Critical Care Obstetrics part 73 potx

The management of ovarian cancer in pregnancy does not greatly differ from that of the non - pregnant patient.. While radiation therapy is employed in non - pregnant women with breast -

The management of ovarian cancer in pregnancy does not greatly differ from that of the non - pregnant patient Many preg-nant women who are diagnosed with an invasive neoplasm are young and have not completed childbearing Fortunately, as most masses are asymptomatic and found incidentally, they are often early stage Fertility - sparing treatment is an appropriate option for that subset of patients whose disease is found to be of low malignant potential (LMP), such as stage IA tumors or germ cell tumors (any stage) While complete surgical staging ( peritoneal washings, biopsies of the parietal and pelvic peritoneal surfaces and diaphragm, omentectomy, and pelvic and aortic lymph node dissections) is necessary to document correct staging, it is not always practical in the gravid patient, especially as gestational age advances The surgeon should attempt to biopsy any area suspi-cious for extraovarian disease if feasible If the patient requires adjuvant chemotherapy, there is a risk of subsequent ovarian failure of varying severity; however, most patients will not suffer from persistent premature ovarian failure, and will be able to conceive with the remaining ovary and uterus after completion

of chemotherapy

Rarely, a patient will have more advanced disease, and more extensive surgery may be required Management is individualized for patients with advanced disease depending on fertility desires, gestational age and extent of disease If the malignancy is diag-nosed when the fetus is mature treatment may be initiated after delivery If the patient does not wish to continue the pregnancy, appropriate cytoreduction and subsequent treatment may be undertaken, and termination of the pregnancy If the pregnancy

is desired, and the fetus is not mature, management becomes more complex In selected patients, if clinically indicated, both ovaries may be removed, the pregnancy continued and subse-quent treatment delayed One option is to offer neoadjuvant che-motherapy until fetal maturity is achieved followed by interval cytoreductive surgery at the time of delivery or shortly thereafter

If the patient chooses to delay therapy after adequate counseling, continuing advances in neonatal intensive care capability allows for much shorter delay in treatment as the threshold for fetal viability decreases Active coordination between the gynecologic oncologist and perinatologist is critical and individualized con-sideration must be given to gestational age, maternal condition, and prognosis

Germ cell tumors are the most common ovarian malignancy found in pregnancy; up to 30% of malignancies in pregnancy are dysgerminomas They are often discovered when a patient pres-ents with torsion or incarceration of a massive ovary This can occur in the late fi rst or early second trimester when the uterus

is rapidly growing out of the pelvis Of note, LDH levels are not affected in pregnancy, and may be employed as a useful tumor marker Alpha fetoprotein levels do change in pregnancy; however, an extremely elevated AFP level may be associated with

an endodermal sinus tumor Standard treatment in these cases is unilateral oophorectomy with pelvic and para - aortic lymph node dissection Fifteen per cent of dysgerminomas can be bilateral, but blind wedge resection or biopsy of a normal - appearing

con-can be closely observed [64,66,70] Masses that persist into the

second trimester, particularly those that are rapidly enlarging,

larger than 8 cm, and/or appear complex and multiseptated, most

often require surgical exploration [64]

