Download amant et al gynecologic cancers in pregnancy. guidelines of a

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Gynecologic Cancers in Pregnancy: guidelines of a second international
consensus meeting
ABSTRACT
Cancer in pregnancy is no longer a rare diagnosis, affecting from 0.05 to 0.1% of pregnancies.
With delayed childbearing and increased rates of malignancies with age, the incidence of
cancer during pregnancy continues to rise. With the scarcity of evidence-based research and
with rapid advances in diagnostic procedures and treatment techniques, there is an essential
need for timely and effective knowledge translation on cancer in pregnancy management. It is
widely accepted that maternal cancer in pregnancy should be optimally treated. However, the
lack of sufficient knowledge creates misperceptions regarding appropriate treatment action;
women often refuse termination for religious and social reasons or deny or delay treatment in
order to protect their fetus, putting themselves at an increased risk of morbidity and mortality.
When the reproductive organs are involved, treatment remains the most challenging.
Objectives To provide timely and effective guidance for pregnant women and health care
providers in order to optimize maternal treatment and fetal protection. To promote effective
management of the mother, fetus, and neonate when administering potentially teratogenic
medications. New insights and more experience were gained since the first consensus meeting
5 years ago.
Methods Members of the ESGO task force ‘Cancer in Pregnancy’ in concert with other
international experts reviewed the existing literature on their respective areas of expertise. The
summaries were subsequently merged into a complete manuscript that served as a basis for
discussion during the consensus meeting. All participants approved the final manuscript.
Results In the experts’ view, cancer can be successfully treated during pregnancy in
collaboration with a multidisciplinary team, optimizing maternal treatment while considering
fetal safety. In order to maximize the maternal outcome, cancer treatment should follow a
standard treatment protocol as for non-pregnant patients. Iatrogenic prematurity should be
avoided. Individualization of treatment and effective psychological support is imperative to
provide throughout the pregnancy period. Diagnostic procedures, including staging
examinations and imaging, such as magnetic resonance and sonography, are preferable. Pelvic
surgery, either open or laparoscopic, as part of a treatment protocol, may reveal beneficial
outcomes and is preferably performed by experts. Most standard regimens of chemotherapy
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can be administered from 14 weeks gestational age onwards. Apart from cervical and vulvar
cancer, as well as important vulvar scarring, the mode of delivery is determined by the
obstetrician. Term delivery is aimed for. Breastfeeding should be considered based on
individual drug safety and neonatologist-breastfeeding expert’s consult.
Conclusions Despite limited evidence-based information, cancer treatment during pregnancy
can succeed. State-of-the-art treatment should be provided for this vulnerable population in
order to preserve maternal and fetal prognosis.
Keywords: cancer; pregnancy; chemotherapy; consensus; gynecologic
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INTRODUCTION
The diagnosis of cancer during pregnancy is on the rise. Based on an estimation that 0.050.1% of pregnancies is affected, it is calculated in Europe that 2500-5000 new cases of cancer
are diagnosed during pregnancy annually. The concurrence of cancer and pregnancy
complicates treatment in each stage, including diagnostic, treatment, delivery, postpartum,
and neonatal periods. Management of gynecological cancer is one of the most complicated
and requires a team of dedicated experts. The ultimate goal of cancer treatment during
pregnancy is to achieve a prognosis similar to that of non-pregnant women.1 Since treatment
of cancer in pregnancy is a tremendous therapeutic challenge, and given the scarcity of
evidence-based information and clear guidelines, clinicians have long been reluctant to treat
pregnant cancer patients. A physician’s survey in 2011 showed that
contrary to new
evidence, termination of pregnancy, delay of treatment and also iatrogenic preterm delivery is
often preferred, mainly by physicians in non-academic hospitals.2
It is of paramount importance to disseminate experts’ knowledge, updated treatment
protocols, new evidence-based information, and appropriate treatment techniques in order to
optimize treatment success of pregnancies complicated with cancer. An International
Consensus meeting of leading experts was first held on the 3rd of July 2008, in order to create
a comprehensive protocol.3 Since 2008, our knowledge on the management of cancer in
pregnancy has increased considerably. These include better documentation of the
pharmacokinetics of chemotherapy, as well as maternal and fetal outcomes, more
individualized clinical experience, and new treatment techniques. Moreover, we now have a
wider consensus incorporating the French guidelines, which differed in the first protocol.
Such knowledge is essential for a more confident approach to cancer treatment during
pregnancy. We organized a second International Consensus meeting in order to review the
novel information in the field and to adjust the existing protocols. In preparation for the
second consensus meeting, we identified the experts based on their scientific and clinical
focus or active membership in the ‘cancer in pregnancy’ task force of the European Society of
Gynecologic Oncology (ESGO). We also consulted more experts in related fields, including
those residing outside of Europe, resulting in an additional emphasis on teratogenic, obstetric,
and neonatal aspects. The members were divided into small groups and assigned a topic based
on their area of expertise. Each group reviewed the literature, and the information collected
was used for a first draft on each particular topic. These contributions were merged into one
draft that was circulated to all participants before the meeting, scheduled on the 17th of May
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2013, in Leuven, Belgium. The manuscript was systematically discussed, and changes were
made in accordance to agreements made during the meeting. Final changes were made after
the meeting, and the manuscript circulated among the experts until consensus was obtained.
All participants of the meeting also coauthored the paper.
Since 2008, this field has seen significant progress in research, diagnostic measures, treatment
methodology, as well as ethical considerations, which have collectively contributed to
treatment success and should be delivered to the treating physician.
