High-Risk Pregnancy Management in Women with Hypopituitarism

Home , Hypopituitarism

KKu¨bler1,2, D Klingmu¨ller2, U Gembruch1 and WM Merz1 1Department of Obstetrics and Gynecology, University of Bonn, Bonn, Germany and 2Institute for Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany

obstetric complications.1 To assess specific risks during gestation Pregnancy after complete loss of pituitary function is uncommon. However, and parturition of women lacking pituitary hormones, we advances in fertility treatment have led to increased pregnancy rates in performed a literature review revealing adverse pregnancy outcome. hypopituitary women. We hereby present a literature review of pregnancies Furthermore, we compared affected cases with published controls affected by hypopituitarism, including a comparison with published and identified significantly higher rates of cesarean delivery, controls; further, we add one case report of severe hypopituitarism where transverse lie and small for gestational age (SGA) neonates, third-trimester oxytocin supplementation was performed. As only limited indicating the need for close maternal and fetal surveillance. information is available on management and outcome, our purpose was to We assumed that the adverse pregnancy outcome might reflect determine obstetric complications associated with deficiency of pituitary uterine dysfunction caused by hormone deficiency, including lack hormones. The analysis of 31 pregnancies in 27 women revealed that of oxytocin. Oxytocin is a potent uterotonic agent, synthesized in hypopituitary women are at increased risk: postpartum hemorrhage the hypothalamic nuclei, transported to the posterior pituitary and occurred in 8.7%, transverse lie in 16%; 42.4% of the newborns were small released into the general circulation in a pulsatile manner.2 for gestational age. These findings are supposedly the result of uterine Oxytocinergic pathways may be adversely affected in hypopituitary dysfunction caused by hormone deficiency. Oxytocin supplementation was women, resulting in alterations of delivery and lactation. To performed with the aim to establish physiologic conditions and to prevent compensate for oxytocin deficiency, we performed supplementation postpartum uterine inertia. In this case substitution may have contributed between the gestational age (GA) of 34 þ 0 weeks and delivery in a to correct fetal presentation but did not prevent postpartum hemorrhage. patient lacking pituitary hormones. The rationale for this Further investigations into both oxytocin-dependent and -independent experimental treatment was to enhance uterine function. We mechanisms regulating uterine contractions and contractility are necessary hypothesized that oxytocin substitution may augment uterine to develop strategies for prevention of uterine inertia in oxytocin-deficient contractility, thereby preventing fetal malpresentation and pregnancies. postpartum hemorrhage (PPH). This is the first report of third- Journal of Perinatology (2009) 29, 89–95; doi:10.1038/jp.2008.116 trimester oxytocin substitution in hypopituitarism because a search Keywords: oxytocin; hypopituitarism; high-risk pregnancy; malpresen- of Medline (English language; search terms: oxytocin, tation; postpartum hemorrhage supplementation, substitution, pregnancy) revealed no other cases.