It has generally been advised that surgical exploration be

undertaken at approximately 16 – 20 weeks gestation This is a

time when physiological cysts have regressed and the placenta is

hormonally functional and the fetus is supported independent of

the corpus luteum If an oophorectomy which removes a

func-tional corpus luteum is required during the fi rst trimester, the

pregnancy should be supported with supplemental progesterone

to prevent spontaneous abortion If the mass is discovered in the

third trimester, defi nitive work - up, management, and surgical

exploration can usually be deferred until after vaginal delivery or

during cesarean section

The various options available for the surgical approach must

also be considered Traditionally, patients in these clinical

situa-tions have undergone open laparotomy More recently with

tech-nologic advances more surgical options are now available for use

in the pregnant patient The use of minimally invasive techniques

(including robotic surgery) has been shown to be generally safe

and effective In any surgical approach, the gravid uterus should

be manipulated as little as possible to minimize any potential risk

of spontaneous preterm labor, rupture of membranes or any

other potential complication that may lead to fetal loss If the

mass is benign, unilateral cystectomy is performed whenever

pos-sible and the contralateral ovary should then be inspected to

ensure normal appearance While most masses in pregnancy are

confi ned to a single ovary, it is not uncommon to fi nd bilateral

involvement

There are currently insuffi cient data to determine the optimal

management of patients who require surgery during pregnancy

These decisions should be made on a case - by - case basis in

con-sultation with the patient and all involved medical personnel The

general emphasis in surgical management should be removal of

the mass, and confi rmation of the diagnosis with minimal impact

on the pregnancy

Ovarian c ancer

One in 20 000 pregnancies is complicated by an ovarian

malig-nancy [56,57,71] Approximately 1 in 1000 pregnant women

undergo some sort of exploratory surgery to evaluate an adnexal

mass, and 1 – 5% of these masses are found to be malignant

[72,73] This percentage is lower than found in non - pregnant

women, likely owing to that fact that pregnancy occurs in younger

women and that most masses found in pregnancy are corpus

luteum cysts or some other benign simple cyst The majority of

ovarian neoplasms found in pregnancy are teratomas or

cystad-enomas [63,65,70] Most malignancies found in pregnancy are

classically germ cell tumors; however, with the increasing trend

of delaying childbearing, there has more recently been an increase

in epithelial ovarian malignancies

National Cancer Institute, will affl ict over 178 000 women in

2008 It is one of the most common causes of cancer death in women, second only to lung cancer It is apparent that the inci-dence of breast cancer during pregnancy is increasing, likely sec-ondary to recent trends toward delaying childbearing into the third and fourth decade of life As many as 3 in 10 000 gravid women will have a pregnancy complicated by carcinoma of the breast [3,85,86]

The evaluation of a breast mass during pregnancy should not differ from that of a non - pregnant patient and therefore should not be delayed Mammography may be of use but is associated with a higher rate of a false - positive test when compared with non - pregnant women because of the increased density of breast tissue in pregnancy Because of this an ultrasound may be a useful

fi rst step in the diagnostic process Magnetic resonance imaging (MRI) of the breast may also be useful in prenatal diagnosis of breast cancer; data are currently limited on its use in pregnancy, but it appears to be a safe modality [87 – 90]

If a mass appears suspicious for malignancy on radiographic evaluation, a biopsy is indicated Ideally, this is acquired through

a core biopsy A fi ne needle aspiration may also yield the diagno-sis but requires a pathologist with experience in pregnancy - asso-ciated breast cancer [91]

If a malignancy is discovered further evaluation is mandatory

In non - pregnant patients, this has been achieved through careful history and physical exam, serologic tests and chest X - ray; bone scans and CT are also performed in patients at high risk or who have suspected metastases Traditionally, CT has been avoided in pregnancy because of concerns about exposure of the fetus espe-cially during the fi rst trimester MRI may be selectively used in patients where metastasis is suspected

When matched for stage and other prognostic factors, preg-nancy does not appear to worsen the prognosis [92 – 94] In those women who have no evidence of metastasis, surgical manage-ment may be defi nitive [91] For smaller tumors, breast - conserving surgery can be performed; if the tumor is larger, the patient may require more substantial surgical management with modifi ed radical or total mastectomy with axillary node staging [95] While radiation therapy is employed in non - pregnant women with breast - conserving surgery [96,97] , this is avoided in pregnancy, because of the potential radiation exposure to the fetus In node - positive or advanced cases, chemotherapy is rec-ommended; current recommendations include cyclophospha-mide, doxorubicin, and 5 - fl uorouracil Methotrexate can also be used beyond the fi rst trimester [98]

Individualization of care and good communication amongst a multidisciplinary care team including the obstetrician/perina-tologist, neonaobstetrician/perina-tologist, and surgical and medical oncologists is extremely important Traditionally, women have been counseled

to abort pregnancy; however, therapeutic abortion has not been shown to alter disease course or improve survival rates in preg-nant women with breast cancer [92] In addition, with advancing neonatal intensive care technology, the threshold for fetal matu-rity has decreased, and patients who present at earlier gestations

tralateral ovary is generally no longer accepted procedure For

those with advanced disease beyond stage IA, adjuvant

chemo-therapy is indicated, usually with fi rst - line chemo-therapy comprising

bleomycin, etoposide, and cisplatin (BEP) The recurrence rate

of stage IA disease is approximately 10%, but the majority of these

cases are cured with chemotherapy or radiation therapy [74]

