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Page 1: Limb deformations in oligohydramnios sequence: …ibis-birthdefects.org/start/pdf/limbdeformations.pdf · Limb Deformations in Oligohydramnios Sequence: Effects of Gestational Age

Limb Deformations in Oligohydramnios Sequence:Effects of Gestational Age and Durationof Oligohydramnios

Caitlin Christianson,1 Dale Huff,2,3 and Elizabeth McPherson1,4*1Department of Genetics, Magee-Womens Hospital, Pittsburgh, Pennsylvania2Department of Pathology, Magee-Womens Hospital, Pittsburgh, Pennsylvania3Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania4Department of Human Genetics, University of Pittsburgh Graduate School of Public Health,Pittsburgh, Pennsylvania

In order to study the pathogenesis of prena-tal deformities, we reviewed maternal histo-ries, delivery records, pathology reports, ra-diographs, and photographs of 90 fetuseswith prenatally documented oligohydram-nios at gestational ages from 14 weeks toterm. The causes of oligohydramnios in-cluded premature rupture of membranes(44 cases), fetal renal insufficiency (25cases), idiopathic (15 cases), and twin–twintransfusion (6 cases). The fetuses weregrouped according to gestational age at de-livery and duration of oligohydramnios.Sixty-three fetuses (70%) had documentedcontractures. As expected, contractureswere more frequent with earlier onset andlonger duration of oligohydramnios. Duringthe 2nd trimester, the frequency of contrac-tures in fetuses with oligohydramnios was77% compared to 52% in the 3rd trimester (x2

= 5.33, 1 df, P = .02). Considering all gesta-tional ages together, 57% of fetuses had con-tractures after less than 2 weeks of oligohy-dramnios compared to 81% of fetuses with alonger duration of oligohydramnios ((x2 =6.23, 1 df, P < .02). The type of contracturevaried with gestational age. Clubfoot wasthe most frequent at all ages, but hand con-tractures such as camptodactyly were com-mon only in the 2nd trimester while thebroad flat hand originally described in Pot-ter sequence was found almost exclusivelyin the fetuses with oligohydramnios in the3rd trimester. Of the 63 fetuses with oligo-hydramnios and contractures, 25 (40%) hadeither additional malformations or family

history that could explain contractures in-dependent of oligohydramnios. Am. J. Med.Genet. 86:430–433, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: oligohydramnios; limb defor-mations; contractures; fetalakinesia

INTRODUCTION

Oligohydramnios results in a sequence of effects onthe fetus including facial and limb deformations as wellas pulmonary hypoplasia. Limb deformities due to oli-gohydramnios are sometimes difficult to distinguishfrom those due to intrinsic fetal causes. In order tolearn about the effects of oligohydramnios, regardlessof cause, on the fetal limbs throughout the 2nd and 3rdtrimesters, we chose to include in our study previablefetuses, stillbirths, and DE&C specimens as well asliveborn infants with documented oligohydramnios ofat least 24-hr duration. The requirement for docu-mented oligohydramnios eliminated cases with prema-ture rupture of membranes (PROM) but normal amni-otic fluid volume in which oligohydramnios sequencewould not be expected. The shorter interval allowed usto investigate the cause of contractures in fetuses withrelatively brief periods of oligohydramnios. Because fe-tuses with multiple anomalies were not excluded, thestudy also provides an estimate of the frequency ofother anomalies in fetuses with a history of oligohy-dramnios or PROM.

MATERIALS AND METHODS

All autopsy, surgical pathology, and placental pa-thology reports at Magee-Womens Hospital from the1995 through 1998 were screened for mention of con-tractures, renal abnormalities, oligohydramnios, orpremature rupture of membranes. The mothers’ chartswere reviewed to determine the cause, time of onset,and duration of oligohydramnios. All cases with clinical

*Correspondence to: Elizabeth McPherson, M.D., Departmentof Genetics, Magee-Womens Hospital, 300 Halket Street, Pitts-burgh, PA 15237. Email: [email protected]

Received 13 January 1999; Accepted 10 May 1999

American Journal of Medical Genetics 86:430–433 (1999)

© 1999 Wiley-Liss, Inc.