TERATOGENIC EFFECTS
A teratogen is defined as a substance or environmental hazard which, while acting during
gestation, can adversely affect the embryo or fetal development. In pregnancies complicated
by cancer, maternal stress and diagnostic and treatment procedures may all contribute to their
teratogenicity. Genetic variability in drug metabolism, the administered dose, the timing and
duration of exposure, and permeability across the placental barrier can modify the teratogenic
potentials.4, 5 Teratology domains include death (miscarriage, stillbirth), major malformations
and minor anomalies, intrauterine growth retardation or large for gestational age neonates,
organ dysfunction, long-term neurodevelopment outcomes, increased mutagenicity, and
impaired fertility. Resultant fetal outcomes are often contingent upon the stage of fetal
development and time, “critical windows of exposure”.5-9 The first 8-14 days post-conception
are known as the “all or none” period, where exposure to a teratogen is likely to result in
unfavorable outcomes or death of the conceptus. Morphological defects are mostly limited to
exposures in the first trimester and up to 14 weeks (eyes, genitalia, and hemopoietic system
develop longer, and the central nervous system (CNS) develops throughout pregnancy and
postpartum).10, 11 The risk is exacerbated if exposure occurs during gastrulation (3-5 weeks
post-conception), a time of rapid cell differentiation. Throughout the second and third
trimesters, the fetus’ growth, CNS development, and organ maturation may be negatively
impacted.6, 12 The DNA of the fetus may be altered at any time during pregnancy, resulting in
possible future oncogenic or genetic mutations.5, 13
Treatment management, which may include surgery, radiotherapy, chemotherapy, treatments
with targeted agents, and immunosuppressives in mono- or poly-therapy, are potentially
teratogenic. However, one must consider that even in healthy, unexposed pregnancies, women
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have an inherent risk for aversive outcomes, with baseline risks of miscarriage (up to 15%),1416
stillbirths (0.5%),15,
17
major fetal malformations (1-3%),15,
18
and IUGRs (4-8%).19,
20
Women should be provided with such information in order to properly assist her in the
decision-making process
GENERAL MANAGEMENT
Psychological support
The diagnosis of cancer in pregnancy is a dramatic event that poses difficult dilemmas for the
pregnant patient, her family and treating physicians. Therefore, the importance of
psychological support for those who are undergoing or have undergone cancer-complicated
pregnancies should not be underestimated. Previous studies, despite slight flaws in
methodology, have shown both a significant portion of female cancer patients who require
and desire psychological support do not receive it21 as well as the positive effect of
psychological intervention, observed in behavioral and social changes in the remainder of
patients. Improvements in patients’ coping skills, social interaction, social adjustment as well
as stress and anxiety management were observed.22
Staging examinations
Staging examinations are performed as in non-pregnant women and are important as far as
they will alter and determine appropriate therapeutic procedures that optimally treat the
mother while maximally protecting the fetus, with an additional concern for preventing an
accumulation of low-dose radiation. Ultrasonography and magnetic resonance imaging (MRI)
techniques are preferred. MRI in cervical cancer patients can help determine tumor size in
three dimensions, stromal invasion, degree of healthy stroma, vaginal and parametrial
invasion, and also lymph node infiltration.23 As stated by the American College of Radiology,
present data have not documented any deleterious effects of MRI exposure on the developing
fetus in any trimester of pregnancy.24 Previously inconclusive information on Gadolinium for
imaging during MRI scans has been updated since the first consensus meeting. Gadolinium (a
category C drug according to the U.S. Food and Drug Administration) should only be used if
absolutely essential. No adverse effects to the neonate have been found after gadolinium
exposure in all three trimesters.25 However, gadolinium crosses the placenta and is excreted
by the fetal kidney into amniotic fluid; it remains unknown how long it stays in this space
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with the potential for dissociation of gadolinium ion from its chelate molecule (which then
becomes toxic).24 An MRI without gadolinium, can also provide sufficient information on
parametrial invasion. In small series, MRI features of pregnant cervical cancer patients were
comparable to non-pregnant patients, and allowed for tailored treatment planning. A good
correlation between MRI findings and pathology specimens was also found.26,
27
Also,
intravenous gadolinium is not essential for examination of an adnexal mass in pregnancy,
since this is mainly applied to document the presence of solid components in a cystic adnexal
mass, but this can easily be seen by gray-scale and Doppler sonography.28
Although ionizing examinations of distant parts of the maternal body expose the fetus to low
doses of radiation, the accumulation of which may harm the fetus. The general rule when
performing radiologic and nuclear medicine examinations during pregnancy is that the
radiation doses should be kept as low as reasonably achievable (ALARA) if not avoided.29 In
the general population, 100 mGy is the accepted threshold radiation dose for a measurable
increase in induced cancers,29 most likely the threshold dose for fetuses is lower. The fetal
dose from nuclear medicine examinations is variable and depends on factors related to
maternal uptake and excretion of the radiopharmaceutical, passage across the placenta, fetal
uptake and physical decay rate of the radioactive compound. The estimated fetal radiation
exposure during FDG-PET studies,30 ranged between 1.1 to 2.43 mGy, which is significantly
below the threshold dose for deterministic effects (50 to 100 mGy) as well as the yearly
background from natural causes (3.4 mSv).30 Chest X-ray exposes the fetus to a negligible
dose of the order of 0,1mSv; 1mSv being the dose to the mother.30 A CT scan of the thorax
with abdominal shielding is possible in cases of high suspicion for mediastinal, pleural and/or
lung metastases.
Though small case series have been published for breast cancer31 and melanoma,32 the use of
sentinel lymph node detection with a radiocolloid in cervical cancer mothers during
pregnancy has not yet been assessed and is still under investigation in non-pregnant patients.
Therefore, it should not be used during pregnancy. The sentinel lymph node procedure for
unifocal vulvar tumors smaller than 4 cm is standard practice in non-pregnant patients.
However, in regards to its use in pregnancy, the benefits of this procedure should be
outweighed against the fetal risks. Only one report documents the uncomplicated use during
pregnancy.33 It is calculated to be safe since the low tracer dosages and the retention of the
tracer in the inguinal nodes result in a fetal exposure below the threshold dose.33 However, the
current estimation of nuclear medicine associated doses is not considered accurate with
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variations up to 50% calculated for doses absorbed by the mother. The dosage to the patient is
of the order of a few mSv.30 Little data is available to assess the risk posed to the unborn
child. The use of blue dye is avoided due to the possibility of anaphylactic allergic reactions.
Due to the limited clinical data available, sentinel lymph node detection should only be used
after carefully considering maternal safety and risk of nodal recurrence.
The number of studies conducted on serum tumor markers during pregnancy is limited.