The sex - cord stromal tumors are uncommon in pregnancy

When they occur in pregnancy, they are less frequently associated

with hormonal manifestations and more frequently associated

with hemorrhagic rupture leading to hemoperitoneum than in

non - pregnant cohorts These patients tend to do well and can

usually be managed with conservative measures This most

com-monly involves unilateral salpingo - oophorectomy, though some

patients have undergone postoperative chemotherapy and/or

radiation therapy, as well as complete surgical staging

Chemotherapy is necessary for most patients diagnosed with

epithelial ovarian cancer Attention must be given to the drug ’ s

mechanism of action and side - effect profi le, especially in the

preg-nant patient Various other factors must also be taken into account

including nutritional status (which can alter protein - binding and

serum free - drug concentration), maternal habitus (which can

affect fat sequestration of the agent), and the expanded plasma

volume found in the pregnant state (which can affect an agent ’ s

pharmacokinetics) [75 – 77] The potential for transplacental

passage must also be considered since chemotherapeutic agents

tend to non - selectively kill rapidly dividing cells found in both

carcinomas and fetal tissues [78] The most susceptible period for

the fetus is the fi rst trimester when organogenesis occurs [79] The

risk of malformation and spontaneous abortion can be minimized

by deferring administration of chemotherapy until after this

criti-cal time Folate antagonists can increase the risk of malformations

[75] and supplemental folic acid should be administered in such

cases in an effort to reduce the risk of an anomaly If chemotherapy

must be given during the fi rst trimester, the issue of potential

tera-togenicity must be fully understood by the patient when deciding

whether to continue or abort the pregnancy

Chemotherapy administered during second and third

trimes-ter has been associated with low birth weight, intrautrimes-terine growth

restriction, and premature delivery [75,80] These pregnancies

should be closely followed, with antenatal monitoring of fetal

growth and functional well - being Administration of

chemother-apy near the time of delivery should be avoided if possible A

3 - week buffer period prior to a planned delivery date may prevent

potential complications close to term Long - term follow - up

studies of children who were exposed to antineoplastic agents

in utero demonstrate normal birth weights, educational

perfor-mance, and reproductive capacity [81 – 84]

Non - gynecologic c ancers in p regnancy

Breast

Cancer of the breast is the most common malignancy in women

of all ages and, according to American Cancer Society and the

likely secondary to the pregnancy - associated increase in production of adrenocorticotropic hormone (ACTH) and melanocyte -stimulating hormone (MSH); however, a clear association between increased MSH in pregnancy and melanoma has not been established [110] With regard to the effects of estrogen on melanocytes, previous animal studies have shown an increase in melanocyte activity; this has not been the case with pregnancy, oral contraceptive use, and hormone replacement therapy, none

of which have shown a direct association with melanoma [105,111]

Until recently, melanoma occurring in pregnancy was thought

to carry a poorer prognosis compared with non - pregnant con-trols Earlier anecdotal reports suggesting this association have been countered by more recent studies showing no major differ-ences in tumor location, presentation or prognosis in pregnancy [103,105,112,113] There does, however, seem to be an increased tumor thickness associated with pregnancy [114,115] With respect to overall survival rates, there is no signifi cant difference between pregnant patients and their non - pregnant counterparts [104,112,116] The current standard of care in non - pregnant patients has now changed from routine lymph node dissection towards sentinel node mapping and sampling, with formal lymphadenectomy if the sentinel node contains evidence of metastasis [104,117,118] In pregnant patients, this can be under-taken with a 99m Tc - sulfur colloid which has a fetal dose of less than 100 mGy [119,120]

Surgical treatment of melanoma is dictated by tumor stage Since many pregnant patients have stage I disease, most undergo wide local resection with or without regional lymph node dissection Prophylactic chemotherapy or immunotherapy

is generally avoided during pregnancy, although this is dependent

on tumor stage and maternal prognosis If the tumor is noted

to have distant metastases, palliation may be the goal of therapy Notably, the only adjuvant agent proven to be effective

in improving survival, though modest, in non - pregnant cohorts

is high - dose interferon - α2b; there are no reports involving the use of immunotherapy in melanoma in the pregnant state [104]