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and/or ultrasound evidence of oligohydramnios at least24 hr prior to delivery were selected for further studyregardless of the cause of the oligohydramnios. Be-cause ruptured membranes sometimes reseal, allowingreaccumulation of amniotic fluid, infants born towomen with premature rupture of membranes wereincluded only if there was also ultrasound documenta-tion of oligohydramnios during the 2 weeks precedingdelivery. In twin pregnancies, each twin was consid-ered as a separate fetus and included only if oligohy-dramnios was documented.

For the 90 cases identified, details of maternal andfamily history were recorded from the mothers’ charts.The autopsy or surgical pathology reports of deceasedinfants or fetuses and medical records of liveborn in-fants were examined for mention of any malformations,disruptions, or deformities, with special attention tothe presence or absence of contractures. In cases wherethere was any uncertainty, the presence or absence ofcontractures and other signs of oligohydramnios se-quence was confirmed by review of photographs andradiographs obtained at the time of autopsy.

The study cases were grouped according to gesta-tional age at delivery and duration of oligohydramnios.Duration of oligohydramnios was based on clinical evi-dence of rupture of membranes or ultrasound docu-mentation, whichever occurred first. In cases with se-vere renal anomalies, oligohydramnios was assumed tobe of over 2 weeks duration, even if no ultrasound evi-dence was available for that time period.

RESULTS

We identified 90 fetuses with documented oligohy-dramnios at least 24 hr before delivery. Eight fetuseswere delivered before 16 weeks, 22 at 16 to 20 weeks,35 at 20 to 24 weeks, and 25 after 24 weeks gestation.Overall, 44 fetuses had oligohydramnios due to PROMand/or chronic placental abruption, 25 fetuses had re-nal insufficiency, 15 had idiopathic oligohydramnios,and 6 had oligohydramnios due to twin–twin transfu-sion.

Contractures were noted after as little as 1 day ofoligohydramnios, and were common in all groups (15/22 4 68% at <1 week, 9/20 4 45% at 1–2 weeks), butthe highest rate of contractures (39/48 4 81%) oc-curred after >2 weeks. In the 2nd trimester, 50/65(77%) of fetuses with oligohydramnios had contrac-tures compared to only 13/25 (52%) in the 3rd trimester(x2 4 5.33, 1 df, P 4 .02). The frequency of contrac-tures was approximately the same for each 1-monthperiod within the 2nd trimester (6/8 at <16 weeks, 17/22 at 16–20 weeks, and 27/35 at 20–24 weeks). Thetype of contractures was dependent on gestational age.Clubfoot was the most frequent contracture at all ages,occurring in two thirds of 2nd-trimester fetuses andhalf of 3rd-trimester fetuses. Camptodactyly was mostfrequent in the youngest fetuses (53% at <20 wks, 34%at 20–24 weeks, and 20% at >24 weeks, x2 4 6.95, 2 df,P < .05). The broad, flat hands described in the originalreports of Potter sequence were found almost exclu-sively in the 3rd trimester (0 at <20 weeks, 1/35 4 3%at 20–24 weeks, 7/25 4 27% at >24 weeks). Other risk

factors such as multiple anomaly syndromes or siblingsaffected with contractures in the absence of oligohy-dramnios were identified in 25/63 (40%) of fetuses withcontractures and none of the 27 without contractures.The fetuses with other anomalies included 2 with chro-mosomal disorders (trisomy 21, isotetrasomy 9p), 11with other known syndromes (Meckel–Gruber, mul-tiple pterygium, caudal regression (5), amniotic bands(3), VACTERL) and 10 with isolated nonrenal malfor-mations or multiple anomalies not suggestive of anyknown syndrome. Of those with a positive family his-tory, 1 had a monozygotic twin with contractures de-spite polyhydramnios, 1 (who also had an abdominalwall defect) had a dizygotic twin with contractures de-spite normal amniotic fluid, and 1 had a previous sibwith fetal hypokinesia sequence.