During normal pregnancy, tumor markers including hCG, alfa-fetoprotein, CA 15.3, SCC and
CA 125 can be elevated. 3.3% to 20.0% of CA15-3 measurements are above the cut-off level
(max 56 U/ml in the third trimester). 3.1% and 10.5% of SCC measurements are above cut-off
levels (max 4.3 µg/L in the third trimester). Up to 35% of CA 125 levels are above cut-off;
being highest in the first trimester (max 550 U/ml). Inhibin B, AMH, HE4 and LDH levels
were not elevated in maternal serum during normal pregnancy, therefore they could be used
for differential diagnosis.34, 35
Treatment
Treatment of cancer in pregnancy creates a conflict between optimal maternal therapy and
fetal well-being. The goal of treating cancer-complicated pregnancy is to reach as close to the
standard prognosis as possible. Treatment should be similar to non-pregnant cancer patients
whenever possible with adaptations and concerns explained in detail below. A checklist of
standard care for high-risk pregnant women can be found in Table 1. A physician’s survey in
2011 showed that in contrary to new evidence, termination of pregnancy, delay of treatment
and also iatrogenic preterm delivery is often preferred, mainly by physicians in non-academic
hospitals.2
Given the complex social issues that arise with a cancer diagnosis in association with
pregnancy, it is important to assess the pregnant or postpartum woman for psychological
distress. Supportive care at home is highly recommended.
Radiotherapy
Radiotherapy of cancers of the abdomen and pelvic regions is contraindicated due to the
possibility of serious adverse effects to the fetus.15 Therapeutic doses of radiation can induce
microcephaly, mental retardation, micropthalmia, cataracts, iridial defects, skeletal anomalies
and fetal death.10
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Surgery during pregnancy
Surgery is an essential part of oncologic treatment, particularly for gynecological cancers.
Surgery during pregnancy is not rare, with approximately 0.5−2% of pregnant women
undergoing non-obstetric surgery.36,
37
Surgery methodology and outcome is dependent on
gestational age and the stage of fetal development. If the expected delivery date is
forthcoming, one could consider delaying surgery until postpartum. In specific cases,
operations could directly follow caesarean section. For cases where surgery cannot be avoided
or postponed, we present the following protocol.
Surgery Protocols
Standard anesthetic procedures are safe during pregnancy.38 Regarding surgery during the
first trimester, reports have shown an association between surgery during gastrulation
(between 3rd and 5th week after conception) and neural tube defects.39, 40 Therefore, surgery
during this time period should be avoided. In general, abdominal surgery should be
undertaken in the second trimester, because the risk of miscarriage is decreased, and the size
of the uterus still allows a certain degree of access. Every procedure after 20 weeks
gestational age should be performed in the “left lateral tilt” position to avoid vena cava
compression and maintain cardiac preload. In the past 5 years, additional research has been
conducted concerning laparoscopic surgery during pregnancy. It was found that pregnant
patients may undergo laparoscopic surgery safely during pregnancy (<26-28 weeks).41
Depending on the procedure and experience of the surgeon, laparoscopic surgery for more
advanced gestational ages is possible and a comparable complication rate to laparotomy.42, 43
There are no randomized controlled trials that compare laparoscopy and laparotomy for
benign ovarian masses in pregnancy.44 There is an increased risk for fetal loss after
laparoscopy for appendectomy (pooled RR of 1.91 [1.31-2.77]),45 but it is unknown whether
those results can be applied to a laparoscopic approach for gynecologic surgery. We
recommend four prerequisites for surgical interventions during pregnancy: a maximal
laparoscopic procedure time of 90 minutes, a pneumoperitoneum with a maximal intraabdominal pressure of 10-13 mmHg, open introduction and an experienced surgeon. These
conditions will allow for an effective surgery while minimizing potential risks to the fetus.
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Precautions during surgery
A stable maternal condition is the best guarantee for fetal well-being. Knowledge of the risks
associated with surgery during pregnancy and careful monitoring of the maternal condition
during surgery is vital for maternal and fetal health. Significant risks of surgery during
pregnancy include preterm delivery, miscarriage and fetal distress.46 In addition to the risk of
fetal loss, surgery may cause hypercapnia, perforation of enlarged uterus and reduced blood
flow due to both increased abdominal pressure and use of carbon dioxide. Furthermore, the
hemodynamic and physiological changes in pregnancy have important consequences for perioperative monitoring.47 Monitoring of hemodynamic parameters is crucial to prevent hypoxia,
hypotension and hypoglycemia. A pregnant patient is also at risk for aspiration, because of the
pregnancy-associated gastro-esophageal reflux.
The placenta lacks the ability to auto-regulate flow, and its perfusion is determined primarily
by maternal blood pressure. Hypotension will therefore result in a shunting of blood away
from the placenta/fetus, and fetal hypoxia will occur shortly after the onset of hemorrhage or
hypovolemia. One of the earliest signs of maternal distress is fetal distress, and the fetal
condition can be critical by the time maternal hypotension manifests.47 Cardiotocography
(CTG) monitoring during surgery (vulvar cancer or laparoscopy) is therefore advisable in case
intervention is needed for fetal distress (depending on gestational age, local policy, parent’s
consent). A fetal sleep pattern should be discerned from fetal distress.
Post-operative Care
Postoperatively, fetal well-being needs to be assessed by CTG or ultrasound. After surgery,
adequate analgesia (paracetamol, non-steroidal anti-inflammatory drugs [NSAIDs], tramadol
and morphine) and antiemetics (metoclopramide, meclizine, alizapride and ondansetron) can
be prescribed.48,
49
NSAIDs administered in the third trimester of pregnancy may be
associated with premature closure of the ductus arteriosus and possible pulmonary
hypertension in the neonate in 50-80% of cases.50 Although data are limited, there is a
consensus that tocolytic agents are indicated when manipulation of the pregnant uterus is
unavoidable. After surgery on upper parts of the body, an expectant—and, if necessary,
therapeutic—management is advised. Pregnancy is a procoagulant state.51 Therefore, a
prophylaxis with either unfractionated or low-molecular-weight heparin is advisable.