The standard chemotherapy agent used to treat melanoma is dacarbazine Several studies are currently investigating the use of combination chemotherapy and radiation therapy in malignant melanoma [121] Therapeutic abortion has not been shown to improve survival There is at least one case report of a pregnant patient with progressive metastatic disease who was treated with combination chemotherapy during pregnancy and who died due

to systemic complications after giving birth to an unaffected infant that developed normally [76]

While transplacental tumor metastasis is exceedingly rare, melanoma is the most commonly cited tumor to have placental and fetal metastases [122 – 125] Up to a third of placental metas-tases are attributed to melanoma; according to Alexander [126] ,

27 of 87 cases of metastatic placental disease were attributed to malignant melanoma with fi ve of six affected infants dying of metastatic melanoma Reports of spontaneous regression in the

will likely have an improved risk/benefi t ratio with delay of

treatment

As previously discussed, if the patient requires adjuvant

chemotherapy, there is a risk of varying degrees of ovarian

failure, although most patients will not suffer from persistent

premature ovarian failure and will be able to conceive after

completion of chemotherapy Subsequent pregnancy after

treatment of breast cancer does not appear to worsen the

prog-nosis of breast cancer when compared to patients, matched for

age and stage, who did not become pregnant [99] Studies have

also shown that the number of subsequent pregnancies, the

inter-val between treatment and subsequent pregnancy, and

termina-tion of pregnancy versus continuing pregnancy to delivery does

not affect maternal outcome [100] Notwithstanding, patients are

counseled to delay subsequent pregnancy for at least 2 – 3 years,

as risk of recurrence is greatest during this interval after

treatment

Melanoma

Melanoma is one of the most common cancers diagnosed during

pregnancy, although the exact incidence during this period is

unknown [101,102] The median age for patients diagnosed with

melanoma is 45 years; 30 – 40% of patients are reproductive age,

and up to 8% of these women are pregnant at the time of

diag-nosis With the increasing trend toward delaying childbearing

among other reasons, the incidence of melanoma found in

preg-nancy has increased drastically in the past 5 decades [103,104]

The estimated incidence is approximately 0.14 – 2.8 cases per 1000

births [105] However, according to Salopek and colleagues

[106] , cases of melanoma are greatly underreported, with a large

proportion of patients being treated on an outpatient basis, and

thus never entering a tumor registry

The vast majority of melanomas arise from the pigment -

producing melanocytes, usually from a pre - existing nevus

Therefore, any nevus that appears suspicious in appearance

should be biopsied Characteristics that have classically been

described as associated with invasive disease include, but may not

be limited to, irregular lesions or changes in shape or contour,

surface elevation or increase in thickness, itching, bleeding or

ulceration, or discolorations

Once diagnosed, these cancers are clinically staged Fortunately,

the majority, between 50 and 85%, of pregnant patients with

melanoma have stage I disease [105,107,108] Prognosis in stage

I disease is dictated by tumor thickness (epidermis, dermis,

sub-cutaneous fat) as measured with the Clark classifi cation or the

Breslow scale

While melanomas are generally not considered to be

hormon-ally dependent or responsive, there has been concern for various

endocrinologic factors that occur during pregnancy which could

potentially infl uence the course and prognosis of the tumor

There is a well - known association with increased pigmentation

of nipples, vulva, linea nigra, and/or pre - existing nevi in

preg-nancy that begins in the fi rst trimester, and typically disappears

shortly after the birth [109] This increase in pigmentation is

Conclusion

The treatment of any cancer occurring in pregnancy must be individualized A multidisciplinary team consisting of a perina-tologist, neonaperina-tologist, and gynecologic, surgical and/or medical oncologist should be assembled to extensively counsel the patient

on all treatment options based on tumor stage and the prognosis based on immediate treatment versus delayed treatment Each case should be evaluated on a case - by - case basis, and each patient should be counseled and managed with respect to their desires for the current pregnancy and future fertility

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Critical Care Obstetrics, 5th edition Edited by M Belfort, G Saade,

M Foley, J Phelan and G Dildy © 2010 Blackwell Publishing Ltd.