Introduction Normal functions of the hypothalamic–pituitary-target axes are Methods important for the regulation of feto-maternal homeostasis. A search was performed using Medline (October 1965 to April 2006) Consequently, deficiency of pituitary hormones may affect with the following MeSH or keyword terms (single and in conception, pregnancy and delivery. Although advances in artificial combination): hypopituitarism, oxytocin, pregnancy, delivery and reproductive techniques (ARTs) provide methods to restore fertility outcome. Titles and abstracts published in English were searched in hypopituitary women, only few cases of successful pregnancy for relevant information and hard copies retrieved for further and parturition have been published, reporting high rates of information. References were analyzed by hand to identify additional publications. From all identified articles, two Correspondence: Dr WM Merz, Department of Obstetrics and Gynecology, University of Bonn, investigators selected the reports to be reviewed and extracted data Sigmund Freud Strasse 25, Bonn 53127, Germany. E-mail: [email protected] from these. As pregnancy in hypopituitarism is rare, we accepted Received 14 March 2008; revised 25 June 2008; accepted 5 July 2008 case reports as well as retrospective trials. Unpublished data or Pregnancy management in hypopituitarism KKu¨bler et al 90 published abstracts were not included. We did not attempt to group of hypopituitary pregnancies (n ¼ 16) and the ART control contact authors. group (n ¼ 16),35, respectively. A total of 28 documents comprising 63 pregnancies in 40 As only few cases were observed in the study group, the women were identified.1,3–29 Inclusion criteria for the study statistical analysis was obtained by simulation procedure with the group were as follows: pregnancies conceived by ART, resulting statistical software ‘R’ (version 2.1.0, The R Foundation for in viable babies. We further evaluated causes of hypopituitarism Statistical Computing, Vienna, Austria). Distributions were and considered only cases where posterior pituitary damage compared using the Fisher’s exact test. The level of statistical was likely.30,31 The following cases were excluded: significance was set at P<0.05. subclinical hypopituitarism (n ¼ 16);4,6,8,11–13,17,19,25,28,29 cause of hypopituitarism not specified (n ¼ 1);21 first-trimester miscarriages (n ¼ 15).1,4,12,19 Sixteen case Case reports3,5–7,9,10,14–16,18,20,22–24,26,27 describing the outcome of A 35-year-old woman had undergone subtotal excision of a 18 pregnancies and one trial1 reporting 13 pregnancies in nine craniopharyngioma at the age of 8 years. The resulting pituitary women were included in the analysis. The following data were insufficiency was treated with substitution of L-thyroxine, analyzed: baseline characteristics (age at diagnosis and pregnancy, hydrocortisone, desmopressin and growth hormone. At 12 years of cause and therapy of hypopituitarism, ovulation induction, age, recurrence was diagnosed and reoperation performed. obstetric history); course of pregnancy (pregnancy-specific Subsequently, she underwent radiation therapy for residual tumor. complications, drug substitution); delivery (mode of delivery Post-interventional panhypopituitarism was diagnosed and (MOD), GA); puerperium (onset of lactation, maternal complete substitution of pituitary hormones initiated. The patient complications) and fetal outcome (birth weight, perinatal remained disease-free thereafter. At the age of 19, menstrual cycle morbidity and mortality). Weight centiles corrected for GA and was established by combined oral contraceptives. The patient singleton versus multiple pregnancy were calculated according to requested fertility treatment at the age of 30 years and ovulation ethnicity and sex.32–34 In case the sex was not reported, the centile induction with gonadotropins was performed. The third cycle of was adjusted as a minimum for both sexes. in vitro fertilization (IVF) with intracytoplasmic sperm injection To determine specific pregnancy-related risks in hypopituitary (ICSI) resulted in a singleton intrauterine pregnancy. Progesterone women, the study group was compared to published controls.35–37 was substituted until 12 weeks’ GA. Assessment of adequate The analysis was limited to singleton pregnancies because substitution of pituitary hormones involved both clinical and complication rates are higher for multiple pregnancies. Owing to biochemical evaluations. Hydrocortisone dosage had to be the fact that comparisons may be hampered by maternal increased from 5 mg daily preconceptionally to 10 mg per day (17 differences between the groups we tried to adjust as many weeks’ GA), 15 mg per day (24 weeks’ GA) and 25 mg per day (32 confounding factors as possible. Matching criteria for published weeks’ GA) for the remaining pregnancy. L-Thyroxine (125 mg per epidemiological studies were as follows: singleton pregnancies day) and desmopressin (0.4 mg per day) did not require received after ART, mean maternal age, proportion of primiparity adjustment. The patient was referred to our department for p20% and mean GAp1 week difference, date of parturition antenatal care at 16 þ 4 weeks’ GA and was seen monthly until between 1965 and 2005, delivery in developed countries and 34 þ 0 weeks’ GA. No maternal complications occurred and fetal definition of adverse outcome. The following pregnancy development was normal. complications were analyzed: SGA (birth weight p10th centile), As oxytocin-deficiency was presumed, we performed third- transverse lie at term (confirmed by cesarean section), PPH (blood trimester substitution. After obtaining informed consent loss requiring blood transfusion and/or blood loss resulting in incremental doses of intravenous (i.v.) oxytocin under hysterectomy and/or medical treatment to induce uterine cardiotocographic monitoring were administered at 34 þ 0 weeks’ contractions), cesarean delivery (in case of one woman with more GA to define the amount of oxytocin required to induce uterine than one pregnancy, the repeat cesarean section was excluded1). contractions. Regular contractions were recorded at a dose of 3 Comparing the various indications for cesarean delivery between milliunits per min oxytocin. With nasal bioavailability of one-tenth the groups, no significant differences were found for the following compared to i.v. application, the patient was started on spray- criteria: fetal distress (31.25% (5/16) vs 31.25% (5/16); P ¼ 1), administered oxytocin (0.25 U, q.i.d.). Cardiotocography was lack of progress in labor or failed induction of labor (31.25% performed in regular intervals (34 þ 4, 35 þ 4 and 37 þ 0 weeks’ (5/16) vs 12.5% (2/16); P ¼ 0.4), previous cesarean section or GA) to monitor the effect of spray application. Substitution scarred uterus (0% (0/16) vs 6.25% (1/16); P ¼ 1), abnormal was well tolerated; the only adverse reaction consisted of presentation (25% (4/16) vs 18.75% (3/16); P ¼ 1), obstetric deteriorating rhinorrhea. Application was therefore switched indications (12.5% (2/16) vs 25% (4/16); P ¼ 0.65) and absent to i.v. oxytocin and carried out every second day from 37 þ 1 medical indication (0% (0/16) vs 6.25% (1/16); P ¼ 1) in the to 38 þ 4 weeks’ GA.