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Chemotherapy
During pregnancy, multiple physiological changes occur affecting the major pharmacokinetic
processes including absorption, distribution, metabolism and excretion (ADME). Changes in
drug metabolism begin at four weeks of gestation, progressively increase, and are more
pronounced in the third trimester of pregnancy. Physiological pharmacokinetic changes have
been shown in humans to result in a decrease in plasma drug exposure (AUC - Area Under
the Curve) and peak plasma concentration and an increase in distribution volume and
clearance.52 In the largest follow up study in breast cancer; there was no survival difference
between women with cancer treatment during pregnancy and stage-matched non-pregnant
women.53, 54 Thus, despite the “dilution” of chemotherapy during pregnancy, current data do
not show worse outcomes in pregnant women who receive chemotherapy compared to nonpregnant women. Therefore, we advocate that chemotherapy dosages are based on actual
patients’ weight and height during pregnancy.
Pharmacokinetics and transplacental passage of chemotherapy
Pharmacokinetics
The elevation of endogenous hormones such as progesterone and estrogen during normal
pregnancy alters the hepatic microsomal oxidase system where elevated or reduced rates of
hepatic metabolism may result in altered transformation of drugs. The cholestatic effect of
estrogen may interfere with biliary drug clearance.52, 55, 56 Therapeutic concentrations of the
active drug may also be affected by hemodynamic changes that take place throughout
pregnancy. Cardiac output and blood volume increase by 50% primarily due to an increase in
plasma volume of 45%, leading to an increase of hepatic and renal perfusion and an increased
glomerular filtration rate which may result in an increased renal elimination. Total body water
also increases by 5-8%, due to the expansion of the extracellular fluid space and the growth of
new tissue. Body water as well accumulates in the fetus, placenta and amniotic fluid, which
collectively contributes to an increase in volume of distribution and may lower the
concentration of drugs and increase their elimination half-life.3, 52, 56 As pregnancy advances
the plasma volume expands at a higher rate than the increase in albumin production, creating
a dilutional hypoalbuminemia which might increase the fraction of unbound drugs.52
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Transplacental transfer
Any chemical substance administered to mother is able to permeate, to some degree, across
the placenta. Transplacental transfer of substances is mediated by passive diffusion, active
transport, facilitated diffusion, and also phagocytosis and pinocytosis.57,
58
Transplacental
transfer of (chemotherapeutic) drugs mainly occurs by passive diffusion, which is based on
physicochemical drug characteristics. By passive diffusion, the amount and rate of transfer are
primarily determined by the concentration gradient of the drug between the maternal and fetal
circulation and placental blood flow. Furthermore, physicochemical properties of drugs such
as lipid solubility, ionization constant (pKA), molecular weight (MW) and protein binding are
critical for placental transfer. Uncharged, low MW (under 500 g/mol), lipid soluble and
unbound compounds can easily cross the human placenta.59 The placenta and more specific
the syncytiotrophoblast and fetal capillary endothelium further express ATP-binding cassette
(ABC) efflux transporters including P-glycoprotein (P-gp: MDR 1/ABCB1), Breast Cancer
Resistance Protein (BCRP/ABCG2) and Multidrug Resistance Protein 1-3 and 5 (MRP 1-3
and 5/ABCC1-3 and 5) which actively extrude substrates to the maternal circulation. Most of
the chemotherapeutic drugs (e.g. anthracyclines, taxanes) are substrates of these ABC drug
transporters.57, 60, 61 A variety of experimental models have been used to study transplacental
transfer. The placenta is a barrier for taxanes; however, platin salts cross the placenta. The
latter is also evident from DNA adducts that are found in amniotic fluid, placental tissue and
fetal blood. An updated summary of the transplacental transfer fates in different experimental
conditions is depicted in Table 2.
Effects of Chemotherapy Exposure
Further evidence has accumulated on the effects of chemotherapy during pregnancy. The
resent information supports the previous evidence that chemotherapy after the first trimester is
not associated with increased rates of birth defects above the rate in the general population
(3%).5,
20, 53, 62-64
Although, intrauterine growth restriction and transient myelosuppression
have been reported and need to be investigated at birth.5, 65
Anthracyclines have notorious cardiotoxic effects, and are uncommonly used in gynecologic
cancers. The evidence for acute and chronic fetal cardiotoxicity, however, after antenatal
exposure to chemotherapy, including anthracyclines, is low. In a pilot study (n=10) there was
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no evidence for acute fetal cardiotoxity after anthracycline exposure.66 Chronic cardiotoxicity
was investigated in larger studies:64,
67
electrocardiograms, systolic and diastolic functions
were normal. A significant smaller shortening fraction, ejection fraction and interventricular
septum thickness was noted, though the values remained in the normal range. Therefore,
treatment with anthracyclines should be used with caution until more supportive data
accumulates and should be avoided if possible.
Major concerns arise over the possible effects of chemotherapy on the developing brain,
which is potentially vulnerable to damage throughout the entire gestation. Long-term
neurobehavioral outcomes remain undefined due to limited and mainly retrospective followup data, although reassuring findings have been reported in small series.68 Recently, a
disharmonious intelligence profile (median follow-up of 22.3 months) was reported, but an
important bias by prematurity was suggested.64 Moreover, internalizing and externalizing
psychological problems were also observed. These findings support the hypothesis that more
subtle changes in neurodevelopment are possible and need to be prospectively investigated.
Behavioral and emotional issues deserve further attention as maternal health status during
early development might also affect child’s behavior.
Side effects of chemotherapy are reduced by the use of supportive drugs. Although data are
lacking, the clinical impression is that pregnant patients suffer less from these side effects.
