LIVER TRANSPLANTATION AND PREGNANCY

PREGNANCY AND LIVER DISEASE

1089-3261/99 $8.00

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LIVER TRANSPLANTATION AND PREGNANCY Ernest0 P. Molmenti, MD, Ashok B. Jain, MD, Nancy Marino, RN, MS, CCTC, Nitin K. Rishi, MD, Igor Dvorchik, PhD, and J. Wallis Marsh, MD

Although the first liver transplant was performed in 1963, it was not until 15 years later that the first successful reported pregnancy in a liver allograft recipient occurred.26As opposed to patients with endstage liver disease, in which pregnancy is very unlikely, a successful transplant allows for the resumption of menstrual cycles5 and subsequent pregnancies. It is expected that the number of pregnancies and deliveries will increase as this patient population enlarges. No blinded, randomized controlled studies have been undertaken (or are expected to occur) to investigate the teratogenicity of immunosuppressive drugs. 'IMMUNOSUPPRESSIVE AGENTS

Corticosteroids Use of corticosteroids during pregnancy has been associated with fetal growth retardation and an increment in infants with low birth ~ e i g h t s .l3~No , teratogenic activity has been associated with their use. This work was supported by Project Grant No. DK-29961 from the National Institutes of Health, Bethesda, Maryland, and from research grants from the Veterans Administration Medical Center.

From the Thomas E. Starzl Transplantation Institute, Department of Surgery, University Health Center of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania

CLINICS IN LIVER DISEASE VOLUME 3 * NUMBER 1 * FEBRUARY 1999

163

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MOLMENTI et a1

Azathioprine

Although azathoprine crosses the placenta, it is thought to have no significant teratogenic potential.I2Its use by pregnant women may lead to fetal growth retardation as well as newborn-fetal immunosuppression and bone marrow toxicity. The latter usually is not evident in the absence 6, 8,23 of maternal le~kopenia.~, Cgclosporine

Cyclosporine readily crosses the placenta and achieves fetal blood levels in 37% to 64% of maternal concentration^.^, 9, 13, 25 It is believed to be nonteratogenic, but it can cause growth retardati~n.'~ Tacrolimus

Tacrolimus readily crosses the placenta. It has, so far, not been associated with any teratogenic activity. Its use during pregnancy may lead to low birth weight, transient perinatal hyperkalemia and mild, reversible renal impairment.

0KT3 Anecdotal reports show no apparent deleterious fetal effects.12 PREGNANCY UNDER AZATHIOPRINE AND CYCLOSPORINE IMMUNOSUPPRESSION: GENERAL OBSERVATIONS

Pregnancy under immunosuppression based on azathioprine or cyclosporine is a period characterized by difficulties for both mother and infant.2 A 1987 compilation7 reported 1569 pregnancies in 1009 kidney transplant recipients, with a 30% incidence of new-onset hypertension or preeclampsia, a 15% incidence of significant renal dysfunction (most frequently secondary to serious rejection), a 20% incidence of intrauterine growth retardation, and a 45% to 60% rate of preterm delivery. Unfortunately, the introduction of cyclosporine in 1983 only seemed to worsen the incidence of hypertension.' Pregnancies in liver transplant recipients have been less frequent than pregnancies after renal transplant recipients. Scantlebury et alZ2 reported 20 pregnancies in 17 patients after liver transplant. The first four were with azathioprine immunosuppression, the remaining 16 under cyclosporine. Interestingly, one of the patients treated with azathioprine has been off immunosuppression since her delivery 17 years ago. The rate of hepatic allograft dysfunction in this group was 37% during

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pregnancy and 53% in the postpartum period. Other common complications encountered included hypertension, preeclampsia, and premature delivery. The Philadelphia-based National Cyclosporine Registryl8 reported an updated number of 500 live deliveries in 335 women after kidney and extrarenal organ transplantation. Of these, 37 mothers were liver recipients, and 35 were on a cyclosporine-based regimen. Findings in this group included drug-treated hypertension (46%), eclampsia/ preeclampsia (21%), allograft rejection (17%), and graft loss (5.7%).19 There was a high rate of prematurity and low birth weight among these infants.