Journal of Perinatology Pregnancy management in hypopituitarism KKu¨bler et al 91

Elective cesarean delivery on request was performed without Compared to the current cesarean delivery rate in ART complications under combined spinal–epidural anesthesia at pregnancies, the incidence of operative deliveries in women with 38 þ 6 weeks’ GA and a viable fetus was delivered (cephalic hypopituitarism is striking (Table 3). Indications were presentation, female, 2950 g (25th centile), Apgar score 9/10/10, heterogeneous; of note however is the high malpresentation rate of umbilical artery blood pH 7.34). For surgery, the patient received a 25% (10% breech lie, 15% transverse lie) in singleton pregnancies. single stress-dose of hydrocortisone (200 mg) that was tapered to Transverse lie in particular was significantly more common the maintenance level of 25 mg per day. After the delivery of fetus (Table 3). However, we cannot exclude that the high cesarean and placenta, uterine atony occurred that responded to i.v. oxytocin section rate is due to obstetricians’ recommendations rather than (cumulative dose 39 U) and i.v. prostaglandin-E2 analog medical necessity. sulprostone (cumulative dose 525 mg). Estimated blood loss was Our review also revealed a higher trend in PPH compared to the 800 ml. After delivery, the patient was started on methylergometrin given incidence, although this did not reach statistical significance (0.75 mg per day, p.o.), prostaglandin-E1 analog misoprostol (Table 3). (2 mg per day, p.r.) and oxytocin (48 U, nasal per day) to promote Thus, pregnancies in women with hypopituitarism require uterine involution. However, subinvolution was diagnosed the fifth special antenatal care. Serial ultrasound for fetal growth postoperative day by clinical and sonographic examination (soft, assessment is recommended. In case of malpresentation, the tender uterus with retained blood clots in the uterine cavity); it was decision on external cephalic version versus cesarean delivery needs successfully treated by a single infusion of 23 U oxytocin and to be taken after considering additional risk factors. Regarding 0.4 mg methylergometrin. The further course was normal with PPH, active management may be beneficial. daily doses of methylergometrin (0.75 mg) and misoprostol Altogether, we hypothesized oxytocin to be involved in the (0.6 mg) until the 18th day after delivery. following mechanisms: Braxton–Hicks contractions of late Despite regular intake of desmopressin, diabetes insipidus gestation contributing to correct fetal presentation; and increased developed on postpartal day 5, manifesting with polydipsia and myometrial contractility preventing uterine inertia and PPH. These polyuria (intake 7500 ml, output 8750 ml). Symptoms responded considerations were the rationale for oxytocin supplementation in well to an increase of desmopressin dosage (0.6 mg per day) with our patient. gradual normalization of serum osmolality. Lactation never The biological function of oxytocin was demonstrated in commenced. monkeys, where increased oxytocin concentrations were related to Neonatal adaptation was unremarkable; the newborn was rising levels of nocturnal uterine activity.38 In the uterine smooth discharged home together with the mother on the 11th day of life. muscle oxytocin has a direct uterotonic effect, whereas in the 39 choriodecidual tissue it releases prostaglandins PGE2 and PGF2a. Membrane-bound oxytocin receptor (OT-R) transduces the 40 Results oxytocin effect. OT-R density within the myometrium increases towards term. In addition, oxytocin itself controls its receptor with a We evaluated 31 pregnancies in 27 women (25 singleton, 5 twin blunted effect on binding sites after prolonged exposure.41 Both and 1 triplet pregnancy). myometrial receptor density and receptor susceptibility to induce Details on medical history, pregnancy, delivery and postpartum contractile responses are involved in uterine tone. In guinea pigs, course are listed in Table 1. A summary of maternal characteristics contractility increased gestation dependent due to not yet defined in hypopituitary and published control pregnancies is presented in cell-signaling processes despite unchanged oxytocin-binding Table 2. Comparison of complication rates in hypopituitary and characteristics.42 Accordingly, enhanced smooth muscle control pregnancies is given in Table 3. No neonatal complication contractility has been demonstrated after repetitive oxytocin or congenital anomaly was reported. stimulation, presumably mediated by increased sensitivity of OT-R.43 Still the role of oxytocin in parturition has been questioned as delivery proceeds normally in oxytocin-deficient mice.44 This Discussion finding could be peculiar to mice; however, in our review, five Our literature review revealed pregnancies in women with vaginal deliveries were reported suggesting that parturition in hypopituitarism to be high risk for mother and fetus. humans may be regarded as being independent from circulating On the fetal side, the high SGA rate is in contrast to the oxytocin. Accordingly, it has been postulated that oxytocin from published incidence in singleton ART pregnancies (Table 3) and different sources contributes to the various stages of labor, with supposedly the result of poor placental function. Whether this uterine oxytocin supporting the initiation of parturition and uteroplacental dysfunction is due to lack in uterine preparedness1 pituitary oxytocin the expulsive phase.39 In the postpartum course, or lack in responsiveness of neuroendocrine feedback mechanisms pituitary oxytocin is involved in uterine involution, whereas the remains to be elucidated. relevance of locally produced oxytocin in puerperium is unknown.

