Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that affects women of childbearing age. Although most pregnancies are successful with reported live birth rates of 85%,

 SLE pregnancies remain high-risk. The challenges posed by such pregnancies arise from increased maternal risk of flares,

 as well as increased fetal risks of intrauterine growth restriction (IUGR), pregnancy loss6 and preterm birth (PTB).

 In this review, we consider what is known about the immunology of lupus in pregnancy as well as the maternal and fetal risks and outcomes. 

It is amazing how little is still known about the immunology of SLE in pregnancy. Gonadal and adrenal steroid hormones are dysregulated in SLE pregnancies.

 In normal pregnancies, estrogen and progesterone stimulate Th2 and inhibit Th1 cytokines, while dehydroepiandrosterone sulfate (DHEA-S) plays an immunosuppressive role. Levels of these three hormones are significantly lower in SLE pregnancies, particularly during the second and third trimesters, possibly due to placental compromise.

In pregnant SLE patients, prolactin levels are elevated in the second trimester and peak in the third trimester.

 High prolactin level correlates with pregnancy disease activity

Cytokine imbalances have also been found in pregnancies complicated by SLE, regardless of whether the disease is clinically active or inactive. Increases in interleukin (IL)-6, a Th2 cytokine, are lower than expected and IL-10, B-cell growth factor, is persistently elevated.

In the PROMISSE Study, overactivation of the complement pathway, detected by increased Bb and SC5b-9 (products of this pathway), was present early in 487 SLE pregnancies when compared with 204 healthy pregnancies.

 Increased Bb and SC5b-9 correlated with adverse pregnancy outcomes, which included fetal/neonatal death, preterm delivery or preeclampsia and/or IUGR.

 In one SLE pregnancy, mutations in complement system regulatory proteins were found.

These proteins are highly expressed on trophoblast membranes and prevent excessive complement activation in uncomplicated pregnancies.

Angiogenic imbalance is present in SLE pregnancies complicated by preeclampsia. In a case-control study using stored serum samples, soluble fms-like tyrosine kinase-1 (sFlt1), an anti-angiogenic factor, was significantly higher in pregnant patients with SLE who had preeclampsia.

 Elevation of sFlt1, as early as 12 to 15 weeks, correlated strongly with adverse pregnancy outcomes.

Given the number and breadth of the immunologic, endocrine, and angiogenic changes in pregnancies complicated by SLE, it is no wonder that they are associated with multiple adverse outcomes. However, these changes have not been integrated in a way that would be useful clinically at the individual patient level.

Lupus-affected pregnancies are at risk for renal flares,

 preeclampsia, cesarean delivery and a twenty-fold increase in maternal mortality.


	Multiple case- control studies have yielded conflicting results regarding the likelihood of flares during pregnancy. While some centers found no difference in flare rates,

others have found increased risk of flare (Table 1)

 in pregnant compared to non-pregnant women with SLE. The differences are likely due to patient selection rather than study design or definition of flare. In particular, studies that included African-Americans, lupus nephritis and women with unplanned pregnancies have shown higher flare rates.

Patients with organ-specific lupus activity during the 6 months prior to conception were more likely to have persistence of, or an increase in, the same type of activity during pregnancy.

 Most of the flares were mild to moderate in intensity

 and manageable with small increases in prednisone. Severe flares constituted only 2% to 20% of flares.

 There has been no overall pattern of timing of flares, with some studies showing flares early

Patients with SLE who have lupus nephritis constitute a special population that has been studied separately. Case-control studies that evaluated risk of flares in lupus nephritis concluded that pregnancy does not increase risk for renal flares. However, the study population included mostly white women in complete or partial remission at time of conception (Table 2).

 Compared to patients without lupus nephritis, pregnant women who have nephritis are at increased risk of renal flare.

Lupus activity (manifested as mild, moderate or severe disease flares) in the months prior to conception is a major predictor of pregnancy activity. Studies with more than one-third of their patients with active disease at conception reported flare rates ranging from 45% to 70%,

 while those with predominantly inactive or stable disease at conception reported flare rates lower than 20%.

In patients with lupus nephritis, renal disease activity prior to or at the time of conception, and shorter renal disease remission duration were predictors of pregnancy flare.

 Renal flares occurred in 5% of pregnancies in women who were in complete remission prior to conception compared to 40% of pregnancies in those who had active renal disease.

 Renal activity within 4 months prior to conception was the strongest predictor.

 Kidney biopsy early in pregnancy is safe and informative in patients with suspected renal flares. In a case series of 11 patients with SLE who underwent kidney biopsy during pregnancy, all but one underwent a change in management as a result of findings on renal biopsy and none had biopsy-related complications.