This may be explained by recent data on the pharmacokinetics of various anti-cancer agents
during pregnancy. Pregnant patients have lower plasma exposure to chemotherapy, making
the systematic use of supportive drugs dispensable.52, 69 If needed, however, the antiemetics,
ondansetron and metoclopramide appear safe to use during pregnancy.49, 70 There are no data
on the use of aprepitant in pregnant patients. When repeated administration of corticoids is
planned, prednisolone is preferred since this is strongly metabolized in the placenta and rarely
crosses the fetomaternal barrier.71 Several studies tried to elucidate the safety of granulocytecolony stimulating factors during pregnancy.72-74 Although obstetrical complications were not
reported, there is only limited evidence for safety.75 Also on the use of erythropoietin during
pregnancy little information is available in literature. Erythropoietin administration is
considered safe, it does not seem to cross the placenta (MW 30400 Dalton) and no teratogenic
effects were found among the small number of women treated during organogenesis.76,
77
Both pregnancy and oncological disease increase the risk of embolism. Prophylactic use of
low molecular weight heparins may be considered if several risk factors are present (obesities,
pelvic surgery, immobilization). If antibiotics are required, preferred drugs in pregnancy are
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penicillines, cephalosporines, carbapenems, piperacilline+tazobactam, erythromycin or
clindamycin.78 A summary of the most important supportive drugs and their fetal safety
profile is depicted in Table 3.
Monitoring of pregnant patient with a gynecological cancer
At diagnosis it is important to determine the exact gestational age and exclude preexisting
fetal anomalies by ultrasonography.
Medical Assessment
It is important to assess the direct and indirect (treatment linked) cancer effects on the general
maternal health and pregnancy. Special attention is needed for cardiac assessment (EKG,
echocardiogram, Holter) in women exposed to anthracyclines and/or chest radiation, as well
as pulmonary function testing for women exposed to bleomycin or chest radiation Renal and
liver functioning as well as evaluation of neuropathy and ototoxicity in case of exposure to
platinum-based therapy are other important things for medical personnel to consider to better
assess the situation and appropriate solutions. With regards to prenatal diagnosis, we note that
non-invasive testing is preferable. However, in case an invasive test is indicated, the tumor
site should be taken into account and avoided in the determination of the access way
(transvaginal/cervical or transabdominal).
Obstetrical management
In pregnancies complicated by cancer, the standard of care for high risk pregnant women
should be adhered to (see also Table 1). Consultation with neonatologists and proper
counseling is recommended to better understand the course of pregnancy, feto-neonatal
outcomes and possible complications.
CERVICAL CANCER
Diagnosis and staging of cervical cancer
The diagnostic approach to cervical cancer during pregnancy is similar to that of non-pregnant
women.27,
13
79
Lymphadenectomy (laparoscopic or laparotomic) can safely be performed
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between the 13th and 22nd weeks of pregnancy. Based on 32 published cases (Table 4), it
appears that a majority of patients have been operated on before the 22nd week of pregnancy,
yielding a median of 19 lymph nodes (range, 6-72). Increasing gestational age represents an
obstacle for satisfactory lymphadenectomy in terms of minimal number of 10 lymph nodes
suggested by FIGO (Figure 1). The technical procedure is dependent on the surgeon’s
experience and preference. Based on these considerations, we divide management based on
the potential to perform a pelvic lymphadenectomy at around 22-25 weeks of pregnancy.
Management of invasive cancer
Pregnancy non-preserving management
In case pregnancy preservation is not aimed for, management is similar to non-pregnant
women. Especially for advanced stage disease, termination of pregnancy and subsequent
standard treatment is advocated. Radical hysterectomy should be performed with fetus in
utero during early pregnancy or after hysterotomy to reduce the volume of the uterus (during
the same procedure) Pelvic radiotherapy causes spontaneous abortion during the first
trimester and fetal death within the first month after external beam radiation during the second
trimester. The advantages and disadvantages of hysterotomy before radiotherapy should
individually be balanced. When hysterotomy is performed before initiating radiotherapy, there
is no replanning of the radiation field, there are less obstetrical complications (bleeding,
diffuse intravascular coagulation) and there is less psychological distress.80 However, the
procedure may be associated with postoperative adhesions that enhance radiotherapy toxicity,
a potential delay of treatment in case of wound infection, and a risk of wound metastasis.
Pregnancy-preserving management
Treatment of cervical cancer during pregnancy remains experimental, especially in case of
large volume tumors. Pregnancy sparing treatment should only be offered, in carefully
selected cases, to motivated patients after sufficient explanation of the limited experience.
Cancer diagnosed before 22-25 weeks of pregnancy
If microscopic invasion after colposcopy is suspected, diagnostic conization is preferably
performed at 12-20 weeks of pregnancy. In stage IA1, conization alone is a sufficient and
relatively safe treatment during pregnancy.81 For higher stages of cervical cancer, pelvic
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lymphadenectomy is proposed in order to diagnose the high-risk disease (with positive nodes)
that may necessitate termination of pregnancy and application of standard treatment.
In IA2 and IB1 tumors, smaller than 2 cm and with negative nodes, a simple trachelectomy or
large conization is proposed82-85 (Figure 2) (similar to fertility-sparing surgery) as several
studies in non-pregnant patients86-88 have shown rates of parametrial involvement to be less
than 1%, thereby justifying this less radical surgery.89, 90 In the absence of obstetrical safety
data of such a procedure during pregnancy, we propose to tailor the resection volume
according to the tumor diameters. Regarding radical trachelectomy (abdominal or vaginal),
several cases are described during pregnancy (Table 5). Apart from the technically
challenging procedure, which is associated with significant blood loss and prolonged surgery,
the obstetrical results are poor when 6 out of 19 described cases (32 %) result in early
abortions related to the procedure. Thus, based on these data we cannot recommend a radical
trachelectomy during pregnancy.
For patients with an IB1 tumor, larger than 2 cm and with negative pelvic lymph nodes,
NACT (neoadjuvant chemotherapy) is proposed until fetal maturity (Figure 2). Alternatively,
the chemotherapy can be administered without performing a lymphadenectomy, followed by
surgical staging after delivery.
Recent updates in literature suggest that delay of treatment until after delivery is a possibility
when the lymph nodes are negative. In a recent review, 76 IB1 cases of delayed treatment are
reported with a 95% rate of survival at a mean follow-up of 37.5 months.91 The median delay
is 16 weeks and no recurrences are reported for patients with microscopically proven negative
pelvic nodes. When progressive disease is observed, either by clinical examination or MRI,
termination of pregnancy or NACT is advocated.
