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Contents: Medical Complications of Pregnancy: Clinical Expert Series

Nonobstetric Surgery During Pregnancy

Tolcher, Mary Catherine MD, MSc; Fisher, William E. MD; Clark, Steven L. MD

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doi: 10.1097/AOG.0000000000002748
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“The only thing we have to fear is fear itself”—Franklin Delano Roosevelt, first Inaugural Address.1

Nonobstetric surgery during pregnancy is not rare, occurring in 1–2% of all pregnant women.2 Gastrointestinal surgery (principally appendectomy and cholecystectomy) is the most common type of surgery performed during pregnancy (45%) followed by orthopedic procedures (24%).3 The performance of surgery in pregnant women has historically been avoided whenever possible, at times in situations in which surgery would clearly be indicated in an identical, nonpregnant patient. This reluctance to operate stems primarily from concerns regarding surgery-related miscarriage, teratogenesis, and preterm birth. In addition, fears regarding the potential fetal effect of necessary perioperative diagnostic tests may contribute to the general reluctance of physicians to thoroughly evaluate such conditions and perform the appropriate surgical procedures.

Traditional teaching suggests that surgery during the first trimester carries with it an increased risk of pregnancy loss, that surgical procedures during the second trimester are associated with minimal risk, and that surgery during the third trimester is accompanied by an increased risk of preterm birth.4 However, a critical review of the medical literature suggests that these time-honored dogmas are largely based on inappropriate extrapolations from minimal, poor-quality data. We believe that diagnostic and therapeutic approaches based on such assumptions have transformed the current reluctance to perform necessary surgical procedures into one of the major risks of surgical disease to pregnant women today. Although we discuss in detail each of these areas of presumed risk, we first note that four concerns affect the proper interpretation of much of the available literature regarding the risks of surgery during pregnancy.

First, many of these studies are old and contain data from women undergoing surgery many decades ago when diagnostic testing, surgical techniques, and perioperative maternal–fetal care were very different than today.5,6 Although the desire to expand published series by the inclusion of older data is understandable given the relatively low numbers of these procedures in any single center, the relevance of such data to current practice is questionable. A second problem is the tendency to combine data from vastly disparate types of surgery into a single report, which then presents outcome data as being representative of surgery during pregnancy.2,3,6 Third, studies published in surgical or medical journals often focus on maternal outcomes and contain insufficient detail regarding pregnancy outcomes to be of use in actually assessing the perinatal risks of operation compared with nonoperation during pregnancy.1–3,5,6 For example, one study of surgery involving cardiopulmonary bypass during pregnancy reported a rate of preterm birth of 52%.5 However, a careful reading of this article reveals that many of these women were delivered either before surgery or at a time remote from surgery. Indeed, only two women had preterm contractions after surgery, and these resolved in association with magnesium sulfate tocolysis. Clearly such data do not support the conclusion that operating on a woman in late pregnancy leads to an increased risk of preterm labor and birth, a conclusion suggested by simply citing the observed rate of preterm delivery.

Finally, and perhaps most importantly, any such study must be analyzed in the context of an appropriate control group. Cosmetic surgery aside, all surgery is performed as a result of the presence of significant underlying disease, much of which is itself known to be associated with complications of pregnancy. Thus, comparisons of the outcomes of women undergoing an indicated surgical procedure using as controls the general population of pregnant women, rather than matched women with the same conditions who do not undergo surgery, are of little value. These recurrent themes, influencing virtually all studies dealing with surgery in pregnancy, have historically served to the disadvantage of pregnant women with surgical disease. This review, undertaken with these specific issues in mind, suggests the need to abandon many traditionally accepted but scientifically inappropriate conclusions regarding risks of surgery during pregnancy.

DIAGNOSTIC IMAGING

Specific imaging studies commonly precede many types of surgery, either for diagnostic purposes or to guide the surgeon’s intraoperative approach. Both diagnostic ultrasonography and magnetic resonance imaging appear to be safe at all stages of gestation even when the fetus itself is the focus of the imaging procedure.7–10 On the other hand, both standard radiography and computed tomography involve the use of ionizing radiation, which has the potential to cause both teratogenesis and fetal central nervous system injury in high doses at certain stages of fetal development. In evaluating the potential effect of these tests on the fetus, an understanding of dosimetry is essential.