	Women who have SLE-affected pregnancies are three times more likely to suffer from preeclampsia.

 Reported rates of preeclampsia range from 13% to 35% in lupus-affected pregnancies.

Presence of hypertension is the main predictor of preeclampsia.

 Hypertensive patients are 40 times more likely to have pregnancies complicated by preeclampsia.

 Lupus nephritis is also a predictor, especially when combined with prolonged disease duration (14% per month), previous renal flares (with a relative risk of 10), and active nephritis.

Major fetal complications of pregnancy affected by SLE include pregnancy loss, preterm birth, IUGR, and neonatal lupus.  


	Fetal loss rates for pregnancy complicated by lupus have decreased over the past 40 years, from a mean of 40% to 17%.

 In patients with SLE, pregnancy loss occurs mostly during the first trimester. Attribution of early losses to SLE is often not possible, as early pregnancy losses are also common in the general population. Second-trimester losses are mostly associated with secondary antiphospholipid syndrome (APS).

We have found that proteinuria
	(> 500 mg in a 24-hour urine collection or a urine protein-to-creatinine ratio
	> 0.5 g; OR = 2.1), secondary APS (APS in the setting of another autoimmune disorder; OR = 3.4), hypertension (blood pressure > 140/90 mm Hg; OR = 4.4) and thrombocytopenia (platelet count < 150,000; OR = 3.0) at the first prenatal visit in patients with SLE is predictive of pregnancy loss. We coined the acronym PATH (proteinuria, antiphospholipid syndrome, thrombocytopenia and hypertension) to remember these risk factors.

 Increased lupus disease activity in the first and second trimester,

 particularly when combined with low complement levels

or second-
	trimester positive anti-dsDNA antibodies,

 is associated with higher risk of pregnancy loss.

In our center, only presence of lupus anticoagulant at the first pregnancy visit (not a past history of positivity) predicted loss of that pregnancy.

 Thus, if lupus anticoagulant is positive, we recommend low-dose aspirin and low-molecular-weight heparin.

 In patients with thrombosis due to secondary APS, full anticoagulation is indicated and should be done with unfractionated or low-molecular-weight heparin.

A history of pregnancy loss in the first pregnancy is not a predictor of poor outcomes in future pregnancies.

 In an Australian cohort, 90% of women with SLE and a history of first pregnancy loss had a live-born infant, with no recurrence of perinatal death.


	PTB is the most frequent adverse pregnancy outcome in SLE,

 with a reported incidence of approximately 50%.

 PTB can be spontaneous, such as preterm labor or premature rupture of membranes (PROM), or indicated for maternal or fetal complications such as preeclampsia, IUGR or fetal distress. 

Maternal hypertension is an important predictor of PTB.

 In the Hopkins study, mean diastolic blood pressure correlated with preterm delivery.

 Use of low-dose aspirin therapy was not predictive of better outcome, but instead was predictive of increased PTB,

 likely due to a clinician sensing that the patient was already at high risk.

Disease activity, particularly in the second trimester and when combined with hypocomplementemia or anti-dsDNA antibodies, is a risk factor for PTB.

 In the Hopkins cohort, 45% of patients who delivered preterm had a high physician global assessment of disease activity and 70% were on 20 mg or more of prednisone.

 Active, but not quiescent lupus nephritis during pregnancy (defined as achievement of 50% reduction in urine protein/creatinine ratio 4 months prior to conception)  is associated with a higher incidence of PTB (46.3% compared to 25.9%, respectively).

Low estradiol, elevated ferritin and elevated uric acid

 levels at mid-gestation and maternal serum alpha-fetoprotein (AFP) levels

 have been found to be potential markers of subsequent PTB.

In the Hopkins cohort, PROM occurred in 40% of preterm SLE pregnancies and was also common in term SLE pregnancies.

 Occurrence of PROM did not correlate with disease activity, prednisone use, or serologic tests. In the same cohort, preeclampsia or pregnancy-induced hypertension was the reason for PTB in 32%, while spontaneous premature labor occurred in only 11%.

IUGR affects 20% to 30% of pregnancies complicated by SLE.

 Mean birth weight was significantly less for infants born to mothers with SLE than mothers without SLE

. This effect became more marked the longer the gestational period, suggesting that IUGR simply becomes worse as the pregnancy progresses.

Despite the fact that infants of mothers with SLE are more likely to be premature and to have IUGR, they tend to do well.

 Fewer than 2% had an Apgar score below 7.

 Risk of neonatal intensive care unit admission, however, was three times higher in infants born to mothers with SLE.