Diabetes Mellitus

Martin N Montoro

Departments of Medicine and Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Introduction

The outcome of pregnancy in women with diabetes mellitus has

steadily improved over the last several decades However, women

with pregestational diabetic complications still have elevated

fetal, neonatal and maternal morbidity and mortality At the

highest risk are those with severe retinal, renal, or ischemic heart

disease Advances in the medical treatment of diabetes and in

obstetric and neonatal care have improved the outcome of

preg-nancy in women with complicated diabetes Until recently, many

women with complicated diabetes mellitus were advised to avoid

pregnancy or have a therapeutic abortion if they became

preg-nant At present, absolute recommendations against pregnancy

are few and limited to women with unusually severe

complica-tions, particularly ischemic heart disease

Obtaining optimal diabetic control before pregnancy is of

paramount importance because at present, perinatal mortality

due to congenital anomalies accounts for over 50% of perinatal

losses Emphasis should be placed on preconceptual diabetic

control since organogenesis may be complete by the time the

pregnancy is recognized

Diabetic r etinopathy

Course of r etinopathy d uring p regnancy

Publications on the prevalence and risk factors affecting the

pro-gression of diabetic retinopathy during pregnancy still vary

widely One study reports a rate of progression as high as 78% in

women with pre - existing retinopathy [1] while another reports a

much lower rate of 5% [2] Still others report that sight -

threat-ening deterioration during pregnancy is not more common than

in non - pregnant, age - and duration - matched type 1 diabetic

women controls [3] The fi ndings of the Diabetes Control and Complications Trial (DCCT) [4] are considered to be very important since conducting future similar studies will be diffi cult

to accomplish (180 women with 270 pregnancies compared to

500 women who did not become pregnant and followed for an average of 6.5 years, all with type 1 diabetes) These investigators reported a 1.63 - fold greater risk of worsening retinopathy in the intensive treatment group versus a 2.48 - fold increase in the con-ventionally treated group The increased risk peaked during the second trimester but persisted for as long as 1 year postpartum The risk of progression was attributed to “ a pregnancy effect ” as well as an additional effect resulting from establishing rapid dia-betic control The worsening that occurred during pregnancy did not result in long - term morbidity Of the 270 pregnancies, 183 were in women who had absent or minimal changes (only micro-aneurysms) just before pregnancy The progression to severe reti-nopathy in this group was extremely low (1.6%) Patients who progressed to severe retinopathy commonly had lesions before pregnancy [5] Other studies have shown a higher (up to 33%) rate of background retinopathy developing during pregnancy in women without detectable lesions before pregnancy However, those lesions were considered mild, did not require treatment and regressed after delivery [3,6 – 9]

The sudden institution of tight diabetic control may also be a factor in the worsening of retinopathy [4] However, not all studies confi rm these fi ndings Lauszus et al report that tight diabetic control may actually prevent the progression of retinopa-thy rather than contribute to its worsening [10]

Is t here a “ p regnancy f actor ” ?

Several publications have reported on the levels of vasoactive hormones in pregnant women with and without diabetes fol-lowed with serial retinal photographs before, during and up to

6 12 months postpartum Levels of plasma atrial natriuretic peptide (ANP) and angiotensin II were not statistically signifi -cantly different in type 1 diabetic women compared with healthy controls Both groups showed retinal arteriolar constriction during pregnancy and in the diabetic women the change in

duration Another independent variable is the degree of meta-bolic control, with the highest risk involving women poorly con-trolled before pregnancy and who are brought rapidly under tight control [3,4] Elevated blood pressure (acute or chronic) is also associated with worsening retinopathy, and pre - eclampsia seems

to be a potent risk factor for exacerbation of retinal disease [1,3] (Table 51.1 )

Management

The management of severe retinopathy during pregnancy remains controversial because there are no studies that have included photocoagulation as an independent variable In addition, since retinopathy may regress after delivery it has been argued that treatment during pregnancy might not be needed [23] Even though some regression may occur postpartum, most centers recommend treatment during pregnancy if signifi cant neovascu-larization occurs, the same advice as for non - pregnant patients [24] Ideally, treatment should be completed before conception

in order to prevent or minimize progression during pregnancy

If proliferative retinopathy worsens during pregnancy, treatment may prevent further progression and preserve vision

