Critical Care Obstetrics part 73 potx

Cancer in the Pregnant Patient 709 The management of ovarian cancer in pregnancy does not greatly differ from that of the non - pregnant patient. Many pregnant 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 suspicious 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 diagnosed 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 subsequent treatment delayed. One option is to offer neoadjuvant chemotherapy 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 presents 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 functional 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 possible 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 consultation 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 malignancy [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. Chapter 50 710 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 incidence of breast cancer during pregnancy is increasing, likely secondary 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 diagnosis but requires a pathologist with experience in pregnancy - associated 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 especially during the fi rst trimester. MRI may be selectively used in patients where metastasis is suspected. When matched for stage and other prognostic factors, pregnancy does not appear to worsen the prognosis [92 – 94] . In those women who have no evidence of metastasis, surgical management 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 recommended; 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/perinatologist, neonatologist, 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 pregnant women with breast cancer [92] . In addition, with advancing neonatal intensive care technology, the threshold for fetal maturity 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 chemotherapy is indicated, usually with fi rst - line 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 commonly 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 pregnant 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 critical 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 trimester has been associated with low birth weight, intrauterine 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 chemotherapy 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 Cancer in the Pregnant Patient 711 likely secondary to the pregnancy - associated increase in produc- tion 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 controls. Earlier anecdotal reports suggesting this association have been countered by more recent studies showing no major differences 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 undertaken 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 - α 2b; 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 metastases 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 prognosis 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 interval between treatment and subsequent pregnancy, and termination 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 diagnosis. With the increasing trend toward delaying childbearing among other reasons, the incidence of melanoma found in pregnancy 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 hormonally 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 pregnancy that begins in the fi rst trimester, and typically disappears shortly after the birth [109] . This increase in pigmentation is Chapter 50 712 Conclusion The treatment of any cancer occurring in pregnancy must be individualized. A multidisciplinary team consisting of a perinatologist, neonatologist, 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. References 1 Landis SH , Murray T , Bolden S , Wingo PA . Cancer statistics, 1998 . CA Cancer J Clin 1998 ; 48 : 6 – 29 . 2 Landis SH , Murray T , Bolden S , Wingo PA . Cancer statistics, 1999 . CA Cancer J Clin 1999 ; 49 : 1 , 8 – 31 . 3 Dinh TA , Warshal DP . The epidemiology of cancer in pregnancy . In: Barnea ER , Jauniaux E , Schwartz PE , eds. Cancer and Pregnancy . London : Springer , 2001 : 1 – 5 . 4 Smith LH , Danielsen B , Allen ME , et al. Cancer associated with obstetric delivery: results of linkage with the California cancer registry . Am J Obstet Gynecol 2003 ; 189 : 1128 – 1135 . 5 Mazze RI , Kallen B . Reproductive outcome after anesthesia and operation during pregnancy: a registry study of 5405 cases . Am J Obstet Gynecol 1989 ; 161 : 1178 – 1185 . 6 Stepp KJ , Sauchak KA , O ’ Malley DM , et al. Risk factors for adverse outcomes after intraabdominal surgery during pregnancy . Obstet Gynecol 2002 ; 99 : 23S . 7 Kort B , Katz VL , Watson WJ . The effect of nonobstetric operation during pregnancy . Surg Gynecol Obstet 1993 ; 177 : 371 – 376 . 8 Soriano D , Yefet Y , Seidman DS , et al. Laparoscopy versus laparotomy in the management of adnexal masses during pregnancy . Fertil Steril 1999 ; 71 : 955 – 960 . 9 Akira S , Yamanaka A , Ishihara T , et al. Gasless laparoscopic ovarian cystectomy during pregnancy: comparison with laparotomy . Am J Obstet Gynecol 1999 ; 180 : 554 – 557 . 10 Al - Fozan H , Tulandi T . Safety and risks of laparoscopy in pregnancy . Curr Opin Obstet Gynecol 2002 ; 14 : 375 – 379 . 11 Mathevet P , Nessah K , Dargent D , Mellier G . Laparoscopic management of adnexal masses in pregnancy: a case series . Eur J Obstet Gynecol Reprod Biol 2003 ; 108 : 217 – 222 . 12 Stepp K , Falcone T . Laparoscopy in the second trimester of pregnancy . Obstet Gynecol Clin North Am 2004 ; 31 : 485 – 496 , review vii. 13 Lachman E , Schienfeld A , Voss E , et al. Pregnancy and laparoscopic surgery . J Am Assoc Gynecol Laparosc 1999 ; 6 : 347 – 351 . 