DISCUSSION

Amniotic fluid is necessary for fetal development. Fe-tuses with insufficient fluid volume often develop oli-gohydramnios sequence, characterized by facial com-pression (loose skin folds, especially beneath the eyes,flattened and beaked nose, large, flat ears), pulmonaryhypoplasia, and positional deformities such as asym-metric club feet, major joint contractures, and broad,flat hands with redundant skin. Although oligohy-dramnios (or Potter) sequence was initially describedin neonates with renal anomalies [Potter, 1946], othercauses of oligohydramnios such as premature ruptureof membranes (PROM) or uteroplacental circulatorydisorder lead to the same final result [Graham, 1988;Thomas, 1974]. Several previous studies have been fo-cused on the duration of ruptured membranes neces-sary to produce anomalies, especially pulmonary hypo-plasia, in liveborn premature infants. Nimrod et al.[1984] reported pulmonary hypoplasia in 9% and skel-etal abnormalities in 12% of premature infants withprolonged premature rupture of membranes (PPROM)for more than 1 week prior to delivery. Eight of the 9cases of lung hypoplasia occurred in infants with rup-ture of membranes prior to 26 weeks of gestation. Con-tractures were also more common in infants with ear-lier onset and longer duration of PROM. Thibeault etal. [1985] studied preterm infants with PROM for morethan 5 days. Only half had documented oligohydram-nios, and in this group, 2/3 had positional limb defor-mities and 91% required assisted ventilation. In an-other study [Rotschild et al., 1990], pulmonary hypo-plasia was noted in only 14/88 infants with PROMlonger than 7 days and occurring before 29 weeks ofgestation. The relatively low incidence of lung hypopla-sia is probably due to inclusion of cases with normalamniotic fluid volume despite PROM. Skeletal anoma-lies were found primarily in cases with severe oligohy-dramnios of extended duration. McIntosh and Harrison[1994] found compression deformities in 21% of pre-term infants with PROM at least 4 days prior to deliv-ery. The infants with compression deformities had amedian PROM duration of 28 days compared to only 7days for the infants without deformities, but contrac-tures were observed as early as 4 days after ROM insome fetuses. Recently, Kurkinen-Raty et al. [1998]

Limb Deformations in Oligohydramnios Sequence 431

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compared 78 premature infants with rupture of mem-branes greater than 24 hr before delivery to 78 controlsmatched for gestational age, but without prolongedrupture of membranes. The infants with prolonged pre-mature rupture of membranes (PPROM) had a higherincidence of contractures (8% vs. 0%) and pulmonaryhypoplasia (12% vs. 0%) relative to controls. Within thePPROM group, the infants with contractures had a me-dian duration of ROM 54 days prior to delivery com-pared to 7 days for the infants without contractures.The differing rates of contractures among these studiespresumably reflect differences in the frequency and se-verity of oligohydramnios as well as differences in thetype of skeletal deformities that were counted.