Dosimetry

There are two classes of radiation effects: deterministic and stochastic. Deterministic effects include malformations, growth restriction, intellectual disability, microcephaly, and death; these complications result from damage to multiple cells, whereas stochastic effects result from damage to a single cell, which may later lead to carcinogenesis.8 Exposure to high doses of radiation (greater than 50–100 mGy, or 5–10 rads) during the first 2 weeks after conception is thought to be an all or none deterministic phenomenon, resulting in either fetal death or no effect. Because most organogenesis takes place between weeks 2 and 8 after conception, fetal anomalies would be potentially affected by very high doses of radiation (greater than 200 mGy, or 20 rads) during this timeframe.9 Severe intellectual disability may occur at lower doses (greater than 60 mGy, or 6 rads) early in pregnancy (8–15 weeks of gestation) and microcephaly may occur with doses greater than 200 mGy (20 rads) during this timeframe with an estimated intelligence quotient point loss of 25 points per 1,000-mGy (100 rad) exposure.9 Higher doses (greater than 250 mGy, or 25 rads) are needed to effect intellectual development of fetuses between 16 and 25 weeks of gestation.9 A 10- to 20-mGy (1–2 rad) exposure may also increase the lifetime risk of leukemia twofold (background risk of 1/3,000).9 Fetal gonad and thyroid injury are other areas of theoretical concern with certain types and doses of radiation exposure generally unrelated to preoperative surgical diagnostic tests.

Similarly, the Radiological Society of North America states that no deterministic effect is expected to occur at doses less than 100 mGy (10 rads) and no stochastic effects at less than 20–50 mGy (2–5 rads).8 Fortunately, virtually all pertinent radiographic procedures are associated with fetal exposure far below these levels (Table 1).

Table 1.
Table 1.:
Expected Fetal Radiation Exposure by Type of Imaging Examination

Gadolinium Contrast

The use of gadolinium-based contrast in pregnancy is considered controversial because there is limited evidence to guide use. Gadolinium can cross the placenta and has been found to be teratogenic at high doses in animal studies.9 In addition, some human data exist suggesting a possible link between gadolinium magnetic resonance imaging exposure and rare skin conditions as well as stillbirth.7 Despite recognized limitations of this study design, there is consensus that the use of gadolinium contrast should be avoided when diagnostic accuracy will not be significantly compromised.8 However, given a lack of definitive data demonstrating significant clinical risk in humans, the use of gadolinium contrast is appropriate in clinical circumstances where its use is expected to aid in appropriate and timely diagnosis and treatment for pregnant women, particularly beyond the first trimester.8–10 No data exist on the use of newer, superparamagnetic iron oxide contrast in pregnancy.9

Nuclear Imaging

Nuclear imaging may be recommended in pregnancy for evaluations including ventilation–perfusion scanning of the lungs for pulmonary embolism or assessment of the thyroid, renal system, brain, or bone. Most nuclear imaging procedures result in fetal exposure less than 5 mGy and are considered safe in pregnancy.9 Technetium 99m and Xenon 133 are the most commonly administered isotypes and may be utilized in pregnancy; however, radioactive iodine is contraindicated during pregnancy as a result of its concentration in the fetal thyroid with resultant functional suppression. These tests are only rarely indicated as part of a preoperative surgical evaluation.

Table 1 may be used as a guide when considering radiologic procedures during pregnancy. When complex or unusual procedures are contemplated, a request to the radiologist for estimated dosimetry may assist in decision-making. In general, however, the most common hazard involving diagnostic imaging during pregnancy is underutilization of necessary diagnostic tests as a result of unfounded fears of fetal radiation exposure. This underutilization may in turn contribute to reluctance to perform those indicated surgical procedures that are predicated on preoperative diagnostic imaging.