14 Fatum M , Rojansky N . Laparoscopic surgery during pregnancy . Obstet Gynecol Surv 2001 ; 56 : 50 – 59 . 15 Friedman JD , Ramsey PS , Ramin KD , Berry C . Pneumoamnion and pregnancy loss after second - trimester laparoscopic surgery . Obstet Gynecol 2002 ; 99 : 512 – 513 . 16 Hunter JG , Swanstrom L , Thornburg K . Carbon dioxide pneumoperitoneum induces fetal acidosis in a pregnant ewe model . Surg Endosc 1995 ; 9 : 272 – 279 . infant are exceedingly rare [127] . Other reported cancers to have metastasized to the products of conception include breast, lung, maxilla, vulvar, neuroendocrine and pancreatic cancer, lymphoma, leukemia, and one case of vaginal sarcoma. Other n on - gynecologic c ancers Hodgkin ’ s lymphoma is the most common hematologic malignancy found in women of reproductive age. The median age of presentation is 30 years, and it been reported to occur in 1 in 1000 to 1 in 6000 pregnancies [128 – 130] . Non - Hodgkin ’ s lymphoma is rarer than Hodgkin ’ s disease in this age group as this disease typically presents after the childbearing years. Nevertheless a recent increase in the incidence of Hodgkin ’ s lymphoma in pregnancy can be attributed to trends toward delaying childbearing and the increased incidence of human immunodefi ciency syndrome (HIV). The condition frequently presents as painless enlargement of the supradiaphragmatic lymph nodes, particularly supraclavicular, along with various “ B ” symptoms such as fever, night sweats, malaise, weight loss, and pruritus. In pregnancy, radiologic work - up may be limited by a desire to avoid exposing the fetus to ionizing radiation. The protocol may be modifi ed to include chest radiograph, bone marrow biopsies, and abdominal imaging. Computed tomography (CT) can be adjusted to reduce the amount of radiation exposure to the fetus, and magnetic resonance imaging (MRI) may provide an alternative to CT which avoids ionizing radiation exposure of the fetus. Treatment usually involves radiation and/or chemotherapy. Once the diagnosis of lymphoma is made, consultation and coordination with a hematologic oncologist are important. Colorectal cancers are common in women overall, but are relatively rare in age groups less than 40 years. One report cites fewer than 250 cases of colon cancer occurring with concomitant pregnancy, and of these, approximately 80% occur in the rectum [131 – 133] . Presentation may include abdominal pain, nausea, vomiting, constipation, or bloody stool; diagnosis can be diffi cult as most of these symptoms can also be found in normal pregnancy. Work - up may involve digital rectal exam, occult blood testing, and fl exible sigmoidoscopy or colonoscopy. Carcinoembryonic antigen (CEA) can be elevated in normal pregnancy, and may not provide useful insight into cases of colorectal cancer. Once diagnosed, treatment does not differ from non - pregnant patients. Surgical intervention can be timed with respect to the gestational age and the mother ’ s desire to keep or abort the fetus. Vaginal delivery may be possible, however this is usually not recommended with larger rectal lesions in which labor dystocia or hemorrhage may occur, necessitating urgent or emergent surgical intervention [134] . Other gastrointestinal cancers, such as gastric cancer [135 – 137] , hepatocellular carcinoma [138 – 141] , and pancreatic cancer [142,143] are exceedingly rare during the childbearing years. Few case reports exist in the literature regarding these rare malignancies. Other tumors reported in pregnancies include renal [144 – 146] , thyroid [147 – 149] , bone and soft tissue [150] , carcinoid [151] , and brain tumors [152 – 154] . 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Dildy. © 2010 Blackwell Publishing Ltd. 51 Pregnancy in Women with Complicated 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 pregnancy 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 pregnant. At present, absolute recommendations against pregnancy are few and limited to women with unusually severe complications, 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 progression 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 diabetic 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 retinopathy 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 retinopathy 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 followed 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 Chapter 51 718 duration. Another independent variable is the degree of meta- bolic control, with the highest risk involving women poorly controlled 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 absolute 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 ophthalmologist 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 ophthalmologist 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 pregnancy 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 associated 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, subsequent 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 pregnancy. 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 development 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 variable 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! . 344 – 348 . Comment in Obstet Gynecol 2005 ; 105 : 447 ; author reply 447 – 448. 717 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy also be used beyond the fi rst trimester [98] . Individualization of care and good communication amongst a multidisciplinary care team including the obstetrician/perinatologist, neonatologist,. 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