Limb contractures and lung hypoplasia occur notonly when fetal movement is limited by oligohydram-nios, but also when fetal akinesia is due to intrinsicneuromuscular abnormalities. Fetuses with severeneuromuscular abnormalities usually fail to swallowand develop polyhydramnios, which predisposes toPROM. Distinguishing oligohydramnios sequence fromfetal akinesia due to intrinsic neuromuscular abnor-malities may be difficult if a mother with unrecognizedpolyhydramnios presents with oligohydramnios follow-ing rupture of membranes. Although contracturescaused by neuromuscular abnormalities tend to bemore symmetrical than those due to oligohydramniosand the facial appearance is different [Rodriguez andPalacios, 1991], akinesia due to neuromuscular anoma-lies may be difficult to distinguish from that due tocompression, especially when examination of the brainis limited as in dilation and curettage specimens ormacerated stillbirths. Of particular concern is the situ-ation in which a fetus is noted to have contracturesafter only a few days of oligohydramnios. The distinc-tion between oligohydramnios sequence due to PROMand fetal akinesia sequence due to intrinsic neuromus-cular anomalies may be vital for assessment of recur-rence risk and planning for prenatal diagnosis of sub-sequent pregnancies.

Our data show increasing frequency of contracturesin younger fetuses with longer duration of oligohy-dramnios in accord with previous studies, but the totalincidence of contractures is higher (63/90 4 70%). Thiscan be attributed in part to early gestational age be-cause 72% of our subjects were delivered in the 2ndtrimester. Another factor contributing to the high inci-dence of contractures in our study is the exclusion ofsubjects without documentation of oligohydramnios.Our results are similar to those of Thibeault et al.[1985] who found contractures in two thirds of theirsubjects with documented oligohydramnios. Other in-vestigators reporting fewer skeletal deformities pro-vide no information on the incidence or severity of oli-gohydramnios in their subjects. Furthermore, because97% of our subjects had an autopsy, documentation ofall anomalies including contractures may be more com-plete.

The type of contractures varies with gestational age.Clubfeet are frequent regardless of gestational age orduration of oligohydramnios, but the type of hand ab-normality is dramatically age-dependent. Potter’soriginal report on renal agenesis [1946] described club-

feet but made no mention of the hands. Thomas [1974],who was the first to document that Potter sequenceresults from oligohydramnios of any cause, used theterm “spadelike” to describe the broad, flat hands inoligohydramnios sequence. We observed this type ofhand frequently in 3rd trimester cases, especially thosewith oligohydramnios lasting more than 2 weeks (5/10with renal disease, 2/6 with other causes of prolongedoligohydramnios). In 2nd-trimester fetuses, the clinicalpicture is different with frequent hand contractures,primarily camptodactyly. Typical “Potter hand” is ex-tremely rare in the 2nd trimester, even in fetuses withrenal insufficiency. Our only observation of Potterhand in the 2nd trimester was in a 20-week fetus withcaudal dysgenesis and bilateral renal agenesis, but6/14 other 2nd-trimester fetuses with renal insuffi-ciency had camptodactyly. This finding is importantbecause the combination of camptodactyly and equino-varus feet has traditionally been associated with thefetal akinesia sequence [Graham, 1988]. Our observa-tion of camptodactyly in 2nd-trimester fetuses withvarious causes of oligohydramnios, including renal dis-ease, suggests that the initial response to oligohydram-nios may include camptodactyly, but with increasingsize of the fetus and increasing duration of oligohy-dramnios the hand may become broad and flat withloose skin. In the 2nd trimester, camptodactyly cannotbe used to distinguish between akinesia due to neuro-muscular anomalies and that due to oligohydramnios.

Twinning is a risk factor for oligohydramnios due toPROM and/or twin–twin transfusion. Thirteen infantsfrom 11 twin pregnancies (8 monozygotic, 2 like-sexdichorionic, 1 unlike sex pair) were included in ourstudy. Six were twin–twin transfusion donors while 7(including two recipients of twin–twin transfusions)had PROM. Only 3 of the twin pairs (the two withPROM in the twin–twin transfusion recipient and onepair with simultaneous PROM in both sacs) were con-cordant for oligohydramnios, but only the 2 donor twinshad contractures. One monozygotic pair with twin–twin transfusion was concordant for contractures eventhough only 1 fetus had oligohydramnios, and the un-like sex pair was also concordant for contractures eventhough only 1 twin had oligohydramnios. Twinningclearly increases the risk of oligohydramnios, butamong the twins with documented oligohydramnios,the incidence of contractures was not significantly dif-ferent from that in singletons (8/13 4 61% in twins vs.51/77 4 66% in singletons).