TERATOGENESIS OF ANESTHETIC AGENTS

As noted by Kuczkowski,11 virtually every drug in the pharmacopeia has been demonstrated to possess teratogenic characteristics in some species under some set of circumstances at some point during gestation. However, none of the commonly available agents used for general anesthesia, including propofol, ketamine, etomidate, or succinylcholine, has proven to be teratogenic in humans. Thus, the choice of anesthetic agents should be based on standard anesthetic considerations.4 The placental transfer of neuromuscular-blocking agents is minimal, and such agents are widely utilized for direct fetal injection and paralysis during fetal surgical procedures without ill effects. Nitrous oxide is associated with unique theoretical concerns as a result of its inhibition of methionine synthase activity and its potential effects on DNA production and myelin deposition.11–13 However, despite being a staple for many of the 75,000 nonobstetric surgical procedures performed annually during pregnancy in the United States, and some enthusiasm for its use during labor, actual detrimental clinical effects of nitrous oxide on the developing human fetus have yet to be demonstrated. According to the American College of Obstetricians and Gynecologists, “no currently used anesthetic agents have been shown to have any teratogenic effects in humans when using standard concentrations at any gestational age.”4

A more critical concern is the rapid passage of most general anesthetic agents across the placenta with the potential for severe neonatal depression should delivery be necessary during maternal surgery.14 Although such cases are uncommon, the availability of an expert neonatal team to provide aggressive respiratory support should perioperative delivery be indicated is an essential component of safe surgery during pregnancy beyond the point of fetal viability. Despite the relative safety of general anesthesia during pregnancy, a regional anesthetic approach is preferable, when feasible, to reduce the known increased risk of aspiration during pregnancy as well as the aforementioned possibility of neonatal depression.14,15 However, general anesthesia will often be required and in skilled hands can be generally performed without complication or fear of teratogenesis at any gestational age.4 Recently, the U.S. Food and Drug Administration issued a warning regarding potential risks of prolonged (greater than 3 hours) anesthetic exposure on brain development in young children and fetuses.16 This warning has been highly criticized for its poor scientific quality, the lack of involvement of appropriate medical specialists in development of the warning, an absence of evidence of adverse effect on human fetuses, and the potential negative effect of such a warning on the willingness of patients to consent to medically necessary procedures.17,18 In addition, any indicated surgical procedure lasting more than 3 hours invariably involves life-threatening conditions in which definitive benefit outweighs theoretical risk.17,18 The American College of Obstetricians and Gynecologists has emphasized that this ill-advised warning should not discourage the performance of any indicated surgical procedure.17

EARLY PREGNANCY LOSS

The occurrence of miscarriage as a consequence of surgery during early pregnancy is a common concern for both pregnant women and their physicians. Traditionally, the risk of such pregnancy loss has been considered to be small, but significantly increased during the first trimester.4 However, a critical review of the literature suggests that such concerns are likely to be unfounded. A large systematic review of the English language literature including 54 studies describing outcomes in more than 12,000 women undergoing surgery during pregnancy demonstrated a miscarriage rate of 10.5% among women undergoing surgery in the first trimester.6 Superficially, such data may be worrisome. However, these data are difficult to interpret both as a result of a lack of a control group and because serious surgical illness or injury is itself often associated with pregnancy loss. This may be the result of direct involvement of the fetus or uterus (for example, transplacental passage or direct uterine involvement by bacteria or viruses in cases of maternal sepsis), the effect of maternal hemodynamic compromise on placental perfusion or oxygenation (like in shock of any etiology), or an indirect effect of inflammatory mediator release on uterine perfusion or uterine activity. Because published series examining risks of pregnancy loss as a result of surgery are generally not controlled, such data cannot distinguish the effect of the disease for which surgery was performed from the effects of surgery itself.

Generally, the risk of miscarriage in the first trimester in the general population is 25–30% with the risk decreasing to 8–10% once the pregnancy is recognized clinically.19–21 Because awareness of early pregnancy and of subsequent loss in a woman undergoing surgery is enhanced given the near universal performance of a pregnancy test on women of reproductive age undergoing surgery, the perceived relative rate of miscarriage among women undergoing surgery may be inflated. Whether the most appropriate available control group for assessing the risk of surgery during early pregnancy is the actual loss rate of 25–30% or a loss rate of 8–10% among clinically recognized pregnancies, the reported loss rate of 10% among women undergoing surgery in the first trimester strongly supports a conclusion that rates of early pregnancy loss are not significantly increased by surgery during the first trimester of pregnancy.