In IB2 and higher stage tumors, NACT is the only way to preserve pregnancy (Figure 2). The
therapeutic value of a pelvic staging lymphadenectomy before the start of the chemotherapy is
unknown but the procedure can add in the decision-making process to continue the pregnancy
or not. Depending on the gestational age and pelvic nodal status on imaging, a para-aortic
lymph node sampling can also be performed. Data on the oncological safety of NACT for
these tumors during pregnancy are still sparse, especially in patients with IIA2, IIB and higher
stages in the early second trimester. The goal of NACT is to stabilize the tumor while
simultaneously preventing tumor dissemination.92 Concerning newly reviewed literature on
NACT, 50 cases are identified in English literature including half of patients with stage IB1
disease (see Table 6). The average age of patients is 32.4 years, with cancer diagnosed at 19.2
weeks of pregnancy. Chemotherapy allows the pregnancy to be continued until 33.2 weeks on
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average. The response to chemotherapy in 6.25% of the patients was complete, in 62.5%
partial, in 28.1% the disease stabilized and in 3.1% the disease progressed. The chemotherapy
used was always platinum-based, alone or in combination with paclitaxel, vincristine, 5-FU,
cyclophosphamide or bleomycin. Chemotherapy was administered at a 3-week interval.
Overall survival rate is 79% (34/43) at a median follow-up of 24 months. The survival rate is
94% (15/16) in IB1 stage at a median follow-up of 12 months (one patient with small cell
cancer died). In stage IB2 the overall survival rate is 70% (12/17) and progression-free
survival is 58.9% at a median follow-up of 27 months (Table 7). Higher stage patients have a
survival rate of 70% (7/10) at a median follow-up of 14 months (see Table 8). These
oncological results need to be interpreted cautiously as the follow-up is short and variable
chemotherapy regimens have been used.
The currently recommended regimen is platinum-based chemotherapy, (cisplatin 75 mg/m2)
preferably with paclitaxel (175 mg/m2) at a 3 week interval.93 In view of recent contradictory
data on weekly schedules of paclitaxel,72, 94 a three-weekly schedule of paclitaxel 175 mg/m2
seems preferable. This schedule is used with an acceptable short-term safety in 27 pregnant
patients in the literature.95 An alternative to cisplatin that has a better maternal toxicity profile
is carboplatinum (AUC 5-6). There is no evidence of a difference in the effect of NACT on
survival by dose intensity.92
When analyzing response during pregnancy to NACT using a single platin agent versus platin
+ paclitaxel, a statistically significant difference in favor of combination therapy is found
(Cochran-Armitage trend test at p=0,049), therefore a combination therapy is preferred. This
is in concordance with data of non-pregnant patients (Figure 3). Regarding the dose of
platinum agents, cisplatin is used in pregnant patients at doses ranging from 20 mg/m2 for 5
days, up to 75 mg/m2 (given on day 1, day 1 = day 21), with cumulated doses up to 500
mg/m2.96 Data on the use of gemcitabine, vinorelbine and topotecan during pregnancy are
very limited, and should be avoided in pregnant patients.96, 97
Cancer diagnosed after 22-25 weeks of pregnancy
At this gestational age, a complete pelvic and/or para-aortic lymphadenectomy is difficult to
perform; therefore the decision-making cannot rely on the nodal status. In IA2 and IB1
tumors smaller than 2 cm, we propose delay of treatment until fetal maturity, with delivery
after discussion with a neonatologist. When progressive disease is observed, either by clinical
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examination or MRI, early delivery or NACT is advocated. Alternatively, NACT can be
started straight away. For higher stages, NACT is the only way to preserve pregnancy and
reach fetal maturity. Patients should be carefully informed that limited experience is available
for this treatment during pregnancy, and larger series are needed to evaluate oncological
safety.
OVARIAN CANCER
Most ovarian cysts during pregnancy are physiological and will disappear naturally. In case of
a persisting cyst, ultrasonography is performed. When the cyst is benign and asymptomatic,
we opt for watchful waiting. The risk of complications such as torsion has been found to be
around 8%.98 A staging procedure is proposed when there is high suspicion for preinvasive or
invasive cancer. Surgical procedures should be performed with utmost care. Key point of the
surgery is to avoid cyst rupture. An adnexectomy instead of cystectomy is thus preferred. If
possible, surgery is performed after 14 – 16 weeks of gestation. At this stage the placenta is
capable of sufficient hormonal supply in case of bilateral adnexectomy.
Borderline
As in fertility-sparing surgery, when a borderline tumor is suspected or confirmed by frozen
section, surgical staging consists of unilateral salpingo-oophorectomy (removal of a fallopian
tube and an ovary), infracolic omentectomy (partial excision of omentum), appendectomy
(only for mucinous tumors), and peritoneal biopsies. A recent study discovered a high
incidence of advanced stage tumors with 20% of the patients finally diagnosed as stage II to
III. Since the pelvic peritoneum and pouch of Douglas cannot be reliably examined during
pregnancy, the authors recommended up-front salpingo-oophorectomy with planned restaging
surgery postpartum.99 During follow-up, there was no progression to invasive cancer.
Invasive early stage
Invasive epithelial ovarian cancer during pregnancy is uncommon and the evidence is mainly
based on case reports or small series ranging from 10-27 cases.100-105 Since most cases are
diagnosed at an early stage, surgical staging with preservation of the uterus and contralateral
ovary is indicated. Standard treatment as for non-pregnant women should be strived for.
Patients with stage IA grade 2-3, IB, IC and IIA, additionally require a lymphadenectomy and
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platinum-based chemotherapy, though the order can be discussed. When staging is not
complete after the first surgery, chemotherapy can be initiated during pregnancy with
completion of staging postpartum, thereby avoiding risks of a second surgery during
pregnancy.