	Neonatal lupus consists of neonatal lupus rash or congenital heart block due to transplacental transfer of anti-Ro and anti-La antibodies. The rash usually resolves by about 6 months. Cardiac manifestations, including heart block and cardiomyopathy, are associated with 20% mortality and 60% rate of permanent cardiac pacing.

 Anti-Ro-positive women without previously affected pregnancies have a 2% estimated risk of  congenital heart block.

 The rate of congenital heart block when a previous pregnancy resulted in cutaneous or cardiac neonatal lupus is 20%.

 Weekly fetal cardiac monitoring (by echocardiography assessing PR intervals, valvulopathy, and myocardial function) between weeks 16 and 24 is recommended. Fluorinated steroids are given-to prevent cardiomyopathy-when a fetal echocardiograph detects heart block.

 To date, hydroxychloroquine is the only drug that has shown to be beneficial in decreasing incidence of neonatal lupus.

Preconception preparation is key. Prior to pregnancy, it is essential to assess disease activity (especially renal) in a patient, know which treatments she is taking for SLE (to switch to medications allowed in pregnancy),  and be aware of whether she is anti-Ro- and La-positive and has APS. 

Hydroxychloroquine should be maintained or initiated in all pregnancies complicated by SLE. We tell patients that it is desirable in pregnancy-for both mother and fetus. The safety of hydroxychloroquine in pregnancy was first demonstrated by Parke et al.

 Other studies have confirmed the drug’s lack of fetal toxicity and congenital abnormalities.

 Maintaining hydroxychloroquine during pregnancy offers maternal benefits. It decreases disease activity and flares,

 particularly joint and constitutional flares.

 In the Hopkins cohort, among patients with low disease activity who discontinued hydroxychloroquine, 30% developed high disease activity during pregnancy compared to only 3% of those taking hydroxychloroquine.

 Hydroxychloroquine has an anti-thrombotic
	effect

 and should be used in pregnancies complicated by SLE in view of the 10-fold increase in thrombosis risk.

 Hydroxychloroquine also reduces neonatal morbidity. Rates of prematurity and IUGR were lower in 41 pregnancies complicated by SLE exposed to hydroxychloroquine compared to
	77 pregnancies not exposed to hydroxychloroquine.

 Neonates born to mothers who continued hydroxychloroquine had higher gestational age, birth weight, and Apgar scores.

Nonsteroidal anti-inflammatory drugs (NSAIDS) should be avoided in the second and third trimesters. They have been shown to increase risk of premature closure of ductus arteriosus and impair fetal renal function.

Increases in prednisone to doses equal or greater than 10 mg should be avoided. Exposure to glucocorticoids did not increase risk of major anomalies, but did increase risk of cleft palate in pregnancies to women who did not have SLE.

 Exposure to prednisone during the first trimester, in the general population, was associated with increased rates of miscarriage, PTB and low birth weight.

 It was not possible to separate out the effects of the underlying conditions from the effects of prednisone. Moreover, prednisone use in pregnancy was shown to be associated with increased risk of gestational diabetes when used in patients with idiopathic thrombocytopenia

A limited number of steroid-sparing agents are available for treatment and maintenance of disease control during pregnancy. Methotrexate, mycophenolate, and cyclophosphamide must be stopped prior to conception. In particular, we recommend that mycophenolate be stopped 3 months prior to conception and azathioprine substituted (after first ensuring safety by thiopurine methyltransferase testing). During that period, monitoring can be done for occurrence of renal flares on azathioprine.

 A low risk of flares was observed in patients with lupus nephritis who were switched from mycophenolate to azathioprine, compared to those who were initially on azathioprine and maintained on it.

 If renal flare occurs, activity can be controlled by returning to mycophenolate prior to pregnancy. Once a patient’s flares are controlled, she can be switched to azathioprine plus tacrolimus (again waiting to make sure the combination does control the renal lupus, prior to conception).

Azathioprine has not been associated with major congenital anomalies or poor pregnancy outcomes at daily doses not exceeding 2 mg/kg.

 Azathioprine safety is explained by absence of the enzyme inosinate pyrophosphorylase in the immature fetal liver. This enzyme is essential to convert azathioprine to its active metabolite mercaptopurine.

Tacrolimus has been used successfully for maintenance and control of flares during pregnancy in nine patients with lupus nephritis, with no congenital abnormalities reported.

 In a retrospective review of 15 pregnancies complicated by SLE, tacrolimus use was not associated with adverse fetal and maternal outcomes.

Most pregnancies exposed to rituximab (monoclonal antibody against CD20 present on B cells) resulted in uncomplicated live births with no pattern of congenital anomalies.

