Maternal Medical Disorders of Fetal Significance

Diagnostic Imaging

Ultrasonography and magnetic resonance imaging (MRI) are not associated with fetal risk and should be considered the imaging of choice for pregnant patients. Diagnostic radiography, computed tomography (CT) scans, and nuclear medicine studies may be associated with fetal radiation exposure, even when studies target specific anatomy remote from the pregnant uterus ( Table 9.1 ). The fetal consequences of radiation exposure are both dose and time dependent ( Table 9.2 ). However, for most diagnostic procedures, actual fetal exposure is relatively low.

If possible, the practitioner should limit the amount of radiographic testing performed during pregnancy, but indicated studies should never be withheld because of pregnancy. Lead shielding of the abdomen and pelvis and careful selection of the type of study should be undertaken to minimize the fetal dose. To simplify the various measures of exposure, 1 radiation absorbed dose (rad), 1 Roentgen equivalents man (rem), 10 milliGray (mGy), and 10 milliSievert (mSv) can be considered equivalent.

If the amount of fetal exposure is less than 5 rad, there appears to be no significant increased risk of malformations. While an increased risk of childhood cancer has been reported in case-control studies with prenatal radiation doses of greater than 10 mGy, prospective studies and larger meta-analyses have not consistently replicated this association between fetal radiation exposure and risk of cancer. Iodinated contrast agents have not been shown to be teratogenic. Despite a theoretical concern about fetal hypothyroidism, there have been no reported cases resulting from the use of these agents.

MRI has not been shown to have adverse effects on the fetus and there are no precautions or contraindications specific to pregnant patients. While historically it was recommended that MRI be avoided in the first trimester, the American College of Radiology has stated no special consideration is recommended for any trimester in pregnancy. The use of gadolinium contrast in pregnancy remains controversial given its ability to cross the placenta and concentrate in amniotic fluid. A large, retrospective study found prenatal gadolinium exposure associated with rheumatologic, inflammatory, or infiltrative skin disorders (adjusted hazard ratio, 1.36; 95% confidence interval [CI] 1.09 to 1.69) and increased risk of stillbirth and neonatal demise (adjust RR, 3.70; 95% CI 1.55 to 8.85) when compared to unexposed pregnancies. Ultimately, gadolinium contrast should only be used during pregnancy when close consultation with radiology specialists determines that the benefits for diagnosis far outweigh the aforementioned risks. In the postpartum period, the use of all contrast agents, including gadolinium, is considered safe during lactation and the American College of Obstetricians and Gynecologists (ACOG) recommends that breastfeeding not be interrupted.

Surgery During Pregnancy

Approximately 2% of pregnant patients require surgery for a non-obstetrical condition. The most common indications are appendicitis and cholecystitis followed by orthopedic procedures. Indicated surgery during pregnancy is relatively safe. While the potential for adverse perinatal outcomes is slightly increased when compared with patients not requiring surgery, the delay of necessary procedures clearly increases the risk of poor maternal or fetal outcomes. A review of 54 studies regarding surgery during pregnancy concluded the following:

• 1.

  The risk of maternal death is low.

• 2.

  Surgery and general anesthesia do not appear to be major risk factors for spontaneous abortion.

• 3.

  Elective termination rates are similar to the general population.

• 4.

  The rate of congenital anomalies does not appear to be increased.

• 5.

  Acute appendicitis, particularly with peritonitis, appears to be a risk of surgery-induced labor or fetal loss.

• 6.

  Urgent surgical procedures should be performed when needed.