PRETERM BIRTH COMPARED WITH PRETERM CONTRACTIONS

Surgery during the third trimester of pregnancy has traditionally been linked to an increased risk of preterm labor. Such data carry with them the implicit assumption that some proportion of women in preterm labor will experience preterm birth. In analyzing these data, establishing the validity of this premise is critical. Recent carefully conducted trials of tocolytic agents have served to emphasize the critical distinction between preterm contractions and preterm labor and the difficulty in making such a distinction prospectively.22,23 None of the studies examining the effects of surgery on preterm labor have used the rigorous diagnostic criteria for true preterm labor now deemed essential for studies involving preterm birth, its causes, and prevention.22,23 For example, in one retrospective study of 77 women who underwent abdominal surgery during pregnancy, preterm labor was described in 26% of women who underwent surgery in the second trimester as compared with 82% who underwent surgery in the third trimester.24 However, only 16% of patients felt to be in labor actually delivered before term. Because the literature clearly demonstrates the inefficacy of any tocolytic regimen in preventing preterm birth, it follows that few of the women diagnosed with postsurgical preterm contractions were actually in labor.22 In addition, it is well-established that the prevalence of spontaneous uterine contractions increases with gestational age; thus, a higher rate of detected uterine contractions would be expected in any population of pregnant women in whom contraction monitoring was undertaken in the third compared with the second trimester with or without surgery. Clearly, preterm birth rather than preterm labor is the appropriate endpoint for such studies. Indeed, in the largest available systematic review, the rate of preterm birth was only 8.2% compared with a rate of preterm birth in the general obstetric population in the United States of 10–12%.6 In this risk analysis, the type of surgery must also be considered. In a study of 778 patients who underwent appendectomy between 24 and 36 weeks of gestation, 22% of delivered within the first week after surgery with no increased risk of preterm delivery after the first postoperative week.25 That women with an acute and potentially life-threatening suppurative intra-abdominal process would have a higher rate of preterm labor and delivery than the well-woman population is not unexpected. However, the additional contribution of a curative operative procedure to this rate is speculative and, in our opinion, highly doubtful.

In addition, although women undergoing surgery in late pregnancy may sometimes deliver prematurely, any potential excess rate of preterm birth among these women may be accounted for by the increased severity of underlying maternal illness in women who require surgical compared with medical treatment for a given condition and enhanced morbidity in women whose surgery is delayed until the condition has worsened as a result of reluctance to operate during pregnancy. This conclusion is supported by the observation of a fetal loss rate of 10.9% compared with 2.6%, respectively, in pregnant women with acute appendicitis with or without appendiceal perforation and peritonitis. The occasional need for planned preterm delivery to facilitate a surgical approach in late pregnancy may also contribute to the observed rate of perioperative preterm birth.

The physiologic effects of surgery or any physical injury as well as many disease states include an increase in cortisol, inflammatory cytokines, and acute phase reactants.26 Because both infection and noninfection disease processes may result in a similar inflammatory response, it is impossible to distinguish the relative effects of each on uterine activity or labor. Indeed, noninfection inflammatory conditions such as nephrolithiasis and nonsurgical infection conditions such as pyelonephritis also increase the risk of preterm labor.27–29 All these factors suggest that conflating an association with causation is a particularly tenuous undertaking in dealing with surgical disease in pregnancy. It seems particularly inappropriate to combine the risks of preterm delivery in women undergoing surgery in the presence of an infection–inflammatory intraabdominal condition such as appendicitis with those undergoing operative procedures resulting from diseases with negligible risk of direct uterine involvement. Studies that discuss the obstetric risks of surgery during pregnancy based on cumulative outcomes of widely disparate types of disease states and surgical procedures are of little value to the clinician considering a specific operative intervention in a specific patient.