 Transient B-cell depletion in infants has been reported in three pregnancies exposed to rituximab less than 12 weeks before delivery. The recommendation remains to stop rituximab 12 months prior to conception.

Seventy-seven pregnancies exposed to belimumab (monoclonal antibody against B-cell activating factor) resulted in 38 live births and four congenital anomalies. The latter were chromosomal, urogenital, neural tube, and cardiovascular anomalies.

Three issues regarding SLE in pregnancies were highlighted in recent studies. First, during pregnancy, patients with SLE do not visit their rheumatologists as often as they should. This is of concern and could indicate that patients are ignoring their disease while focusing on pregnancy.

Second, immunosuppressant use decreased in women with SLE during pregnancy. This is possibly due to inappropriate concern about fetal safety of these drugs,

 since azathioprine and tacrolimus therapy are permissible in pregnancy. Controlling lupus activity remains key to a successful pregnancy outcome. 

Third, inadequate counselling and use of contraceptives in patients with SLE who are at risk of pregnancies contributes to an increased number of unplanned pregnancies.

The authors report no potential conflicts of interest with regard to this article.

Petri M. Hopkins Lupus Pregnancy Center: 1987 to 1996. 

Zulman JI, Talal N, Hoffman GS, Epstein W V. Problems associated with the management of pregnancies in patients with systemic lupus erythematosus. 

Petri M, Howard D, Repke J. Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. 

Ruiz-irastorza G, Lima F, Alves J, et al. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. 

Clowse MEB, Jamison M, Myers E, James AH. A national study of the complications of lupus in pregnancy. 

Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. 

Petri M, Howard D, Repke J, Goldman DW. The Hopkins Lupus Pregnancy Center: 1987-1991 update. 

Doria A, Cutolo M, Ghirardello A, et al. Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus. 

Jara LJ, Pacheco-Reyes H, Medina G, Angeles U, Cruz-Cruz P, Saavedra MA. Prolactin levels are associated with lupus activity, lupus anticoagulant, and poor outcome in pregnancy. 

Doria A, Ghirardello A, Iaccarino L, et al. Pregnancy, cytokines, and disease activity in systemic lupus erythematosus. 

Kim MY, Guerra MM, Kaplowitz E, et al. Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies. 

Salmon JE, Heuser C, Triebwasser M, et al. Mutations in complement regulatory proteins predispose to preeclampsia: A genetic analysis of the PROMISSE cohort.

Holmes CH, Simpson KL, Okada H, et al. Complement regulatory proteins at the feto-maternal interface during human placental development: distribution of CD59 by comparison with membrane cofactor protein (CD46) and decay accelerating factor (CD55). 

Qazi U, Lam C, Karumanchi SA, Petri M. Soluble Fms-like tyrosine kinase associated with preeclampsia in pregnancy in systemic lupus erythematosus. [Erratum appears in J Rheumatol. 2008 Apr;35(4):729]. 

Kim MY, Buyon JP, Guerra MM, et al. Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: Results of the PROMISSE study. 

Koh JH, Ko HS, Lee J, et al. Pregnancy and patients with preexisting lupus nephritis: 15 years of experience at a single center in Korea. 

Lockshin MD, Reinitz E, Druzin ML, Murrman M, Estes D. Lupus pregnancy. Case-control prospective study demonstrating absence of lupus exacerbation during or after pregnancy. 

Meehan RT, Dorsey JK. Pregnancy among patients with systemic lupus erythematosus receiving immunosuppressive therapy. 

Urowitz MB, Gladman DD, Farewell VT, Stewart J, McDonald J. Lupus and pregnancy studies. 

Georgiou PE, Politi EN, Katsimbri P, Sakka V, Drosos AA. Outcome of lupus pregnancy: a controlled study. 

Borella E, Lojacono A, Gatto M, et al. Predictors of maternal and fetal complications in SLE patients: a prospective study. 

Articles

Maternal and fetal outcomes complicated by SLE require that patient, rheumatologist, and ob/gyn work as a team.  

Lupus in pregnancy

Nothing can compare to the old days of medicine when residents were literally “residents” of the hospital, but demands on US medical trainees are still unique in the Western world. 

Last month I worked 3 weeks in a row without a break and by the end of it I was bone tired and mentally drained. My Sunday night was going just as I had planned and I was relishing my last few hours of freedom when I received a group-text from one of the senior residents asking if anyone could fill in for the night call resident, who was sick.

When it became clear that I was the only one available, I somewhat reluctantly donned my scrubs, went hunting for my stethoscope, and headed to the hospital.  