Journal of Perinatology ora fPerinatology of Journal 92 Table 1 Clinical data of women with hypopituitarism

Baseline characteristics Pregnancy Delivery Postpartum course

Case Age at Age at Cause of Therapy Pregestational Ovulation Gravida/ Complications Substitution MOD Indications GA Sex, weight Lactation Maternal number, diagnosis pregnancy pituitary substitution induction para/ (centile) complications reference (years) (years) insufﬁciency abortus

1 22 28 CP S, Rx NR GnRH pump III/0/II None NR CD Obstetric NR NR NR NR hypopituitarism in management Pregnancy 29 19 27 NR NR C, L-T4, EP HMG, HCG I/0/0 Hyperlipemia, C, L-T4, CD Preeclampsia, 36 F 1800 g (5), NR PPH (TAH), preeclampsia, progestative triplets F 1800 g (5), status epilepticus, triplets agents M 1800 g (5) diabetes insipidus 314 35 37 P S Bromocriptine HMG III/0/II None Progesterone NR NR 31 M NR NR NR 410 23 29 Sh F C, L-T4, EP HMG, HCG III/II/0 None C, L-T4 ECD Transverse lie, 35 F 2200 g (25) AG None PROM 55 24 28 CP S C, L-T4, V, EP HMG, HCG I/0/0 None C, L-T4, V Forceps NR 40 M 2500 g (8) NR NR 66 18 28 A S, Rx L-T4, estrogen HMG, HCG I/0/0 Twins L-T4 CD Failed IOL 40 NR 2800 g AG None (min 25),

NR 2500 g KKu

(min 10) ¨bler 76 32 34 A S, Rx C, L-T4, CDr HPG, HCG III/0/II Threatened C, L-T4, CDr CD Transverse lie 40 M 3500 g (50) AG None tal et abortion 86 25 29 A S, Rx C, L-T4 HMG, HCG I/0/0 Twins L-T4 CD NR 39 NR 2700 g AG None (min 25), NR 2800 g (min 40) 915 25 29 A S, Rx C, L-T4, V HMG, HCG III/I/I None C, L-T4, CDr CD Failed IOL 42 M 3750 g (50) NR Diabetes insipidus 1022 19 27 CP S C, L-T4 HMG, HCG, estrogen I/0/0 Hyperemesis NR CD Fetal distress 40 F 2764 g (8) NR None 117 18 27 A S, Rx, rS C, L-T4 HMG, HCG I/0/0 Hyperemesis C, L-T4 Vacuum History of 38 NR 4010 g AG PPH (transfusion, brain surgery (min 95) methergin) 1224 22 27 G Rx C, L-T4, D, HMG, HCG I/0/0 Twins C, L-T4, D CD Breech lie, 37 M 2080 g (5), NR None terguride transverse lie F 2380 g (25) 131 NR 32 P Rx NR HMG I/0/0 None C, L-T4, V, ECD Fetal distress 38 F 2040 g (3) AG None bromocriptine 141 NR 29 CP S NR HMG III/0/II None C, L-T4 ECD PROM, 34 M 2540 g (50) AG None transverse lie, arm prolapse 151 NR NR CP S NR HMG IV/I /II None C, L-T4 ECD PROM, breech lie 35 F 2650 g (50) AG None 161 8 34 CP S NR HMG I/0/0 None C, L-T4, V ECD Failure to progress 38 M 3450 g (50) LA None 171 8 NR CP S NR HMG II/I/0 None C, L-T4, V CD Previous CD 38 F 2620 g (10) LA None 181 13 38 T NR NR GnRH pump I/0/0 None C, L-T4, V CD Failure to progress 38 M 3245 g (50) LA None 191 NR 42 Sh F NR HMG NR NR C, L-T4 NR NR NR NR NR Psychotic reaction 201 NR 31 A S NR HMG II/0/I Nausea and C, L-T4 CD Fetal growth 38 M 2560 g (3) AG None vomiting restriction Table 1 Continued