Proliferative retinopathy is no longer considered to be an abso-lute contraindication for pregnancy, given current treatment pos-sibilities However, these patients remain at high risk, and have

to be monitored closely They should be advised of their risk on

an individual basis and before pregnancy if at all possible General guidelines are as follows

1 The highest risk for worsening retinopathy involves women

(i) with diabetes for 5 – 10 years or longer, (ii) with diabetes which is poorly controlled and brought under tight control very rapidly, (iii) with chronic hypertension and (iv) developing pre eclampsia/eclampsia

2 An ophthalmologist should examine any patient with diabetes

of longer than 5 years ’ duration before pregnancy, each trimester, and within 3 months after delivery If the diabetes has been present for fewer than 5 years, the treating physician should perform periodic ophthalmoscopic exams If any changes are noted, or if any visual symptoms develop, referral to an ophthal-mologist is warranted However, since early lesions may be easily missed by non - ophthalmologists it could be argued that all patients should have at least one examination by an ophthal-mologist before or in early pregnancy All diabetic women with documented retinopathy should be followed in conjunction with

an ophthalmologist during pregnancy and postpartum

arteriolar diameter did not correlate with retinopathy, arterial

blood pressure or HbA1c levels One interesting fi nding was

that diabetic women who smoked did not show retinal

vaso-constriction during pregnancy [11] , although smoking is an

independent risk factor for worsening retinopathy

Other studies have reported on the possible role of vasoactive

mediators and retinopathy during pregnancy In one study,

plasma renin activity (RAS) and ANP were signifi cantly lower in

diabetic compared with non - diabetic women throughout

preg-nancy and postpartum The authors speculate that the lower

levels of RAS and ANP may contribute to hyperdynamic blood

fl ow and progression of retinopathy in diabetic pregnancies

However, no signifi cant differences were found in the levels of

other natriuretic peptides (BNP and CNP), angiotensin II,

aldo-sterone or adrenomedullin [12]

The insulin - like growth factor system has also been studied in

pregnant diabetic women and higher levels of insulin - like growth

factor - 1 (IGF - 1) were found to be signifi cantly associated with

worsening retinopathy (as well as with higher birth weight) [13]

Levels of IGF - 1, IGF binding protein - 1, highly phosphorylated

IGF binding protein - 1, and IGF binding protein - 3 were not

asso-ciated with progression of retinopathy [14]

Is t here an i nsulin e ffect?

After the fi rst rapid - acting insulin analog, Lispro was introduced,

there were concerns, based on case reports, about its potential for

worsening retinopathy during pregnancy [15] However,

subse-quent publications involving larger series have shown that it is

both safe and effective during pregnancy [16,17] Insulin Aspart,

another rapid - acting insulin analog, has also been reported to be

safe and effective during pregnancy [18,19] These two insulin

analogs are preferred over regular insulin because they are much

more effective than regular insulin in controlling postprandial

serum glucose levels A newer rapid - acting analog, insulin

Glulisine has been recently released but reports of its safety

during pregnancy are absent There are also two long - acting

insulin analogs available for use, insulin Glargine and insulin

Detemir The limited data on Glargine indicates that it is

prob-ably safe in animals [20] as well as in humans [21] There is no

information at present about the use of insulin Detemir in

preg-nancy The main concern about the use of insulin analogs in

pregnancy has been their higher binding affi nity for the IGF - 1

receptor and thus the potential for generating higher IGF - 1 levels

However, at least with insulin Lispro, those concerns have not

been found to be clinically relevant [16 – 17,22] Therefore, insulin

does not appear to be a factor affecting the progression or

devel-opment of retinopathy during pregnancy

Other i mportant f actors

Most studies reporting on diabetic retinopathy and pregnancy

agree that the duration of diabetes is a strong independent

vari-able associated with worsening retinopathy during pregnancy

The longer the duration of diabetes mellitus the higher the risk

of worsening retinopathy [1 – 3,12] , particularly after 5 – 10 years ’

Table 51.1 Highest risk for retinopathy during pregnancy

Diabetes of long duration ( > 5 years, particularly > 10 years) Rapid glucose normalization after prolonged poor control Coexisting hypertension of any type (chronic hypertension, pre - eclampsia, eclampsia)

Treat pre - existing retinopathy before conception!