Since appendectomy is the most common nonobstetric surgery performed during pregnancy (1 in 766 births), the data regarding outcomes are relatively robust. Anatomic changes in pregnancy can confound the diagnosis while a reluctance to operate on a pregnant patient can delay treatment and worsen outcomes. The negative appendectomy rate in pregnancy is higher when compared with nonpregnant cases (23% vs. 18%). The rates of fetal loss and early delivery are higher for complex appendicitis (6% and 11%, respectively) versus simple appendicitis (2% and 4%, respectively). Unfortunately, surgery for appendicitis and the finding of a normal appendix is still associated with an increased risk of loss (3% to 4%). While laparoscopy is being utilized increasingly during pregnancy, there may be an associated increased risk of loss when compared with laparotomy for suspected appendicitis. Ultimately, the type of surgical procedure, whether laparoscopic versus open, should be determined by the surgeon, in consultation with the obstetrics team.

Guidelines to optimize outcomes for pregnant patients undergoing surgery are relatively straightforward. Anesthetic options are unchanged when compared with nonpregnant patients, as both regional and general anesthesia can be safely administered. If general anesthesia is being used, extra care must be taken to protect the maternal airway from aspiration given the anatomic and physiologic oropharyngeal changes, reduced gastrointestinal motility, and displaced stomach that may contain significant residual contents hours after eating. In the second and third trimesters, a lateral decubitus position is preferred to reduce venacaval compression, thus optimizing both maternal venous return and uteroplacental perfusion. Preoperative counseling with an obstetrician and neonatologist is recommended, particularly if the gestational age is greater than or equal to 22 weeks to give the surgical team direction regarding interventions should fetal distress be encountered. Fetal heart rate monitoring, if feasible, can also facilitate the assessment of fetal status.

Medication Usage

Maternal medication use during pregnancy requires the provider to understand two basic principles:

• Alterations of maternal anatomy and physiology may alter the effective dose.

• Maternal medications may enter the fetal circulation with resulting fetal exposure.

There are significant physiologic alterations in pregnancy that may affect the bioavailability, distribution, clearance, and half-life of a medication. Absorption is altered due to nausea and vomiting, gastric volume and pH changes, increased gastrointestinal transit time, and differences in the activity of drug-metabolizing enzymes in the gut. Increased body weight and plasma volume as well as reduced albumin alter the volume of distribution. Hepatic and placental enzymatic activity and increased glomerular filtration rates will influence drug clearance. Examples of medication classes that often require increased dosing through gestation include thyroid function modulators, antiepileptics, antihypertensives, and medication assisted therapies (MAT) for substance use disorder.

With the discovery that certain medications may induce congenital malformations, notably thalidomide in the early 1960s, the Food and Drug Administration (FDA) developed a maternal drug classification system with escalating categories (A through D) signifying increased fetal risk, and a standalone Category X denoting medications that were contraindicated in pregnancy. Most drugs (65% to 70%) were labeled category C, meaning that animal studies had shown potential adverse effects, however, no adequate human studies were available to corroborate. With half of all pregnant women receiving prescription drugs in categories C and D, the actual utility of this classification system became questionable. In 2015 the FDA published the “Pregnancy and Lactation Labeling Rule,” eliminating the ABCDX classification for any new drug applications and retroactively labeling prescription drugs approved after 2001. The new labels include a summary of known fetal and newborn risks, considerations for lactation and breastfeeding, latest available data, and information for pregnant patients to participate in ongoing registries for the medication. In addition to pregnant patients, the expanded labeling also includes information on the potential impact medications may have on both male and female reproductive potential. Ultimately, such information should be utilized by both patients and physicians as part of a shared decision-making process, with the understanding that maternal benefit will most often outweigh weak or theoretical fetal risks when it comes to recommending indicated medical treatments in pregnancy.

Systemic Lupus Erythematosus

SLE or lupus is a chronic multiorgan disease with a wide clinical spectrum. Advancements in reproductive and autoimmune care have improved maternal and fetal outcomes, reflected by the reduction of fetal loss rates from 43% to 17% between 1960 and 2000. In the absence of antiphospholipid antibody syndrome (APS) or significant renal insufficiency, fertility does not seem impacted. As with most autoimmune conditions, there is no uniform agreement on whether pregnancy alters the disease course. However, risk factors associated with a lupus flare include active disease within 6 months before conception, history of multiple flares, and discontinuation of hydroxychloroquine.