PREGNANCY UNDER TACROLIMUS IMMUNOSUPPRESSION: THE UNIVERSITY OF PllTSBURGH EXPERIENCE At the University of Pittsburgh Medical Center, we evaluated 35 deliveries that occurred between October 1990, and March 1998, in 27 liver recipients.

Maternal Findings Demographics Table 1 summarizes the full range of original liver diseases for 27 women. The mean age of the women was 29.2 ? 5.5 (18.3-41) years. Forty-nine percent of the babies (n = 17) underwent delivery by cesarean section, which is about twice the average incidence observed in the general population (see Table 1). Twelve of the women involved were unable to conceive before the transplant, whereas another eight were not able to complete their pregnancies (see Table 1). All 27 women survived their single (n=19) or double (n=8) pregnancies; 24 are still living. All but 1 of the 24 has remained with stable liver function postpartum. The only patient who lost her graft was noncompliant during the second of her two successful pregnancies and was retransplanted for chronic rejection 19 months after delivery (pregnancy llb). The three deaths were not related directly to the pregnancies. The first was a 20-year-old woman (pregnancy 7) who, during the first trimester of her pregnancy, developed systemic cytomegalovirus (CMV) infection and gave birth at 23 weeks to a 587-g infant, who died hours later. Although she recovered quickly, the woman required retransplantation 30 months later for de novo hepatitis C infection; she survived for only 16 weeks post-transplantation. The second death was that of a 25year-old woman (pregnancy 12) who died of crack-cocaine overdose 40 months after delivery. The third death (pregnancy 3) occurred 67 months postpartum from hepatitis C infection, renal failure, and gastrointestinal bleeding.

Caroli

Caroli PNC-C PNC-C PNC-E

PBC NANB NANB AIH PNC-C FHF PNC-E PNC-e PNC-C PNC-C AIH AIH HBV HBV

la

lb 2a 2b 3

4 5 5b 6 7 8 9a 9b 10a lob lla llb 12 13

Patient

Diagnosis Before Transplant

35.4 31.2 36.9 18.3 20.2 33.5 31.5 35.6 34.6 36.5 23.5 25.8 24.6 30.5

27.5 25.5 27.4 32.6

25.8

Mother's Age (yr)

70.4 22.3 90 20 6.1 43.7 18.4 67.6 17.7 39.7 32.8 65.3 45.3 29.1

38.6 97 120.6 34.4

17.9

Months from TransDlant to Deiivery

'

19.6 22.3 90 20 5.8 24.9 18.4 67.6 17.7 39.7 29.7 57.2 41.6 28.7

29.4 17.1 40.6 21.1

8.7

Mothers on Tacrolimus to Delivery

Table 1. MATERNAL AND INFANT CHARACTERISTICS

33 40 34 38 23* 35 37 37 24% 32 39 28 36 40

34 35 40 34

36

BOY BOY

Girl

BOY

Girl

-

Girl

BOY

Girl

BOY -

Girl Girl Girl

Girl

BOY

Girl

BOY

BOY

1712 3912 3000 2580 587* 2594 2438 2585 510* 1565 3374 1632 1215 3310

2438 2180 2410 1850

2236

(gj

(wk) BoylGirl

Birth Weiaht

Gestation Period

Cesarean Vaginal Vaginal Vaginal Vaginal Vaginal Vaginal Vaginal Cesarean Cesarean Vaginal Vaginal Cesarean Cesarean

Cesarean Vaginal Vaginal Cesarean

Cesarean

Vaginal or Cesarean

Fetal distress Fetal distress

Preeclampsia

Previous cesarean Previous cesarean Abruptio placenta

Previous cesarean

Reason for Cesarean Section

Previous Obstetric History

Wilson Wilson PBC PSC PSC HBV FHF Wilson AIH Congenital hepatic fibrosis PNC-C NANB PSC Caroli AIH AIH