HYPOXIC FETAL INJURY AND INTRAOPERATIVE FETAL HEART RATE MONITORING

Perhaps the most evidence-based concern regarding adverse effects of nonobstetric surgery during pregnancy involves the potential for fetal hypoxia in the presence of maternal hypoxia or hypotension.30,31 Preferential perfusion to vital maternal organs (brain, heart, and adrenal glands) in any maternal shock state will result in an early reduction in uterine and fetal perfusion. These concerns are real and must be considered in surgical procedures involving a significant risk of maternal hypoxia or hypotension attributable either to the nature of the surgery or the associated anesthetic technique. Although such concerns are most commonly seen in cardiovascular or neurosurgical procedures (discussed subsequently), there are two key questions that should be addressed before any surgical procedure during pregnancy: 1) Is there a significant risk of intraoperative maternal hypotension or hypoxia? 2) Is continuous electronic fetal heart rate monitoring technically feasible during the operation? If the answer to these questions is in the affirmative, intraoperative fetal monitoring is generally warranted. We note that the achievement of a gestational age in which delivery might be considered need not be an essential prerequisite to intraoperative monitoring; intraoperative fetal compromise, as evidenced by a fetal heart rate pattern suggesting hypoxia, has, in a number of cases both in our experience and in the literature, been detected and corrected with nonsurgical manipulation of maternal oxygen delivery or hemodynamic support systems.5,32–35 In many of these situations, delivery was not a consideration either as a result of early gestational age or technical difficulties in performing simultaneous nonobstetric surgery and cesarean delivery without compromising maternal health. With an appropriate understanding of fetal physiology and the availability of knowledgeable specialists, fetal resuscitation is often possible; cesarean delivery is not always the only way to improve intraoperative fetal oxygenation or perfusion.34

SPECIFIC SURGICAL CONSIDERATIONS

Neurosurgery

Common neurosurgical conditions encountered during pregnancy include brain tumors, intracranial hemorrhage, traumatic brain injury, and spinal surgery.36 The prone position for neurosurgery may cause difficulties with fetal monitoring and the ability to accomplish emergent cesarean delivery.37 One small case series showed that the prone position decreased the systolic/diastolic ratio of umbilical artery blood flow, suggesting a positive effect of this position on uterine blood flow.38

Osmotic diuretics, including mannitol, are often used to relieve elevated intracranial pressure in such cases. Although there is a theoretical concern for fetal hyperosmolality with mannitol use,39 the drug is not contraindicated in pregnancy and the benefits likely outweigh the risks. The use of intraoperative maternal hypothermia, utilized for adult neuroprotection, is an additional concern during certain neurologic procedures.40 We note, however, that therapeutic hypothermia has been shown to improve neurologic outcomes in the setting of traumatic brain injury and hypoxic encephalopathy for children by blocking damaging inflammatory cascades. Based on several reports, hypothermia can result in fetal bradycardia.41–45 However, fetal bradycardia resulting from maternal hypothermia is reversible on maternal rewarming and does not warrant delivery.

Of greater concern is the use of neurosurgical hypotensive anesthetic techniques, which, although sometimes essential for maternal well-being, would be expected to consistently result in fetal hypoperfusion with the potential for fetal neurologic injury. In our experience, this represents a fetal risk that cannot be reliably mitigated. In addition, emergent cesarean delivery during such neurosurgical procedures is particularly fraught with technical difficulties, which may seriously jeopardize the mother. When hypotensive techniques are deemed essential for maternal health, and surgery cannot be safely delayed, delivery before the operation is often a better choice, despite significant prematurity.

Cardiothoracic Surgery

The physiologic changes of pregnancy include increased blood volume and cardiac output and decreased systemic vascular resistance, which can worsen cardiac function in women with pre-existing cardiac conditions.46 The peak changes typically occur in the early third trimester and are maintained until after delivery. Severe decompensation, particularly with mitral or aortic valvular disease, may require cardiothoracic surgical intervention. Although maternal outcomes are generally good, some reports suggest that rates of maternal morbidity and mortality in women undergoing cardiothoracic surgery during pregnancy are somewhat higher than seen in the nonpregnant patient, despite the fact that such patients are generally younger than the general population of patients undergoing cardiac surgery.5,47,48 However, as with the other types of surgery discussed previously, the contribution of decisions to delay cardiovascular surgery as a result of concurrent pregnancy until full-blown decompensation has occurred likely contributes to such outcomes. One recent review began with the observation that cardiac surgery during pregnancy is reserved for cases of failure of medical treatment and then went on to document the fact that all patients in their report presented late and with life-threatening conditions.46 As might be expected under such circumstances, perinatal outcomes were poor. We have seen a number of women with valvular disease referred for care in the late second or early third trimester of pregnancy hypoxic and in frank congestive failure. In all too many of these cases, the severity of valvular compromise identified earlier in pregnancy clearly made the likelihood of tolerating a sustained 50% increase in intravascular volume as pregnancy progressed virtually impossible; early, scheduled valve replacement in the first trimester would likely have obviated the need for emergent surgery in a critically ill patient in the third trimester when fetal oxygenation and perfusion requirements were higher. We believe that the fear of complications of surgery during pregnancy often results in delay and, as with other types of surgery, may become a self-fulfilling prophecy.