A total of 25 fetuses with oligohydramnios had atleast one additional risk factor that might explain theobserved contractures. Two twin pairs (1 MZ, 1 DZ)were concordant for contractures, but not for oligohy-dramnios, 1 had a non-twin sib with fetal akinesia, and23 had nonrenal malformations including 13 with rec-ognizable conditions (5 caudal dysgenesis, 3 amnioticbands, 1 trisomy 21, 1 isotetrasomy 9p, 1 Meckel, 1lethal multiple pterygium, 1 VATER), 6 with malfor-mations not a recognized syndrome, and 4 with appar-ently isolated malformations (limb deficiency, dia-phragmatic hernia, abdominal wall defect, congenitalheart disease). The fetus with abdominal wall defecthad a DZ twin with contractures, but no abdominal

432 Christianson et al.

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wall defect and no oligohydramnios. Among fetuseswith additional malformations or a family history ofmalformations, the incidence of contractures was 24/254 96% compared to 35/65 4 54% among those withoutadditional risk factors. This observation suggests thatsuch risk factors may account for a significant propor-tion of all observed contractures.

Although the incidence of contractures increaseswith earlier onset and longer duration of oligohydram-nios, occasional contractures are observed after as littleas 24 hr of documented oligohydramnios. Possible ex-planations include underestimation of the duration ofoligohydramnios and/or heterogeneity of cause for thecontractures. Even in infants with oligohydramnios,contractures may be due to other causes as suggestedby the nonrenal malformations or family historiesdocumented in 28% of our cases overall, but in 40% ofthose with contractures. The type of contracture, espe-cially in the hands depends on gestational age. In the2nd trimester the broad, flat Potter hand is rare whilecamptodactyly, which has traditionally been attributedto neuromuscular akinesia, is common in 2nd-trimester fetuses with oligohydramnios sequence.Even in fetuses with well-documented oligohydram-nios, detailed evaluation and investigation for otherpossible causes are necessary to distinguish between

oligohydramnios sequence and fetal akinesia sequencedue to neuromuscular abnormalities of the fetus.

REFERENCES

Graham JM. 1988. Smith’s recognizable patterns of human deformation.Philadelphia: W.B. Saunders. p 106–116.

Kurkinen-Raty M, Koivisto M, Jouppila P. 1998. Perinatal and neonataloutcome and late pulmonary sequelae in infants born after pretermpremature rupture of membranes. Obstet Gynecol 92:408–415.

McIntosh N, Harrison A. 1994. Prolonged premature rupture of mem-branes in the preterm infant: a 7-year study. Eur J Obstet Gynecol57:1–6.

Nimrod C, Varela-Gittings F, Machin G, Campbell D, Wesenberg R. 1984.The effect of very prolonged membrane rupture on fetal development.Am J Obstet Gynecol 148:540–543.

Potter E. 1946. Bilateral renal agenesis. J Pediatr 29:68–76.

Rodrı́guez JI, Palacios J. 1991. Pathogenetic mechanisms of fetal akinesiadeformation sequence and oligohydramnios sequence. Am J Med Genet40:284–289.

Rotschild A, Ling EW, Puterman ML, Farquharson D. 1990. Neonataloutcome after prolonged preterm rupture of the membranes. Am JObstet Gynecol 162:46–52.

Thibeault DW, Beatty EC, Hall RT, Bowen SK, O’Neill DH. 1985. Neonatalpulmonary hypoplasia with premature rupture of fetal membranes andoligohydramnios. J Pediatr 107:273–277.

Thomas IT. 1974. Oligohydramnios, cause of the nonrenal features of Pot-ter syndrome, including pulmonary hypoplasia. J Peds 84:811–814.

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