33.7 25.2 33.2 41 33 26.2

32.6 34.1 24.3 28.9 32.1 23.9 19.8 26.8 26.9 22.3

51.4 101 4 75 22 76

49.2 67.6 33.5 43.2 81 66.2 38.5 95.1 37.2 31.7 51.4 101 24 75 22 76

48.4 67.2 33.5 43.2 81 46.7 38.5 70.9 37.2 31.7 38 39 40 37 37 37

40 40 36 40 41 36 38 40 36 40

Girl

BOY

Girl

BOY

BOY

Girl

Girl BOY

BOY

Girl

BOY

Girl Girl

BOY

BOY

Girl

2430 3570 3690 2040 2890 2580

4346 3693 3693 2897 3600 2159 2711 3324 2280 3522

Vaginal Cesarean Cesarean Cesarean Cesarean Vaginal

Vaginal Vaginal Cesarean Vaginal Vaginal Vaginal Cesarean Vaginal Cesarean Cesarean

Failure to progress Failure to progress Malposition Failure to progress

Abruptio placenta Prophylactic

Failure to progress

Delayed labor

AIH = autoimmune hepatitis; PNC-C = cryptogenic; PNC-E = ethanol; FHF = fulminant hepatic failure; HBV = hepatitis B virus; NANB = non-A non-B hepatitis; PBC = primary biliary cirrhosis; PNC = postnecrotic cirrhosis; PCS = primary sclerosing cholangitis; g = gravida; p = parity. *Premature b a b y 4 i e d . Mod@dfrom Jain A, Venkataramanan R, Fung JJ, et al: Pregnancy after liver transplantation under tacrolimus. Transplantation 61:559-565, 1997; with permission.

22 23 24 25 26 27

14a 14b 15 16a 16b 17 18 19 20 21

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Allograft Function and Survival Mean liver function was not affected by the pregnancies; however, six patients had perturbations of their liver function during the pregnancy, and four had abnormalities after delivery. Anicteric rejection with elevations in transaminases or canalicular enzymes was observed during pregnancies 4, 5a, 6, 22, and 26 at 14, 16, and 33 weeks, respectively. Three women (pregnancies 4, 8, and 27) had similar findings but in the postpartum period. These events were resolved with modest increases in the tacrolimus immunosuppression or steroid boluses. The only example of chemical jaundice (bilirubin peaked at 2.9 mg/dL) occurred in pregnancy llb, probably secondary to noncompliance. Immunosuppression Table 1 shows the duration of tacrolimus treatment and the interval from transplantation to delivery. Before conception, 14 of the 27 women had been converted from cyclosporine to tacrolimus because of persistent rejection or excessive steroid dependence. Prednisone was not given before or during 21 of the 35 pregnancies. Azathioprine (50 mg/d) was given in addition to tacrolimus in only two cases (pregnancies 6 and 27) because high doses of tacrolimus (48-64 mg/d) were required to maintain modest trough concentrations (0.3-0.5 ng/mL). Table 2 shows mean tacrolimus doses and trough concentrations obtained during one pregTable 2. EFFECT OF PREGNANCY ON IMMUNOSUPPRESSION

Before Mean Standard deviation Median First trimester Mean Standard deviation Median Second trimester Mean Standard deviation Median Third trimester Mean Standard deviation Median Postpartum Mean Standard deviation Median

Tacrolimus Dose* (mg/d)

Tacrolimus Levelt (nglmL)

9.6 3.3 10.0

0.7 0.3 0.6

9.7 3.1 10.0

0.7 0.4 0.7

9.5 3.9 8.0

0.6 0.4 0.5

10.1 3.8 10.0

0.5 0.3 0.5

9.3 3.9 10.0

0.8 0.3 0.8

*Excludes patients 6 and 22. tPlasma level. Modifedfrorn Jain A, Venkataramanan R, Fung JJ, et al: Pregnancy after liver transplantation under tacrolimus. Transplantation 64559-565, 1997; with permission.

LIVER TRANSPLANTATION AND PREGNANCY

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nancy (pregnancies 6 and 22 were excluded in these computations because of the unusually high doses of tacrolimus required). Renal Function Mean blood urea nitrogen and creatinine concentrations were stable during and after pregnancy as tacrolimus doses were adjusted at the first sign of nephrotoxicity. Two women (pregnancies 8 and 10) had preexisting hypertension that required augmentation of treatment during the pregnancy. Only one woman (pregnancy 5) developed hypertension during the first trimester. She was treated with methyldopa for only 1 week. Six of the 27 women developed hyperkalemia and were treated with fludrocortisone. Insulin-dependent Diabetes Mellitus (IDDM)