Risk factors for poor pregnancy outcomes in patients with lupus include proteinuria, renal insufficiency, APS, thrombocytopenia, or active maternal disease at the time of conception ( Table 9.3 ). Those with nephritis, APS, or who have anti-Sjögren syndrome related-antigen A (anti-SSA or anti-Ro antibodies) may have increased risks of altered perinatal outcomes. Adverse outcomes include spontaneous abortion and intrauterine growth restriction (IUGR), and the risk of superimposed preeclampsia and stillbirth are potentially increased. Therefore, assessment of the patient’s baseline disease activity, as well as exploration for evidence of multiorgan system dysfunction, is vital to aid in counseling and management. Comanagement with rheumatologists and/or nephrologists is vital to improving maternal and fetal outcomes.

Initial prenatal evaluation of a patient with lupus includes taking a history, such as disease activity, organ system involvement, and current medical therapy. The latter is important in determining whether there is an increased fetal risk, as some medications used are generally contraindicated during pregnancy (methotrexate, mycophenolate mofetil). Fortunately, most patients planning pregnancy are not using these agents. Prednisone, azathioprine, and hydroxychloroquine are more commonly used medications with reasonable safety profiles during pregnancy.

Chemical screening for disease activity should be performed. This includes anti-double-stranded DNA and complement levels. Antiphospholipid antibodies, anti-Ro, and anti-La (otherwise known as anti-Sjögren syndrome related-antigen B or anti-SSB) antibodies should be measured. The patient should also have baseline assessments for proteinuria, renal function, hepatic enzymes, and platelet count not only to assess her status but also to formulate a baseline profile ( Table 9.4 ). Since a lupus flare may mimic preeclampsia, a comparison of her repeated studies against those obtained earlier may be helpful, as the management of these two conditions differs.

Medication management, including type and amount, is dictated by disease activity and the presence of APS. Most patients are managed with steroids, hydroxychloroquine, or azathioprine, and alterations of these should probably not be dictated by pregnancy. While there may be theoretical concerns with their usage, these drugs have to be balanced against the risk of uncontrolled lupus ( Table 9.5 ).

Disease activity should include serial assessment of maternal symptoms as well as complement and anti-double-stranded DNA levels. Fetal evaluation includes serial ultrasounds and antepartum testing. An increase in the patient’s blood pressure or level of proteinuria may represent either a lupus flare or preeclampsia. Differentiation between the two is challenging, but every effort should be made to do so, as therapies for both are different.

Antiphospholipid Antibody Syndrome

APS was originally described as an autoimmune disease characterized by circulating antiphospholipid antibodies (aPL) and venous thrombosis, recurrent pregnancy loss, and occasionally thrombocytopenia. This disorder may be isolated or associated with other autoimmune diseases. The presence of aPL is found in about 1% to 5% of healthy women. However, these antibodies are found in 15% of women who have recurrent abortions and in 30% to 40% of those with SLE. The presence of aPL in the latter is a risk factor for a poor pregnancy prognosis.

Few women with aPL will develop the disease, and the prevalence of APS is estimated to be only 50/100,000. The diagnosis of APS must include clinical criteria (vascular thrombosis, unexplained death of a morphologically normal fetus >10 weeks’ gestation, premature birth <34 weeks due to preeclampsia or placental insufficiency, or ≥3 weeks otherwise unexplained abortions <10 weeks), as well as the presence of aPL (lupus anticoagulant, anticardiolipin antibody, or anti-β ₂ -glycoprotein antibody) on greater than two occasions, at least 12 weeks apart. For those with a prior history of venous or arterial thrombosis, prophylactic anticoagulation with heparin throughout pregnancy and continuing through 6 weeks’ postpartum is usually recommended. In patients with recurrent pregnancy loss, low-dose aspirin and heparin may reduce pregnancy loss by 50%. Therefore even in the absence of a thrombotic history, in those with a history of stillbirth or recurrent pregnancy loss, prophylactic heparin and low-dose aspirin should be offered during pregnancy for up to 6 weeks’ postpartum.