Baseline characteristics Pregnancy Delivery Postpartum course

211 NR NR A S NR HMG IV/I/II Twins, IUFD, C, L-T4 NVD (IOL) F 26 F 660 g (10), NR NR APH (abruptio F 740 g (25) placentae) 221 NR 34 Sh F NR HMG NR Twins, PROM, C, L-T4 NVD (IOL) F 26 NR NR NR IUFD 231 NR 33 CP S NR FSH I/0/0 Ovarian C, L-T4, V ECD Fetal distress 39 M 2580 g (3) AG NR hyperstimulation (abruptio syndrome, PIH placentae) 241 NR NR CP S NR HMG II/I/0 None C, L-T4, V CD Previous CD 39 M 2960 g (10) AG NR 251 NR 42 A S NR HMG I/0/0 None C, L-T4 CD Failed IOL 40 M 3980 g (90) AG NR 263 20 24 Sh F C, L-T4, EP HMG, HCG II/I/0 Preeclampsia, C, L-T4 CD Fetal distress NR M 2170g AG None placental insufﬁciency 2720 26 32 A S C, L-T4, EP GH, HMG, HCG NR None C, L-T4 NR NR 39 M 3780 g (75) NR None 2826 23 32 A S, Rx L-T4 HMG, HCG I/0/0 None L-T4 CD PTL, PROM, 33 F 2000 g (50) NR None

fetal distress KKu hypopituitarism in management Pregnancy 2927 25 34 A S, rS C, L-T4, D, EP HMG II/0/0 None C, L-T4, D CD Breech lie 39 F 3200 g (50) AG None ¨bler (extra-uterine

gravidity) al et 3018 26 31 L S C, L-T4, D, EP HMG, HCG I/0/0 Oligohydramnios C, L-T4, D CD IOL, failure to 38 F 2490 g (5) LA None progress 3123 8 34 CP S, Rx C, L-T4, D, GH, EP HMG, HCG I/0/0 None C, L-T4, D NVD F 37 F 3450 g (90) AG None

Abbreviations: A, adenoma; AG, agalactosis; APH, antepartum hemorrhage; C, cortisone; CP, craniopharyngioma; CD, cesarean delivery; CDr, controlled drinking; D, desmopressin; ECD, emergency cesarean delivery; EP, estrogen–progestin combination; F, female; FSH, follicle stimulating hormone; G, germinoma; GA, gestational age; GH, growth hormone; GnRH, gonadotropin-releasing hormone; HCG, human chorionic gonadotropin; HMG, human menopausal gonadotropin; HPG, human pituitary gonadotropin; IOL, induction of labor; IUFD, intrauterine fetal demise; L, lymphocytic hypophysis; LA, lactation; L-T4, L-thyroxine; M, male; NR, not reported; NVD, normal vaginal delivery; P, prolactinoma; PIH, pregnancy- induced hypertension; PPH, postpartum hemorrhage; PROM, premature rupture of membranes; PTL, preterm labor; rS, recurrent surgery; Rx, radiotherapy; S, pituitary surgery; Sh, Sheehan’s syndrome; T, tuberculoma; TAH, total abdominal hysterectomy; V, arg-vasopressin. ora fPerinatology of Journal 93 Pregnancy management in hypopituitarism KKu¨bler et al 94

Table 2 Maternal characteristics in hypopituitary and published control pregnancies

Mean maternal age (year) Primipara (%) Mean GA (week) Date of parturition Location of parturition

Hypopituitary pregnancies n ¼ 25 32 68 38 1965–2002 Developed countries (94%)

Control pregnancies, reference n ¼ 26036 32 NR 39 1983–1993 Israel n ¼ 14035 32 84 39 1988–1994 Belgium n ¼ 18537 NR 69 38 1995–2002 Hungary

Abbreviations: GA, gestational age; NR, not reported.

Table 3 Comparison of obstetric complications in hypopituitary and published control pregnancies

Hypopituitary pregnancies Control pregnancies, reference P-value

SGA 8/21 (38%) 33/260 (12.7%)36 0.005 Cesarean delivery 16/18 (89%) 16/140 (11.4%)35 0.00000000002 Transverse lie 3/20 (15%) 3/140 (2.1%)35 0.03 Postpartum hemorrhage 1/19 (5.26%) 2/185 (1%)37 0.26

Abbreviation: SGA, small for gestational age.

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Journal of Perinatology