There were no cases of new-onset, insulin-dependent diabetes. Of the two women (pregnancies 4 and 10) who were insulin-dependent before conception, one (pregnancy 10) became insulin free by her second pregnancy and remained insulin free thereafter. Infections There was one case of Salmonella infection during the third trimester (pregnancy 4), and one case of CMV gastroenteritis during the first trimester (pregnancy 7). One woman (pregnancy 1) had a toenail infection during her first pregnancy, and a bout of pneumonia and cesareanwound infection after her second delivery. Fetal Findings

Survival

Two infants died at 2 hours and 2 days postpartum. These infants were born at 23 and 24 weeks' gestation, respectively, and their respective birth weights were 587 g (pregnancy 7) and 510 g (pregnancy 10a). The mother of the first newborn had systemic CMV infection during the first trimester of her pregnancy; the second experienced worsening hypertension, IDDM, and preeclampsia with proteinuria. One infant was born with a unilateral nonfunctional cystic kidney. Except for these events, all remaining 33 babies are alive, healthy, and growing. Development at Birth

Table 1 shows birth weights and gestational periods. Forty-nine percent (n = 17) of the babies were born at less than 37 weeks gestation (premature), and 51% (n = 18) were term babies.l0rl4 Development of Newborn Babies The 33 babies who survived the perinatal period have been followed for a mean period of 39.2 5 24.1 months (median 36 months).

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Perinatal Complications Two babies of birth weights 1632 g and 2711 g (pregnancies l l b and 18, respectively) required ventilatory support. One woman (pregnancy 12) delivered by cesarean section because of fetal distress. The infant required extended hospitalization for supplemental oxygen. Table 3 shows metabolic studies performed at the time of delivery. Hyperkalemia and high creatinine levels resolved spontaneously in 24 to 48 hours in nine babies except in pregnancy 4. This infant was a 1712-g baby born by emergency cesarean section for abruptio placenta at 33 weeks. Although anuric for 36 hours, the newborn’s creatinine peaked at 4.8 mg/dL and started to decline to normal levels by the third postnatal day. Table 3 summarizes aldosterone and renin concentrations in maternal plasma and cord plasma as well as serum creatinine and potassium in the newborn. Reliable correlations between aldosterone, renin, and serum creatinine levels could not be established because of wide variations in the aldosterone and renin concentrations. MaternaIFetal and Blood-Brain Barriers to Tacrolimus Table 4 illustrates maternal tacrolimus levels at the time of delivery, followed by subsequent trough levels. These plasma maternal levels

Table 3. METABOLIC STUDIES AT THE TIME OF DELIVERY Plasma Aldosterone (ngldL)” Patient la lb 2b 3 4 5a 6 8 10 11 12 13

Mother*

62 8

-

61 58 3 27 80 28

Plasma Renin (ng/mW)

Cord

Mothers

43 15 11 32 40 4 49 70 23

2.8 5 15.4 7 10

Newborn (serum)

Cord

Creatininetll

K+ (mEq/L)ll

-

1.1 1.3

10.9 6.8 5.5 8.2 6.1 4 7 7.5

1.2 3.2 1.3 -

27.1 4 8.6

-

3.2 1 0.9 2 0.8 -

-

6 6.6 -

*Aldosterone, ng/dL (1 ng/dL = 0.028 nmol/L, SI units). Kreatinine, mg/dL (1 mg/dL = 88.4 Fmol/L, SI units). *Supine: n12 - 9 ng/dL. §d:less than 0.7 (low); 0.7-3.2 (medium); greater than 3.2 (high). /Id: 0.1-0.6 lld: 3.7-5.9 men; 4.1-5.3 women From Jain A, Venkataramanan R, Fung JJ, et a1 Pregnancy after liver transplantation under tacrolimus. Transplantation 64559-565, 1997; with permission.