Neonatal Lupus

Anti-Ro and anti-La antibodies can be present in asymptomatic women. The former are more often seen in women with Sjögren syndrome but can be also found in women with other autoimmune disorders. These antibodies cross the placenta and have been associated with congenital heart block. In the absence of a prior infant with congenital heart block, the prospective fetal risk is low, at 2%. However, in patients with a prior history of an affected fetus or neonate, the recurrence risk is 15% to 20%. The morbidity and mortality of these infants are significant, the latter ranging between 10% and 29%. Other consequences include the potential need for a pacemaker or cardiac transplantation.

The injury to the atrioventricular node most often occurs between 16 and 24 weeks, and there is the potential for fibrosis that can extend to the endocardium and myocardium. No prenatal interventions have been shown to reverse complete heart block. However, there may be some improvement in outcome with the use of fluorinated steroids if second-degree heart block is detected. There are potential fetal consequences of maternal steroids, including adrenal insufficiency, as well as neurodevelopmental and growth abnormalities. It is suggested that women exhibiting these antibodies undergo fetal echocardiography beginning in the second trimester (16 to 18 weeks) and repeated every 1 to 2 weeks until 28 weeks. In those with a prior child affected with congenital heart block, the use of hydroxychloroquine may be associated with a reduced risk of recurrence.

Immune Thrombocytopenia

Approximately 7% to 10% of pregnancies are complicated by thrombocytopenia. The most common etiology is gestational thrombocytopenia (75%), followed by preeclampsia (15% to 20%) and immune thrombocytopenia (ITP) (3%). By definition, ITP is immune mediated, and the responsible antibody may cross the placenta. The incidence is approximately 1/1000 pregnancies, but more significant disease (maternal platelet count <50 × 10 ⁹ /L) is rare occurring in 0.85/100,000 pregnancies. ITP is associated with an increased risk of neonatal thrombocytopenia, with 15% to 50% of newborns having platelets less than 100 × 10 ⁹ /L, 8% to 30% less than 50 × 10 ⁹ /L, and 1% to 5% less than 20 × 10 ⁹ /L. Unfortunately, there is no variable that accurately predicts the potential for neonatal thrombocytopenia. There is no correlation between the maternal and neonatal platelet count, nor does the use of steroids or IVIg not seem protective. A history of a prior affected child or maternal splenectomy may increase the neonatal risk of thrombocytopenia. Over the years, a number of interventions had been proposed in the past to reduce the risk of spontaneous fetal or neonatal bleeding. Strategies such as performing a routine cesarean section, fetal scalp platelet assessment in labor, or percutaneous fetal scalp platelet counts were not found to be helpful and were potentially associated with increased maternal or fetal morbidity. Therefore it is recommended that the delivery mode should not be altered for the diagnosis of ITP.

Maternal management for this condition in the first and second trimesters of pregnancy is essentially unchanged when compared with a nonpregnant patient. If the maternal platelet count is greater than 30,000/μL, no treatment is necessary. Below this threshold, or if there is evidence of spontaneous bleeding, corticosteroids and intravenous immunoglobulin are usually first-line therapies. Both are relatively safe during pregnancy and usually associated with a good maternal response. Refractory cases are difficult to manage. Large-dose anti-D antibody administration and splenectomy are options when initial therapy fails.

Gestational thrombocytopenia (GTP) is a benign condition that sometimes can be difficult to delineate from ITP. However, the salient features include a lack of prior maternal history of severe thrombocytopenia and a maternal platelet count that is usually above 80,000/μL. Other potential causes for a low platelet count should be explored, including severe preeclampsia, autoimmune disease, medication usage, and viral illness. True GTP has no associated risk of neonatal thrombocytopenia. One potential consequence of GTP may be the reluctance of some anesthesiologists to place a regional anesthetic if the platelet count is too low.