And so began “signout,” the transfer of responsibility from the day team to me.  Information on medical and surgical histories, issues and complaints, and likelihood of patients spontaneously dying overnight all were relayed to me as the resident “coming on.” Like two friends fighting to pay the check, the “day” resident and I each volleyed responsibility for last-minute tasks: 

“I’ll just finish this discharge summary, then I’ll be done.” 

“No, you’ve been working all day, I’ll do it, go home!”

“It’s okay, I should have done this earlier-“

With signout completed, I was now responsible, during the night, for every patient in the hospital with a gynecological concern.  Consults in the emergency room and phone calls from patients at home with gynecologic issues would also fall to me. With all these unfamiliar patients, many of whom were very sick with cancer or recovering from major surgery, the idea wasn’t to heal. It was simply to keep them alive overnight.

Of course, I was never completely alone. There is a chain of authority that night residents can climb with questions, starting with the senior resident working on labor and delivery, moving up to a junior attending “on call” from home, all the way up to the senior attendings. But sometimes calling for backup isn’t an option. There is a certain compulsion not to phone the sleeping attending at home, especially for small problems we’re expected to know how to fix on our own. 

And then, it’s 3 am and I’m being “hammer-paged,” as nurses, emergency room staff and patients calling the telephone consult service all vie for my attention:

“Patient in bed 22 says she has 9/10 pain, have already given oxycodone and Tylenol, she cannot get Motrin due to kidney disease, what do you want to do?”

“Patient calling from home has had heavy bleeding since 6 am; call back immediately.”

“Hi, consult in the ED. 79-year-old with chemo-resistant ovarian cancer, now with likely small bowel obstruction, please come see her asap, thanks”

Each page is triaged for severity, corralled into a “to-do list of importance.” Then I do a quick mental calculation of the best path to take through the hospital to tick off as many tasks as efficiently as I can. All the while, there is paperwork to complete and an escalating mountain of notes to write. I do my best to document as I go, because in a few short hours, I’ll be signing out to the day team. 

It feels like any mistake I make has dramatic consequences. Forget to ask a patient what medications they take? I won’t know she needs insulin and might send her into diabetic ketoacidosis. Overlook an obvious lab order? The morning attending will lay the blame on the day resident for the life-threatening electrolyte imbalance that I missed.

Night call is a game of constantly spinning plates, managing multiple sources of anxiety, scribbling notes as I clutch a phone in the crook of my neck and mouth apologies to the emergency medicine resident, who has been waiting 2 hours for my treatment recommendations. Residents are expected to be experts in their field, but I often find myself scouring medical websites on my phone looking for answers on the way to a patient awaiting my keen clinical input. 

And then finally, slowly, the morning approaches. My phone rings and I meet the day resident for another signout. This time, I’m the one recounting the events of the past shift-everything that happened overnight, everything I did for every patient who came in, everything still waiting to be done. Usually I will sign out to a more senior resident, whose gentle probing about each patient reveals the important details I forgot to gather. Kindly the resident will reassure me, promise it gets easier with time, and then repeat the “signout” pantomime:

“I still have a consult sitting in the ED I need to get to…”

“I can’t make you do that! It was my fault.”

Leaving the hospital at this time of day carries a unique warmth. Against the flow of foot traffic headed toward the hospital elevators, I lope toward the parking lot, nodding knowingly at other who recognize the semi-delirious smile of a night resident going home. 

After my first few night shifts, I was anxious about turning off my pager, nervous that someone might get sick or die if I didn’t immediately answer, or that I’d miss a call from an angry attending who couldn’t comprehend my treatment plan from the night before. But now I understand the meaning of signout, that informal but very real transfer of power and responsibility at the beginning and end of each day. I relish the moment I can turn off my pager, when I can cut the cord tying me to the hospital, to the impossible responsibility of caring for several dozen very sick strangers, and instead crawl into a familiar bed to pretend I am a lazy teenager again, sleeping deep into the late afternoon. 

Responsibility, anxiety, and expectations converge for an on-duty resident.

Night call siren song


	A 40-year-old G3P3003 in for her annual exam complained of heavy, painful periods, which had previously failed to respond to treatment with cyclical progestins. She requested a hysterectomy. Her exam revealed a moderately enlarged uterus. Her weight was 250 lb, with a body mass index of 42.9 kg/m

. Ultrasound revealed a 12.3 x 5.0 x 7.03-cm uterus, 1.9 x 1.6 x 1.9-cm fibroid, and 18-mm endometrium. The woman’s left ovary had an exophytic area, thought to be a paraovarian cyst. 