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Table 4. TACROLIMUS CONCENTRATIONS IN PERINATAL SPECIMENS

Patient

la

Days Delivery

Ot 1 2 3

lb 2b 3 4

5

6 7 8

9 10 11 12 13 14 18

Mean Standard deviation Median

0 1 0

0 1 2 0 1 2 0 1 2 0 1 2 3 0 2 0 0 1 2 3 0 1 2

0 0 0 0 1 2 O* 0

Mother Blood (ng/mL) 0.4 0.5 4.1 0.4 3.2 1.1 0.5 0.9 2.6 0.7 0.7 2.1 4.3 1.9

Colostrum (ng/mL)

Placenta (nglg) 5.6

Cord Blood Baby Blood (nglmL) (nglmL) 0.1

0.4 1.9 0.4

8.8 0.4

1

0.4 0.1 1.9

3.1 1.4 0.6

2.6 0.3 0.3 3.2 1.6 1.2 1.6 1.3 2 1.6 0.8 0.8 0.3 2.5 1.1 2.1 1.7 0.6 0.4

0.2

0.3

0.1 0.1 9.3

0.9 0.4

8.5

0.5

1.1

0.4

1.6

0.9 0.9

0.5 0.9 0.6 0.4 0.8 3 0.3

1.1(11.3)$ 0.6 (6.1)$ 1.46 0.79 1.10 0.48

5.9 (58.63)$

1.15

2.8

0.7

4.30 3.40

0.77

1.7 0.1 0.08 (8.4)$ 0.21 (1.7)$ 0.54 0.56

0.4

0.4

0.08 (8.4)$ 0.3 (2.9)$ 0.71

‘Except for patients 14 and 18, values of maternal, cord, and baby blood were for plasma, and the plasma method was modified for the placenta and colostrum assays. tDay 0 = day of delivery. $Plasma estimated concentration is about one tenth of the whole blood or tissue concentration measured by microparticulate enzyme immunoassay method (IMX,Abbott Laboratories, Abbott Park, IL)in patients 18 and 19. From Jain A, Venkataramanan R, Fung JJ, et a 1 Pregnancy after liver transplantation under tacrolimus. Transplantation 64.559-565,1997; with permission.

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were higher than the cord blood levels in 11 of the 12 pregnancies for which they were available. The only exception was pregnancy 4, in which a cesarean section was undertaken because of abruptio placenta. This baby also exhibited transient postnatal anuria. The mean ratio of cord plasma to maternal plasma levels of tacrolimus was 0.36. Three of four infants (pregnancies 3,4, and 13), in which plasma tacrolimus levels were obtained on consecutive days, cleared the drug rapidly. The infants were partially protected from tacrolimus toxicity in utero by a placental barrier. Except for the case of abruptio placenta, all obtained placental samples (n=9) had drug levels 2 to 56 times those found in the cord blood. In pregnancy 14, a venous tacrolimus level taken from the infant at the time of placental delivery was seven times lower than that observed in the placenta (see Table 4). In pregnancies l b and 7, tacrolimus concentration in amniotic fluid was less than 0.2 ng/ mL. The cerebrospinal fluid tacrolimus concentration of the newborn in pregnancy 3 was below detectable limits (<0.1 ng/mL). In 6 women in whom 10 breast milk samples were obtained, tacrolimus levels were almost half the values obtained simultaneously in maternal blood samples (median ratio 0.5). CONCLUSION Pregnancy after transplantation does not seem to have deleterious effects on allograft function or survival, and results so far indicate pregnancy to be safe and successful for both mother and child. Infants born to mothers receiving tacrolimus tend to be premature and of low birth weight. Tacrolimus is transmitted from mother to fetus in significant amounts and may cause transient renal impairment in the newborn, although this may also reflect the renal function of the mother.'O, l6 In a similar manner, the hyperkalemia observed in these babies may be a reflection of the immature renal function of newborns that is observed under nontransplant circumstances also.21Breast feeding does perpetuate the exposure of the newborn to drugs with nephrotoxic and immunosuppressive side effects. It is not possible to determine whether the hyperkalemia seen in newborns is similar to that seen in adults and that is thought to be caused by low aldosterone and renin 1e~els.l~ The incidence of hypertension, preeclampsia, and allograft dysfunction under tacrolimus-based immunosuppression compares favorably with previous reports. There were no allografts lost as a result of pregnancy. It is advisable for women to wait 2 years after liver transplantation before actively seeking conception, although successful pregnancies have been encountered within the first year after transplantation. This is based on the observation that the two infant deaths in this series occurred in conceptions temporally close to the liver transplantation. In cases in which management problems related to the transplant have not been fully resolved, this 2-year waiting period should be extended. In pregnancy 7, the period from transplantation to conception was only a few

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weeks, and in case 10a it was slightly under 1 year. In the latter case, preexisting hypertension developed into preeclampsia during the period of steroid weaning while the mother had transient IDDM. This same woman conceived and went through a successful pregnancy after a 14month rest period without recurrence of these problems.