The use of cardiopulmonary bypass in surgery poses specific challenges with respect to fetal perfusion and oxygenation, and fetal mortality rates up to 30% have been reported.5,35,48 In cases in which cardiopulmonary bypass is required, the shortest possible periods of mild hypothermic or normothermic perfusion with a strategy of high flow–high pressure perfusion have been recommended. Maternal acid-base monitoring is important during this type of surgery as well. Comprehensive recommendations for cardiopulmonary bypass parameters in pregnancy have been previously described.5,35,48 During cardiopulmonary bypass, fetal monitoring may help guide adjustments to pump perfusion parameters; such adjustments may result in resolution of an abnormal fetal heart rate pattern and allow delivery to be avoided. Such cases are highly complex, and the decision to continue attempts to reverse abnormal fetal heart rate patterns or to interrupt the primary procedure for an emergent cesarean delivery is a difficult one. We have seen both successful resolution of intraoperative fetal hypoxia with specific pump adjustments and the need for simultaneous cesarean delivery with a secondary operative team. A multidisciplinary approach to planning in a center with experience in such procedures is obviously essential, to both optimize maternal and fetal outcome and minimize psychological trauma to nonobstetric team members.

Laparoscopic Abdominal Surgery

Like in the nonpregnant population, laparoscopic surgery has been shown to decrease operative time, postoperative pain, hospital length of stay, recovery time, and wound complications as compared with laparotomy during pregnancy.49,50 In the past, concerns about uterine injury and pneumoperitoneum prohibited laparoscopic surgery during pregnancy. The concern with pneumoperitoneum was based on studies of ewes that showed that CO2 insufflation induced maternal hypercapnia, which led to fetal hypercapnia, tachycardia, and hypertension.51 In recent decades, however, evidence has mounted to suggest that laparoscopy, even at advanced gestational ages, can be undertaken safely and is the preferred treatment modality for many conditions52–56 Indeed, even direct intrauterine CO2 insufflation is increasingly utilized for fetal surgical procedures without ill effect.57 Laparoscopy may allow better abdominal exploration with less uterine manipulation as compared with laparotomy. Initial port placement may be accomplished with the open (Hasson), closed (Veress), or optical trocar techniques, depending on the fundal height and experience of the surgeon. Left subcostal entry or ultrasound-guided entry have also been described to avoid uterine injury.58 CO2 insufflation pressures of 10–15 mm Hg have been recommended by the Society of American Gastrointestinal and Endoscopic Surgeons for the pregnant patient.58

DISCUSSION

A critical review of the available evidence in the context of known principles of maternal and fetal physiology does not support the historic causal relationship between nonobstetric surgery and either early pregnancy loss or preterm birth. In addition, neither essential preoperative diagnostic procedures nor the administration of general anesthetic agents appears to be teratogenic. We do not imply that any surgical procedures during pregnancy should be undertaken lightly or without proper indications. There is no place for elective surgery at any stage of pregnancy. Rather, we feel that the concept of surgery during pregnancy needs to be demystified. When the risks of intraoperative maternal hypotension and hypoxia are minimal, or can be mitigated by appropriate modification of surgical or anesthetic technique, both the available literature and a consideration of known principles of maternal and fetal physiology suggest that surgery at any stage of pregnancy does not subject either the mother or fetus to significant risks beyond those associated with the disease itself or the complications of surgery in nonpregnant individuals. On the other hand, in procedures involving significant risk of maternal cardiorespiratory compromise (predominantly cardiovascular and neurosurgical procedures), or when the physical approach to the primary surgical site is obstructed by the enlarged uterus, this sanguine assessment must be modified. However, even in such cases, careful preoperative planning and preparation by an experienced surgery, neonatal, anesthesia, and maternal-fetal medicine team will often allow successful surgery without fetal compromise or delivery. With few exceptions, the indications for surgery in the pregnant woman are similar to those for the nonobstetric population.

Withholding indicated surgery from a pregnant woman as a result of fears of teratogenesis, pregnancy loss, or preterm birth would appear to be unfounded and may significantly contribute to both maternal and neonatal morbidity. Such fears may themselves be a significant contributor to maternal and fetal morbidity associated with surgical disease in pregnancy.

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