Five weeks later, the patient returned for a consultation about treatment. In addition to hysterectomy, the physician discussed uterine artery embolization (UAE), leuprolide acetate, and myomectomy. The patient chose a hysterectomy. The preoperative consent had the “standard” risks of surgery, including damage to surrounding tissues, and listed the discussed alternatives to surgery. Pertinent preoperative labs revealed hemoglobin and hematocrit (H/H) 12.4 g/dL and 41.2%, respectively, and random blood glucose 173 mg/dL. Blood urea nitrogen (BUN) and creatinine (Cr) levels were normal. Urinalysis (UA) showed trace bacteria.


	Six days after the preoperative appointment, the patient underwent laparoscopic hysterectomy with bilateral salpingo-oophorectomy (BSO). A uterine manipulator with a paracervical ring was used for uterine manipulation. A bipolar sealing device was used for salpingo-oophorectomy and management of the uterine arteries. A circumferential vaginal incision was made with an L-shaped electrosurgical hook. The cuff was closed vaginally, as the laparoscopic needle drivers were broken. No evidence of bleeding or bladder injury or leakage was found on laparoscopy after cuff closure. A vaginal pack was placed postoperatively. Cystoscopy was not performed. The operating time was 96 minutes, with 75 cc of blood loss. 

While in the postoperative area, the patient was noted to have blood-tinged urine that cleared within 30 minutes. On postoperative Day 1, she was doing well, with 2000 mL of urine output after surgery and a stable blood count. The vaginal pack was removed, and she was discharged. Pathology revealed a 231-g uterus, with mild chronic endocervicitis, proliferative endometrium, and adenomyosis. Both ovaries were normal with a hydatid cyst of Morgagni.


	Three days later the patient was readmitted with an ileus, dehydration, and acute renal failure. She had tachycardia (119-131 bpm), a distended abdomen, and rare bowel sounds. An abdominal x-ray revealed an ileus.

White blood cell (WBC) count 16,600 cells/mcL (4000 -11,900)

UA 3+ protein; red blood cell (RBC) count 25-50 per high-power field (HPF); WBC: 50-100 per HPF

The patient was treated with rehydration and an oral gastric tube. A Foley catheter was placed with the recorded urine output: 0009 = 800 cc; 0809 = 800 cc; 24 hours = 1600 cc. The next day her BUN was 22 mg/dL and Cr 1.41 mg/dL. The patient’s primary care physician (PCP) was consulted on Hospital Day 1. He documented that the patient began eating and was tolerating a normal diet and voiding normally. He confirmed that dehydration led to the increased BUN and Cr. A discrepancy was found in two notes: the PCP documented, “She has not had dysuria, hesitancy, or frequency.” A nurse documented, “Loss of bladder control. Started October 17 [2 days post-operatively].” On Hospital Day 2 of the readmission there was leaking around the Foley catheter. It was replaced with clear urine returned. An intravenous pyelogram (IVP) had been ordered on admission but was cancelled with a note about the elevated Cr. The patient improved clinically with normalization of her BUN and Cr. She was discharged on Hospital Day 4.


	Eleven days postoperatively (6 days after rehospitalization) the patient was seen with complaints of urinary urgency and some difficulty controlling her urine. UA revealed 2+ leukocytes and was positive for nitrites. The patient was diagnosed with a urinary tract infection (UTI) and urgency and treated with sulfamethoxazole/trimethoprim and tolterodine. 

On evaluation 1 week later, she was unable to control her urine. Entertaining the possibility of a vesicovaginal fistula (VVF), the gynecologist referred the patient to a urologist. She patient was seen 12 days later (18 days after surgery). The urologist documented, “Urinary incontinence since her surgery.” Exam revealed a cystocele and a rectocele, with no obvious fistula. UA revealed
	2+ leukocytes. An IVP revealed delayed extrusion of contrast into the vagina. On cystoscopy approximately 5 weeks after the initial surgery, the urologist found a dime-sized eschar, with fluid entering the vagina. A large eschar was found in the vagina, near the cuff. The patient was referred to a university hospital for management of VVF. 


	The patient was seen 3 months later (4 months after the original surgery) by the university urologist, who confirmed presence of a 10-mm VVF. Approximately 4 weeks later, the patient underwent laparotomy, cystotomy, and excision of VVF, approximately 1.5 cm from the right ureter. Pathology revealed fibrosis and chronic inflammation. Areas of marked chronic inflammation with extensive granulomatous inflammation with foreign body type giant cells were identified. The patient had an uncomplicated postoperative course and, after passing a voiding trial, had her indwelling catheter removed.