References 1. Armenti VT, Ahlswede KM, Ahlswede BA, et al: National Transplantation Pregnancy Registry: Outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 57502, 1994 2. Bumgardner GL, Matas AJ: Transplantation and pregnancy. Transplantation Reviews 6139, 1992 3. Burrows DA, ONeil TJ, Dorrells T L Successful twin pregnancy after renal transplant maintained on cyclosporine A immunosuppression. Obstet Gynecol 72459461, 1988 4. Cote CJ, Muewissen JH, Pickering RJ: Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr 85:324-328, 1974 5. Cundy TF, OGrady JG, Williams R Recovery of menstruation and pregnancy after liver transplantation. Gut 31:337-338, 1990 6. Davison JM, Dellagrammatikas H, Parkin J M Maternal azathioprine therapy and depressed haemopoiesis in babies of renal allograft patients. Br J Obstet Gynaecol 92:233-239,1985 7. Davison JM: Renal transplantation and pregnancy. Am J Kidney Dis 9:374, 1987 8. Dewitte DB, Buick MK, Cyran SE, et al: Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. J Pediatr 105:625-628,1984 9. Flechner SM, Katz AR, Rogers AJ, et al: The presence of cyclosporine in body tissues and fluids during pregnancy. Am J Kidney Dis 5:60-63, 1985 10. Guignard JP: Renal function in a newborn infant. Pediatr Clin North Am 29:777, 1982 11. Jain A, Venkataramanan R, Fung JJ, et al: Pregnancy after liver transplantation under tacrolimus. Transplantation 64.559-565, 1997 12. Laifer S A Pregnancy after transplantation. In Lee RV (ed): Current Obstetric Medicine, vol2. St. Louis, Mosby-Year Book, 1993, p p 1-23 13. Lewis GJ, Lamont CAR, Lee HA, et al: Successful pregnancy in a renal patient taking cyclosporine. BMJ 286:603, 1983 14. Lubchenco LO, Hansman C, Boyd E: Intrauterine growth in length of head circumference as estimated from live birth at gestational ages from 26 to 42 weeks. Pediatrics 37403-408, 1966 15. McCauley J, Takaya S, Fung JJ, et al: The question of FK506 nephrotoxicity. Transplant Proc 23:1444, 1991 16. Metha KP, Kamik SR, Sathe A, et al: Renal parameters during infancy. Indian Pediatr 29:1385, 1992 17. Pickrell MD, Sawers R, Michael J: Pregnancy after renal transplantation: Severe intrauterine growth retardation during treatment with cyclosporine A. BMJ 296:825, 1988 18. Radomski JS, Ahlswede BA, Jarrell BE, et a1 Outcomes of 500 pregnancies in 335 female kidney, liver, and heart transplant recipients. Transplant Proc 271089, 1995 19. Radomski JS, Moritz MJ, Munoz SJ, et al: National Transplantation Pregnancy Registry: Analysis of pregnancy outcomes in female liver transplant recipients. Liver Transplantation and Surgery 1:281,1995 20. Reinisch JM, Simon NG, Karow WG, et al: Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Science 202:346-438, 1978 21. Satlin LM: Maturation of renal potassium transport. Pediatr Nephrol 5:260, 1991 22. Scantlebury V, Gordon R, Tzakis A, et al: Childbearing after liver transplantation. Transplantation 49317,1990

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23. Schardein J L Chemically Induced Birth Defects, ed 1. New York, Marcel Dekker, 1985, p 495 24. Scott J R Fetal growth retardation associated with maternal administration of immunosuppressive drugs. Am J Obstet Gynecol 128:668-676, 1977 25. Venkataramanan R, Koneru 8,Wang CCP, et al: Cyclosporine and its metabolites in mother and baby. Transplantation 46:468469, 1988 26. Walcott WO, Derick DE, Jolley JJ, et al: Successful pregnancy in a liver transplant patient. Am J Obstet Gynecol 132340, 1978

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