Recent findings show that in mucinous tumors, grading is not reliable and the treatment is
determined using the microscopic growth patterns. Whereas an expansive growth pattern
relates to an excellent outcome after extirpation of the cyst only, tumors with infiltrative
growth are high grade.106, 107
Invasive advanced stage
Standard treatment (debulking to no residual tumor) for advanced stage ovarian cancer is not
possible when the pregnancy is continued. With poor maternal prognosis and limited
experience, termination of pregnancy remains an appropriate option. When maintaining
pregnancy, a suboptimal cytoreduction during pregnancy will unnecessarily jeopardize fetal
health and is therefore not recommended. Therefore, NACT until fetal maturity and complete
cytoreduction after delivery is the best way to treat advanced ovarian cancer during
pregnancy.
Combination therapy of paclitaxel and carboplatin should be the choice of treatment, as used
by non-pregnant ovarian cancer patients.108-116 In the absence of data on the systemic use of
bevacizumab, we do not recommend its use during pregnancy. Bevacizumab is an
immunoglobulin that may theoretically cross the placenta, depending on the stage of
pregnancy. One report describes early pregnancy loss after intraocular bevacizumab.117
Non-epithelial ovarian tumors
Non-epithelial ovarian neoplasms (germ cell, sex-cord stromal tumors) are usually stage I
when diagnosed in pregnancy and are primarily treated by surgical resection. Indications for
adjuvant chemotherapy are the same as for non-pregnant patients. The number of cycles of
chemotherapy for yolk sac tumors cannot be based on the tumor marker; 6 cycles of
chemotherapy are recommended. In non-pregnant patients, the combination of bleomycin18
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etoposide-cisplatin (BEP) is used for non-epithelial ovarian tumors. Alternatively, during
pregnancy paclitaxel-carboplatin or cisplatin-vinblastin-bleomycin can be used. Paclitaxel is
an active drug in germ cell tumors118-121 whereas vinca alkaloids have been used for a long
time, and many reports cite their use as relatively safe during pregnancy.5, 122-127
VULVAR CANCER
During pregnancy, the standard surgical treatment should be provided depending on the tumor
diameter, stage of disease and gestational age.
In clinically node-negative patients, radical local excision or radical vulvectomy with uni- or
bilateral lymph node dissection or sentinel node procedure is performed. The surgical margins
need to be radical (2 cm macroscopically and 8 mm microscopically)128, 129 in order to avoid
the need for post-operative radiotherapy in pregnancy. Since genital vascularisation is
markedly increased in the third trimester, surgery may result in higher blood loss, and the
treatment of cases diagnosed after 36 weeks of gestation might be delayed in the postpartum
period. Patients with sentinel node metastasis require additional treatment. In cases with
isolated tumor cells in the sentinel lymph node and negative inguinal nodes adjuvant
radiotherapy might be avoided.130 When nodal involvement is evident after inguinofemoral
lymphadenectomy, pregnancy is terminated or delivery is planned depending on the
gestational age followed by postpartum irradiation. Delay of radiotherapy by 6-8 weeks is
within the safety limits.131
When preoperative examinations suggest inguinal lymph node involvement, the prognosis is
less favorable and inguinal radiotherapy to prevent local groin recurrence becomes vital.
Immediate treatment is then mandatory and termination of the pregnancy in the first and
second trimester is indicated. In the third trimester, a caesarean section is performed, followed
by standard treatment. NACT to reduce tumor size for locally advanced disease remains
experimental.
DELIVERY PLANNING
Timing of Delivery
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A 3-week interval between the last cycle of chemotherapy and the delivery avoids problems
associated with hematopoietic suppression in both the mother and the child (bleeding,
infections, anemia) and avoids presence of cytotoxic drugs in the neonate. For all patients, a
term delivery (>37 weeks gestation) is preferred. However, deterioration of maternal
condition or the need for radiotherapy may indicate a need for preterm delivery. When a
patient is diagnosed after 30 weeks gestation, one cycle of chemotherapy during pregnancy
(max 35 weeks), followed by term delivery >37 weeks, is preferable to a late preterm delivery
without chemotherapy during pregnancy.
Mode of delivery
A natural vaginal birth is normally preferred whenever possible in the absence of
complicating factors. However, in which cases caesarean section is necessary, has been
debated. Since the 2009 protocol, some progress has been made in delivery methods, leading
to the following recommendations.
Advantages of a vaginal birth also apply to the oncological population and include reduced
blood loss, operative and infection risk, shorter duration of hospitalization and better
preservation of reproductive future. This is especially important for patients with
myelosuppression after chemotherapy.
Caesarean section is indicated in case of cancer metastasis to the long bones to avoid the risk
of fractures by lithotomy position. Active pushing can also be contra-indicated in central
nervous system metastasis causing increased intracranial pressure. Assisted vaginal delivery
can then be safely offered in most cases.
Cervical intraepithelial neoplasia is not an indication for caesarean section.132 The overall
impact of mode of delivery on the oncological outcome of cervical cancer is controversial.133135
In the presence of cervical cancer, vaginal delivery may contribute to a higher risk of
lymphovascular dissemination, major bleeding, birth canal obstruction, infection, cervical
laceration and cancer cell implantation at the episiotomy site. Reviewing published cases of
episiotomy recurrences, we encountered 7 fatal cases after vaginal delivery (Table 9).
Cesarean section is therefore recommended in case cervical cancer is still present. A corporeal
uterine incision avoiding the lower uterine part in order to prevent wound metastasis is
preferred. In addition, Cesarean section enables complementary surgical treatment of the
cancer, when indicated. In patients operated for vulvar cancer during pregnancy, vulvar
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scarring and the risk for vulvar trauma can be an indication for cesarean section. Vaginal
delivery in the presence of vulvar cancer needs individual consideration.136
The placenta should be examined for metastatic disease. Maternal metastasis to the fetus is
exceptional. For gynecological malignancies only one case report of placental metastasis of
cervical cancer, one case of vaginal angioblastic sarcoma and one case of vulvar melanoma
was reported in literature.137-139 We recommend microscopic examination by a pathologist, if
metastases are present, follow-up of the infant for development of malignant disease is
advised.
Postpartum Management
Breastfeeding during chemotherapy is not completely contraindicated. Breastfeeding safety
should be considered based on individual drugs according to their pharmacokinetic properties.