Failure to communicate treatment options to patient

Failure to perform surgery within the standard of care (SOC)

Failure to detect bladder injury at surgery

Failure to provide adequate postoperative care

The plaintiff’s expert was critical of the preoperative work-up, specifically lack of an endometrial biopsy or hysteroscopy for abnormal uterine bleeding (AUB), particularly noting the patient’s increased risk of endometrial hyperplasia or cancer due to morbid obesity. The expert also stated that magnetic resonance imaging should have been performed to diagnose adenomyosis, which he felt was the primary cause of the patient’s AUB. He testified that a hysterectomy should not have been the recommended option. Rather, less invasive approaches, such as endometrial ablation or UAE, should have been performed, eliminating risk of VVF. Further, the patient should have had better glucose control, as her preoperative glucose (random = 170 mg/dL) placed her at greater risk of poor wound healing. He expressed no concerns about the surgical technique or a breach of the SOC from the time of original postsurgical discharge until she was readmitted. He stated the ileus was a result of urine leakage into the peritoneal cavity. He admitted that bladder spasms are a known transient phenomenon after a hysterectomy. He testified that there was a thermal injury to the bladder, worsened by poor glucose control. However, he could not state that a fistula would not have developed if the patient’s elevated blood sugar had been aggressively treated. 

The plaintiff testified that she had not requested a hysterectomy. However, the defense attorney countered with the patient-completed intake form that stated her reason for the original gynecologic visit was, “Annual exam and talk about hyst.”  The patient also testified that she leaked all over herself beginning the day after surgery, not substantiated by chart documents. 

The defendant testified the patient desired hysterectomy and removal of both ovaries. He discussed treatment options on two separate office visits prior to surgery, further discussing hormone replacement following hysterectomy and BSO. The defendant admitted he did not have cystoscopy privileges. 

The defense expert testified that although it was appropriate to discuss endometrial ablation and UAD with patients, it is not necessary to encourage their use. Hysterectomy is within the SOC for definitive therapy for menorrhagia. The expert stated that the patient was not a suitable candidate for endometrial ablation, due to the her adenomyosis and relatively young age, which both predisposed to treatment failure. Further, the woman’s morbid obesity placed her at risk for endometrial hyperplasia and cancer. Although endometrial sampling is recommended prior to surgery for AUB, this oversight had no impact on the ultimate outcome.

The defense expert testified that the procedure described in the operating notes comported with the SOC. Although cystoscopy was not performed, it is acknowledged that some hospitals, as in this case, do not grant general gynecologists cystoscopy privileges. The expert stated that the postoperative care rendered was
	appropriate, as was discharge timing. This expert testified that there was no substantiated evidence that a random glucose < 200 mg/dL leads to poor surgical healing. 

The defense expert stated that the care rendered during the patient’s initial rehospitalization was appropriate, with timely diagnostic procedures and consultations. With an elevated Cr, it was appropriate to cancel the ordered IVP. With rehydration, rapid resolution of the elevated BUN and Cr did not support a ureteral injury or peritoneal accumulation of urine. Outflow of clear urine from the Foley catheter did not support presence of a VVF. Further, even if a fistula had been diagnosed at that time, treatment would have been postponed. 

At her initial postoperative office visit, the defendant reasonably diagnosed bladder control issues due to bladder spasms and a UTI, with appropriate treatment rendered. At the subsequent visit he appropriately considered a VVF and referred the patient appropriately to urology for further evaluation and treatment, with appropriate care rendered.

With less than an hour’s deliberation, the jury rendered a defense verdict.  

Patient communication and preoperative consent are the main issues in this case.

Vesicovaginal fistula after laparoscopic hysterectomy 

Every 15 minutes a baby is born with neonatal abstinence syndrome (NAS), a condition whose incidence has increased 5-fold since 2004.

 There are also increasing reports of opioid overdoses in breastfed babies whose mothers are ultrarapid metabolizers of codeine and tramadol.

 The opioid epidemic clearly has hit obstetricians and pediatricians full bore. However, lost in discussions about how to mitigate the problem has been a growing state policy divide that pits protecting infant health against preserving maternal autonomy. There is now an increasingly bright line in state policies between states that have enacted punitive laws treating drug use during pregnancy as child abuse, and a possible crime, and states that have laws emphasizing supportive or preventive policies and practices.

Advocates of criminalization note that failure to impose strict and clear expectations and consequences for illicit use of opioids has had the dual social impact of enabling bad behaviors and recklessly endangering the health of innocent newborns, thereby warranting a punitive policy response. Moreover, they note, care for these infants consumes $1.5 billion per year in health care costs that are frequently borne by state Medicaid coffers.

