low body weight, advancing age, rheumatoid arthritis, long-term glucocorticoid therapy, and excessive alcohol and cigarette use.⁸

Symptoms typically include unilateral or bilateral prodromal pain with a sharp or achy character that is localized to the mid-thigh, upper thigh, or groin.⁹ If an AFF is suspected, we recommend performing a bilateral exam and obtaining radiographs.

If characteristic features are found (eg, signs of focal cortical thickening or beaking) and pain arises in the opposite limb, obtain a radiograph of the contralateral femur. If radiographs are negative but suspicion remains, order magnetic resonance imaging or a bone scan, to identify a cortical fracture line, bone and marrow edema, or hyperemia.⁵

Begin treatment by discontinuing bisphosphonates

Upon identification of an AFF, discontinue bisphosphonates and initiate calcium and vitamin D supplementation.⁵ Prophylactic surgical fixation may also be necessary to accelerate healing and prevent fracture propagation and further pain.

Our patient. Due to the longevity of the symptoms and the bilateral stress fractures noted on the bone scan, our patient chose to proceed with intramedullary nailing of the bilateral femurs (FIGURES 3 and 4). On postop Day 1, she was able to ambulate using a walker and to participate in bilateral weight-bearing (as tolerated). She was discharged to a skilled nursing facility, where she progressed to full weight-bearing without aid. On follow-up (one year postop), the patient reported no residual leg pain and was able to work out 5 days per week. Radiographs of her femurs demonstrated healed fractures and stable position of the intramedullary nails.

THE TAKEAWAY

An increased suspicion for AFFs due to bisphosphonate use can lead to earlier diagnosis and decreased morbidity for patients. Use of femoral imaging can promote detection and reduce financial burden.

To help prevent AFFs from occurring, we recommend reevaluating the need for continued bisphosphonate therapy after 2 to 5 years of treatment. Continued surveillance is also advisable throughout the duration of their use.

ACKNOWLEDGMENT
The authors wish to acknowledge Dr. Maurice Manring for his help in preparing this manuscript.

THE CASE

A 67-year-old woman presented to our orthopaedic clinic with a 2-year history of bilateral thigh and knee pain and weakness of her legs. She had no history of trauma, and the pain, which was localized to the distal anterior thighs and patellofemoral area, was 7/10 at rest and worse with standing and walking.

Her medical history was significant for osteoporosis (diagnosed in 2004), hypertension, hypothyroidism, gastroesophageal reflux disease, and menopause (age 54). Her original dual-energy x-ray absorptiometry (DEXA) scan did not reveal the presence of any previous fractures. She was started on calcium and vitamin D supplementation and oral alendronate (70 mg once a week). She took alendronate for 4 years until 2008, when it was stopped due to nausea. She was then started on zoledronic acid (5 mg IV annually). She received 5 infusions of zoledronic acid between 2008 and 2013; she did not have an infusion in 2012. Her medication list also included lisinopril, omeprazole, naproxen, cyclobenzaprine, and a multivitamin. She had normal renal function (estimated glomerular filtration rate >60 mL/min/1.73 m²) and she did not drink alcohol or use tobacco.

In the 2 years prior to her visit to our clinic, she had been evaluated by her primary care provider, an orthopedic sports medicine specialist, 2 spinal surgeons, and a physiatrist. She had also undergone 30 physical therapy sessions. Bilateral femur radiographs (FIGURE 1) ordered by her orthopedist 6 months earlier demonstrated no evidence of fracture, but did show an incidental enchondroma in the right distal diaphysis and bilateral thickening of the lateral femoral cortices.

Finally, with no relief in sight, her obstetrician suggested that she might be experiencing myalgias attributable to her zoledronic acid infusions. She was subsequently referred to us.

The physical exam revealed a thin female with a body mass index of 21. She had mild tenderness on palpation of the bilateral anterior thighs and knees. There was no pain with hip or knee range of motion and minimal pain in the bilateral lower extremities with axial loading. The patient had normal sensation, did not have an antalgic gait, and exhibited 5/5 strength bilaterally in all distributions of the lower extremities.

THE DIAGNOSIS

Due to continued pain despite negative x-rays, we obtained a 3-phase bone scan of the pelvis and bilateral femurs. Delayed images showed moderately increased activity in the mid-right and mid-left lateral femoral diaphyses at the cortex and confirmed stress fractures (FIGURE 2).

DISCUSSION

Bisphosphonates are considered first-line therapy for osteoporosis, according to current evidence-based guidelines.¹ These medications inhibit osteoclast activity and can bind to the bone for more than 10 years.^2,3 (In women with bone mineral density scores ≤ –2.5, the number needed to treat is 21.^1,4)

If radiographs are negative, but suspicion remains, an MRI or a bone scan should be ordered.

Patients taking bisphosphonates, however, are susceptible to atypical femoral fractures (AFFs), which are stress or insufficiency fractures associated with minimal or no trauma.⁵ The pathophysiology remains unknown at this time, but AFFs may result from changes in bone remodeling that occur when a bone experiences repetitive microtrauma, leading to lateral cortical thickening of the femur.^6,7 Incidence of AFFs in patients taking bisphosphonates is estimated to be between 3.2 and 50 cases per 100,000 person-years; however, this risk increases to approximately 100 per 100,000 person-years with long-term use.⁵ Other risk factors include low body weight, advancing age, rheumatoid arthritis, long-term glucocorticoid therapy, and excessive alcohol and cigarette use.⁸

Symptoms typically include unilateral or bilateral prodromal pain with a sharp or achy character that is localized to the mid-thigh, upper thigh, or groin.⁹ If an AFF is suspected, we recommend performing a bilateral exam and obtaining radiographs.

If characteristic features are found (eg, signs of focal cortical thickening or beaking) and pain arises in the opposite limb, obtain a radiograph of the contralateral femur. If radiographs are negative but suspicion remains, order magnetic resonance imaging or a bone scan, to identify a cortical fracture line, bone and marrow edema, or hyperemia.⁵

Begin treatment by discontinuing bisphosphonates

Upon identification of an AFF, discontinue bisphosphonates and initiate calcium and vitamin D supplementation.⁵ Prophylactic surgical fixation may also be necessary to accelerate healing and prevent fracture propagation and further pain.

Our patient. Due to the longevity of the symptoms and the bilateral stress fractures noted on the bone scan, our patient chose to proceed with intramedullary nailing of the bilateral femurs (FIGURES 3 and 4). On postop Day 1, she was able to ambulate using a walker and to participate in bilateral weight-bearing (as tolerated). She was discharged to a skilled nursing facility, where she progressed to full weight-bearing without aid. On follow-up (one year postop), the patient reported no residual leg pain and was able to work out 5 days per week. Radiographs of her femurs demonstrated healed fractures and stable position of the intramedullary nails.