The LactMed website, which is updated biweekly and neonatologist-breastfeeding experts,
should be consulted. In case of doubt, breastfeeding is not advisable, especially since a safe
alternative is available. Oncological treatment can be continued immediately after vaginal
delivery, and one week after uncomplicated cesarean section.140
NEONATOLOGIST/PEDIATRICIAN PERSPECTIVE
The duration of gestation, the maternal disease and the toxicity of treatments in conjunction
with the timing of the interventions are factors that may affect early postnatal and long term
outcomes of children born to mothers with cancer.
All neonates need to be examined at birth, by a neonatologist, to assess the neonate's
transition from intrauterine to extrauterine life and to detect congenital malformations and
actual or potential diseases. Anthropometric measurements (weight, length, head
circumference) should be obtained to assess fetal growth according to gestational age. In
cases of chemotherapy exposure, the neonates need to be investigated for hematological,
immunological, cardiac and neurological disorders, all of which have to be monitored long
term. Infants and children should be screened for cancer development,141, 142 and reproductive
development.
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Effect of prematurity
Prematurity and, in particular, “late preterm birth” (34+0 to 36+6 weeks gestation), is the
most common neonatal outcome reported in neonates born to pregnant cancer patients. Most
of these neonates are delivered preterm, primarily due to oncological management reasons.
Where possible, prematurity should be avoided.
Deliveries that are very early are associated with an increased risk of mortality, morbidity and
adverse neurodevelopmental outcome: the lower the gestational age, the higher the risk.143-145
Mortality rates decrease from about 65% at 23 weeks gestation to 39% at 24 weeks, 24% at
25 weeks and 7% at 28 weeks (data from the Vermont Oxford Network 2011 collecting
clinical outcome data for infants weighing between 401 and 1500 g at birth from over 950
Neonatal Intensive Care Units around the world). The overall incidence of severe disabilities
(defined as cerebral palsy, severe cognitive impairment or neurosensory deficits) shows a
similar inverse relationship with gestational age at birth.143, 146 The incidence decreases from
approximately 31% in neonates born at 23 weeks to 13% at 27 weeks (data from Vermont
Oxford Network Follow-up).
Even late preterm neonates show a higher vulnerability to develop diseases in the early
neonatal period compared to term neonates. Mortality rates show a 3-fold increase (7.1
deaths/1000 live births between 34 and 36 weeks gestation) compared to term born controls.
As well, morbidity rates approximately double for each additional gestational week earlier
than 38 weeks (from 5.9% if born at 37 weeks’ gestation to 51.7% at 34 weeks’ gestation).147
Late preterm neonates have an increased risk of temperature instability, respiratory distress
syndrome, excessive weight loss/dehydration requiring intravenous infusion, sepsis,
hypoglycemia, and jaundice that require phototherapy.148,
149
A growing body of literature
suggests that infants born late preterm have higher risks of later childhood neurological
morbidity (poor school performance, early intervention services and/or special education
needs);150-154 although caution is needed when interpreting these results, as confounding
maternal, obstetrical and neonatal factors also need to be considered.
CONCLUSION
Cancer is the second leading cause of mortality in women during the reproductive years.
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Effective treatment of gynecological cancers during pregnancy is achievable. The presence of
cancer during pregnancy creates a challenging conflict between maternal care and fetal wellbeing. Oncologic treatment needs to be individualized while placing an emphasis on optimal
maternal care, by adhering to standard (non-pregnant) treatment protocols, with consideration
for fetal safety. Treatment protocol should be developed on an individual basis considering
maternal morbidity, effective treatment, and maximal probability of survival. Comprehensive
counseling on treatment options, pregnancy outcome, and potential teratogenicity should be
given to the patient before treatment is initiated. The complexities that arise with treating
cancer in pregnancy demand for a supportive multidisciplinary team that includes a
neonatologist, perinatologist, oncologist, obstetrician, teratologist, and toxicologist, and
provides psychological support throughout the entire pregnancy and postpartum. It was found
that the staging of the cancer’s progression should be performed as in non-pregnant woman,
although with additional efforts to prevent radiation accumulation. Previously inconclusive
information regarding the use of Gadolinium in MRI scans has been updated, and the
suggestions for its use are included in this protocol. Some precautions should be given in
planning a surgery during the gastrulation period, considering the potential association with
neural tube defects. In addition, abdominal surgeries should be scheduled during the second
trimester, when the size of the uterus still allows a certain degree of access and the risk of
miscarriage is still low. It is imperative that surgical procedures after 20 weeks gestation be
performed in the “left lateral tilt” position so as to avoid vena cava compression and maintain
cardiac preload. An updated summary of chemotherapy treatment, considering gestational age
of initiation and termination, was provided in this protocol, focusing on the effectiveness of
maternal treatment and fetal and neonatal safety. A complete and updated guide to optimal
delivery methods is included, as well as novel postpartum management related both the
mother and the neonate. Neonatal prematurity has been identified as the most common,
adverse outcome associated with cancer-complicated pregnancies; guidelines on prematurity
prevention were provided in the present report. Finally, specific gynecological cancers were
described in context with the unique issues that they may pose for treatment and during
pregnancy. The treatment and prognosis of cervical cancer during pregnancy needs further
research. A matched case-control study of 132 women diagnosed with cervical cancer during
pregnancy is currently being performed by members of the ESGO task force. The crucial role
of lymphadenectomy as part of staging in particular is a large step towards individualization
of treatment based on more accurate staging and risk assessment. How this will be
implemented in clinical practice, and whether it will improve maternal prognosis is certainly
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an area of future research. In addition, the long term maternal prognosis and health of the
children needs to be better documented. The ESGO ‘Cancer in Pregnancy’ task force aimes to
explore
this
field
and
welcomes
more
international
collaborators
(http://www.esgo.org/task_forces/Pages/CancerinPregnancy.aspx).
Current
related
research
and
expert
knowledge,
which
support
and
strengthen
recommendations from our previously guidelines published in 2009, is included. Knowledge
on optimal management is still limited; nevertheless, cumulative research and clinical
experience over the last number of years have advanced our understanding of the management
of cancer during pregnancy. This knowledge will assist physicians and families in making
informed decisions regarding maternal treatment and fetal safety.
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