 In contrast, critics of punitive policies argue that criminalizing prenatal opioid use deters mothers from seeking appropriate care; brands women with a criminal stigma; and in some cases, destroys families by removing the newborn from the custody of the mother. They also argue that racial and economic profiling targets poorer women and that criminalizing a pregnant woman for opioid abuse is another step on the slippery slope of restricting or eliminating reproductive choice.

As is the case with many hot-button issues, our nation is sharply divided as to how the government, particularly states, should best protect the interests of pregnant mothers, their fetuses, and newborn children in the face of the opioid crisis. We offer here what we hope is a balanced, reasoned perspective on this subject. 

Opioid use disorder (OUD) in pregnancy is associated with all the same risks to the mother as in non-pregnant women: overdose death, serious infections from intravenous injections and needle sharing, domestic violence, criminal behavior, and sexually transmitted diseases. Indeed, substance abuse is now a major risk factor for pregnancy-associated deaths.

 Obstetrical risks of untreated OUD include fetal growth restriction, abruption, stillbirth, and preterm labor.

 Depression is present during the antenatal period in 30% of affected women and 40% of such postpartum women.

 The major newborn risk is NAS, which is present in up to 80% of newborns whose mothers have OUD.

 Affected newborns display irritability, feeding difficulties, and sleep abnormalities. The severity of these complications has led the American College of Obstetricians and Gynecologists (ACOG) to recommend universal screening for OUD using validated tools such as questionnaires. Identification of addicted mothers would allow for prompt referral for medication-assisted treatment (MAT) with opioid agonist pharmacotherapy and appropriate behavioral and social counseling and support to optimize both obstetrical and neonatal outcomes. 

The Federal Child Abuse Protection and Treatment Act of 1988 (P.L. 93-247), amended as part of the Comprehensive Addiction and Recovery Act of 2016 (P.L. 114-22 and P.L. 114-198) requires that states receiving certain federal funds develop reporting systems and notification protocols to child protective services along with guidelines for determining if and how drug use during pregnancy should be classified by state law as child abuse. In response, three states (Tennessee, Alabama and South Carolina) enacted “fetal assault” laws criminalizing opioid use during pregnancy under chemical endangerment laws. Tennessee’s law allowed a woman to be prosecuted for use of a narcotic while pregnant if her infant was born addicted to or harmed by the drug and the addiction or harm was a result of her illegal use while pregnant.

 It carried a maximum penalty of 15 years in prison. This law sunset in 2016. Alabama prosecuted 479 women for drug use during pregnancy from 2006 to 2015 before the law was modified in 2016 to exclude prescription drugs.

 The South Carolina statute is the broadest, as it does not mention controlled substances but targets prenatal OUD and other prenatal substance abuse affecting viable fetuses through its child abuse and endangerment laws.

 It should be noted that while many convictions in these states have been upheld, others have been overturned on appeal.

 Of note, in Alabama and South Carolina, the majority of state supreme court judges determined that the word “child” includes a fetus, a finding with implications for abortion access, should Roe v. Wade be further modified or overturned. 

Wisconsin, Minnesota, Oklahoma, and both North and South Dakota have child protection laws permitting detention of ostensibly abusing pregnant women, with some states assigning a guardian ad litem to represent the fetus with provisions for removing the child from the mother once born.

 Wisconsin investigated 389 women in 2017 and removed 33 babies from maternal custody after birth.

 However, states cannot routinely and easily identify a woman while pregnant as a potential opioid abuser unless she consents to a screening test. Non-consensual diagnostic tests of mothers have been deemed unconstitutional by the U.S. Supreme Court,

 but of course newborn infants may be tested. 

Anything that an adult may do that is likely to cause death or serious bodily injury to a child can be deemed a crime of reckless endangerment. This is long-established common law that has, in many jurisdictions, been translated into statute. “Reckless indifference,” a leap above simple negligence, is the general standard for criminalizing adult acts against children. Twenty-three states and the District of Columbia consider substance use during pregnancy to be child abuse under civil child-welfare statutes, and three states consider it grounds for civil commitment.

 Moreover, 24 states and the District of Columbia require health care professionals to report suspected prenatal drug use, and eight states require providers to test for prenatal drug exposure if they suspect drug use. 

As more states turn to punitive policies to discourage OUD among pregnant women, Dr. Lockwood and Dr. Wolfson examine what the ob/gyn's role in the debate should be. 

Vol. 64 No 03

Lupus in pregnancy

Night call siren song

Vesicovaginal fistula after laparoscopic hysterectomy

‘Policing’ pregnant women during the opioid epidemic

Hydatidiform mole: Recognition and management

Irregular vulvar mass in a postmenopausal woman